PMID- 25142325 TI - Effect of mobile phase on electrospray ionization efficiency. AB - Electrospray (ESI) ionization efficiencies (IE) of a set of 10 compounds differing by chemical nature, extent of ionization in solution (basicity), and by hydrophobicity (tetrapropylammonium and tetraethylammonium ion, triethylamine, 1 naphthylamine, N,N-dimethylaniline, diphenylphthalate, dimethylphtahalate, piperidine, pyrrolidine, pyridine) have been measured in seven mobile phases (three acetonitrile percentages 20%, 50%, and 80%, and three different pH adjusting additives, 0.1% formic acid, 1 mM ammonia, pH 5.0 buffer combination) using the relative measurement method. MS parameters were optimized separately for each ion. The resulting relative IE data were converted into comparable logIE values by anchoring them to the logIE of tetrapropylammonium ion taking into account the differences of ionization in different solvents and thereby making the logIE values of the compounds comparable across solvents. The following conclusions were made from analysis of the data. The compounds with pK(a) values in the range of the solution pH values displayed higher IE at lower pH. The sensitivity of IE towards pH depends on hydrophobicity being very strong with pyridine, weaker with N,N-dimethylaniline, and weakest with 1-naphthylamine. IEs of tetraalkylammonium ions and triethylamine were expectedly insensitive towards solution pH. Surprisingly high IEs of phthalate esters were observed. The differences in solutions with different acetonitrile content and similar pH were smaller compared with the pH effects. These results highlight the importance of hydrophobicity in electrospray and demonstrate that high hydrophobicity can sometimes successfully compensate for low basicity. PMID- 25142327 TI - How to successfully achieve an academically productive radiology department. PMID- 25142326 TI - EF8 is involved in photoperiodic flowering pathway and chlorophyll biogenesis in rice. AB - KEY MESSAGE: A DTH8/Ghd8 allele suppresses flowering by altering the expression patterns of the 'florigen' genes, but also negatively regulates chlorophyll biogenesis. Flowering time is a critical agronomic trait determining the growing season, regional adaptation and yield potential in rice (Oryza sativa L.). We characterized a mutant named early flowering 8 (ef8) selected from an ethyl methanesulfonate (EMS)-treated population of indica cultivar 93-11. It showed earlier flowering, less grains per main panicle and slightly darker green leaves than the wild-type 93-11 under natural long-day conditions, but was not significantly different from 93-11 under natural short-day conditions. We isolated the Early Flowering 8 (EF8) gene by map-based cloning. EF8 encodes a putative HAP3 subunit of the CCAAT-box-binding transcription factor, which is localized to the nucleus. EF8 was expressed in various tissues, especially in leaves, with a rhythmic expression pattern. Our data showed that EF8 delayed flowering time under long-day conditions by altering the rhythmic expression patterns of 'florigen' genes Hd3a and RFT1. We also found that EF8 negatively regulates the expression of chlorophyll biosynthetic genes to reduce the chlorophyll content. Our data indicate that EF8 plays an important role in rice photoperiodic flowering pathway as well as yield potential and chlorophyll biogenesis and will be an important target for rice breeding programs. PMID- 25142328 TI - How to prepare successful scientific manuscripts: practical advice from editors of radiology journals. PMID- 25142330 TI - Imaging in congenital pulmonary vein anomalies: the role of computed tomography. AB - Pulmonary venous anomalies comprise a wide spectrum of anatomical variations and their clinical presentations may vary from the relatively benign single partial anomalous pulmonary venous connection (PAPVC) to the critical obstructed total anomalous pulmonary venous connection (TAPVC). We briefly review the common anomalies encountered, while highlighting the utility that computed tomographic angiography (CTA) provides for this spectrum of extracardiac vascular malformations and connections. CTA has established itself as an invaluable imaging modality in these patients. A detailed knowledge of the CTA imaging findings in pulmonary venous anomalies is crucial to guide clinical decision making in these patients. PMID- 25142333 TI - Long-term globular adiponectin administration improves adipose tissue dysmetabolism in high-fat diet-fed Wistar rats. AB - Adiponectin administration to obese or type 2 diabetic patients is still far off, due to its expensive costs and absence of studies demonstrating the effectiveness of its chronic administration. We performed long-term globular adiponectin administration, testing its usefulness in improving adipose tissue metabolism. Adiponectin (98 upsilong/day) was administered through a subcutaneous minipump with continued release (28 days) to Wistar rats fed a high-fat diet. Adiponectin decreased body weight and adipocyte size, while decreasing circulating leptin levels. More, adiponectin was able to increase IkappaBalpha and PPARgamma levels and to prevent high-fat diet-induced impairment of insulin signalling, especially in epididymal adipose tissue. This resulted in improved glucose profile. High-fat diet caused an impairment of lipolysis in epididymal adipose tissue, which was partially restored by adiponectin treatment. Long-term globular adiponectin administration was able to improve pathways of insulin signalling and lipid storage in adipose tissue of high-fat diet-fed rats, contributing to a better metabolic profile. PMID- 25142334 TI - Urinary CD80 levels as a diagnostic biomarker of minimal change disease. AB - BACKGROUND: Early diagnosis of minimal change disease (MCD) in nephrotic syndrome (NS) patients remains challenging. Doctors often make a diagnosis of MCD using invasive renal biopsy. CD80, a transmembrane protein, is present on podocytes in a number of experimental models of NS. Urinary CD80 levels are significantly elevated in MCD but not in focal segmental glomerulosclerosis (FSGS) or other glomerulopathies. The purpose of this study was to investigate the feasibility of using urinary CD80 levels as a biomarker for the diagnosis of MCD. MATERIALS AND METHODS: A total of 165 subjects, 129 men and 36 women, were enrolled in this study. Urinary samples were collected from 37 patients with MCD, 27 patients with FSGS, 30 patients with other glomerulopathies, and 71 healthy people. Using ELISA, experimental values were compared with those produced by kidney biopsy samples. RESULTS: The concentration of urinary CD80 was significantly higher in the active MCD group (689.66 +/- 378.21 ng/g creatinine) than in the FSGS group (123.49 +/- 167. 88 ng/g creatinine, P < 0.00), other glomerulopathies group (152.37 +/- 220. 14 ng/g creatinine, P < 0.001) and the control group (81.83 +/- 23.01 ng/g creatinine; P < 0.001). A cutoff value of 328.98 (ng/g creatinine) was proposed, with a sensitivity of 81.1 % and specificity of 94.4 %. The area under the receiver operating characteristic (ROC) curve for the urinary CD80 to diagnose MCD was 0.925 (95 % confidence interval: 0.873-0.978). CONCLUSIONS: This experiment has preliminarily confirmed urinary CD80 as a non-invasive diagnostic biomarker. It may have significant value in the diagnosis of MCD. PMID- 25142335 TI - The genome of Eimeria falciformis--reduction and specialization in a single host apicomplexan parasite. AB - BACKGROUND: The phylum Apicomplexa comprises important unicellular human parasites such as Toxoplasma and Plasmodium. Eimeria is the largest and most diverse genus of apicomplexan parasites and some species of the genus are the causative agent of coccidiosis, a disease economically devastating in poultry. We report a complete genome sequence of the mouse parasite Eimeria falciformis. We assembled and annotated the genome sequence to study host-parasite interactions in this understudied genus in a model organism host. RESULTS: The genome of E. falciformis is 44 Mb in size and contains 5,879 predicted protein coding genes. Comparative analysis of E. falciformis with Toxoplasma gondii shows an emergence and diversification of gene families associated with motility and invasion mainly at the level of the Coccidia. Many rhoptry kinases, among them important virulence factors in T. gondii, are absent from the E. falciformis genome. Surface antigens are divergent between Eimeria species. Comparisons with T. gondii showed differences between genes involved in metabolism, N-glycan and GPI anchor synthesis. E. falciformis possesses a reduced set of transmembrane transporters and we suggest an altered mode of iron uptake in the genus Eimeria. CONCLUSIONS: Reduced diversity of genes required for host-parasite interaction and transmembrane transport allow hypotheses on host adaptation and specialization of a single host parasite. The E. falciformis genome sequence sheds light on the evolution of the Coccidia and helps to identify determinants of host-parasite interaction critical for drug and vaccine development. PMID- 25142336 TI - Adsorption of "soft" spherical particles onto sinusoidally-corrugated substrates. AB - We utilize a Monte Carlo simulation scheme based on the bond fluctuation model to simulate settlement of "soft" adhesive particles onto sinusoidally-corrugated substrates. Particles are composed of a hard inner core with a "soft" adhesive shell made of surface-grafted polymer chains. These chains adhere to surface lattice sites via pair wise non-specific interactions acting between the substrate and the last two segments of the polymer grafts on the particle. This simulation scheme is aimed at comprehending single particle adsorption behavior to find the highest adhesion energy locations for given test surfaces and elucidate test surfaces that reduce adhesion energy. Parameters in this study are set by the particle, the substrate and an interaction parameter between the two. Particle parameters include core diameter (D), grafting density of polymer (sigma) and length of grafted polymer (N). Substrate parameters include wavelength (lambda) and amplitude (A). Our results show that the wavelength of substrate features plays a significant role in the settlement of single particle systems. At lambda = D/2 we observe a minimum in the adhesion energy and at lambda = D we observe a uniform settlement location of the particles. Increasing N leads to a reduction in the effectiveness of substrate topography to direct the settlement of individual particles into specific sites on the substrate. PMID- 25142338 TI - Study of the chelating properties of Ge(OH)2 functionality as metal binding group for Zn2+ cation in simplified protease-like environments: a DFT analysis. AB - The development of protease's inhibitors is an active field of research in the pharmaceutical industry. As concerns the design of new inhibitors, the theoretical study of the binding patterns and energies of known metal binding groups (MBGs) toward Zn(2+) using quantum-chemical calculations may offer a better understanding of their interaction models and may be useful for the improvement and design of novel ZBGs. Here the properties of gem-Ge(OH)(2)-based compounds as ZBG were assessed theoretically using DFT calculations. [Zn(Imdz)(2) R - OH(2)](2+) complexes (Imdz =imidazole rings; R = imidazole ring, acetic acid molecule or acetate anion) were used to partially reproduce the coordination sphere in metalloproteases (ACE, amgiotensin converting enzyme, and TLN, thermolysine) being inhibited by related compounds (i.e., silanediols). The MBG- Zn(2+) interaction was analyzed through the energy of the reaction: [Zn(Imdz)(2) R - OH(2)](2+) + L -> [Zn(Imdz)(2) R - L](2+) + H(2)O using DFT (M06L/cc-pVDZ) in gas-phase and in solution (IEF-PCM). Although the functional used (M06L) has proven its efficiency to study systems containing transition metal governed by non-covalent interactions, dispersion effects were implemented by the correction of the computed energies using the DFT-D3 program. Accounting for dispersion effects produced a systematic increase of c.a. 13 kJ mol(-1) on the energies, whereas the effect of solvent goes in the opposite direction (i.e., BE under the IEF-PCM model are on average 125 kJ mol(-1) lower). The Ge(OH)(2) - Zn(2+) interaction seems to be similar (or even stronger) than the Si(OH)(2) -Zn(2+). Their better performance as ZBG is explained by the combined NBO-AIM analysis. The results of this work may encourage the preparation, isolation, and experimental assay of the chelating properties of these compounds, which may propose a new family of protease's inhibitors. PMID- 25142339 TI - Oral trauma following rigid endoscopy and a novel approach to its prevention - prospective study of one hundred and thirteen patients. PMID- 25142337 TI - Structural basis of valmerins as dual inhibitors of GSK3beta/CDK5. AB - Development of multi-target drugs is becoming increasingly attractive in the repertoire of protein kinase inhibitors discovery. In this study, we carried out molecular docking, molecular dynamics simulations, molecular mechanics Poisson Boltzmann surface area (MM-PBSA) binding free energy calculations, principal component analysis (PCA), and dynamical cross-correlation matrices (DCCM) to dissect the molecular mechanism for the valmerin-19 acting as a dual inhibitor for glycogen synthase kinase 3beta (GSK3beta) and cyclin-dependent kinase 5 (CDK5). Detailed MM-PBSA calculations revealed that the binding free energies of the valmerin-19 to GSK3beta/CDK5 were calculated to be -12.60 +/- 2.28 kcal mol( 1) and -11.85 +/- 2.54 kcal mol(-1), respectively, indicating that valmerin-19 has the potential to act as a dual inhibitor of GSK3beta/CDK5. The analyses of PCA and DCCM results unraveled that binding of the valmerin-19 reduced the conformational dynamics of GSK3beta/CDK5 and the valmerin-19 bound to GSK3beta/CDK5 might occur mostly through a conformational selection mechanism. This study may be helpful for the future design of novel and potent dual GSK3beta/CDK5 inhibitors. PMID- 25142340 TI - The place of four-dimensional ultrasound in evaluating fetal anomalies. AB - OBJECTIVE: To analyze the capability of four-dimensional surface rendering mode ultrasound (4D SRM USG) in the detection of fetal abnormalities, and also compare it with 2D USG. MATERIALS AND METHODS: A total of 1,379 pregnant women were enrolled in the study, and they all underwent 2D USG screening. In the same session, they were all subsequently screened using 4D USG. The findings of both methods were compared. RESULTS: A total of 194 fetal anomalies were detected in 176 of 1,379 pregnant women by 2D USG. When all cases, including superficial and non-superficial anomalies, were evaluated together, we found that 2D USG was significantly better than 4D SRM USG in detecting anomalies (p < 0.001). However, 4D SRM USG was superior to 2D USG in terms of image quality, clarity, the distinction between the surrounding structures, and intelligibility among the cases with a superficial anomaly (p < 0.005). CONCLUSION: 4D USG is superior to 2D USG in detecting malformations related to fetus face, spine, extremities, abdominal wall, and the body surface. However, 4D SRM USG detected only approximately half of the cases with anomalies, and showed a better quality of image in only 15 % of all cases. Therefore, 4D SRM USG may only be suitable for use as a complementary tool in the evaluation of fetal anomalies, especially those of the face, spine, extremity, and abdominal wall. PMID- 25142341 TI - Sexual concerns among kidney transplant recipients. AB - BACKGROUND: Little is known about the specific sexual concerns of kidney transplant (KTx) recipients. The primary objectives of this study were to: (i) describe the importance of sexuality to KTx recipients; (ii) investigate the sexual concerns of KTx recipients; and (iii) examine the relationship between sexual concerns and quality of life (QOL). A secondary objective was to examine potential sexual concern differences by gender, pre-transplant dialysis status, and donor type. METHODS: This study employed a cross-sectional, descriptive, correlational design. Sexual concerns were identified using the Sexual Concerns Questionnaire, which contains seven subscales. QOL was measured with the SF-8 and the QOL Uniscale. RESULTS: Nearly 73% of subjects rated sexuality as important. Subscales indicating highest area of sexual concerns were communication with healthcare providers about sexuality (Mean (M) = 2.70) and sexual pleasure concerns (M = 2.45). Higher concern ratings regarding health consequences of sexual activity, quality of sexual relationship, sexual pleasure, sexual functioning problems, and pessimistic beliefs about treatment were significantly, inversely related to QOL. Women had significantly higher scores on the Sexual Pleasure and Communication with Healthcare Providers subscales than men. CONCLUSIONS: This study reports the sexual concerns of KTx recipients' who are an average of four yr since surgery, and the relationship of these concerns to QOL. PMID- 25142342 TI - Persistence and dioxin-like toxicity of carbazole and chlorocarbazoles in soil. AB - Halogenated carbazoles have recently been detected in soil and water samples, but their environmental effects and fate are unknown. Eighty-four soil samples obtained from a site with no recorded history of pollution were used to assess the persistence and dioxin-like toxicity of carbazole and chlorocarbazoles in soil under controlled conditions for 15 months. Soil samples were divided into two temperature conditions, 15 and 20 degrees C, both under fluctuating soil moisture conditions comprising 19 and 44 drying-rewetting cycles, respectively. This was characterized by natural water loss by evaporation and rewetting to -15 kPa. Accelerated solvent extraction (ASE) and cleanup were performed after incubation. Identification and quantification were done using high-resolution gas chromatogram/mass spectrometer (HRGC/MS), while dioxin-like toxicity was determined by ethoxyresorufin-O-deethylase (EROD) induction in H4IIA rat hepatoma cells assay and multidimensional quantitative structure-activity relationships (mQSAR) modelling. Carbazole, 3-chlorocarbazole and 3,6-dichlorocarbazole were detected including trichlorocarbazole not previously reported in soils. Carbazole and 3-chlorocarbazole showed significant dissipation at 15 degrees C but not at 20 degrees C incubating conditions indicating that low temperature could be suitable for dissipation of carbazole and chlorocarbazoles. 3,6-Dichlorocarbazole was resistant at both conditions. Trichlorocarbazole however exhibited a tendency to increase in concentration with time. 3-Chlorocarbazole, 3,6-dibromocarbazole and selected soil extracts exhibited EROD activity. Dioxin-like toxicity did not decrease significantly with time, whereas the sum chlorocarbazole toxic equivalence concentrations (?TEQ) did not contribute significantly to the soil assay dioxin-like toxicity equivalent concentrations (TCDD-EQ). Carbazole and chlorocarbazoles are persistent with the latter also toxic in natural conditions. PMID- 25142343 TI - Temporal variability of MODIS aerosol optical depth and chemical characterization of airborne particulates in Varanasi, India. AB - Temporal variation of airborne particulate mass concentration was measured in terms of toxic organics, metals and water-soluble ionic components to identify compositional variation of particulates in Varanasi. Information-related fine particulate mass loading and its compositional variation in middle Indo-Gangetic plain were unique and pioneering as no such scientific literature was available. One-year ground monitoring data was further compared to Moderate Resolution Imaging Spectroradiometer (MODIS) Level 3 retrieved aerosol optical depth (AOD) to identify trends in seasonal variation. Observed AOD exhibits spatiotemporal heterogeneity during the entire monitoring period reflecting monsoonal low and summer and winter high. Ground-level particulate mass loading was measured, and annual mean concentration of PM2.5 (100.0 +/- 29.6 MUg/m(3)) and PM10 (176.1 +/- 85.0 MUg/m(3)) was found to exceed the annual permissible limit (PM10: 80 %; PM2.5: 84 %) and pose a risk of developing cardiovascular and respiratory diseases. Average PM2.5/PM10 ratio of 0.59 +/- 0.18 also indicates contribution of finer particulates to major variability of PM10. Particulate sample was further processed for trace metals, viz. Ca, Fe, Zn, Cu, Pb, Co, Mn, Ni, Cr, Na, K and Cd. Metals originated mostly from soil/earth crust, road dust and re suspended dust, viz. Ca, Fe, Na and Mg were found to constitute major fractions of particulates (PM2.5: 4.6 %; PM10: 9.7 %). Water-soluble ionic constituents accounted for approximately 27 % (PM10: 26.9 %; PM2.5: 27.5 %) of the particulate mass loading, while sulphate (8.0-9.5 %) was found as most dominant species followed by ammonium (6.0-8.2 %) and nitrate (5.5-7.0 %). The concentration of toxic organics representing both aliphatic and aromatic organics was determined by organic solvent extraction process. Annual mean toxic organic concentration was found to be 27.5 +/- 12.3 MUg/m(3) (n = 104) which constitutes significant proportion of (PM2.5, 17-19 %; PM10, 11-20 %) particulate mass loading with certain exceptions up to 50 %. Conclusively, compositional variation of both PM2.5 and PM10 was compared to understand association of specific sources with different fractions of particulates. PMID- 25142344 TI - Water resources: the prerequisite for ecological restoration of rivers in the Hai River Basin, northern China. AB - The competition for water resources between humans and river ecosystems is becoming ever more intense worldwide, especially in developing countries. In China, with rapid socioeconomic development, water resources to maintain river ecosystems are progressively decreasing, especially in the Hai River Basin (HRB), which has attracted much attention from the Chinese government. In the past 56 years, water resources have continuously decreased in the basin, such that there is 54.2 % less surface water now compared with then. Water shortages, mainly due to local anthropogenic activities, have emerged as the main limiting factor to river ecological restoration in the HRB. However, the South-to-North Water Diversion Project, the largest such project in the world, presents a good opportunity for ecological restoration of rivers in this basin. Water diverted from the Danjiangkou Reservoir will restore surface water resources in the HRB to levels of 30 years ago and will amount to more than 20 billion m(3). Our findings highlight the fact that water resources are crucial for river ecological restoration. PMID- 25142345 TI - Polycyclic aromatic hydrocarbons (PAHs) in Crassostrea rhizophorae and Cathorops spixii from the Caroni Swamp, Trinidad, West Indies. AB - Dietary exposure to polycyclic aromatic hydrocarbons (PAHs) may pose serious threats to human health. However, within the Caribbean, quantitative assessments regarding the risks associated with dietary PAH exposure remain sparse. This study investigated PAH presence in edible biota from the Caroni Swamp and quantitatively assessed the potential health threat to human consumers. Mangrove oysters (Crassostrea rhizophorae) and Madamango sea catfish (Cathorops spixii) collected from seven sites in the Caroni Swamp were analysed for 16 priority PAHs. Total PAH levels ranged from 109 +/- 18.4 to 362 +/- 63.0 ng/g dry wt. in Crassostrea rhizophorae and 7.5 +/- 0.9 to 43.5 +/- 25.5 ng/g dry wt. in Cathorops spixii (average +/- standard deviation). Benzo[a]pyrene levels in Crassostrea rhizophorae at all sites exceeded international guidelines from British Colombia (Canada) and the European Union (EU). Incremental lifetime cancer risk (ILCR) values based on the ingestion of Crassostrea rhizophorae ranged from 8.4 * 10(-6) to 1.6 * 10(-5) and slightly exceeded the commonly used 1 * 10(-6) acceptable level of risk. Information from this study is important in understanding the potential health risks posed by PAHs, it is critical towards the protection of public health, and it serves as a useful baseline for comparison with future work. PMID- 25142346 TI - Motivational Basis of Personality Traits: A Meta-Analysis of Value-Personality Correlations. AB - We investigated the relationships between personality traits and basic value dimensions. Furthermore, we developed novel country-level hypotheses predicting that contextual threat moderates value-personality trait relationships. We conducted a three-level v-known meta-analysis of correlations between Big Five traits and Schwartz's (1992) 10 values involving 9,935 participants from 14 countries. Variations in contextual threat (measured as resource threat, ecological threat, and restrictive social institutions) were used as country level moderator variables. We found systematic relationships between Big Five traits and human values that varied across contexts. Overall, correlations between Openness traits and the Conservation value dimension and Agreeableness traits and the Transcendence value dimension were strongest across all samples. Correlations between values and all personality traits (except Extraversion) were weaker in contexts with greater financial, ecological, and social threats. In contrast, stronger personality-value links are typically found in contexts with low financial and ecological threats and more democratic institutions and permissive social context. These effects explained on average more than 10% of the variability in value-personality correlations. Our results provide strong support for systematic linkages between personality and broad value dimensions, but they also point out that these relations are shaped by contextual factors. PMID- 25142347 TI - Establishment of a primary hepatocyte culture from the small Indian mongoose (Herpestes auropunctatus) and distribution of mercury in liver tissue. AB - The present study established a primary hepatocyte culture for the small Indian mongoose (Herpestes auropunctatus). To determine the suitable medium for growing the primary hepatic cells of this species, we compared the condition of cells cultured in three media that are frequently used for mammalian cell culture: Dulbecco's Modified Eagle's Medium, RPMI-1640, and William's E. Of these, William's E medium was best suited for culturing the hepatic cells of this species. Using periodic acid-Schiff staining and ultrastructural observations, we demonstrated the cells collected from mongoose livers were hepatocytes. To evaluate the distribution of mercury (Hg) in the liver tissue, we carried out autometallography staining. Most of the Hg compounds were found in the central region of hepatic lobules. Smooth endoplasmic reticulum, which plays a role inxenobiotic metabolism, lipid/cholesterol metabolism, and the digestion and detoxification of lipophilic substances is grown in this area. This suggested that Hg colocalized with smooth endoplasmic reticulum. The results of the present study could be useful to identify the detoxification systems of wildlife with high Hg content in the body, and to evaluate the susceptibility of wildlife to Hg toxicity. PMID- 25142348 TI - Comparative survey of bacterial and archaeal communities in high arsenic shallow aquifers using 454 pyrosequencing and traditional methods. AB - A survey of bacterial and archaeal community structure was carried out in 10 shallow tube wells in a high arsenic groundwater system located in Hetao Basin, Inner Mongolia by 16S rRNA gene based two-step nested PCR-DGGE, clone libraries and 454 pyrosequencing. 12 bacterial and 18 archaeal DGGE bands and 26-136 species-level OTUs were detected for all the samples. 299 bacterial and 283 archaeal 16S rRNA gene clones for two typical samples were identified by phylogenetic analysis. Most of the results from these different methods were consistent with the dominant bacterial populations. But the proportions of the microbial populations were mostly different and the bacterial communities in most of these samples from pyrosequencing were both more abundant and more diverse than those from the traditional methods. Even after quality filtering, pyrosequencing revealed some populations including Alishewanella, Sulfuricurvum, Arthrobacter, Sporosarcina and Algoriphagus which were not detected with traditional techniques. The most dominant bacterial populations in these samples identified as some arsenic, iron, nitrogen and sulfur reducing and oxidizing related populations including Acinetobacter, Pseudomonas, Flavobacterium, Brevundimonas, Massilia, Planococcus, and Aquabacterium and archaeal communities Nitrosophaera and Methanosaeta. Acinetobacter and Pseudomonas were distinctly abundant in most of these samples. Methanogens were found as the dominant archeal population with three methods. From the results of traditional methods, the dominant archaeal populations apparently changed from phylum Thaumarchaeota to Euryarchaeota with the arsenic concentrations increasing. But this structure dynamic change was not revealed with pyrosequencing. Our results imply that an integrated approach combining the traditional methods and next generation sequencing approaches to characterize the microbial communities in high arsenic groundwater is recommended. PMID- 25142349 TI - Effect of soil HHCB on cadmium accumulation and phytotoxicity in wheat seedlings. AB - The accumulation of cadmium (Cd) in wheat seedlings under single and joint stress of galaxolide (HHCB) and Cd was investigated, and their phytotoxicity and oxidation stress including chlorophyll (CHL), malondialdehyde (MDA), superoxide dismutase, and perosidase were assessed. The results showed that the accumulation of Cd in wheat seedlings increased with an increase in the concentration of Cd in soil. The low concentration of HHCB inhibited the accumulation of Cd, while the high concentration of HHCB induced the accumulation of Cd. The content of CHL increased significantly in treatments with 1-50 mg kg(-1) Cd. However, the content of CHL under joint stress of Cd and HHCB was significantly lower than that in the control. Besides, the content of MDA in wheat leaves and roots was also significantly affected by HHCB and Cd, particularly by their joint stress. Co-contamination of HHCB significantly affected the activity of antioxidant enzymes in wheat seedlings stressed by Cd. In a word, HHCB could aggravate the phytotoxicity of Cd to wheat seedlings. PMID- 25142350 TI - Response of growth and superoxide dismutase to enhanced arsenic in two Bacillus species. AB - Species differences in inorganic arsenic tolerance were investigated by comparing the responses of Bacillus subtilis (B. subtilis) and Bacillus thuringiensis (B. thuringiensis) to elevated concentrations of As(III) and As(V). The cell densities in treatments were always lower during the experiment compared to controls, with the exception of exposure to 1.0 mg As(V) l(-1) on the first day. It was also found that relative growth rate (RGR) of B. thuringiensis was lower than that of B. subtilis. Furthermore, RGR of each Bacillus species was negative correlation with toxicity of inorganic arsenic. However, total cell number still increased in each treatment according to cell density and RGR assays. Superoxide dismutase (SOD) activity of both Bacillus species was promoted by As(III) and As(V), especially under high arsenic concentration condition. In addition, SOD activity of B. thuringiensis was higher than that of B. subtilis during the same exposure time. In lipid peroxidation assay, thiobarbituric acid-reactive substances (TBARS) content of each Bacillus species had a significant increase with increment of arsenic concentration. Moreover, significant difference was observed between the two Bacillus species under high arsenic concentration. TBARS content of B. thuringiensis was higher than that of B. subtilis, indicating that effect of arsenic on cell membranes of B. thuringiensis was much more than that of B. subtilis. These results suggest that the two Bacillus species could adapt and live in high arsenic aquifers, although their growth and cell membranes were affected by As treatment in a way. PMID- 25142351 TI - The enzyme toxicity and genotoxicity of chlorpyrifos and its toxic metabolite TCP to zebrafish Danio rerio. AB - Chlorpyrifos is a broad-spectrum organophosphorus insecticide (O,O-diethyl -O 3,5,6-trichloro-2-pyridyl phosphorothioate) that is used in numerous agricultural and urban pest controls. The primary metabolite of chlorpyrifos is 3,5,6 trichloro pyridine-2-phenol (TCP). Because of its strong water solubility and mobility, this harmful metabolite exists in the environment in a large amount. Although TCP has potentially harmful effects on organisms in the environment, few studies have addressed TCP pollution. Therefore, this study was undertaken to investigate the effect of chlorpyrifos and TCP on the microsomal cytochrome P450 content in the liver, on the activity of NADPH-P450 reductase and antioxidative enzymes [catalase (CAT) and superoxide dismutase (SOD)], and on reactive oxygen species (ROS) generation and DNA damage in zebrafish. Male and female zebrafish were separated and exposed to a control solution and three concentrations of chlorpyrifos (0.01, 0.1, 1 mg L(-1)) and TCP (0.01, 0.1, 0.5 mg L(-1)), respectively, sampled after 5, 10, 15, 20 and 25 days. The results indicated that the P450 content and the NADPH-P450 reductase and antioxidative enzyme (CAT and SOD) activities could be induced by chlorpyrifos and TCP. DNA damage of zebrafish was enhanced with increasing chlorpyrifos and TCP concentrations. Meanwhile, chlorpyrifos and TCP induced a significant increase of ROS generation in the zebrafish hepatopancreas. In conclusion, this study proved that chlorpyrifos (0.01-1 mg L(-1)) and TCP (0.01-0.5 mg L(-1)) are both highly toxic to zebrafish. PMID- 25142352 TI - Programmed cell death during development of cowpea (Vigna unguiculata (L.) Walp.) seed coat. AB - The seed coat develops primarily from maternal tissues and comprises multiple cell layers at maturity, providing a metabolically dynamic interface between the developing embryo and the environment during embryogenesis, dormancy and germination of seeds. Seed coat development involves dramatic cellular changes, and the aim of this research was to investigate the role of programmed cell death (PCD) events during the development of seed coats of cowpea [Vigna unguiculata (L.) Walp.]. We demonstrate that cells of the developing cowpea seed coats undergo a programme of autolytic cell death, detected as cellular morphological changes in nuclei, mitochondria, chloroplasts and vacuoles, DNA fragmentation and oligonucleosome accumulation in the cytoplasm, and loss of membrane viability. We show for the first time that classes 6 and 8 caspase-like enzymes are active during seed coat development, and that these activities may be compartmentalized by translocation between vacuoles and cytoplasm during PCD events. PMID- 25142353 TI - Surgical management of multilevel cervical spinal stenosis and spinal cord injury complicated by cervical spine fracture. AB - BACKGROUND: There are few reports regarding surgical management of multilevel cervical spinal stenosis with spinal cord injury. Our purpose is to evaluate the safety and feasibility of open-door expansive laminoplasty in combination with transpedicular screw fixation for the treatment of multilevel cervical spinal stenosis and spinal cord injury in the trauma population. METHODS: This was a retrospective study of 21 patients who had multilevel cervical spinal stenosis and spinal cord injury with unstable fracture. An open-door expansive posterior laminoplasty combined with transpedicular screw fixation was performed under persistent intraoperative skull traction. Outcome measures included postoperative improvement in Japanese Orthopedic Association (JOA) score and incidence of complications. RESULTS: The average operation time was 190 min, with an average blood loss of 437 ml. A total of 120 transpedicular screws were implanted into the cervical vertebrae between vertebral C3 and C7, including 20 into C3, 34 into C4, 36 into C5, 20 into C6, and 10 into C7. The mean preoperative JOA score was 3.67 +/- 0.53. The patients were followed for an average of 17.5 months, and the average JOA score improved to 8.17 +/- 1.59, significantly higher than the preoperative score (t = 1.798, P < 0.05), with an average improvement of 44.7 +/- 11.7%. Postoperative complications in four patients included cerebrospinal fluid leakage, delayed wound healing, pulmonary infection, and urinary system infection. All four patients were responsive to antibiotic treatment; one died from respiratory failure 3 months postoperatively. CONCLUSIONS: The open-door expansive laminoplasty combined with posterior transpedicular screw fixation is feasible for treating multilevel cervical spinal stenosis and spinal cord injury complicated by unstable fracture. Its advantages include minimum surgical trauma, less intraoperative blood loss, and satisfactory stable supportive effect for reduction of fracture. PMID- 25142355 TI - Contributing factors to vehicle to vehicle crash frequency and severity under rainfall. AB - INTRODUCTION: This study combined vehicle to vehicle crash frequency and severity estimations to examine factor impacts on Wisconsin highway safety in rainy weather. METHOD: Because of data deficiency, the real-time water film depth, the car-following distance, and the vertical curve grade were estimated with available data sources and a GIS analysis to capture rainy weather conditions at the crash location and time. Using a negative binomial regression for crash frequency estimation, the average annual daily traffic per lane, the interaction between the posted speed limit change and the existence of an off-ramp, and the interaction between the travel lane number change and the pavement surface material change were found to increase the likelihood of vehicle to vehicle crashes under rainfall. RESULTS: However, more average daily rainfall per month and a wider left shoulder were identified as factors that decrease the likelihood of vehicle to vehicle crashes. In the crash severity estimation using the multinomial logit model that outperformed the ordered logit model, the travel lane number, the interaction between the travel lane number and the slow grade, the deep water film, and the rear-end collision type were more likely to increase the likelihood of injury crashes under rainfall compared with crashes involving only property damage. PRACTICAL IMPLICATIONS: As an exploratory data analysis, this study provides insight into potential strategies for rainy weather highway safety improvement, specifically, the following weather-sensitive strategies: road design and ITS implementation for drivers' safety awareness under rainfall. PMID- 25142354 TI - Spatial and temporal control of fungal natural product synthesis. AB - Despite their oftentimes-elusive ecological role, fungal natural products have, for better or worse, impacted our daily lives tremendously owing to their diverse and potent bioactive properties. This Janus-faced nature of fungal natural products inevitably ushered in a field of research dedicated towards understanding the ecology, organisms, genes, enzymes, and biosynthetic pathways that give rise to this arsenal of diverse and complex chemistry. Ongoing research in fungal secondary metabolism has not only increased our appreciation for fungal natural products as an asset but also sheds light on the pivotal role that these once-regarded "metabolic wastes" play in fungal biology, defense, and stress response in addition to their potential contributions towards human mycoses. Full orchestration of secondary metabolism requires not only the seamless coordination between temporal and spatial control of SM-associated machineries (e.g. enzymes, cofactors, intermediates, and end-products) but also integration of these machineries into primary metabolic processes and established cellular mechanisms. An intriguing, but little known aspect of microbial natural product synthesis lies in the spatial organization of both pathway intermediates and enzymes responsible for the production of these compounds. In this highlight, we summarize some major breakthroughs in understanding the genes and regulation of fungal natural product synthesis and introduce the current state of knowledge on the spatial and temporal control of fungal natural product synthesis. PMID- 25142356 TI - The impact of continuous driving time and rest time on commercial drivers' driving performance and recovery. AB - PROBLEM: This real road driving study was conducted to investigate the effects of driving time and rest time on the driving performance and recovery of commercial coach drivers. METHODS: Thirty-three commercial coach drivers participated in the study, and were divided into three groups according to driving time: (a) 2 h, (b) 3 h, and (c) 4 h. The Stanford Sleepiness Scale (SSS) was used to assess the subjective fatigue level of the drivers. One-way ANOVA was employed to analyze the variation in driving performance. RESULTS: The statistical analysis revealed that driving time had a significant effect on the subjective fatigue and driving performance measures among the three groups. After 2 h of driving, both the subjective fatigue and driving performance measures began to deteriorate. After 4 h of driving, all of the driving performance indicators changed significantly except for depth perception. A certain amount of rest time eliminated the negative effects of fatigue. A 15-minute rest allowed drivers to recover from a two-hour driving task. This needed to be prolonged to 30 min for driving tasks of 3 to 4 h of continuous driving. PRACTICAL IMPLICATIONS: Drivers' attention, reactions, operating ability, and perceptions are all affected in turn after over 2 h of continuous driving. Drivers should take a certain amount of rest to recover from the fatigue effects before they continue driving. PMID- 25142357 TI - Stages of driving behavior change within the Transtheoretical Model (TM). AB - INTRODUCTION: Many older adults voluntarily restrict their driving or stop driving of their own accord. Driving behavior change may occur in stages, as predicted by the Transtheoretical Model of Behavior Change (TM). METHOD: This study explored the process of older driver behavior change within the TM framework using interviews/focus groups with drivers and former drivers aged 71 94 years. Within those groups of drivers, driving behavior was divided into two classes: those who changed their driving with age and those who did not. Those who changed their driving as they aged included people gradually imposing restrictions ("gradual restrictors") and those making plans in anticipation of stopping driving ("preparers"). Participants who did not change their driving included those who employed lifelong driving restrictions ("consistent") and those who made no changes ("non-changers"). RESULTS: Preliminary support for TM within the driving context was found; however, further exploration of driving behavior change within this framework is warranted. PRACTICAL APPLICATIONS: It is important to continue to investigate the factors that might influence driving behavior in older adults. By promoting self-regulation in individuals, it may be possible to help older adults continue to drive, thereby improving older adult's mobility and quality of life. PMID- 25142358 TI - Crossing a two-way street: comparison of young and old pedestrians. AB - INTRODUCTION: Choosing a safe gap in which to cross a two-way street is a complex task and only few experiments have investigated age-specific difficulties. METHOD: A total of 18 young (age 19-35), 28 younger-old (age 62-71) and 38 older old (age 72-85 years) adults participated in a simulated street-crossing experiment in which vehicle approach speed and available time gaps were varied. The safe and controlled simulated environment allowed participants to perform a real walk across an experimental two-way street. The differences between the results for the two lanes are of particular interest to the study of visual exploration and crossing behaviors. RESULTS: The results showed that old participants crossed more slowly, adopted smaller safety margins, and made more decisions that led to collisions than did young participants. These difficulties were found particularly when vehicles approached in the far lane, or rapidly. Whereas young participants considered the time gaps available in both lanes to decide whether to cross the street, old participants made their decisions mainly on the basis of the gap available in the near lane while neglecting the far lane. CONCLUSIONS: The present results point to attentional deficits as well as physical limitations in older pedestrians. Several practical and have implications in terms of road design and pedestrian training are proposed. PMID- 25142359 TI - Changes in driver cannabinoid prevalence in 12 U.S. states after implementing medical marijuana laws. AB - OBJECTIVE: To determine if cannabinoid prevalence increased among fatal-crash involved drivers in 12 U.S. states after implementing medical marijuana laws. METHODS: Time series analyses of 1992 to 2009 driver cannabinoid prevalence from the Fatality Analysis Reporting System. RESULTS: Increased driver cannabinoid prevalence associated with implementing medical marijuana laws was detected in only three states: California, with a 2.1 percentage-point increase in the percentage of all fatal-crash-involved drivers who tested positive for cannabinoids (1.1% pre vs. 3.2% post) and a 5.7 percentage-point increase (1.8% vs. 7.5%) among fatally-injured drivers; Hawaii, with a 6.0 percentage-point increase (2.5 vs. 8.5) for all drivers and a 9.6 percentage-point increase (4.9% vs. 14.4%) among fatally-injured drivers; and Washington, with a 3.4 percentage point increase (0.7% vs. 4.1%) for all drivers and a 4.6 percentage-point increase (1.1% vs. 5.7%) among fatally-injured drivers. Changes in prevalence were not associated with the ease of marijuana access afforded by the laws. DISCUSSION: Increased prevalence of cannabinoids among drivers involved in fatal crashes was only detected in a minority of the states that implemented medical marijuana laws. The observed increases were one-time changes in the prevalence levels, rather than upward trends, suggesting that these laws may indeed provide marijuana access to a stable population of patients as intended, without increasing the numbers of new users over time. Although this study provides some insight into the potential impact of these laws on public safety, differences between states in drug testing practices and regularity, along with the fairly recent implementation of most medical marijuana laws, suggest that the long-term impact of these laws may not yet be known. PRACTICAL APPLICATIONS: It is recommended that nationwide standardization of drug testing procedures and criteria be considered to improve the consistency of testing both between and within jurisdictions. PMID- 25142360 TI - Estimating the over-involvement of suspended, revoked, and unlicensed drivers as at-fault drivers in California fatal crashes. AB - INTRODUCTION AND METHOD: Quasi-induced exposure analysis was used to estimate annual fatal crash involvement rates for validly licensed, suspended or revoked (S/R), and unlicensed drivers in California from 1987 through 2009 using fatal crash data obtained from the National Highway Traffic Safety Administration's Fatality Analysis Reporting System and crash culpability determinations from the California Highway Patrol's Statewide Integrated Traffic Records System. RESULTS: Although there was some year-to-year fluctuation in the annual estimates, S/R and unlicensed drivers were over-involved as at-fault drivers in fatal crashes during every year of the 23-year time period relative to validly licensed drivers. The fatal crash involvement ratios combined across all years were 0.86 for validly licensed drivers, 2.23 for S/R drivers, and 2.34 for unlicensed drivers. Hence, compared to validly licensed drivers, the odds of being at-fault for a fatal crash were 160% higher for S/R drivers (involvement ratio=2.60) and 173% higher for unlicensed drivers (involvement ratio=2.73). The excess risks of S/R and unlicensed drivers are somewhat lower than estimates found in a prior study using the same technique, but the results nonetheless provide evidence that S/R and unlicensed drivers are much more hazardous on the road than are validly licensed drivers and emphasize the importance of using strong countermeasures-including vehicle impoundment-to reduce their high crash risk. These findings support interventions to help reduce driving among S/R and unlicensed drivers. PMID- 25142361 TI - To brake or to accelerate? Safety effects of combined speed and red light cameras. AB - INTRODUCTION: The present study evaluates the traffic safety effect of combined speed and red light cameras at 253 signalized intersections in Flanders, Belgium that were installed between 2002 and 2007. METHOD: The adopted approach is a before-and-after study with control for the trend. RESULTS: The analyses showed a non-significant increase of 5% in the number of injury crashes. An almost significant decrease of 14% was found for the more severe crashes. The number of rear-end crashes turned out to have increased significantly (+44%), whereas a non significant decrease (-6%) was found in the number of side crashes. The decrease for the severe crashes was mainly attributable to the effect on side crashes, for which a significant decrease of 24% was found. PRACTICAL APPLICATIONS: It is concluded that combined speed and red light cameras have a favorable effect on traffic safety, in particular on severe crashes. However, future research should examine the circumstances of rear-end crashes and how this increase can be managed. PMID- 25142362 TI - Work-related injury underreporting among young workers: prevalence, gender differences, and explanations for underreporting. AB - INTRODUCTION: Although notifying an employer of a lost-time work-related injury is a legal requirement in many jurisdictions, employees frequently do not report such injuries. METHOD: Based on data from 21,345 young part-time Canadian workers (55% male), we found that 21% of respondents had experienced at least one lost time injury, with about half reporting the injury to an employer and a doctor. RESULTS: Respondents provided 10 reasons for avoiding reporting lost-time injuries, with perceived low severity of the injury, negative reactions of others, and ambiguity about whether work caused the injury as the most common ones. Additional analysis of these categories revealed that young males cited concern about their self-identity as a reason for not reporting an injury more often than young females did. We discuss the findings in terms of implications for management practice (i.e., educating young workers about accurate injury reporting) and public policy. PRACTICAL APPLICATIONS: Targeted campaigns should be developed for young workers, especially young male workers, who are less likely to report injuries than young female workers, to understand the importance of and to encourage injury reporting. PMID- 25142363 TI - Aggravating and mitigating factors associated with cyclist injury severity in Denmark. AB - INTRODUCTION: Denmark is one of the leading cycling nations, where cycling trips constitute a large share of the total trips, and cycling safety assumes a top priority position in the agenda of policy makers. The current study sheds light on the aggravating and mitigating factors associated with cyclist injury severity on Danish roads by examining a comprehensive set of accidents involving a cyclist and a collision partner between 2007 and 2011. METHOD: This study estimates a generalized ordered logit model of the severity of cyclist injuries because of its ability to accommodate the ordered-response nature of severity while relaxing the proportional odds assumption. RESULTS: Model estimates show that cyclist fragility (children under 10 years old and elderly cyclists over 60 years of age) and cyclist intoxication are aggravating individual factors, while helmet use is a mitigating factor. Speed limits above 70-80 km/h, slippery road surface, and location of the crash on road sections are aggravating infrastructure factors, while the availability of cycling paths and dense urban development are mitigating factors. Heavy vehicle involvement and conflicts between cyclists going straight or turning left and other vehicles going straight are aggravating vehicle involvement factors. Practical applications: The results are discussed in the context of applied policies, engineering, and traffic management solutions for bicycle safety in Denmark. PMID- 25142364 TI - Validation of the principles of injury risk zones for motorcycle protective clothing. AB - INTRODUCTION: The distributions of motorcycle crash impacts and injuries were compared to the four impact risk zones and protective performance specified in the European Standard for motorcycle clothing (EN 13595). METHODS: Crashed motorcyclists' (n=117) injuries and clothing damage were categorized by body area into the four risk zones. Three levels of protection were defined: protective clothing with impact protection, protective clothing only and non-protective clothing. RESULTS: The distribution of impact/injury sites corresponded to the predictions of EN 13595, with the proportion of all injuries decreasing from 43.9% in Zone 1, to 18.0%, 16.7%, and 11.5% in Zones 2 to 4, respectively. Protective clothing modified the distribution of injuries with substantially more injuries (OR=2.69, 95% CL: 20.1-3.59) at unprotected impact sites. PRACTICAL APPLICATION: These findings support an appropriate framework for determining performance specifications for the manufacture of motorcycle clothing that will effectively reduce the risk of injury in crashes. PMID- 25142365 TI - Costs of occupational injuries and diseases in Quebec. AB - PROBLEM: Occupational injuries and diseases are costly for companies and for society as a whole. This study estimates the overall costs of occupational injuries and diseases in Quebec, both human and financial, during the period from 2005 to 2007. METHOD: The human capital method is used to estimate lost productivity. A health indicator (DALY) is used in combination with a value of statistical life (VSL) to estimate, in monetary terms, the pain and suffering costs resulting from occupational injuries. RESULTS: The costs of occupational injuries and diseases occurring in a single year in Quebec are estimated at $4.62 billion, on average, for the 2005-2007 period. Of this amount, approximately $1.78 billion is allocated to financial costs and $2.84 billion to human costs. The average cost per case is $38,355. In view of the limitations identified in the study, it can be argued that this is an underestimation of the costs. Result analysis allows the injury/disease descriptors and industries for which the costs are highest to be identified. PRACTICAL APPLICATIONS: The results of these estimates are a relevant source of information for helping to determine research directions in OHS and prevention. The methodology used can be replicated for the purposes of estimating the costs of injuries and diseases in other populations. PMID- 25142366 TI - The Driver Behaviour Questionnaire: a North American analysis. AB - INTRODUCTION: The Driver Behaviour Questionnaire (DBQ), originally developed in Britain by Reason et al. [Reason, J., Manstead, A., Stradling, S., Baxter, J., & Campbell, K. (1990). Errors and violations on the road: A real distinction? Ergonomics, 33, 1315-1332] is one of the most widely used instruments for measuring driver behaviors linked to collision risk. METHOD: The goals of the study were to adapt the DBQ for a North American driving population, assess the component structure of the items, and to determine whether scores on the DBQ could predict self-reported traffic collisions. RESULTS: Of the original Reason et al. items, our data indicate a two-component solution involving errors and violations. Evidence for a Lapses component was not found. The 20 items most closely resembling those of Parker et al. [Parker, D., Reason, J. T., Manstead, A. S. R., & Stradling, S. G. (1995). Driving errors, driving violations and accident involvement. Ergonomics, 38, 1036-1048] yielded a solution with 3 orthogonal components that reflect errors, lapses, and violations. Although violations and Lapses were positively and significantly correlated with self reported collision involvement, the classification accuracy of the resulting models was quite poor. PRACTICAL APPLICATIONS: A North American DBQ has the same component structure as reported previously, but has limited ability to predict self-reported collisions. PMID- 25142367 TI - Scanning secondary derived crashes from disabled and abandoned vehicle incidents on uninterrupted flow highways. AB - INTRODUCTION: Extent of secondary crashes derived from primary incidents involving abandoned and disabled vehicles are presented in this paper. METHOD: Using years 2004 to 2010 incident and crash data on selected Tennessee freeways, the study identified secondary crashes that resulted from disabled and abandoned vehicle primary incidents. The relationship between time and distance gaps before the secondary crash with respect to individual incident characteristics were evaluated through descriptive statistics and linear regression. RESULTS: The time and distance gap analysis indicated that a large portion of secondary crashes occurred within 20 min after the primary incidents and within a distance of 0.5 miles upstream. While 76% of incidents involved shoulder, most secondary crashes were related to the closing of right lanes. Overall, 58% of the secondary crashes occurred within 30 min after the occurrence of the primary incidents. Most of the vehicles in the incidents that involved towing and caused secondary crashes were towed or removed out of the travel way within 60 min from the time of occurrence. The study found that most (95%) secondary crashes were property damage only (PDO), while 49% were rear-end crashes. The negative binomial model was used to evaluate the impact of roadway geometry and traffic factors associated with frequency of these secondary crashes. It was found that the posted speed limit, congested segments, segments with high percentages of trucks, and peak hour volumes increased the likelihood of secondary crash occurrence. Roadway segments with wider medians, shoulders, and multilanes decrease the likelihood of secondary crashes caused by abandoned and disabled vehicles as the primary incidents. Practical applications The paper recommends that wider shoulders be provided on any section of freeway to accommodate abandoned or disabled vehicles to avoid blocking of travel lane(s). PMID- 25142368 TI - On-road all-terrain vehicle (ATV) fatalities in the United States. AB - BACKGROUND: The study was designed to describe the characteristics of all-terrain vehicle (ATV) rider fatalities and fatal crashes involving ATVs that occur on public roads. METHODS: Information on fatal crashes occurring on public roads during the years 2007-2011 was obtained from the Fatality Analysis Reporting System (FARS). RESULTS: There were 1,701 ATV rider deaths during the 5-year study period, including 1,482 drivers, 210 passengers, and 9 with unknown rider status. An additional 19 non-ATV occupants, primarily motorcyclists, died in crashes with ATVs. About half of the ATV passenger deaths were teenagers or younger, and the majority of passenger deaths were female. Ninety percent of the fatally injured drivers were 16 or older, and 90% were male. The crashes were most likely to occur in relatively rural states, and in rural areas within states. Only 13% of drivers and 6% of passengers killed wore helmets. Forty-three percent of the fatally injured drivers had blood alcohol concentrations (BACs) of 0.08% or greater. Seventy-five percent of the fatal crashes involved single ATVs; 5% involved multiple ATVs but no non-ATV vehicles, and 20% involved ATVs and non ATVs, usually passenger vehicles. Speeding was reported by police as a contributing factor in the crash for 42% of ATV drivers in single-vehicle crashes and 19% of ATV drivers in multiple-vehicle crashes. PRACTICAL APPLICATIONS: Although ATVs are designed exclusively for off-road use, many ATV occupant deaths occur on roads, despite most states having laws prohibiting many types of on-road use. Attention needs to be given to ways to reduce these deaths. PMID- 25142369 TI - Crash and traffic violation rates before and after licensure for novice California drivers subject to different driver licensing requirements. AB - INTRODUCTION: How do crash and traffic violation rates for novice 16-17-year-old drivers change over the months before and after licensure under a graduated driver licensing (GDL) program relative to those for older novices who are not subject to GDL? METHOD: Plots and Poisson regression comparing overall rates and subtypes of crashes and traffic violations among California novice drivers ages 16 to 35 years over time before and after unsupervised licensure. RESULTS: Majorities of 16-year-olds (57%) and 17-year-olds (73%) actually hold their learner permits longer than the required 6 months; majorities (67%-81%) of age 18 or older novices hold their learner permits less than 6 months. Crash rates of novice 16- and 17-year-olds-as well as most other age groups-are highest almost immediately after they are licensed to drive unsupervised, after which their rates decline quickly during their first year of licensure and at a slower rate for the second and third years. Novice 16- and 17-year-olds' traffic violation rates reach their zenith long after their total crash rates peak and decline, whereas violation rates for older novices peak during their first year of licensure. Over 70% of 16- and 17-year-old novices are crash-free for the first 3 years of licensure. CONCLUSIONS: While novice 16- and 17-year-olds' highest crash rates occur almost immediately after they are licensed, their peak traffic violation rates are delayed until around the time they turn age 18. Both pre licensure crash rates and post-licensure crash peaks were more pronounced for some older age groups of novices than was the case for 16-17-year-olds. PRACTICAL APPLICATIONS: Extending learner permit holding periods for 16-17-year-old novices appears consistent with their actual behavior; requiring older novices particularly those ages 18 to 20-to hold permits for minimum periods may reduce their initial crash rates. PMID- 25142370 TI - Racial and ethnic disparities in fatal unintentional drowning among persons less than 30 years of age--United States, 1999-2010. AB - BACKGROUND: In the U.S., almost 4,000 persons die from drowning annually. Among those 0-29 years, drowning is in the top three causes of unintentional injury death. METHODS: To describe racial/ethnic differences in drowning rates by age of decedent and drowning setting, CDC analyzed 12 years of mortality data from 1999 through 2010 for those <=29 years. RESULTS: Compared to whites, American Indians/Alaska Natives were twice, and blacks were 1.4 times, as likely to drown. Disparities were greatest in swimming pool settings, with drowning rates among blacks aged 5-19 years 5.5 times higher than those among whites. CONCLUSIONS: Drowning rates for black children and teens are higher than those of other race/ethnicities, especially in swimming pools. PRACTICAL APPLICATION: The practicality and effectiveness of current drowning prevention strategies varies by setting; however, basic swimming skills can be beneficial across all settings and may help reduce racial disparities. PMID- 25142371 TI - A 10-year review of the Centers for Disease Control and Prevention's Heads Up initiatives: bringing concussion awareness to the forefront. PMID- 25142372 TI - Automated thresholding and analysis of microCT scanned bread dough. AB - Computer aided x-ray microtomography is an increasingly popular method to investigate the structure of materials. Continuing improvements in the technique are resulting in increasingly larger data sets. The analysis of these data sets generally involves executing a static workflow for multiple samples and is generally performed manually by researchers. Executing these processes requires a significant time investment. A workflow which is able to automate the activities of the user would be useful. In this work, we have developed an automated workflow for the analysis of microtomography scanned bread dough data sets averaging 5 GB in size. Comparing the automated workflow with the manual workflow indicates a significant amount of the time spent (33% in the case of bread dough) on user interactions in manual method. Both workflows return similar results for porosity and pore frequency distribution. Finally, by implementing an automated workflow, users save the time which would be required to manually execute the workflow. This time can be spent on more productive tasks. PMID- 25142373 TI - Bevacizumab and ranibizumab for neovascular age-related macular degeneration: an updated meta-analysis of randomised clinical trials. AB - PURPOSE: Neovascular age-related macular degeneration (AMD) is the main cause of central vision loss among individuals aged 50 years or older in developed countries. The aim of this study was to review systematically the effect of bevacizumab compared to ranibizumab in patients with AMD at 1 year. METHODS: A systematic review was performed on Medline, Embase, and the Cochrane Library and Trial registers to October 2013. Eligibility criteria for selecting studies were randomised controlled trials (RCT) comparing bevacizumab with ranibizumab in patients with neovascular AMD. Odds ratio (OR) and mean difference (MD) estimates were synthesized under fixed- and random-effects models. Heterogeneity was assessed using the Q statistic and I(2). RESULTS: Five RCTs were included, representing 2,686 randomised patients. The meta-analysis confirmed the non inferiority of bevacizumab compared to ranibizumab for change in visual acuity at 1 year (MD 0.57 letters, -1.80 to 0.66, p = 0.37, I(2) = 0 %). Better anatomical results were found for ranibizumab. Bevacizumab was associated with a 34 % increase in the number of patients with at least one serious systemic adverse event (OR 1.34, 1.08 to 1.66, p = 0.01, I(2) = 0 %). CONCLUSIONS: The pooled evidence confirmed that, compared with ranibizumab, bevacizumab was associated with equivalent effects on visual acuity at 1 year and with a higher risk of systemic serious adverse events. The current available data do not show which types of adverse events occur more frequently. In practice, bevacizumab should be used under a risk-management plan until further studies have been carried out to assess accurately the increased risk of systemic adverse events. PMID- 25142374 TI - Acute anterior uveitis and undiagnosed spondyloarthritis: usefulness of Berlin criteria. AB - PURPOSE: Inflammatory back pain, the main symptom in spondyloarthritis, is defined by the presence of two or more positive responses among the four items of Berlin Criteria. This study assesses the value of these criteria in detecting previously undiagnosed spondyloarthritis after an episode of acute anterior uveitis. METHODS: Records of patients addressed for etiological diagnosis after an acute anterior uveitis (April 2006 to November 2013) were retrospectively analysed. Patient characteristics, the presence of back pain, Berlin Criteria, the final diagnosis, and the ASAS classification criteria for spondyloarthritis were collected and analysed. RESULTS: The study included 102 patients (59.8% women). The mean age was 44.5 years. Uveitis cases were mainly unilateral (73.5%) and recurrent (58.8%). Twenty-one patients had some type of spondyloarthritis, 20 fulfilling retrospectively the ASAS criteria. Back pain with at least two positive items from Berlin Criteria was 61.9% sensitive and 97.5% specific in diagnosing spondyloarthritis. Considering only one positive item increased the sensitivity (90.5%) but decreased the specificity (91.4%). CONCLUSIONS: Acute anterior uveitis may be the key symptom that reveals a formerly undiagnosed spondyloarthritis. A referral to a rheumatologist should be considered in presence of back pain, even without fulfilment of the classical definition with Berlin Criteria. PMID- 25142375 TI - Comparison of retinal detachment surgery outcome among patients undergoing pars plana vitrectomy with and without relaxing retinotomy. AB - The purpose of this four year retrospective study was to compare the anatomical and functional outcomes of complicated retinal detachment (RD) surgery by pars plana vitrectomy (PPV) with and without retinotomy. The main outcome measures were primary anatomical success (defined as retinal re-attachment at the final follow-up after a single operation, with or without silicone in situ), final anatomical success, final best-corrected visual acuity (BCVA) and postoperative complications. Baseline characteristics did not differ between the groups, although there was a borderline significant trend for the retinotomy group to be associated with worse pre-surgical ocular pathology. With a mean follow-up of 18 (+/- 7.8) months, primary anatomical success was achieved in 76.7% (33 of 43) of the retinotomy group eyes vs. 67.8% (40 of 59) of the eyes in the group without retinotomy. Final anatomical success rates for the retinotomy group and no retinotomy group were 100 and 93.2% respectively. The final BCVA was 1.57 LogMAR with retinotomy and 1.38 without retinotomy, an improvement in both groups. The incidence of postoperative complications was similar in the two groups, while the frequency of macular holes was higher in the retinotomy group. A similar degree of improvement in BCVA following both surgeries indicates their similar efficacy and justifies their performance even in complicated eyes in order to improve the patients' quality of life. With neither approach superior to the other, the choice of method should be left to the surgeon. PMID- 25142376 TI - High performance current and spin diode of atomic carbon chain between transversely symmetric ribbon electrodes. AB - We demonstrate that giant current and high spin rectification ratios can be achieved in atomic carbon chain devices connected between two symmetric ferromagnetic zigzag-graphene-nanoribbon electrodes. The spin dependent transport simulation is carried out by density functional theory combined with the non equilibrium Green's function method. It is found that the transverse symmetries of the electronic wave functions in the nanoribbons and the carbon chain are critical to the spin transport modes. In the parallel magnetization configuration of two electrodes, pure spin current is observed in both linear and nonlinear regions. However, in the antiparallel configuration, the spin-up (down) current is prohibited under the positive (negative) voltage bias, which results in a spin rectification ratio of order 10(4). When edge carbon atoms are substituted with boron atoms to suppress the edge magnetization in one of the electrodes, we obtain a diode with current rectification ratio over 10(6). PMID- 25142377 TI - Synthesis, spectroscopic and electrochemical studies of phosphoryl and carbomethoxyphenyl substituted corroles, and their anion detection properties. AB - The synthesis, electrochemical studies and anion detection properties of triphosphoryl () and triester corroles () are reported and compared with triphenylcorrole (). These corroles exhibited typical acid-base binding behaviour in CH3CN and were converted to monoprotonated and dianionic species, respectively. has shown a ~30 fold lower Keq value for monoprotonation than that of in a TFA-CH3CN medium. The detection ability of these corroles was also tested in acetonitrile towards various anions. The observed spectral changes in free base corroles () are due to anion-induced deprotonation rather than the hydrogen bonding interaction between the imino protons of the corrole moiety with anions. and have shown higher equilibrium constants with F(-) ions (4.7 * 10(3) fold higher for and 9.7 * 10(3) fold higher for ) as compared to and are able to detect 0.06 MUM of F(-) ions. The Cu(iii) and Ag(iii) complexes of and exhibited an anodic shift of ~250 mV in first ring oxidation and ~100-150 mV in metal centred reduction as compared to the Cu(iii) and Ag(iii) complexes of . The anodic shift in the redox potentials, lower protonation constants and lower detection limit of anions have been explained in terms of the electron withdrawing nature of the diethylphosphite and carbomethoxy substituents at the meso-phenyl positions of the corrole ring. PMID- 25142378 TI - Factors associated with effects of 90Y-ibritumomab tiuxetan in patients with relapsed or refractory low-grade B cell non-Hodgkin lymphoma: single-institution experience with 94 Japanese patients in rituximab era. AB - This retrospective study analyzes the results of radioimmunotherapy (RIT) with (90)Y-ibritumomab tiuxetan in 94 Japanese patients with relapsed or refractory low-grade B cell non-Hodgkin lymphoma at a single institution. All patients had previously been administered with 1-8 (median 1) regimens of rituximab alone or combined with other chemotherapeutic regimens at a mean age of 64 years. The overall response rate was 90 % and the complete response (CR) rate was 69 %. The median overall survival was not reached and progression-free survival (PFS) was 26 months, respectively, for the early phase 50 patients during a median follow up period of 46.5 months. In this cohort, the PFS rates for the 50 early phase patients who had undergone <=2 and >=3 previous regimens, and for those who achieved CR compared with those who did not (partial response, PR; stable disease, SD; progressive disease, PD) were 38 and 11 months, respectively. Multivariate analysis showed that these two factors were statistically significant (p = 0.0011 and p <0.0001, respectively). The overall incidence of grade >=3 non-hematological toxicity was 9 %. Two patients died of treatment related deteriorating hepatitis C. A second malignancy developed in two patients at 10.5 and 3.5 months after treatment. We recommend administering (90)Y ibritumomab tiuxetan as early in the disease course as possible, and at the latest as a third-line therapy to maximize the benefits of RIT, which should improve the quality of life for patients. PMID- 25142379 TI - Medaka Oct4 is essential for pluripotency in blastula formation and ES cell derivation. AB - The origin and evolution of molecular mechanisms underlying cellular pluripotency is a fundamental question in stem cell biology. The transcription factor Oct4 or Pou5f1 identified in mouse features pluripotency expression and activity in the inner cell mass and embryonic stem (ES) cells. Pou2 identified in zebrafish is the non-mammalian homolog prototype of mouse Oct4. The genes oct4 and pou2 have reportedly evolved by pou5 gene duplication in the common ancestor of vertebrates. Unlike mouse oct4, however, zebrafish pou2 lacks pluripotency expression and activity. Whether the presence of pluripotency expression and activity is specific for mammalian Oct4 or common to the ancestor of vertebrate Oct4 and Pou2 proteins has remained to be determined. Here we report that Oloct4, the medaka oct4/pou2, is essential for early embryogenesis and pluripotency maintenance. Oloct4 exists as a single copy gene and is orthologous to pou2 by sequence and chromosome synteny. Oloct4 expression occurs in early embryos, germ stem cells and ES cells like mouse oct4 but also in the brain and tail bud like zebrafish pou2. Importantly, OlOct4 depletion caused blastula lethality or blockage. We show that Oloct4 depletion abolishes ES cell derivation from midblastula embryos. Thus, Oloct4 has pluripotency expression and is essential for early embryogenesis and pluripotency maintenance. Our results demonstrate the conservation of pluripotency expression and activity in vertebrate Oct4 and Pou2 proteins. The finding that Oloct4 combines the features of mouse oct4 and zebrafish pou2 in expression and function suggests that Oloct4 might represent the ancestral prototype of vertebrate oct4 and pou2 genes. PMID- 25142381 TI - The impact of subjective memory complaints on quality of life in community dwelling older adults. AB - PURPOSE: The aim of this study was to evaluate the impact of memory complaints on quality of life (QOL) in elderly community dwellers with or without mild cognitive impairment (MCI). METHODS: Participants included 120 normal controls (NC) and 37 with MCI aged 65 and over. QOL was measured using the Japanese version of Satisfaction in Daily Life, and memory complaints were measured using a questionnaire consisting of four items. The relevance of QOL was evaluated with psychological factors of personality traits, sense of self-efficacy, depressive mood, self-evaluation of daily functioning, range of social activities (Life Space Assessment), social network size, and cognitive functions including memory. The predictors of QOL were analyzed by multiple linear regression analysis. RESULTS: QOL was not significantly different between the NC and MCI groups. In both groups, QOL was positively correlated with self-efficacy, daily functioning, social network size, Life-Space Assessment, and the personality traits of extraversion and agreeableness; QOL was negatively correlated with memory complaints, depressive mood, and the personality trait of neuroticism. In regression analysis, memory complaints were a negative predictor of QOL in the MCI group, but not in the NC group. The partial correlation coefficient between QOL and memory complaints was -0.623 (P < 0.05), after scores of depressive mood and self-efficacy were controlled. Depressive mood was a common negative predictor in both groups. Positive predictors were Life-Space Assessment in the NC group and sense of self-efficacy in the MCI group. CONCLUSIONS: Memory complaints exerted a negative impact on self-rated QOL in the MCI group, whereas a negative correlation was weak in the NC group. Memory training has been widely practised in individuals with MCI to prevent the development of dementia. However, such approaches inevitably identify their memory deficits and could aggravate their awareness of memory decline. Thus, it is critical to give sufficient consideration not to reduce QOL in the intervention for those with MCI. PMID- 25142380 TI - Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer's disease. AB - Fragmented sleep is a common and troubling symptom in ageing and Alzheimer's disease; however, its neurobiological basis in many patients is unknown. In rodents, lesions of the hypothalamic ventrolateral preoptic nucleus cause fragmented sleep. We previously proposed that the intermediate nucleus in the human hypothalamus, which has a similar location and neurotransmitter profile, is the homologue of the ventrolateral preoptic nucleus, but physiological data in humans were lacking. We hypothesized that if the intermediate nucleus is important for human sleep, then intermediate nucleus cell loss may contribute to fragmentation and loss of sleep in ageing and Alzheimer's disease. We studied 45 older adults (mean age at death 89.2 years; 71% female; 12 with Alzheimer's disease) from the Rush Memory and Aging Project, a community-based study of ageing and dementia, who had at least 1 week of wrist actigraphy proximate to death. Upon death a median of 15.5 months later, we used immunohistochemistry and stereology to quantify the number of galanin-immunoreactive intermediate nucleus neurons in each individual, and related this to ante-mortem sleep fragmentation. Individuals with Alzheimer's disease had fewer galaninergic intermediate nucleus neurons than those without (estimate -2872, standard error = 829, P = 0.001). Individuals with more galanin-immunoreactive intermediate nucleus neurons had less fragmented sleep, after adjusting for age and sex, and this association was strongest in those for whom the lag between actigraphy and death was <1 year (estimate -0.0013, standard error = 0.0005, P = 0.023). This association did not differ between individuals with and without Alzheimer's disease, and similar associations were not seen for two other cell populations near the intermediate nucleus. These data are consistent with the intermediate nucleus being the human homologue of the ventrolateral preoptic nucleus. Moreover, they demonstrate that a paucity of galanin-immunoreactive intermediate nucleus neurons is accompanied by sleep fragmentation in older adults with and without Alzheimer's disease. PMID- 25142382 TI - Reproducibility of microvascular vessel density analysis in Sidestream dark-field derived images of healthy term newborns. AB - OBJECTIVE: Microcirculatory visualization has already been used to investigate buccal and cutaneous microcirculatory alterations in neonates. Still, the reproducibility of these microvascular measurements has never been studied in (premature) neonates. This study aimed to determine the reproducibility of microvascular vessel density in cutaneous and buccal SDF clips in one-day-old term newborns. METHODS: Buccal and cutaneous microcirculations were measured using SDF imaging. Vessel density was independently assessed by two investigators. Reproducibility was assessed from the ICC and Bland-Altman analysis. RESULTS: Reproducibility of vessel density assessment in the buccal area was good, with ICCs for total and PVD of 0.93 (0.88-0.97) and 0.93 (95% CI 0.85-0.97), respectively, and a near zero bias and acceptable limits of agreement in the Bland-Altman analysis. Reproducibility of assessment of the cutaneous microcirculation was poor with ICCs for total and PVD of 0.31 (0-0.70) and 0.37 (0-0.74), respectively, and large biases (3.09 and 2.53) in the Bland-Altman analysis. CONCLUSIONS: Evaluation of buccal microvascular vessel density in SDF derived images in term newborns is reproducible in contrary to the cutaneous vessel density. PMID- 25142383 TI - Factor XIII stiffens fibrin clots by causing fiber compaction. AB - BACKGROUND: Factor XIII-induced cross-linking has long been associated with the ability of fibrin blood clots to resist mechanical deformation, but how FXIII can directly modulate clot stiffness is unknown. OBJECTIVES AND METHODS: We hypothesized that FXIII affects the self-assembly of fibrin fibers by altering the lateral association between protofibrils. To test this hypothesis, we studied the cross-linking kinetics and the structural evolution of the fibers and clots during the formation of plasma-derived and recombinant fibrins by using light scattering, and the response of the clots to mechanical stresses by using rheology. RESULTS: We show that the lateral aggregation of fibrin protofibrils initially results in the formation of floppy fibril bundles, which then compact to form tight and more rigid fibers. The first stage is reflected in a fast (10 min) increase in clot stiffness, whereas the compaction phase is characterized by a slow (hours) development of clot stiffness. Inhibition of FXIII completely abrogates the slow compaction. FXIII strongly increases the linear elastic modulus of the clots, but does not affect the non-linear response at large deformations. CONCLUSIONS: We propose a multiscale structural model whereby FXIII mediated cross-linking tightens the coupling between the protofibrils within a fibrin fiber, thus making the fiber stiffer and less porous. At small strains, fiber stiffening enhances clot stiffness, because the clot response is governed by the entropic elasticity of the fibers, but once the clot is sufficiently stressed, the modulus is independent of protofibril coupling, because clot stiffness is governed by individual protofibril stretching. PMID- 25142384 TI - Young adult dependent coverage: were the state reforms effective? AB - OBJECTIVE: To examine the robustness of findings regarding state-level adult dependent coverage expansions using detailed outcomes that specify coverage source. DATA SOURCES: This study uses the 2001-2009 files of the Current Population Survey's Annual Social and Economic Supplement, covering calendar years 2000-2008, and considers young adults ages 19 through 29. STUDY DESIGN: Difference-in-differences methods were used to estimate the effect of state-level dependent coverage expansions on finely detailed categories of coverage, and falsification tests were used to evaluate the models themselves. PRINCIPAL FINDINGS: Certain published results on state-level parental coverage expansions are flawed, with reported increases driven by changes in spousal coverage. Other published results appear to be in fact driven by parental coverage, but they are not robust to alternative model adjustments. CONCLUSIONS: This study shows evidence that one study's results on "dependent" coverage are in fact driven by changes in rates of spousal coverage. Results from a second study, though not robust to use of a more conventional DD model, would seem to apply most strongly to individuals at ages at which one would typically have lost parental coverage before reform, consistent with a "passive" effect rather than an "active" effect that enrolls previously uninsured youths. PMID- 25142385 TI - [Development of a new position-recognition system for robotic radiosurgery systems using machine vision]. AB - CyberKnife((r)) provides continuous guidance through radiography, allowing instantaneous X-ray images to be obtained; it is also equipped with 6D adjustment for patient setup. Its disadvantage is that registration is carried out just before irradiation, making it impossible to perform stereo-radiography during irradiation. In addition, patient movement cannot be detected during irradiation. In this study, we describe a new registration system that we term "Machine Vision," which subjects the patient to no additional radiation exposure for registration purposes, can be set up promptly, and allows real-time registration during irradiation. Our technique offers distinct advantages over CyberKnife by enabling a safer and more precise mode of treatment. "Machine Vision," which we have designed and fabricated, is an automatic registration system that employs three charge coupled device cameras oriented in different directions that allow us to obtain a characteristic depiction of the shape of both sides of the fetal fissure and external ears in a human head phantom. We examined the degree of precision of this registration system and concluded it to be suitable as an alternative method of registration without radiation exposure when displacement is less than 1.0 mm in radiotherapy. It has potential for application to CyberKnife in clinical treatment. PMID- 25142386 TI - [Diagnostic detection performance of a simulated nodule in chest computed tomography images and gray and color nuclear medicine images: comparison between a medical liquid crystal display monitor and an ordinary liquid crystal display monitor]. AB - The purpose of this study was to evaluate the detection performance of simulated nodules in chest computed tomography (CT) images and nuclear medicine images with an ordinary liquid crystal display (LCD) and a medical LCD (grayscale standard display function: GSDF) and gamma 2.2. We collected 72 chest CT image slices obtained from an LSCT phantom with simulated signals composed of various sizes and CT values and 78 slices of monochrome and color nuclear medicine images obtained from a digital phantom with a simulated signal composed of various sizes and radiation levels. Six observers performed receiver operating characteristic (ROC) analysis using a continuous scale. The area under the ROC curve (AUC) was calculated for each monitor. The average AUC values for detection of chest CT images on a medical LCD (GSDF), medical LCD (gamma 2.2), and ordinary LCD were 0.71, 0.67, and 0.73, respectively. The average AUC values for detection of monochrome nuclear medicine images using a medical LCD (GSDF), medical LCD (gamma 2.2), and ordinary LCD were 0.81, 0.75, and 0.72, respectively. The average AUC values for detection of color nuclear medicine images on a medical LCD (GSDF), medical LCD (gamma 2.2), and ordinary LCD were 0.88, 0.86, and 0.90, respectively. Observer performance for detection of simulated nodules in chest CT images and nuclear medicine images was not significantly different between the three LCD monitors. We therefore conclude that an ordinary LCD monitor can be used to detect simulated nodules in chest CT images and nuclear medicine images. PMID- 25142387 TI - [Impact of dynamic parameters on dose delivery accuracy in volumetric modulated arc therapy]. AB - Volumetric modulated arc therapy (VMAT) is an irradiation method in which the multi-leaf collimator (MLC) shape, gantry speed and dose-rate is continuously varied. Gantry speed and dose-rate are treated as specific dynamic parameters (DPs) in VMAT, so there is a need to confirm the influence of DPs on dose distribution. The purpose of this study was to verify the impact of DPs on the accuracy of dose delivery in VMAT. We adopted an irradiation scenario in which DPs were modified from the original plan without making any changes in the dose distribution. We carried out irradiation and measured the dose distributions using a Delta4 diode array phantom, during which we acquired log files that enabled us to calculate DPs. The results showed that dose errors exceeding 1% or geometric errors greater than 1 mm were not produced by modifying the DPs. We were therefore able to verify the impact of DPs on dose delivery accuracy in VMAT. PMID- 25142388 TI - [Validation of noise reduction in iterative reconstruction: a simulation phantom study]. AB - PURPOSE: In the iterative reconstruction method, image noise tends to increase in proportion to falling available photon count and increasing update number. Image filtering is an important factor in single photon emission computed tomography (SPECT) image reconstruction, but it is frequently treated in a subjective way. The aim of this study was to evaluate the effects of pre-reconstruction filtering and post-reconstruction filtering on the iterative reconstruction process. METHODS: Using simulation phantoms, projection data were reconstructed using ordered subsets expectation maximization (OSEM) with or without compensation for resolution recovery. Pre- and post-reconstruction filtering was performed using a Butterworth filter (BW) (range: 0.3-1.3 cycles/cm) and a Gaussian filter (GA) (range: 0.3-1.3 mm) with various parameters. We evaluated the variances of full width at half maximum (FWHM), coefficients of variation (CV), image contrast and normalized mean squared error (NMSE) values. RESULTS: The FWHM values for pre reconstruction filtering tended to be lower than those observed for post reconstruction filtering. These values were 5.1 mm (pre-reconstruction) and 6.7 mm (post-reconstruction). The CV on pre- and post-reconstruction filtering was 7.5% and 11.6%. Pre-reconstruction filtering reduced image noise more effectively than post-reconstruction filtering. The contrast for pre-reconstruction filtering was similar to that observed after post-reconstruction filtering. However, contrast after filtering with a GA slowly decreased as compared to the BW. NMSE values obtained by pre-reconstruction filtering tended to be lower than those observed for post-reconstruction filtering. CONCLUSIONS: Pre-reconstruction filtering provided SPECT image quality comparable to that from post reconstruction filtering, especially when using the BW. Our results suggest that pre-reconstruction filtering is a beneficial method when applied to the iterative reconstruction method with or without compensation for resolution recovery. PMID- 25142389 TI - [Evaluation of potentially influential factors for positron emission tomography image quality in liver signal-to-noise ratio utilizing a delivery 18F-fluoro-2 deoxy-D-glucose study on Bi4Ge3O12-positron emission tomography/computed tomography]. AB - The purpose of this study was to evaluate the relationship of body habitus, blood glucose level and injected dose, respectively, with BGO (Bi4Ge3O12) positron emission tomography (PET) image quality using commercially available 2-deoxy-2 [18F] fluoro-D-glucose (FDG). We also evaluated the relationship between PET image quality and acquisition time for each weight group. METHOD: One hundred twenty-five patients (66 male, 59 female) were enrolled in the study. We adopted liver signal-to-noise ratio (liver SNR) as an image quality index, derived from the region of interest (ROI) placed on the axial image of the liver. RESULTS: The correlation coefficient between liver SNR and dose per weight was 0.502. The liver SNR indicated a negative relationship with body weight, body mass index (BMI) and cross sectional area of the patient's body, with the correlation coefficients of -0.594, -0.479 and -0.522, respectively. For all weight groups, an extended acquisition time of at least 60 s/bed was necessary to improve liver SNR. CONCLUSION: The findings of this study are potentially of use for designing imaging protocols for the BGO-PET/CT system when using commercially available FDG. It is easy to obtain good image quality for patients of low to average body size with the standard injection dose. However, large patients should be injected, wherever possible, with an FDG dose of up to 5 MBq/kg. The acquisition time in overweight and obese patients should be as longer as possible than in standard weight patients. PMID- 25142390 TI - [Reduction of accompanied deployment failure artifacts using a thick slice sensitivity map to assist with array spatial sensitivity encoding technique imaging]. AB - The array spatial sensitivity encoding technique (ASSET) is a form of parallel imaging (PI). Another scan, called a reference scan (Ref) is required before acquiring the ASSET image. However, artifacts tend to interfere with recognition of the object due to differences between the ASSET scan and Ref. scan. This is because the liver is in contact with the diaphragm, making it susceptible to respiratory motion. Further, since the liver upper edge is surrounded by the lung field, there is a risk of susceptibility artifacts. The purpose of this study was to reduce the accompanied deployment failure artifact using a thick slice sensitivity map. Our data showed it was possible to reduce accompanied deployment failure artifacts, as well as to suppress noise, by increasing the slice thickness of the Ref scan. PMID- 25142391 TI - [Study of heart region of interest setting method in the hepatic functional reserve index of (99m)tc-diethylenetriamine pentaacetic Acid-galactosyl human serum albumin]. AB - In this study we analyzed the influence of region of interest (ROI) selection on the uptake ratio of the liver to the liver plus heart at 15 min (LHL15) during (99m)Tc-galactosyl human serum albumin (GSA) scintigraphy and determined the optimal ROI by evaluating the individual effects of different ROIs in the heart on LHL15. Twenty patients were randomly selected from those who had undergone (99m)Tc-GSA scintigraphy GSA between April 2008 and June 2009. The liver body (L/B) ratio, liver uptake 15 min (LU15), and LHL15 were analyzed and compared among the following ROIs: entire heart, both ventricles, right ventricle, and left ventricle. There were significant differences in the L/B ratio and LU15 values among the different ROIs. However, LHL15 showed a tendency to shift toward a normal value when the size of the ROI was small (only the right or left ventricle), resulting in a lack of distinction between normal and abnormal LHL15 values. Furthermore, setting the entire heart as the ROI was difficult and reproducibility was low. Our results suggest that the use of both ventricles as the ROI provides optimal LHL15 values during (99m)Tc-GSA scintigraphy. PMID- 25142392 TI - [Multicenter trial for optimization of bolus tracking settings and contrast material injection protocol in arterial dominant phase of dynamic computed tomography for diagnosis of hepatocellular carcinoma]. AB - Alongside current improvements in the performance of computer tomography (CT) systems, there has been an increase in the use of bolus tracking (BT) to acquire arterial dominant phase images for dynamic CT at optimal timing for characterization of liver focal lesions. However, optimal BT settings have not been established. In the present study, methods of contrast enhancement and BT setting values were evaluated using a multicenter post-marketing surveillance study on contrast media used in patients with chronic hepatitis and/or cirrhosis who had undergone liver dynamic CT for diagnosis of hepatocellular carcinoma, conducted by Daiichi Sankyo Co., Ltd. The results suggested the contrast injection method to be clinically useful if the amount of iodine per kilogram of body weight is set at 600 mg/kg and the injection duration at 30 s. To achieve a good arterial dominant scan under conditions where the injection duration is fixed at 30 s or the average injection duration is 34 s using the fixed injection rate method, the scan delay time should ideally to be set to longer than 13 s. If using the BT method, we recommend that the BT settings should be revalidated in reference to our results. PMID- 25142393 TI - [Study on the development of a patient dosimetry gown for interventional cardiology procedures]. AB - In recent years, dose justification and optimization have been attempted in percutaneous coronary intervention (PCI); however, deterministic effects have been reported. To prevent radiation skin injuries in PCI, it is necessary to measure the patient entrance skin dose (ESD), but an accurate dose measurement method has not yet been established. In this study, we developed a dosimetry gown that can measure the ESD during PCI using multiple radiophotoluminescence dosimeters (RPLDs). The RPLDs were placed into 84 pockets that were sewn into a dosimetry gown. Patients wear the original dosimetry gown during the procedures, after which we obtain accurate ESD measurements. We believe that this method using RPLDs and a newly-designed dosimetry gown provides accurate ESD measurements during PCI. We expect this system to become a standard method for measuring ESD during PCI. PMID- 25142394 TI - [History of the magnetic resonance imaging research in the Japanese journal of radiological technology]. PMID- 25142395 TI - 3. Application of monte carlo simulations to radiology. PMID- 25142396 TI - [5. Commentary on the image remonstration in the MRI (FFT-method)]. PMID- 25142397 TI - [First step for the international congress, etc]. PMID- 25142398 TI - [Domestic market trends for medical imaging and radiological system]. PMID- 25142399 TI - [Role of the commendation]. PMID- 25142400 TI - Genome and physiology of the ascomycete filamentous fungus Xeromyces bisporus, the most xerophilic organism isolated to date. AB - Xeromyces bisporus can grow on sugary substrates down to 0.61, an extremely low water activity. Its genome size is approximately 22 Mb. Gene clusters encoding for secondary metabolites were conspicuously absent; secondary metabolites were not detected experimentally. Thus, in its 'dry' but nutrient-rich environment, X. bisporus appears to have relinquished abilities for combative interactions. Elements to sense/signal osmotic stress, e.g. HogA pathway, were present in X. bisporus. However, transcriptomes at optimal (~ 0.89) versus low aw (0.68) revealed differential expression of only a few stress-related genes; among these, certain (not all) steps for glycerol synthesis were upregulated. Xeromyces bisporus increased glycerol production during hypo- and hyper-osmotic stress, and much of its wet weight comprised water and rinsable solutes; leaked solutes may form a protective slime. Xeromyces bisporus and other food-borne moulds increased membrane fatty acid saturation as water activity decreased. Such modifications did not appear to be transcriptionally regulated in X. bisporus; however, genes modulating sterols, phospholipids and the cell wall were differentially expressed. Xeromyces bisporus was previously proposed to be a 'chaophile', preferring solutes that disorder biomolecular structures. Both X. bisporus and the closely related xerophile, Xerochrysium xerophilum, with low membrane unsaturation indices, could represent a phylogenetic cluster of 'chaophiles'. PMID- 25142401 TI - Nano-artifact metrics based on random collapse of resist. AB - Artifact metrics is an information security technology that uses the intrinsic characteristics of a physical object for authentication and clone resistance. Here, we demonstrate nano-artifact metrics based on silicon nanostructures formed via an array of resist pillars that randomly collapse when exposed to electron beam lithography. The proposed technique uses conventional and scalable lithography processes, and because of the random collapse of resist, the resultant structure has extremely fine-scale morphology with a minimum dimension below 10 nm, which is less than the resolution of current lithography capabilities. By evaluating false match, false non-match and clone-resistance rates, we clarify that the nanostructured patterns based on resist collapse satisfy the requirements for high-performance security applications. PMID- 25142402 TI - Toxoplasma gondii infection reduces predator aversion in rats through epigenetic modulation in the host medial amygdala. AB - Male rats (Rattus novergicus) infected with protozoan Toxoplasma gondii relinquish their innate aversion to the cat odours. This behavioural change is postulated to increase transmission of the parasite to its definitive felid hosts. Here, we show that the Toxoplasma gondii infection institutes an epigenetic change in the DNA methylation of the arginine vasopressin promoter in the medial amygdala of male rats. Infected animals exhibit hypomethylation of arginine vasopressin promoter, leading to greater expression of this nonapeptide. The infection also results in the greater activation of the vasopressinergic neurons after exposure to the cat odour. Furthermore, we show that loss of fear in the infected animals can be rescued by the systemic hypermethylation and recapitulated by directed hypomethylation in the medial amygdala. These results demonstrate an epigenetic proximate mechanism underlying the extended phenotype in the Rattus novergicus-Toxoplasma gondii association. PMID- 25142403 TI - Impact of suppressing retinoic acid-related orphan receptor gamma t (ROR)gammat in ameliorating central nervous system autoimmunity. AB - Multiple sclerosis (MS) is an immune-mediated chronic central nervous system (CNS) disease affecting more than 400 000 people in the United States. Myelin reactive CD4 T cells play critical roles in the formation of acute inflammatory lesions and disease progression in MS and experimental autoimmune encephalomyelitis (EAE), a well-defined mouse model for MS. Current MS therapies are only partially effective, making it necessary to develop more effective therapies that specifically target pathogenic myelin-specific CD4 T cells for MS treatment. While suppressing T-bet, the key transcription factor in T helper type 1 (Th1) cells, has been demonstrated to be beneficial in prevention and treatment of EAE, the therapeutic potential of retinoic acid-related orphan receptor gamma t (ROR)gammat, the key transcription factor for Th17 cells, has not been well characterized. In this study, we characterized the correlation between RORgammat expression and other factors affecting T cell encephalitogenicity and evaluated the therapeutic potential of targeting RORgammat by siRNA inhibition of RORgammat. Our data showed that RORgammat expression correlates with interleukin (IL)-17 production, but not with the encephalitogenicity of myelin-specific CD4 T cells. IL-23, a cytokine that enhances encephalitogenicity, does not enhance RORgammat expression significantly. Additionally, granulocyte-macrophage colony stimulating factor (GM-CSF) levels, which correlate with the encephalitogenicity of different myelin-specific CD4 T cell populations, do not correlate with RORgammat. More importantly, inhibiting RORgammat expression in myelin-specific CD4 T cells with an siRNA does not reduce disease severity significantly in adoptively transferred EAE. Thus, RORgammat is unlikely to be a more effective therapeutic target for ameliorating pathogenicity of encephalitogenic CD4 T cells. PMID- 25142404 TI - Association between bipolar episodes and fluid and electrolyte homeostasis: a retrospective longitudinal study. AB - OBJECTIVES: Imbalance of fluid and electrolyte homeostasis has been suggested to be associated with the neuropathological processes underlying bipolar disorder. However, longitudinal data regarding the association of bipolar episodes with fluid balance are still lacking. We hypothesized that mania may be associated with a relative fluid retention and hemodilution, and depression with a relative hemoconcentration. METHODS: Patients with bipolar disorder (n = 43) admitted to a mental health center, both with depressive and manic episodes, were retrospectively followed between 2005 and 2013. Fluid balance and electrolyte serum indices were compared between their manic and depressive episodes. We adjusted for physical and psychiatric comorbidities and for psychotropic treatment, using two-way analysis of variance with repeated measures. RESULTS: There was a significant reduction in serum fluid balance indices during mania compared to depression: mean hemoglobin concentration 13.9 +/- 1.4 g/dL versus 14.5 +/- 1.4 g/dL, paired t = -4.2, p < 0.0005; mean hematocrit 41.1 +/- 4.1% versus 42.3 +/- 3.7%, paired t = -3.0, p < 0.005; mean albumin concentration 4.2 +/- 0.3 g/dL versus 4.5 +/- 0.3 g/dL, paired t = -4.5, p < 0.0001; and mean sodium concentration 140.3 +/- 2.0 mEq/L versus 141.0 +/- 2.0 mEq/L, paired t = 2.1, p = 0.04, respectively. Controlling for physical and psychiatric comorbidities and psychotropic treatment did not alter these associations. CONCLUSIONS: Our results support the notion of an imbalance of fluid and electrolyte homeostasis among bipolar episodes, which is suggestive for relative hemoconcentration during depressive episodes and relative hemodilution during manic episodes. These findings may eventually lead to novel therapeutic targets. PMID- 25142405 TI - Pharmacological treatment of attention deficit hyperactivity disorder with co morbid drug dependence. AB - BACKGROUND: Drug dependence is frequent in patients with attention deficit hyperactivity disorder (ADHD). Nevertheless, the efficacy and safety of pharmacological treatments in this population are unclear. METHODS: A systematic review with meta-analysis was performed. Randomised placebo-controlled clinical trials investigating the efficacy of pharmacological treatment in patients with co-occurring ADHD and substance use disorder (SUD) were included. ADHD symptom severity, drug abstinence and all-cause treatment discontinuation were the primary study endpoints. The effects of patient-, intervention- and study-related covariates over the primary outcomes were investigated by means of meta regression. RESULTS: Thirteen studies were included, enrolling a total of 1,271 patients. A small to moderate reduction of ADHD symptoms was found. Meta regression analysis identified the presence of a lead-in period as a covariate associated with reduced efficacy. Conversely, no beneficial effect was observed either on drug abstinence or treatment discontinuation. The efficacy on ADHD symptoms was smaller in studies with a lead-in period. A positive correlation between the efficacy for ADHD and that for SUD was found. CONCLUSIONS: The efficacy of pharmacological interventions for co-occurring ADHD and SUD has been little investigated. Mixed results were obtained: while pharmacological interventions improved ADHD symptoms, no beneficial effect on drug abstinence or on treatment discontinuation was noted. The strength of the recommendation of pharmacological treatment for co-occurring ADHD and SUD is therefore modest. The study was registered with the international prospective register of systematic reviews (PROSPERO): CRD 4212003414. PMID- 25142406 TI - The impact of recreational MDMA 'ecstasy' use on global form processing. AB - The ability to integrate local orientation information into a global form percept was investigated in long-term ecstasy users. Evidence suggests that ecstasy disrupts the serotonin system, with the visual areas of the brain being particularly susceptible. Previous research has found altered orientation processing in the primary visual area (V1) of users, thought to be due to disrupted serotonin-mediated lateral inhibition. The current study aimed to investigate whether orientation deficits extend to higher visual areas involved in global form processing. Forty-five participants completed a psychophysical (Glass pattern) study allowing an investigation into the mechanisms underlying global form processing and sensitivity to changes in the offset of the stimuli (jitter). A subgroup of polydrug-ecstasy users (n=6) with high ecstasy use had significantly higher thresholds for the detection of Glass patterns than controls (n=21, p=0.039) after Bonferroni correction. There was also a significant interaction between jitter level and drug-group, with polydrug-ecstasy users showing reduced sensitivity to alterations in jitter level (p=0.003). These results extend previous research, suggesting disrupted global form processing and reduced sensitivity to orientation jitter with ecstasy use. Further research is needed to investigate this finding in a larger sample of heavy ecstasy users and to differentiate the effects of other drugs. PMID- 25142407 TI - Posttraumatic stress symptoms and tobacco abstinence effects in a non-clinical sample: evaluating the mediating role of negative affect reduction smoking expectancies. AB - The relation between posttraumatic stress symptoms and smoking is well documented but poorly understood. The present investigation sought to evaluate the impact of posttraumatic stress symptoms on subjective and behavioral tobacco abstinence effects both directly and indirectly through negative affect reduction smoking outcome expectancies. Participants included 275 (68.7% male; Mage =43.9, 10+ cig/day) adult non-treatment seeking smokers, who attended two counterbalanced laboratory sessions (16 h of smoking deprivation vs ad libitum smoking), during which they completed self-report measures of withdrawal symptoms and mood followed by a smoking lapse task in which they could earn money for delaying smoking and purchase cigarettes to smoke. Results supported a mediational pathway whereby higher baseline symptoms of posttraumatic stress predicted greater endorsement of expectancies that smoking will effectively reduce negative affect, which in turn predicted greater abstinence-provoked exacerbations in nicotine withdrawal symptoms and negative affect. Posttraumatic stress symptoms also predicted number of cigarettes purchased independent of negative affect reduction expectancies, but did not predict delaying smoking for money. Findings highlight tobacco abstinence effects as a putative mechanism underlying posttraumatic stress disorder (PTSD)-smoking comorbidity, indicate an important mediating role of beliefs for smoking-induced negative affect reduction, and shed light on integrated treatment approaches for these two conditions. PMID- 25142408 TI - National and state patterns of teen births in the United States, 1940-2013. AB - OBJECTIVES: This report presents trends from 1940 through 2013 in national birth rates for teenagers, with particular focus on the period since 1991. The percent changes in rates for 1991-2012 and for 2007-2012 are presented for the United States and for states. Preliminary data for 2013 are shown where available. METHODS: Tabular and graphical descriptions of the trends in teen birth rates for the United States and each state, by age group, race, and Hispanic origin, are presented and discussed. Data are shown for the U.S. territories. RESULTS: Birth rates for U.S. teenagers have generally fallen in the United States since peaking in 1957. The rate fell 57% between 1991 and 2013. The 2013 preliminary rate (26.6 per 1,000 aged 15-19) is less than one-third of the historically highest rate (96.3 in 1957). During 1991-2012, rates fell for all race and Hispanic ethnicity groups, with the largest declines measured for non-Hispanic black teenagers. In the more recent period, 2007-2012, the declines have been steepest for Hispanic teenagers. Birth rates declined significantly for teenagers in all states during 1991-2012; during 2007-2012, rates fell for all but two states. The drop in teen birth rates translates into an estimated 4 million fewer births to teenagers from 1992 through 2012. The declines in teen birth rates reflect a number of behavioral changes, including decreased sexual activity, increases in the use of contraception at first sex and at most recent sex, and the adoption and increased use of hormonal contraception, injectables, and intrauterine devices. PMID- 25142410 TI - Letter to the editor concerning the article 'Geographical ancestry is a key determinant of epidermal morphology and dermal composition'. PMID- 25142409 TI - Involution of eruptive melanocytic nevi on combination BRAF and MEK inhibitor therapy. AB - IMPORTANCE: Eruptive melanocytic nevi (EMN) are characterized by the sudden onset of numerous melanocytic nevi and have been traditionally described in the setting of immunosuppression. Selective BRAF inhibitors such as vemurafenib cause multiple cutaneous adverse effects, including the formation of cutaneous squamous cell carcinoma, as well as EMN. We describe the first reported case, to our knowledge, of involution of BRAF inhibitor-induced EMN following the concomitant addition of a MEK inhibitor, cobimetinib. OBSERVATIONS: A woman in her 20s with a history of metastatic melanoma developed EMN while receiving therapy with vemurafenib, a selective BRAF inhibitor. After disease progression, the patient was placed on a clinical trial that combined vemurafenib with a MEK inhibitor, cobimetinib. Within months, we noted clinical involution of many of her EMN. In addition, numerous preexisting nevi were noted to fade in color on the dual regimen. Over a year after initiating this combination therapy, most of the patient's EMN were no longer clinically evident. CONCLUSIONS AND RELEVANCE: Our case report describing the involution of EMN supports data from previous clinical trials indicating that combination BRAF and MEK inhibition may reduce cutaneous proliferative effects that arise on BRAF inhibitor monotherapy. Further studies are necessary to characterize the biological mechanisms underlying this phenomenon. PMID- 25142411 TI - Nodule on the upper arm. PMID- 25142412 TI - Dynameomics: data-driven methods and models for utilizing large-scale protein structure repositories for improving fragment-based loop prediction. AB - Protein function is intimately linked to protein structure and dynamics yet experimentally determined structures frequently omit regions within a protein due to indeterminate data, which is often due protein dynamics. We propose that atomistic molecular dynamics simulations provide a diverse sampling of biologically relevant structures for these missing segments (and beyond) to improve structural modeling and structure prediction. Here we make use of the Dynameomics data warehouse, which contains simulations of representatives of essentially all known protein folds. We developed novel computational methods to efficiently identify, rank and retrieve small peptide structures, or fragments, from this database. We also created a novel data model to analyze and compare large repositories of structural data, such as contained within the Protein Data Bank and the Dynameomics data warehouse. Our evaluation compares these structural repositories for improving loop predictions and analyzes the utility of our methods and models. Using a standard set of loop structures, containing 510 loops, 30 for each loop length from 4 to 20 residues, we find that the inclusion of Dynameomics structures in fragment-based methods improves the quality of the loop predictions without being dependent on sequence homology. Depending on loop length, ~ 25-75% of the best predictions came from the Dynameomics set, resulting in lower main chain root-mean-square deviations for all fragment lengths using the combined fragment library. We also provide specific cases where Dynameomics fragments provide better predictions for NMR loop structures than fragments from crystal structures. Online access to these fragment libraries is available at http://www.dynameomics.org/fragments. PMID- 25142413 TI - Conditional ablation of NKp46+ cells using a novel Ncr1(greenCre) mouse strain: NK cells are essential for protection against pulmonary B16 metastases. AB - To study gene functions specifically in NKp46+ cells we developed novel Cre mice allowing for conditional gene targeting in cells expressing Ncr1 (encoding NKp46). We generated transgenic Ncr1(greenCre) mice carrying an EGFPcre fusion under the control of a proximal Ncr1 promoter that faithfully directed EGFPcre expression to NKp46+ cells from lymphoid and nonlymphoid tissues. This approach allowed for direct detection of Cre-expressing NKp46+ cells via their GFP signature by flow cytometry and histology. Cre was functional as evidenced by the NKp46+ cell-specific expression of RFP in Ncr1(greenCre) Rosa-dtRFP reporter mice. We generated Ncr1(greenCre) Il2rg(fl/fl) mice that lack NKp46+ cells in an otherwise intact hematopoietic environment. Il2rg encodes the common gamma chain (gammac ), which is an essential receptor subunit for cytokines (IL-2, -4, -7, 9, -15, and -21) that stimulate lymphocyte development and function. In Ncr1(greenCre) Il2rg(fl/fl) mice, NK cells are severely reduced and the few remaining NKp46+ cells escaping gammac deletion failed to express GFP. Using this new NK-cell-deficient model, we demonstrate that the homeostasis of NKp46+ cells from all tissues (including the recently described intraepithelial ILC1 subset) requires Il2rg. Finally, Ncr1(greenCre) Il2rg(fl/fl) mice are unable to reject B16 lung metastases demonstrating the essential role of NKp46+ cells in antimelanoma immune responses. PMID- 25142414 TI - 6,6'-Bieckol inhibits adipocyte differentiation through downregulation of adipogenesis and lipogenesis in 3T3-L1 cells. AB - BACKGROUND: Brown algae have been used for their nutritional value as well as a source of bioactive compounds with antioxidant, anti-inflammatory, antimicrobial and anti-obesity effects. Obesity is an important condition implicated in various diseases, including diabetes, hypertension, dyslipidemia and coronary heart disease. However, anti-obesity effects of Eisenia bicyclis remain unknown. RESULTS: We investigated the anti-obesity effects of 6,6'-bieckol, 6,8'-bieckol, 8,8'-bieckol, dieckol and phlorofucofuroeckol A isolated from E. bicyclis. Anti obesity activity was evaluated by examining the inhibition of differentiation of 3T3-L1 adipocytes and the expression of peroxisome proliferator-activated receptor gamma (PPARgamma), CCATT/enhancer-binding protein alpha (C/EBPalpha) and sterol regulatory element binding protein-1c (SREBP-1c) at the mRNA and protein level. Differentiated 3T3-L1 cells were treated with the purified phlorotannins at concentrations of 10, 25 and 50 ug mL(-1) for 8 days. The results indicated that the purified phlorotannins suppressed the differentiation of 3T3-L1 adipocytes in a dose-dependent manner, without toxic effects. Among the five compounds, 6,6'-bieckol markedly decreased lipid accumulation and expression levels of PPARgamma, C/EBPalpha, SREBP-1c (mRNA and protein), and fatty acid synthase and acyl-coA carboxylase (mRNA). CONCLUSION: These findings suggest that E. bicyclis suppressed differentiation of 3T3-L1 adipocyte through downregulation of adipogenesis and lipogenesis. PMID- 25142415 TI - An elegant microwave assisted one-pot synthesis of di(alpha-aminophosphonate) pesticides. AB - A new class of di(alpha-aminophosphonate) pesticides were prepared by the Kabachnik-Fields reaction under solvent- and catalyst-free conditions with microwave irradiation, and the products were obtained in good-to-excellent yields at shorter reaction time. These compounds were characterized by IR, (1)H, (13)C, (31)P NMR, and mass spectral data. Among them, compounds 4f, 4c, and 4h showed good pesticidal activity against Spodoptera litura, with 92.6, 91.3, and 89.3% mortality. PMID- 25142416 TI - Effects of system net charge and electrostatic truncation on all-atom constant pH molecular dynamics. AB - Constant pH molecular dynamics offers a means to rigorously study the effects of solution pH on dynamical processes. Here, we address two critical questions arising from the most recent developments of the all-atom continuous constant pH molecular dynamics (CpHMD) method: (1) What is the effect of spatial electrostatic truncation on the sampling of protonation states? (2) Is the enforcement of electrical neutrality necessary for constant pH simulations? We first examined how the generalized reaction field and force-shifting schemes modify the electrostatic forces on the titration coordinates. Free energy simulations of model compounds were then carried out to delineate the errors in the deprotonation free energy and salt-bridge stability due to electrostatic truncation and system net charge. Finally, CpHMD titration of a mini-protein HP36 was used to understand the manifestation of the two types of errors in the calculated pK(a) values. The major finding is that enforcing charge neutrality under all pH conditions and at all time via cotitrating ions significantly improves the accuracy of protonation-state sampling. We suggest that such finding is also relevant for simulations with particle mesh Ewald, considering the known artifacts due to charge-compensating background plasma. PMID- 25142417 TI - Regulation of mitochondrial function and cellular energy metabolism by protein kinase C-lambda/iota: a novel mode of balancing pluripotency. AB - Pluripotent stem cells (PSCs) contain functionally immature mitochondria and rely upon high rates of glycolysis for their energy requirements. Thus, altered mitochondrial function and promotion of aerobic glycolysis are key to maintain and induce pluripotency. However, signaling mechanisms that regulate mitochondrial function and reprogram metabolic preferences in self-renewing versus differentiated PSC populations are poorly understood. Here, using murine embryonic stem cells (ESCs) as a model system, we demonstrate that atypical protein kinase C isoform, PKC lambda/iota (PKClambda/iota), is a key regulator of mitochondrial function in ESCs. Depletion of PKClambda/iota in ESCs maintains their pluripotent state as evident from germline offsprings. Interestingly, loss of PKClambda/iota in ESCs leads to impairment in mitochondrial maturation, organization, and a metabolic shift toward glycolysis under differentiating condition. Our mechanistic analyses indicate that a PKClambda/iota-hypoxia inducible factor 1alpha-PGC1alpha axis regulates mitochondrial respiration and balances pluripotency in ESCs. We propose that PKClambda/iota could be a crucial regulator of mitochondrial function and energy metabolism in stem cells and other cellular contexts. PMID- 25142418 TI - A VELOUR post hoc subset analysis: prognostic groups and treatment outcomes in patients with metastatic colorectal cancer treated with aflibercept and FOLFIRI. AB - BACKGROUND: The VELOUR study demonstrated a survival benefit for FOLFIRI + aflibercept versus FOLFIRI + placebo in metastatic colorectal cancer (mCRC) patients who progressed on oxaliplatin-based chemotherapy. Continued divergence of overall survival (OS) curves in the intension to treat (ITT) population, with the survival advantage persisting beyond median survival time, suggested subpopulations might have different magnitudes of survival gain. Additionally, 10% of patients within VELOUR had recurrence during or within 6 months of completing oxaliplatin-based adjuvant therapy (adjuvant fast relapsers)- previously identified as having poorer survival outcomes. METHODS: To determine which patients received the greatest benefit from FOLFIRI-aflibercept, a post hoc multivariate analysis of the VELOUR ITT population was conducted. Prognostic factors identified were applied to the ITT population, excluding adjuvant fast relapsers, to derive OS prognostic profiles. RESULTS: The better efficacy subgroup was identified as patients within VELOUR exclusive of adjuvant fast relapsers and had performance status (PS) 0 with any number of metastatic site or PS 1 with <2 metastatic site. A significant improvement in efficacy outcome was observed with aflibercept in the better efficacy subgroup. Median OS for FOLFIRI aflibercept and FOLFIRI-placebo:16.2 and 13.1 months (adjusted Hazard Ratio [HR] = 0.73; 95% confidence interval [CI]: 0.61-0.86); median progression free survival (PFS): 7.2 and 4.8 months (adjusted HR = 0.68; 95% CI: 0.57-0.80); and objective response rate (ORR): 24% versus 11% respectively. Poorer efficacy subgroup comprised of adjuvant fast relapsers or patients with PS2 or PS1 with >= 2 metastatic sites. In poorer efficacy subgroup, no benefit was seen with aflibercept. Median OS for FOLFIRI-aflibercept and FOLFIRI-placebo: 10.4 and 9.6 months (adjusted HR = 0.97; 95% CI: 0.78-1.21) respectively with no improvement in PFS or ORR. CONCLUSION: This analysis suggests that within VELOUR, patients in the better efficacy subgroup may derive enhanced benefit from treatment with FOLFIRI-aflibercept. These prognostic criteria may guide practitioners toward optimal use of targeted biologicals in appropriate second-line mCRC patients. PMID- 25142419 TI - Distal left main restenosis: dodging that bullet. PMID- 25142420 TI - Precise vessel sizing: a trivial but crucial issue during left main stenting. PMID- 25142421 TI - One stent, two stent, three stent, more. PMID- 25142422 TI - The OPERA study: the tenor or baritone of shorter duration of DAPT? PMID- 25142423 TI - Can intravascular ultrasound-derived minimal lumen area predict functional significance of coronary artery stenosis? PMID- 25142424 TI - Seeing and not believing: understanding the visual-functional mismatch between angiography and FFR. PMID- 25142425 TI - Smaller is better for the radialist. PMID- 25142426 TI - Coronary CT angiography--a Rosetta Stone for understanding and treating bifurcation lesions? PMID- 25142427 TI - Another atrial septal occluder? PMID- 25142428 TI - Sinus venous defect, new important indication for structural interventional cardiology. PMID- 25142429 TI - DYT16 revisited: exome sequencing identifies PRKRA mutations in a European dystonia family. AB - Recessive DYT16 dystonia associated with mutations in PRKRA has until now been reported only in seven Brazilian patients. The aim of this study was to elucidate the genetic cause underlying disease in a Polish family with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism, and to explore further the role of PRKRA in a dystonia series of European ancestry. We employed whole exome sequencing in two affected siblings of the Polish family and filtered for rare homozygous and compound heterozygous variants shared by both exomes. Validation of the identified variants as well as homozygosity screening and copy number variation analysis was carried out in the two affected individuals and their healthy siblings. PRKRA was analyzed in 339 German patients with various forms of dystonia and 376 population-based controls by direct sequencing or high resolution melting. The previously described homozygous p.Pro222Leu mutation in PRKRA was found to segregate with the disease in the studied family, contained in a 1.2 Mb homozygous region identical by state with all Brazilian patients in chromosome 2q31.2. The clinical presentation with young-onset, progressive generalized dystonia and mild parkinsonism resembled the phenotype of the original DYT16 cases. PRKRA mutational screening in additional dystonia samples revealed three novel heterozygous changes (p.Thr34Ser, p.Asn102Ser, c.-14A>G), each in a single subject with focal/segmental dystonia. Our study provides the first independent replication of the DYT16 locus at 2q31.2 and strongly confirms the causal contribution of the PRKRA gene to DYT16. Our data suggest worldwide involvement of PRKRA in dystonia. PMID- 25142430 TI - Standard individual cognitive behaviour therapy for paediatric obsessive compulsive disorder: a systematic review of effect estimates across comparisons. AB - BACKGROUND: Previous meta-analyses of paediatric obsessive-compulsive disorder (OCD) have shown much higher effect size for standard individual cognitive behaviour therapy (SI-CBT) compared with control conditions than for serotonin reuptake inhibitors (SRIs) compared with placebo. Other factors, such as systematic differences in the provided care or exposure to factors other than the interventions of interest (performance bias) may be stronger confounders in psychotherapy research than in pharmacological research. AIMS: These facts led us to review SI-CBT studies of paediatric OCD with the aim to compare the effect estimates across different comparisons, including active treatments. METHOD: We included only randomized controlled trials (RCTs) or cluster RCTs with treatment periods of 12-16 weeks. Outcome was post-test score on the Children's Yale-Brown Obsessive Compulsive Scale (CYBOCS). RESULTS: Thirteen papers reporting from 13 RCTs with 17 comparison conditions were included. SI-CBT was superior to wait list and placebo therapy but not active treatments. Effect estimates for SI-CBT in wait-list comparison studies were significantly larger than in placebo-therapy comparison studies. In addition, the SI-CBT effect estimate was not significantly different when compared with SRIs alone or combined SRIs and CBT. CONCLUSIONS: Performance bias may have inflated previous effect estimates for SI-CBT when comparison contingencies included wait-list. However, the calculated SI-CBT effect estimate was lower but significant when compared with placebo therapy. The effects of SI-CBT and active treatments were not significantly different. In conclusion, our data support the current clinical guidelines, although better comparisons between SI-CBT and SRIs are needed. PMID- 25142431 TI - Somatoform dissociation among Swedish adolescents and young adults: the psychometric properties of the Swedish versions of the SDQ-20 and SDQ-5. AB - BACKGROUND: Somatoform dissociation is supposed to be a vital aspect of the general concept of dissociation. The Somatoform Dissociation Questionnaire-20 (SDQ-20) and the brief version SDQ-5 are self-report instruments constructed to identify somatic dissociation. AIM: In the present study, the psychometric qualities of the Swedish version of the SDQ-20 and its brief version, the SDQ-5, were examined among adolescents and young adults. Reliability and concurrent validity were investigated. METHODS: A total of 512 adolescents and young adults participated in the study: 461 adolescents from a non-clinical sample and 50 adolescents and young adults from a clinical eating disorder outpatient unit. They completed the self-report instruments the SDQ-20, the SDQ-5 (part of SDQ 20), the Linkoping Youth Life Experience Scale (LYLES, a trauma history scale) and the Dissociation Questionnaire-Sweden (Dis-Q-Sweden). RESULTS: Both internal consistency and test-retest reliability of the Swedish version of SDQ-20 were good in both the non-clinical (alpha = 0.83) and the clinical groups (alpha = 0.84); the reliability for the SDQ-5 was, however, lower (non-clinical alpha = 0.50, clinical alpha = 0.64). Significant differences were found between the clinical and non-clinical groups on both somatoform and psychoform dissociation. Correlations between the Dis-Q-Sweden, SDQ-20 and SDQ-5 were generally high. The criterion and convergent validity was acceptable for both scales but somewhat better for SDQ-20 than for SDQ-5. CONCLUSION: The advantage with both the SDQ-20 and the SDQ-5 is that they are short questionnaires, but the results suggests that SDQ-20 is preferable based on the higher-quality psychometric properties of the SDQ-20. PMID- 25142432 TI - Sub-10 nm Au-Pt-Pd alloy trimetallic nanoparticles with a high oxidation resistant property as efficient and durable VOC oxidation catalysts. AB - Sub-10 nm AuPtPd alloy trimetallic nanoparticles (TMNPs) with a high oxidation resistant property were prepared by photo-deposition followed by a high temperature (700-900 degrees C) air annealing process. PMID- 25142433 TI - Risk assessment of clinical outcomes in Asian patients with chronic hepatitis B using enhanced liver fibrosis test. AB - Serum fibrosis markers, such as the enhanced liver fibrosis (ELF) test, have been suggested as alternatives for liver biopsy (LB) in assessing liver fibrosis. We investigated the efficacy of the ELF test in predicting development of liver related events (LREs) in patients with chronic hepatitis B (CHB). A total of 170 patients (103 men; 60.6%) with CHB who underwent LB and serological tests for determining ELFs were enrolled. All patients were followed up to monitor LRE development, defined as hepatic decompensation, hepatocellular carcinoma, and/or liver-related death. The mean age was 45.3 years. During the follow-up period (median, 41 months), 39 (22.9%) patients experienced LREs. In patients with LREs, age, proportion of male gender, ELF test results, age-spleen-platelet ratio (ASPRI), liver stiffness (LS) value, and proportion of histological cirrhosis were significantly higher than those in patients without LREs (all P < 0.05). Areas under the receiver operating characteristic curves to predict LRE development were 0.808 for the ELF test, 0.732 for LS value, 0.713 for histological fibrosis stages using Batts and Ludwig's scoring system, and 0.687 for ASPRI. On multivariate analysis, along with age, the ELF test was an independent predictor of LRE development (adjusted hazard ratio [HR], 1.438; P < 0.001). When we applied a three-tier stratification of our study population using cut-off ELF values of 8.10 and 10.40, patients with low (P = 0.002; adjusted HR: 0.045; 95% confidence interval [CI]: 0.006-0.330) and intermediate (P < 0.001; adjusted HR: 0.239; 95% CI: 0.122-0.469) ELF range were found less likely to develop LREs, compared to those with high ELF range. CONCLUSION: ELF is useful in a noninvasive prediction of LRE development. Transient elastography showed a statistically similar prognostic performance for LREs as the ELF, but other noninvasive tests were inferior. PMID- 25142434 TI - Molecular subtyping of bladder cancer using Kohonen self-organizing maps. AB - Kohonen self-organizing maps (SOMs) are unsupervised Artificial Neural Networks (ANNs) that are good for low-density data visualization. They easily deal with complex and nonlinear relationships between variables. We evaluated molecular events that characterize high- and low-grade BC pathways in the tumors from 104 patients. We compared the ability of statistical clustering with a SOM to stratify tumors according to the risk of progression to more advanced disease. In univariable analysis, tumor stage (log rank P = 0.006) and grade (P < 0.001), HPV DNA (P < 0.004), Chromosome 9 loss (P = 0.04) and the A148T polymorphism (rs 3731249) in CDKN2A (P = 0.02) were associated with progression. Multivariable analysis of these parameters identified that tumor grade (Cox regression, P = 0.001, OR.2.9 (95% CI 1.6-5.2)) and the presence of HPV DNA (P = 0.017, OR 3.8 (95% CI 1.3-11.4)) were the only independent predictors of progression. Unsupervised hierarchical clustering grouped the tumors into discreet branches but did not stratify according to progression free survival (log rank P = 0.39). These genetic variables were presented to SOM input neurons. SOMs are suitable for complex data integration, allow easy visualization of outcomes, and may stratify BC progression more robustly than hierarchical clustering. PMID- 25142435 TI - Isolation and structural elucidation of novel antimicrobial compounds from maggots of Chrysomyis megacephala Fabricius. AB - The excretions/secretions from the maggot of Chrysomyis megacephala Fabricius are traditionally used to treat serious infections in China. In this study, bioassay guided fractionation led to the isolation of three novel antibacterial compounds (1-3), including important fluorinated compounds (3 and 5), together with other nine known compounds from 70% methanol extract of C. megacephala. The structures of the new compounds were elucidated by NMR spectroscopic analysis and high resolution mass spectroscopy. The antibacterial activities of the isolated compounds were evaluated using agar disc diffusion method. New compounds 1 and 2 exhibited moderate activity against Bacillus subtilis with a minimum inhibitory concentration (MIC) of 250 MUg mL(- 1). The most active compounds 3 and 5 displayed a broad spectrum of antimicrobial activity with an MIC of 125 MUg mL(- 1) against G(+) and G(- ) bacteria. The structure of the above-mentioned novel compounds and their antimicrobial activities are herein reported for the first time from the natural product of insects. PMID- 25142436 TI - [Incidental findings in internal medicine]. PMID- 25142438 TI - Increased prediction of right nonrecurrent laryngeal nerve in thyroid surgery using preoperative computed tomography with intraoperative neuromonitoring identification. AB - BACKGROUND: A nonrecurrent laryngeal nerve (NRLN) is a rare but potentially serious anatomical variant. Although the incidence is reported to be 0.3% to 1.3%, it carries a much higher risk of palsy during thyroid surgery. The objective of this study is to investigate the usefulness of computed tomography (CT) for preoperative identification and intraoperative neuromonitoring identification (IONM) of NRLN in thyroid cancer patients. METHODS: The preoperative neck CT scans from 1,574 patients who needed thyroid surgery were examined. Absence of the brachiocephalic artery (BCA) and the presence of arteria lusoria were defined as positive with NRLN. Systematic intraoperative neuromonitoring (IONM) was also carried out for these 1,574 patients to localize and identify NRLN. A negative electromyography (EMG) response from lower vagal stimulation but a positive EMG response from the upper position indicated the occurrence of an NRLN. RESULTS: Nine NRLN (0.57%) were intraoperatively identified out of the 1,574 patients, and no patient with a NRLN showed preoperative clinical symptoms related to NRLN. Prior to the operation, surgeons identified only seven suspected NRLN cases based on identification of arteria lusoria. But a review of CT scans revealed that all cases could be identified by vascular anomalies. All patients were successfully detected at an early stage of operation using intraoperative neuromonitoring (IONM). Postoperative vocal cord function was normal in all patients. CONCLUSIONS: CT of the neck is a reliable method for predicting NRLN before thyroid cancer surgery. However, some image features can be easily missed. Neurophysiology helps the surgeon to identify the NRLNs more precisely. Combining the two evaluation methods may decrease the incidence of nerve palsy, especially in cases of NRLN. Considering that CT is expensive, requires an X-ray, and achieves less information than ultrasound (US) concerning thyroid nodules, we suggest that applying US and IONM is more reasonable. PMID- 25142437 TI - Does glycemic control reverse dispersion of ventricular repolarization in type 2 diabetes? AB - BACKGROUND: Abnormal ventricular repolarization is a predictor of cardiovascular mortality. In this study, we tested the hypothesis that glycemic control reverses abnormal ventricular repolarization in patients with type 2 diabetes. METHODS: We analyzed longitudinal changes in repolarization indices of electrocardiograms in retrospectively enrolled 44 patients with type 2 diabetes and 44 age-matched healthy subjects. RESULTS: In the diabetic group, BMI was greater, levels of HbA1c (10.0 +/- 1.6 vs. 5.6 +/- 0.3%) and triglyceride were higher and level of HDL cholesterol was lower than those in the control group. Although mean QTc intervals were similar (413.6 +/- 18.5 vs. 408.3 +/- 22.7 ms), QT dispersion (41.8 +/- 15.4 vs. 28.7 +/- 7.7 ms) and Tpeak-Tend in lead V5 (83.6 +/- 13.6 vs. 71.3 +/- 10.3 ms) were significantly longer in the diabetic group than in the control group, indicating increased heterogeneity of ventricular repolarization in type 2 diabetes. During follow-up of 36 patients in the diabetic group for 787 +/- 301 days, HbA1c level decreased to 7.3 +/- 1.6%, while BMI did not significantly change. In contrast to HbA1c, QT dispersion (45.8 +/- 15.0 ms) and Tpeak-Tend in lead V5 (83.6 +/- 10.6 ms) were not significantly reduced during the follow-up period. There was no correlation between the change in HbA1c and the change in QT dispersion or Tpeak-Tend. CONCLUSIONS: Increased heterogeneity of ventricular repolarization in type 2 diabetic patients was not reduced during the relatively short follow-up period despite significantly improved glycemic control. PMID- 25142439 TI - Pertussis diagnostics: overview and impact of immunization. AB - In all vaccinated populations, infections with Bordetella pertussis and Bordetella parapertussis continue to cause infections in unvaccinated infants and children, as well as in adolescents and adults with waning immunity. Thus in patients with longer lasting coughs a diagnosis of pertussis should be entertained irrespective of their vaccination status. Due to the non-specific clinical symptoms, clinically suspected cases of pertussis must be verified by laboratory methods. Hyperleukocytosis may be helpful in diagnosis for young infants, but in most cases, nonspecific laboratory tests have no role in pertussis diagnosis. Specific laboratory tests include direct detection of the bacteria or their DNA by culture or PCR, whereas serology serves as an indirect method to diagnose pertussis in those patients who present late in the development of the disease. Serology results can be interpreted in relation to reference values for different populations, but serology is unable to distinguish between vaccination and infection. PMID- 25142440 TI - PEG-ing down (and preventing?) the cause of pegloticase failure. AB - Pegloticase is a powerful but underutilized weapon in the rheumatologist's armamentarium. The drug's immunogenicity leads to neutralizing antibody formation and rapid loss of efficacy in roughly one-half of all patients, which remains an impediment to broader use. New data, however, suggest that drug survival might improve with concomitant immunosuppressive agent (s), which merits further study. Efficacy appears to be unchanged when pegloticase is infused at 3-week (rather than 2-week) intervals. Stretching the time between infusions may also improve patient adherence and allow for earlier identification of transient responders. PMID- 25142441 TI - Commentary: Mendelian randomization study of tobacco smoking and cardiovascular risk factors: hazards of tobacco smoking greatly outweigh any benefits. PMID- 25142442 TI - JC virus nucleotides 376-396 are critical for VP1 capsid protein expression. AB - JC virus (JCV) infection of the brain can cause progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy, and JCV encephalopathy (JCVE). JCVCPN, isolated from the brain of a patient with JCVE, is a naturally occurring strain of JCV with a 143-base pair deletion in the agnogene. Cell culture studies of JCVCPN have shown that the loss of these nucleotides in the agnogene results in impaired expression of VP1 and infectious virion production. To better understand the role of this DNA sequence in JCV replication, we generated a series of deletions in the agnogene on the backbone of a virus which has a mutated agnoprotein start codon preventing agnoprotein expression. We found that deletion of nucleotides 376-396 results in decreased levels of viral DNA replication and a lack of VP1 expression. These results indicate that these nucleotides play a crucial role in JCV replication. PMID- 25142443 TI - The need for gendered discussions of policy reform. Editor's introduction. PMID- 25142444 TI - Addressing violence by female partners is vital to prevent or stop violence against women: evidence from the multisite batterer intervention evaluation. AB - This article presents a reanalysis of data from Gondolf's (2012) article in this journal on reoffending by men in the 15-month period subsequent to participation in batterer intervention programs. Gondolf concludes that violence by the female partners "was relatively low and does not appear to influence the program outcome in terms of men's reassault" (p. 10). The reanalyzed data lead to the opposite conclusion. The policy and practice implications are that the high rate of assault by women, including initiation of violence by female partners, needs to be addressed to enhance the effectiveness of programs to prevent and stop violence against women. PMID- 25142445 TI - A lotus root-like appearance in both the left anterior descending and right coronary arteries. AB - A 60-year-old man was referred to our hospital because of dyspnea on exertion. He was diagnosed with heart failure due to an old myocardial infarction. Myocardial stress perfusion scintigraphy revealed inducible myocardial ischemia. Coronary angiography revealed hazy slit lesions in both the left anterior descending (LAD) and right coronary arteries (RCA). We first performed percutaneous coronary intervention (PCI) on the LAD lesion. Subsequently, we performed PCI for the RCA lesion using multiple imaging modalities. We observed a lotus root-like appearance in both the LAD and RCA, and PCI was successful for both vessels. We describe this rare case in detail. PMID- 25142446 TI - Evolutionary diversification of the vertebrate transferrin multi-gene family. AB - In a phylogenetic analysis of vertebrate transferrins (TFs), six major clades (subfamilies) were identified: (a) S, the mammalian serotransferrins; (b) ICA, the mammalian inhibitor of carbonic anhydrase (ICA) homologs; (c) L, the mammalian lactoferrins; (d) O, the ovotransferrins of birds and reptiles; (e) M, the melanotransferrins of bony fishes, amphibians, reptiles, birds, and mammals; and (f) M-like, a newly identified TF subfamily found in bony fishes, amphibians, reptiles, and birds. A phylogenetic tree based on the joint alignment of N-lobes and C-lobes supported the hypothesis that three separate events of internal duplication occurred in vertebrate TFs: (a) in the common ancestor of the M subfamily, (b) in the common ancestor of the M-like subfamily, and (c) in the common ancestor of other vertebrate TFs. The S, ICA, and L subfamilies were found only in placental mammals, and the phylogenetic analysis supported the hypothesis that these three subfamilies arose by gene duplication after the divergence of placental mammals from marsupials. The M-like subfamily was unusual in several respects, including the presence of a uniquely high proportion of clade-specific conserved residues, including distinctive but conserved residues in the sites homologous to those functioning in carbonate binding of human serotransferrin. The M-like family also showed an unusually high proportion of cationic residues in the positively charged region corresponding to human lactoferrampin, suggesting a distinctive role of this region in the M-like subfamily, perhaps in antimicrobial defense. PMID- 25142447 TI - The coming of age of DNA vaccines. PMID- 25142448 TI - Improving DNA vaccine performance through vector design. AB - DNA vaccines are a rapidly deployed next generation vaccination platform for treatment of human and animal disease. DNA delivery devices, such as electroporation and needle free jet injectors, are used to increase gene transfer. This results in higher antigen expression which correlates with improved humoral and cellular immunity in humans and animals. This review highlights recent vector and transgene design innovations that improve DNA vaccine performance. These new vectors improve antigen expression, increase plasmid manufacturing yield and quality in bioreactors, and eliminate antibiotic selection and other potential safety issues. A flowchart for designing synthetic antigen transgenes, combining antigen targeting, codon-optimization and bioinformatics, is presented. Application of improved vectors, of antibiotic free plasmid production, and cost effective manufacturing technologies will be critical to ensure safety, efficacy, and economically viable manufacturing of DNA vaccines currently under development for infectious disease, cancer, autoimmunity, immunotolerance and allergy indications. PMID- 25142449 TI - Pharyngeal transit in patients with chronic progressive external ophthalmoplegia. AB - PURPOSE: A common presentation of mitochondrial myopathies is chronic progressive external ophthalmoplegia (CPEO). Dysphagia is a complaint in about 50% of cases. METHOD: This investigation evaluated pharyngeal transit in patients with CPEO. Videofluoroscopic swallowing evaluation was performed with paste, liquid and solid boluses in 14 patients with CPEO and in 16 normal volunteers. RESULT: There was no difference between patients and volunteers in the duration of pharyngeal swallowing events with the liquid bolus. Compared to control participants, patients with CPEO had significantly shorter duration of pharyngeal transit for paste and solid boluses, of pharyngeal clearance for paste bolus, and of upper oesophageal sphincter transit for paste and solid boluses. Spontaneous multiple swallows and effortful swallows were performed by patients but not by the volunteers. CONCLUSION: It was concluded that patients with CPEO have shorter pharyngeal transit duration of paste and solid boluses than normal volunteers, which may be a consequence of a spontaneous smaller bolus volume in each swallow and/or effortful swallows. PMID- 25142450 TI - The Human Brain Project: mutiny on the flagship. PMID- 25142451 TI - Sleep disorder associated with antibodies to IgLON5: parasomnia or agrypnia? Authors' reply. PMID- 25142452 TI - Sleep disorder associated with antibodies to IgLON5: parasomnia or agrypnia? PMID- 25142453 TI - Complexity of the endovascular intervention and clinical outcomes in acute ischaemic stroke. PMID- 25142454 TI - Complexity of the endovascular intervention and clinical outcomes in acute ischaemic stroke--authors' reply. PMID- 25142455 TI - Conotoxins: how a deadly snail could help ease pain. PMID- 25142456 TI - David Dodick: working for patients with headache. PMID- 25142457 TI - A brief history of pain. PMID- 25142459 TI - Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. AB - Allodynia (pain due to a stimulus that does not usually provoke pain) and hyperalgesia (increased pain from a stimulus that usually provokes pain) are prominent symptoms in patients with neuropathic pain. Both are seen in various peripheral neuropathies and central pain disorders, and affect 15-50% of patients with neuropathic pain. Allodynia and hyperalgesia are classified according to the sensory modality (touch, pressure, pinprick, cold, and heat) that is used to elicit the sensation. Peripheral sensitisation and maladaptive central changes contribute to the generation and maintenance of these reactions, with separate mechanisms in different subtypes of allodynia and hyperalgesia. Pain intensity and relief are important measures in clinical pain studies, but might be insufficient to capture the complexity of the pain experience. Better understanding of allodynia and hyperalgesia might provide clues to the underlying pathophysiology of neuropathic pain and, as such, they represent new or additional endpoints in pain trials. PMID- 25142458 TI - Adipokines: a link between obesity and dementia? AB - Being overweight or obese, as measured with body-mass index or central adiposity (waist circumference), and the trajectory of body-mass index over the life course have been associated with brain atrophy, white matter changes, disturbances of blood-brain barrier integrity, and risk of all-cause late-onset dementia and Alzheimer's disease. This observation leads us to question what it is about body mass index that is associated with health of the brain and dementia risk. If high body-mass index and central adiposity represent an increase in adipose tissue, then the endocrine function of adipose tissue, mediated by adipose tissue hormones and adipokines, could be a clue to mechanisms that underlie the association with dementia and Alzheimer's disease. Hundreds of adipokines have been identified, creating a complexity that is a challenge to simplify. Nonetheless, adipokines are being investigated in association with clinical dementia outcomes, and with imaging-based measures of brain volume, structure, and function in human beings and in preclinical models of clinical dementia. PMID- 25142460 TI - Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. AB - The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood-and adolescent-onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed. PMID- 25142462 TI - Indispensable pre-mitotic endocycles promote aneuploidy in the Drosophila rectum. AB - The endocycle is a modified cell cycle that lacks M phase. Endocycles are well known for enabling continued growth of post-mitotic tissues. By contrast, we discovered pre-mitotic endocycles in precursors of Drosophila rectal papillae (papillar cells). Unlike all known proliferative Drosophila adult precursors, papillar cells endocycle before dividing. Furthermore, unlike diploid mitotic divisions, these polyploid papillar divisions are frequently error prone, suggesting papillar structures may accumulate long-term aneuploidy. Here, we demonstrate an indispensable requirement for pre-mitotic endocycles during papillar development and also demonstrate that such cycles seed papillar aneuploidy. We find blocking pre-mitotic endocycles disrupts papillar morphogenesis and causes organismal lethality under high-salt dietary stress. We further show that pre-mitotic endocycles differ from post-mitotic endocycles, as we find only the M-phase-capable polyploid cells of the papillae and female germline can retain centrioles. In papillae, this centriole retention contributes to aneuploidy, as centrioles amplify during papillar endocycles, causing multipolar anaphase. Such aneuploidy is well tolerated in papillae, as it does not significantly impair cell viability, organ formation or organ function. Together, our results demonstrate that pre-mitotic endocycles can enable specific organ construction and are a mechanism that promotes highly tolerated aneuploidy. PMID- 25142461 TI - Exclusive multipotency and preferential asymmetric divisions in post-embryonic neural stem cells of the fish retina. AB - The potency of post-embryonic stem cells can only be addressed in the living organism, by labeling single cells after embryonic development and following their descendants. Recently, transplantation experiments involving permanently labeled cells revealed multipotent neural stem cells (NSCs) of embryonic origin in the medaka retina. To analyze whether NSC potency is affected by developmental progression, as reported for the mammalian brain, we developed an inducible toolkit for clonal labeling and non-invasive fate tracking. We used this toolkit to address post-embryonic stem cells in different tissues and to functionally differentiate transient progenitor cells from permanent, bona fide stem cells in the retina. Using temporally controlled clonal induction, we showed that post embryonic retinal NSCs are exclusively multipotent and give rise to the complete spectrum of cell types in the neural retina. Intriguingly, and in contrast to any other vertebrate stem cell system described so far, long-term analysis of clones indicates a preferential mode of asymmetric cell division. Moreover, following the behavior of clones before and after external stimuli, such as injuries, shows that NSCs in the retina maintained the preference for asymmetric cell division during regenerative responses. We present a comprehensive analysis of individual post-embryonic NSCs in their physiological environment and establish the teleost retina as an ideal model for studying adult stem cell biology at single cell resolution. PMID- 25142463 TI - Tbx1 controls the morphogenesis of pharyngeal pouch epithelia through mesodermal Wnt11r and Fgf8a. AB - The pharyngeal pouches are a segmental series of epithelial structures that organize the embryonic vertebrate face. In mice and zebrafish that carry mutations in homologs of the DiGeorge syndrome gene TBX1, a lack of pouches correlates with severe craniofacial defects, yet how Tbx1 controls pouch development remains unclear. Using mutant and transgenic rescue experiments in zebrafish, we show that Tbx1 functions in the mesoderm to promote the morphogenesis of pouch-forming endoderm through wnt11r and fgf8a expression. Consistently, compound losses of wnt11r and fgf8a phenocopy tbx1 mutant pouch defects, and mesoderm-specific restoration of Wnt11r and Fgf8a rescues tbx1 mutant pouches. Time-lapse imaging further reveals that Fgf8a acts as a Wnt11r dependent guidance cue for migrating pouch cells. We therefore propose a two-step model in which Tbx1 coordinates the Wnt-dependent epithelial destabilization of pouch-forming cells with their collective migration towards Fgf8a-expressing mesodermal guideposts. PMID- 25142464 TI - SirT1 is required in the male germ cell for differentiation and fecundity in mice. AB - Sirtuins are NAD(+)-dependent deacylases that regulate numerous biological processes in response to the environment. SirT1 is the mammalian ortholog of yeast Sir2, and is involved in many metabolic pathways in somatic tissues. Whole body deletion of SirT1 alters reproductive function in oocytes and the testes, in part caused by defects in central neuro-endocrine control. To study the function of SirT1 specifically in the male germ line, we deleted this sirtuin in male germ cells and found that mutant mice had smaller testes, a delay in differentiation of pre-meiotic germ cells, decreased spermatozoa number, an increased proportion of abnormal spermatozoa and reduced fertility. At the molecular level, mutants do not have the characteristic increase in acetylation of histone H4 at residues K5, K8 and K12 during spermiogenesis and demonstrate corresponding defects in the histone to protamine transition. Our findings thus reveal a germ cell-autonomous role of SirT1 in spermatogenesis. PMID- 25142465 TI - Prostaglandin D2 acts through the Dp2 receptor to influence male germ cell differentiation in the foetal mouse testis. AB - Through intercellular signalling, the somatic compartment of the foetal testis is able to program primordial germ cells to undergo spermatogenesis. Fibroblast growth factor 9 and several members of the transforming growth factor beta superfamily are involved in this process in the foetal testis, counteracting the induction of meiosis by retinoic acid and activating germinal mitotic arrest. Here, using in vitro and in vivo approaches, we show that prostaglandin D2 (PGD2), which is produced through both L-Pgds and H-Pgds enzymatic activities in the somatic and germ cell compartments of the foetal testis, plays a role in mitotic arrest in male germ cells by activating the expression and nuclear localization of the CDK inhibitor p21(Cip1) and by repressing pluripotency markers. We show that PGD2 acts through its Dp2 receptor, at least in part through direct effects in germ cells, and contributes to the proper differentiation of male germ cells through the upregulation of the master gene Nanos2. Our data identify PGD2 signalling as an early pathway that acts in both paracrine and autocrine manners, and contributes to the differentiation of germ cells in the foetal testis. PMID- 25142466 TI - Histone H3.3 regulates dynamic chromatin states during spermatogenesis. AB - The histone variant H3.3 is involved in diverse biological processes, including development, transcriptional memory and transcriptional reprogramming, as well as diseases, including most notably malignant brain tumors. Recently, we developed a knockout mouse model for the H3f3b gene, one of two genes encoding H3.3. Here, we show that targeted disruption of H3f3b results in a number of phenotypic abnormalities, including a reduction in H3.3 histone levels, leading to male infertility, as well as abnormal sperm and testes morphology. Additionally, null germ cell populations at specific stages in spermatogenesis, in particular spermatocytes and spermatogonia, exhibited increased rates of apoptosis. Disruption of H3f3b also altered histone post-translational modifications and gene expression in the testes, with the most prominent changes occurring at genes involved in spermatogenesis. Finally, H3f3b null testes also exhibited abnormal germ cell chromatin reorganization and reduced protamine incorporation. Taken together, our studies indicate a major role for H3.3 in spermatogenesis through regulation of chromatin dynamics. PMID- 25142468 TI - Hepatitis--cure and prevention. PMID- 25142467 TI - Global discovery and characterization of small non-coding RNAs in marine microalgae. AB - BACKGROUND: Marine phytoplankton are responsible for 50% of the CO2 that is fixed annually worldwide and contribute massively to other biogeochemical cycles in the oceans. Diatoms and coccolithophores play a significant role as the base of the marine food web and they sequester carbon due to their ability to form blooms and to biomineralise. To discover the presence and regulation of short non-coding RNAs (sRNAs) in these two important phytoplankton groups, we sequenced short RNA transcriptomes of two diatom species (Thalassiosira pseudonana, Fragilariopsis cylindrus) and validated them by Northern blots along with the coccolithophore Emiliania huxleyi. RESULTS: Despite an exhaustive search, we did not find canonical miRNAs in diatoms. The most prominent classes of sRNAs in diatoms were repeat-associated sRNAs and tRNA-derived sRNAs. The latter were also present in E. huxleyi. tRNA-derived sRNAs in diatoms were induced under important environmental stress conditions (iron and silicate limitation, oxidative stress, alkaline pH), and they were very abundant especially in the polar diatom F. cylindrus (20.7% of all sRNAs) even under optimal growth conditions. CONCLUSIONS: This study provides first experimental evidence for the existence of short non coding RNAs in marine microalgae. Our data suggest that canonical miRNAs are absent from diatoms. However, the group of tRNA-derived sRNAs seems to be very prominent in diatoms and coccolithophores and maybe used for acclimation to environmental conditions. PMID- 25142469 TI - Paediatric services: the future direction. PMID- 25142470 TI - A Comparison of the Short-term Morbidity and Mortality Between Late Preterm and Term Newborns. AB - INTRODUCTION: Late preterm babies are defined as those born between 34 to 36 completed weeks. There has been a recent increased awareness that this group of babies has a higher incidence of morbidity as compared to term babies. The aim of this study was to evaluate the short-term morbidities occurring in this group of babies managed in the neonatal unit at Singapore General Hospital (SGH). MATERIALS AND METHODS: A retrospective study was done of babies managed in the neonatal unit at SGH from January 2005 to December 2008. Maternal, perinatal and neonatal data were obtained from the departmental database. The outcomes of late preterm infants were compared with term infants. RESULTS: A total of 6826 babies were admitted. Ten percent (681 out of 6826) of babies were late preterm babies, making up 63% (681 out of 1081) of all preterm babies. Late preterm babies had significantly greater need for resuscitation at birth. They also had statistically significant increased risks of developing hyaline membrane disease (2.5% vs 0.1%), transient tachypnoea of the newborn (TTN) (8.1% vs 1.7%), pneumonia (7.0% vs 2.8%), patent ductus arteriosus (PDA) (4.3% vs 1.1%), hypotension (0.7% vs 0%), apnoea (3.7% vs 0%), gastrointestinal (GI) bleeding (1.5% vs 0.3%), polycythaemia (2.2% vs 1.0%), anaemia (3.4% vs 1.2%), thrombocytopenia (3.2% vs 0.6%), hypoglycaemia (6.6% vs 1.7%), neonatal jaundice requiring phototherapy (41.1% vs 12.2%) and sepsis (1.7% vs 0.6%). CONCLUSION: Late preterm infants are indeed a vulnerable group of infants with significant morbidities that need to be addressed and treated. Despite their relatively large size and being almost term, the understanding that late preterm infants are not similar to term infants is important to both obstetricians and neonatologists. PMID- 25142471 TI - Neonatal and Paediatric Extracorporeal Membrane Oxygenation (ECMO) in a Single Asian Tertiary Centre. AB - INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass technique (CPB) which provides life-saving support in patients with refractory cardiorespiratory failure until cardiopulmonary recovery or organ replacement. MATERIALS AND METHODS: This is a single centre retrospective study reporting the largest series of paediatric patients in Singapore who received ECMO support over an 11-year period from January 2002 to December 2012. The objective is to describe the characteristics of the patients and to report the survival to hospital discharge, complications during ECMO and other long-term complications. RESULTS: Forty-eight patients received ECMO during the study period. ECMO was initiated for myocarditis in majority of the paediatric patients whereas postoperative low cardiac output state was the most common indication in the neonatal population. The overall survival rate to hospital discharge was 45.8%. Survival was highest in the neonates with respiratory failure (75%). Haematological and cardiac complications were most common during ECMO. Age group, gender, duration of ECMO, need for renal replacement therapy, acute neurological complications were not associated with mortality. Those needing inotropic support during ECMO had poorer survival while those with hypertension requiring vasodilator treatment had a higher survival rate. The survival rates for ECMO patients more than doubled from the initial 6 years of 23% to 54% in the last 5 years of the study period. Long-term complications encountered included neurological, respiratory and cardiac problems. CONCLUSION: ECMO is a life-saving modality for neonatal and paediatric patients with cardiopulmonary failure from diverse causes. Patients with persistent need for inotropes during ECMO had poorer outcome. Centre experience had an impact on ECMO outcome. PMID- 25142472 TI - Validation of the Paediatric Hearing Impairment Caregiver Experience (PHICE) Questionnaire. AB - INTRODUCTION: The paediatric hearing impairment caregiver experience (PHICE) questionnaire is a 68-item instrument that assesses the stress experienced by caregivers of children with hearing impairment (HI). While the questionnaire has been validated in the United States, it may need to be modified for use in the Singapore context due to the differing healthcare system, costing and culture related to caregiving for children with HI. This study aims to modify and validate the PHICE questionnaire to increase its relevance and ease of use in Singapore. MATERIALS AND METHODS: The original PHICE questionnaire was filled out by 127 caregivers of HI children managed at the otolaryngology clinic of the National University Hospital (NUH). An expert panel was convened to assess the questionnaire for its suitability for use in Singapore. Exploratory factor analysis was conducted to evaluate the underlying factor structure of the original PHICE questionnaire. Items with high cross-loadings were removed and a new factor structure was adopted which was further analysed using confirmatory factor analysis (CFA). Cronbach's alpha (alpha) was computed to determine the internal consistency of the new subscales. RESULTS: Items that are less relevant in Singapore and those with high cross-loadings were removed. A 5-factor structure with only 42 items remaining and corresponding to the factors: " Policy", "Healthcare", "Education", "Support" and "Adaptation" was adopted. CFA suggests a good model fit for the modified questionnaire, improved from the 8 factor structure of the original PHICE. Cronbach's alpha were high (>0.7) for each new subscale. CONCLUSION: The original PHICE questionnaire has been shortened and reorganised in terms of the subscales composition. The resulting instrument is structurally valid and internally consistent. It is a simple and useful tool for identifying factors related to caregiving that can negatively impact rehabilitation outcomes for children with HI in Singapore. Removal of some sign language items makes this modified version less useful for caregivers, places or countries where sign language is the main focus of rehabilitation for children with HI. PMID- 25142473 TI - Hearing Loss in Newborns with Cleft Lip and/or Palate. AB - INTRODUCTION: This study aims to review the results of hearing screens in newborns with cleft deformities. MATERIALS AND METHODS: A retrospective audit of 123 newborns with cleft deformities, born between 1 April 2002 and 1 December 2008, was conducted. Data on the results of universal newborn hearing screens (UNHS) and high-risk hearing screens, age at diagnosis, severity/type of hearing loss and mode of intervention were obtained from a prospectively maintained hearing database. RESULTS: Thirty-one of 123 newborns (25.2%) failed the first automated auditory brainstem response (AABR). Seventy percent of infants (56 out of 80) who passed the UNHS failed the high-risk hearing screens which was conducted at 3 to 6 months of age. Otolaryngology referral rate was 67.5% (83/123); 90.3% of 31 newborns who failed the first AABR eventually required otolaryngology referrals. Incidence of hearing loss was 24.4% (30/123; 25 conductive, 2 mixed and 3 sensorineural), significantly higher than the hospital incidence of 0.3% (OR: 124.9, 95% CI, 81.1 to 192.4, P <0.01). In terms of severity, 8 were mild, 15 moderate, 5 severe, 2 profound. Eighteen out of 30 infants (60%) were detected from the high-risk hearing screens after passing the first AABR. CONCLUSION: These newborns had a higher risk of failing the UNHS and high-risk hearing screen. There was a higher incidence of hearing loss which was mainly conductive. Failure of the first AABR was an accurate predictor of an eventual otolaryngology referral, suggesting that a second AABR may be unnecessary. High-risk hearing screens helped to identify hearing loss which might have been missed out early on in life or which might have evolved later in infancy. PMID- 25142474 TI - Internet addiction in young people. AB - In our technology-savvy population, mental health professionals are seeing an increasing trend of excessive Internet use or Internet addiction. Researchers in China, Taiwan and Korea have done extensive research in the field of Internet addiction. Screening instruments are available to identify the presence of Internet addiction and its extent. Internet addiction is frequently associated with mental illnesses such as anxiety, depression, conduct disorder and attention deficit hyperactivity disorder (ADHD). Treatment modalities include individual and group therapies, cognitive behavioural therapy (CBT), family therapy and psychotropic medications. A significant proportion of Singapore adolescents engaging in excessive Internet use are also diagnosed to have concomitant Internet addiction. Despite the presence of a variety of treatment options, future research in this area is needed to address its growing trend and to minimise its negative psychological and social impact on the individuals and their families. PMID- 25142475 TI - Imaging cardiac sarcoidosis by cardiac positron emission tomography (PET): a local experience using a high-fat, low-to-no carbohydrate protocol. PMID- 25142476 TI - A case of diarrhoea. PMID- 25142477 TI - Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature. AB - Limited numbers of operated patients with chronic thromboembolic pulmonary hypertension (CTEPH) are refractory to pulmonary endarterectomy (PEA) and experience persistent pulmonary hypertension (PH). We retrospectively assessed lung histology available from nine patients with persistent PH (ineffective PEA (inPEA) group) and from eight patients transplanted for distal CTEPH inaccessible by PEA (noPEA group). Microscopically observed peculiarities were compared with the histology of a recently developed CTEPH model in piglets. Pre-interventional clinical/haemodynamic data and medical history of patients from the inPEA and noPEA groups were collected and analysed. Conspicuous remodelling of small pulmonary arteries/arterioles, septal veins and pre-septal venules, including focal capillary haemangiomatosis, as well as pronounced hypertrophy and enlargement of bronchial systemic vessels, were the predominant pattern in histology from both groups. Most findings were reproduced in our porcine CTEPH model. Ink injection experiments unmasked abundant venular involvement in so called small vessel or microvascular disease, as well as post-capillary bronchopulmonary shunting in human and experimental CTEPH. Microvascular disease is partly due to post-capillary remodelling in human and experimental CTEPH and appears to be related to bronchial-to-pulmonary venous shunting. Further studies are needed to clinically assess the functional importance of this finding. PMID- 25142478 TI - Effect of whole body hypothermia on inflammation and surfactant function in asphyxiated neonates. PMID- 25142479 TI - Expert opinion on the cough hypersensitivity syndrome in respiratory medicine. AB - In 2011, a European Respiratory Society Task Force embarked on a process to determine the position and clinical relevance of the cough hypersensitivity syndrome, a disorder characterised by troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure, in the management of patients with chronic cough. A 21-component questionnaire was developed by an iterative process supported by a literature review. 44 key opinion leaders in respiratory medicine were selected and interviewed as to their opinions. There was a high degree of unanimity in the responses obtained, with all opinion leaders supporting the concept of cough hypersensitivity as a clinically useful paradigm. The classic stratification of cough into asthmatic, rhinitic and reflux-related phenotypes was supported. Significant disparity of opinion was seen in the response to two questions concerning the therapy of chronic cough. First, the role of acid suppression in reflux cough was questioned. Secondly, the opinion leaders were split as to whether a trial of oral steroids was indicated to establish a diagnosis of eosinophilic cough. The cough hypersensitivity syndrome was clearly endorsed by the opinion leaders as a valid and useful concept. They considered that support of patients with chronic cough was inadequate and the Task Force recommends that further work is urgently required in this neglected area. PMID- 25142480 TI - Diagnostic yield of specific inhalation challenge in hypersensitivity pneumonitis. AB - Reliable methods are needed to diagnose hypersensitivity pneumonitis. The aim of the study was to establish the diagnostic yield of specific inhalation challenge (SIC) in patients with hypersensitivity pneumonitis. All patients with suspected hypersensitivity pneumonitis in whom SIC was performed (n=113) were included. SIC was considered positive when patients showed a decrease of >15% in forced vital capacity (FVC) or >20% in diffusing capacity of the lung for carbon dioxide, or a decrease of 10% to 15% in FVC accompanied by a temperature increase of 0.5 degrees C within 24 h of inhalation of the antigen. SIC was positive to the agents tested in 68 patients: 64 received a diagnosis of hypersensitivity pneumonitis and SIC results were considered false-positive in the remaining four patients. In the SIC-negative group (n=45), 24 patients received a diagnosis of hypersensitivity pneumonitis and SIC results were considered false-negative, and 21 patients were diagnosed with other respiratory diseases. The sensitivity and specificity of the test were 72.7% and 84%, respectively. Having hypersensitivity pneumonitis caused by an antigen other than birds or fungi predicted a false negative result (p=0.001). In hypersensitivity pneumonitis, positive SIC testing virtually confirms the diagnosis, whereas negative testing does not rule it out, especially when the antigenic sources are not birds or fungi. PMID- 25142481 TI - Quantifying comorbidity in individuals with COPD: a population study. AB - Chronic obstructive pulmonary disease (COPD) has been associated with many types of comorbidity. We aimed to quantify the real world impact of COPD on lower respiratory tract infection, cardiovascular disease, diabetes, psychiatric disease, musculoskeletal disease and cancer, and their impact on COPD through health services. A population study using health administrative data from Ontario, Canada, in 2008-2012 was conducted. Absolute and adjusted relative rates of ambulatory care visits, emergency department visits and hospitalisations for the comorbidities of interest in people with and without COPD were determined and compared. Among 7 241 591 adults, 909 948 (12.6%) had COPD. Over half of all lung cancer, a third of all lower respiratory tract infection and cardiovascular disease, a quarter of all low trauma fracture, and a fifth of all psychiatric, musculoskeletal, non-lung cancer and diabetes ambulatory care visits, emergency department visits and hospitalisations in Ontario were used by people with COPD. Individuals with COPD used about five times more health services for lung cancer, and two times more health services for lower respiratory tract infections and cardiovascular disease than people without COPD. Individuals with COPD use a disproportionate amount of health services for comorbid disease, placing significant burden on the healthcare system. PMID- 25142482 TI - Ageing and the epidemiology of multimorbidity. AB - The world's population is ageing and an important part of this demographic shift is the development of chronic illness. In short, a person who does not die of acute illnesses, such as infections, and survives with chronic illnesses is more likely to develop additional chronic illnesses. Chronic respiratory diseases are an important component of these diseases associated with ageing. This article reviews the relationship between ageing and chronic respiratory disease, and also how certain chronic diseases cluster with others, either on the basis of underlying risk factors, complication of the primary disease or other factors, such as an increased state of inflammation. While death is inevitable, disabling chronic illnesses are not. Better understanding of how individuals can age healthily without the development of multiple chronic illnesses should lead to an improved global quality of life. PMID- 25142483 TI - The chemokine CCL18 characterises Pseudomonas infections in cystic fibrosis lung disease. AB - Cystic fibrosis (CF) lung disease is characterised by chronic Pseudomonas aeruginosa infection and leukocyte infiltration. Chemokines recruit leukocytes to sites of infection. Gene expression analysis identified the chemokine CCL18 as upregulated in CF leukocytes. We hypothesised that CCL18 characterises infection and inflammation in patients with CF lung disease. Therefore, we quantified CCL18 protein levels in the serum and airway fluids of CF patients and healthy controls, and studied CCL18 protein production by airway cells ex vivo. These studies demonstrated that CCL18 levels were increased in the serum and airway fluids from CF patients compared with healthy controls. Within CF patients, CCL18 levels were increased in P. aeruginosa-infected CF patients. CCL18 levels in the airways, but not in serum, correlated with severity of pulmonary obstruction in CF. Airway cells isolated from P. aeruginosa-infected CF patients produced significantly higher amounts of CCL18 protein compared with airway cells from CF patients without P. aeruginosa infection or healthy controls. Collectively, these studies show that CCL18 levels characterise chronic P. aeruginosa infection and pulmonary obstruction in patients with CF. CCL18 may, thus, serve as a potential biomarker and therapeutic target in CF lung disease. PMID- 25142484 TI - Ground-based walking training improves quality of life and exercise capacity in COPD. AB - This study was designed to determine the effect of ground-based walking training on health-related quality of life and exercise capacity in people with chronic obstructive pulmonary disease (COPD). People with COPD were randomised to either a walking group that received supervised, ground-based walking training two to three times a week for 8-10 weeks, or a control group that received usual medical care and did not participate in exercise training. 130 out of 143 participants (mean+/-sd age 69+/-8 years, forced expiratory volume in 1 s 43+/-15% predicted) completed the study. Compared to the control group, the walking group demonstrated greater improvements in the St George's Respiratory Questionnaire total score (mean difference -6 points (95% CI -10- -2), p<0.003), Chronic Respiratory Disease Questionnaire total score (mean difference 7 points (95% CI 2 11), p<0.01) and endurance shuttle walk test time (mean difference 208 s (95% CI 104-313), p<0.001). This study shows that ground-based walking training is an effective training modality that improves quality of life and endurance exercise capacity in people with COPD. PMID- 25142485 TI - Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes. AB - Previously, we demonstrated concordance in differentially expressed genes in sarcoidosis blood and lung, implicating shared dysfunction of specific immune pathways. In the present study, we hypothesised that expression levels of candidate genes in sarcoidosis blood could predict and track with disease outcomes longitudinally. We applied Ingenuity Pathway Analysis to a cross sectional derivation microarray dataset (n=38) to identify canonical pathways and candidate genes associated with sarcoidosis. In a separate longitudinal sarcoidosis cohort (n=103), we serially measured 48 candidate gene transcripts, and assessed their relation to disease chronicity and severity. In the cross sectional derivation study, pathway analysis showed upregulation of genes related to interferon signalling and the role of pattern recognition receptors, and downregulation of T-cell receptor (TCR) signalling pathways in sarcoidosis. In the longitudinal cohort, factor analysis confirmed coregulation of genes marking these pathways and identified CXCL9 as an additional candidate pathway. CXCL9 and TCR factors discriminated between chronic versus nonprogressive disease, and CXCL9 predicted disease outcomes longitudinally. Interferon factor was similarly increased in both disease phenotypes. Factors associated with lung function decline included decreased TCR factor and increased CXCL9. These findings demonstrate blood transcriptomic signatures reflecting TCR signalling and CXCL9 predict sarcoidosis chronicity and correlate with disease severity longitudinally. PMID- 25142486 TI - Exhaled nitric oxide and inhaled corticosteroid dose reduction in asthma: a cohort study. PMID- 25142487 TI - Mechanisms of exercise intolerance in global initiative for chronic obstructive lung disease grade 1 COPD. AB - The purpose of this study was to determine if a dissociation existed between respiratory drive, as estimated by diaphragmatic electromyography (EMGdi), and its pressure-generating capacity during exercise in mild chronic obstructive pulmonary disease (COPD) and whether this, if present, had negative sensory consequences. Subjects meeting spirometric criteria for mild COPD (n=16) and age and sex-matched controls (n=16) underwent detailed pulmonary function testing and a symptom limited cycle test while detailed ventilatory, sensory and respiratory mechanical responses were measured. Compared with controls, subjects with mild COPD had greater ventilatory requirements throughout submaximal exercise. At the highest equivalent work rate of 60 W, they had a significantly higher: total work of breathing (32+/-17 versus 16+/-7 J.min(-1); p<0.01); EMGdi (37.3+/-17.3 versus 17.9+/-11.7% of maximum; p<0.001); and EMGdi to transdiaphragmatic pressure ratio (0.87+/-0.38 versus 0.52+/-0.27; p<0.01). Dyspnoea-ventilation slopes were significantly higher in mild COPD than controls (0.17+/-0.12 versus 0.10+/-0.05; p<0.05). However, absolute dyspnoea ratings reached significant levels only at high levels of ventilation. Increased respiratory effort and work of breathing, and a wider dissociation between diaphragmatic activation and pressure-generating capacity were found at standardised work rates in subjects with mild COPD compared with controls. Despite these mechanical and neuromuscular abnormalities, significant dyspnoea was only experienced at higher work rates. PMID- 25142488 TI - Earlier decline in sniff nasal inspiratory pressure than peak expiratory flow in children with Duchenne muscular dystrophy. PMID- 25142489 TI - Mechanisms of exertional dyspnoea in pulmonary veno-occlusive disease with EIF2AK4 mutations. PMID- 25142490 TI - Autonomic dysregulation: a mechanism of asthma death. PMID- 25142491 TI - Reduced lung function and the risk of out-of-hospital sudden cardiac death. PMID- 25142492 TI - A national trainee-led audit of inguinal hernia repair in Scotland. AB - PURPOSE: This audit assessed inguinal hernia surgery in Scotland and measured compliance with British Hernia Society Guidelines (2013), specifically regarding management of bilateral and recurrent inguinal hernias. It also assessed the feasibility of a national trainee-led audit, evaluated regional variations in practise and gauged operative exposure of trainees. METHODS: A prospective audit of adult inguinal hernia repairs across every region in Scotland (30 hospitals in 14 NHS boards) over 2-weeks was co-ordinated by the Scottish Surgical Research Group (SSRG). RESULTS: 235 patients (223 male, median age 61) were identified and 96 % of cases were elective. Anaesthesia was 91 % general, 5 % spinal and 3 % local. Prophylactic antibiotics were administered in 18 %. Laparoscopic repair was used in 33 % (30 % trainee-performed). Open repair was used in 67 % (42 % trainee-performed). Elective primary bilateral hernia repairs were laparoscopic in 97 % while guideline compliance for an elective recurrence was 77 %. For elective primary unilateral hernias, the use of laparoscopic repair varied significantly by region (South East 43 %, North 14 %, East 7 % and West 6 %, p < 0.001) as did repair under local anaesthesia for open cases (North 21 %, South East 4 %, West 2 % and East 0 %, p = 0.001). Trainees independently performed 9 % of procedures. There were no significant differences in trainee or unsupervised trainee operator rates between laparoscopic and open cases. Mean hospital stay was 0.7-days with day case surgery performed in 69 %. CONCLUSIONS: This trainee lead audit provides a contemporary view of inguinal hernia surgery in Scotland. Increased compliance on recurrent cases appears indicated. National re-audit could ensure improved adherence and would be feasible through the SSRG. PMID- 25142493 TI - Totally endoscopic surgery on diastasis recti associated with midline hernias. The advantages of a minimally invasive approach. Prospective cohort study. AB - PURPOSE: To evaluate prospectively the feasibility and the duration of the plication of both aponeurosis through a totally endoscopic approach to the diastasis recti associated with midline hernias, correcting both pathologies simultaneously and objectively looking at their advantages and complications. METHODS: The prospective cohort study included patients suffering from midline hernias equal to or bigger than 2 cm size and associated diastasis recti, from April 2011 to October 2012. Full endoscopic subcutaneous approach is used to perform the surgery. An ultrasound scan was carried out to identify inter-rectus distances and recurrences in xiphoid, 3 cm supraumbilical and 2 cm subumbilical locations. RESULTS: A total of 21 patients were included in the study, with a mean follow-up of 20 months. The main complication was seroma. A significant reduction in the average distance between the rectus muscles was shown before surgery and at 1 month postoperative measures in all three locations (p < 0.001). No significant differences between the measured distances to the first and second year. A significant improvement at first postoperative year in cosmetic outcome compared with preoperative cosmetic condition (p < 0.001) was confirmed. Back pain improves significantly when diastasis recti is surgically corrected. CONCLUSIONS: Totally endoscopic approach to diastasis recti associated with midline hernias is a feasible and reproducible method. It brings considerable esthetic advantages. Diastasis or hernia recurrences in medium term follow-up have not been observed. Diastasis greater than 6-7 cm or associated with severe musculoaponeurotic laxity of the abdominal wall could benefit from the use of reinforced prosthesis. PMID- 25142494 TI - COMQ-12 scores in adult patients without chronic middle ear disease. AB - OBJECTIVE: To determine the COMQ-12 score in an adult population without active COM. DESIGN: Analysis of COMQ-12 scores in participants without active COM. SETTING: East Anglia, United Kingdom. PARTICIPANTS: 70 healthy volunteers recruited from two local hospitals. MAIN OUTCOME MEASURES: COMQ-12. RESULTS: The median COMQ-12 score overall was two and the modal score was 0 with 27 (39%) participants achieving this score. CONCLUSION: We recommend that the 'normal' values defined in this study be seriously considered before contemplating intervention, especially when patients with low scores are considered for surgery. PMID- 25142495 TI - Evaluation of antibiotic allergy: the role of skin tests and drug challenges. AB - Antibiotic allergies are frequently reported in both adult and pediatric populations. While a detailed drug history is essential in the evaluation of antibiotic allergy, the history is typically insufficient to determine the presence of a drug allergy. The most readily available diagnostic testing for evaluating antibiotic allergies are drug skin testing and drug challenges. This review will focus on updates in the evaluation of antibiotic allergy utilizing immediate skin tests, delayed intradermal testing, drug patch tests, and drug challenges for both adults and children with histories of antibiotic allergies. PMID- 25142496 TI - De novo use of generic tacrolimus in liver transplantation - a single center experience with one-yr follow-up. AB - Use of generic tacrolimus in liver transplantation (LT) could result in cost savings. Generic tacrolimus has been shown to be bioequivalent to innovator tacrolimus in healthy volunteers and renal transplant patients. There are limited data on the de novo use of generic tacrolimus in LT. This study aimed to determine whether the de novo use of generic tacrolimus (Adoport, Sandoz,UK) was associated with differences in outcomes, safety, and cost compared with innovator tacrolimus (Prograf, Astellas, Japan). METHODS: Patients were studied before and after a programmatic change from de novo IS with Prograf to Adoport. Outcomes, tacrolimus levels, doses, and costs were compared for the first-yr post-LT. RESULTS: Ninety-four patients were studied, 46 Prograf, 48 Adoport. No significant differences in rejection, cytomegalovirus infection, acute kidney injury, sepsis, or graft loss were observed between groups. Tacrolimus costs were significantly reduced with the de novo use of Adoport. Day 14 dose normalized levels in Adoport patients showed significant variation but at the day 30 and one yr, there were no significant differences in the doses or levels of tacrolimus between groups. CONCLUSIONS: Adoport is safe and effective compared to Prograf when used de novo in LT patients. Tacrolimus costs were significantly reduced by the use of Adoport. PMID- 25142501 TI - Determination of multiple elements in samples of the medicinal plant Marsdenia tenacissima and estimation of geographic origin via pattern recognition techniques. AB - Multi-element analysis of the medicinal plant Marsdenia tenacissima was used to develop a reliable method of tracing the geographical source of the samples. The concentrations of 27 elements in 128 samples from 4 provinces in China were analyzed by inductively coupled plasma-atomic emission spectroscopy. Pattern recognition techniques, viz. principal component analysis (PCA), cluster analysis (CA), stepwise linear discriminant analysis (SLDA) and k-nearest neighbor analysis (KNN), were used for this purpose. It was verified that 21 elements in the M. tenacissima samples from different regions showed significant differences (P < 0.05). The PCA explained 87.36 % of the variance with the first seven principal component variables, and a score plot produced from the largest three principal components showed that the source area of most samples could be correctly distinguished. The CA showed that samples were separated into three clusters. The SLDA produced an overall correct classification rate of 87.5 % and a cross-validation rate of 85.2 %. The KNN analysis performed ideally, with an average identification rate of 100 % for the training set and 93.33 % for the test set. These results laid the foundation for the application of multi-element analysis combined with pattern recognition techniques for tracing the geographical origin of samples of medicinal plants. PMID- 25142502 TI - De novo transcriptome of the desert beetle Microdera punctipennis (Coleoptera: Tenebrionidae) using Illumina RNA-seq technology. AB - Insects in Tenebrionidae have unique stress adaptations that allow them to survive temperature extremes. We report here a gene expression profiling of Microdera punctipennis, a beetle in desert region, to gain a global view of its environmental adaptations. A total of 48,158,004 reads were obtained by transcriptome sequencing, and the de novo assembly yielded 56,348 unigenes with an average length of 666 bp. Based on similarity searches with a cut-off E-value of 10(-5) against two protein sequence databases, 41,109 of the unigenes (about 72.96%) were matched to known proteins. An in-depth analysis of the data revealed a large number of genes were associated with environmental stress, including genes that encode heat shock proteins, antifreeze proteins, and enzymes such as chitinase, trehalose, and trehalose-6-phosphate synthase. This study generated a substantial number of M. punctipennis transcript sequences that can be used to discover novel genes associated with stress adaptation. These sequences are a valuable resource for future studies of the desert beetle and other insects in Tenebrionidae. Transcriptome analysis based on Illumina paired-end sequencing is a powerful approach for gene discovery and molecular marker development for non model species. PMID- 25142503 TI - Why do satellite imageries show exceptionally high chlorophyll in the Gulf of Mannar and the Palk Bay during the Norteast Monsoon? AB - The Gulf of Mannar (GoM) and the Palk Bay (PB) are two least studied marine environments located between India and Sri Lanka. Exceptionally high chlorophyll a concentration in the GoM and the PB during the Northeast Monsoon (November February) is a consistent feature in satellite imageries, which has been attributed to the intrusion of the Bay of Bengal (BoB) waters. The analyses of the Moderate Resolution Imaging Spectroradiometer (MODIS) and field chlorophyll data collected from 30 locations in the Indian sector of the GoM and the PB in January 2011 showed significant overestimations in the satellite data. This error was much higher in the PB (60-80 %) as compared to the GoM (18-28 %). The multivariate analyses evidenced that the exceptionally high satellite chlorophyll in the PB is contributed largely by turbidity, colored dissolved organic matter (CDOM), and bottom reflectance. The paper cautions that though MODIS is superior in estimating chlorophyll a in optically complex waters, there are still chances of overestimations in regions like the PB. PMID- 25142504 TI - Determination of organochlorine pesticide concentrations in flathead mullet (Mugil cephalus) caught from the western Black Sea coast of Turkey. AB - The objective of this study was to determine the levels of 14 organochlorine pesticides (OCPs) in flathead mullet (Mugil cephalus) caught from the western Black Sea coast of Turkey. The fish samples were caught from five different locations of the western Black Sea coast of Turkey in August 2009. Organochlorine pesticides were extracted from the liver tissues, and then the levels of OCPs were measured using gas chromatography with an electron capture detector. Organochlorine pesticides were detected in all locations. The levels of total OCPs in fish samples ranged between 0.224 and 1.103 MUg g(-1) dry weight in the western Black Sea coast of Turkey. DDT, beta-HCH, and endosulfan I were the dominant OCPs in the fish samples. The levels of DDT in fish samples ranged between 0.081 and 0.186 MUg g(-1) dry weight. The levels of total HCH in fish samples ranged between 0.007 and 0.376 MUg g(-1) dry weight in the western Black Sea coast of Turkey. Although the usage of OCPs was banned in Turkey, the results of this study clearly indicated the presence of OCPs in the western Black Sea coast of Turkey and exposure of living organisms to these chemicals. PMID- 25142506 TI - Architectures of tavorite LiFe(PO4)(OH)(0.5)F(0.5) hierarchical microspheres and their lithium storage properties. AB - Tavorite LiFe(PO4)(OH)0.5F0.5 microspheres with different morphologies were prepared by a facile solvothermal route, and were further investigated as cathode materials for Li-ion batteries. We highly expect that this research can provide a useful fundamental understanding of the shape-dependent electrochemical performance of tavorite electrode materials. PMID- 25142505 TI - Immunology of human schistosomiasis. AB - There is a wealth of immunologic studies that have been carried out in experimental and human schistosomiasis that can be classified into three main areas: immunopathogenesis, resistance to reinfection and diagnostics. It is clear that the bulk of, if not all, morbidity due to human schistosomiasis results from immune-response-based inflammation against eggs lodged in the body, either as regulated chronic inflammation or resulting in fibrotic lesions. However, the exact nature of these responses, the antigens to which they are mounted and the mechanisms of the critical regulatory responses are still being sorted out. It is also becoming apparent that protective immunity against schistosomula as they develop into adult worms develops slowly and is hastened by the dying of adult worms, either naturally or when they are killed by praziquantel. However, as with anti-egg responses, the responsible immune mechanisms and inducing antigens are not clearly established, nor are any potential regulatory responses known. Finally, a wide variety of immune markers, both cellular and humoral, can be used to demonstrate exposure to schistosomes, and immunologic measurement of schistosome antigens can be used to detect, and thus diagnose, active infections. All three areas contribute to the public health response to human schistosome infections. PMID- 25142507 TI - MicroRNA-155 attenuates activation of hepatic stellate cell by simultaneously preventing EMT process and ERK1 signalling pathway. AB - BACKGROUND & AIMS: Epithelial-mesenchymal transition (EMT) process and extracellular signal-regulated kinase 1 (ERK1) signalling pathway play pivotal roles in hepatic stellate cell (HSC) activation, which is associated with the altered expression patterns of microRNAs (miRNAs). miR-155 is considered a typical multifunctional miRNA to regulate many biological processes. However, little attention has been given to the contributions of miR-155 to simultaneous regulation of EMT process and ERK1 pathway during HSC activation. METHODS: Differential expression of miR-155 was assessed in activated HSC, sera and liver tissues from cirrhotic patients. Whether miR-155 could directly interact with 3' untranslated region (3'-UTR) of T cell factor 4 (TCF4) and angiotensin II receptor type 1 (AGTR1) respectively was detected by luciferase reporter assay. The effects of enhanced miR-155 on EMT process and ERK1 pathway, cell apoptosis in HSC activation were also evaluated. RESULTS: A significant decrease in miR-155 expression was observed in activated HSC, sera or liver tissues of cirrhotic patients. MiR-155 was found to simultaneously interact with 3'-UTR of TCF4 and AGTR1 mRNAs, which are known as important regulators associated with EMT and ERK1 pathway repectively. Inhibiting miR-155 expression could stimulate the EMT state and ERK1 pathway activity, thus contributing to HSC activation. Forced miR-155 expression markedly decreased the mesenchymal markers and phosphorylated ERK1 level, and enhanced E-cadherin expression, leading to the synchronous inhibitory effect on EMT and ERK1 pathway and inducing HSC apoptosis. CONCLUSIONS: Our results implicate that miR-155 plays an important role in regulating the pathological network involving EMT process and ERK1 pathway during HSC activation. PMID- 25142508 TI - A Japanese SCA5 family with a novel three-nucleotide in-frame deletion mutation in the SPTBN2 gene: a clinical and genetic study. AB - To date, four families with spinocerebellar ataxia type 5 (SCA5) with four distinct mutations in the spectrin, beta, nonerythrocytic 2 gene (SPTBN2) have been reported worldwide. In the present study, we identified the first Japanese family with SCA5, and analyzed this family clinically and genetically. The clinical features of the five patients in this family revealed late-onset autosomal-dominant pure cerebellar ataxia. We collected DNA samples from the majority of the family members across two generations, and exome sequencing combined with Sanger sequencing revealed a novel heterozygous three-nucleotide in frame deletion mutation (c.2608_2610delGAG) in exon 14 of the SPTBN2 gene. This mutation cosegregated with the disease in the family and resulted in a glutamic acid deletion (p.E870del) in the sixth spectrin repeat, which is highly conserved in the SPTBN2 gene. This is the first three-nucleotide in-frame deletion mutation in this region of the beta-3 spectrin protein highly likely to be pathogenic based on exome and bioinformatic data. PMID- 25142509 TI - Telomerase expression in amyotrophic lateral sclerosis (ALS) patients. AB - Telomerase and telomeric complex have been linked to a variety of disease states related to neurological dysfunction. In amyotrophic lateral sclerosis (ALS) patients, telomerase activity, as human telomerase reverse transcriptase (hTERT) expression, has not been characterized yet. Here, for the first time, we characterized telomerase and related pathway in blood sample and spinal cord from ALS patients compared with healthy controls. We found that hTERT expression level was significantly lower in ALS patients and was correlated either to p53 mRNA expression or p21 expression, pointing out the hypothesis that telomerase inhibition could be a pathogenetic contributor to neurodegeneration in ALS. As a consequence of the reduced telomerase activity, we identified shorter telomeres in leukocytes from sporadic ALS patients compared with healthy control group. PMID- 25142510 TI - Three novel mutations of the FBN1 gene in Chinese children with acromelic dysplasia. AB - Geleophysic dysplasia (GD), acromicric dysplasia (AD) and Weill-Marchesani syndrome (WMS) are rare disorders with overlapping characteristics, such as short stature, short hands and feet, joint limitations, skin thickening, mild facial anomalies, normal intelligence and abnormal skeletal symptoms, with GD distinct by progressive cardiac valvular thickening and WMS distinct by microspherophakia and ectopia lentis. Mutations in FBN1 gene have been identified in AD, GD and WMS patients. By targeted next-generation sequencing of skeletal dysplasia-related genes, including FBN1 and ADAMTSL2, three novel missense mutations, c.5189A>T (p.N1730I), c.5198G>T (p.C1733F), c.5243G>T (p.C1748F), and one known mutation c.5198G>A (p.C1733Y) of FBN1 gene were identified in four probands, respectively. Clinically, p.C1733Y was associated with GD, as reported previously, as well as the novel p.N1730I, whereas p.C1733F and p.C1748F were associated with AD and WMS. Interestingly, different mutations at the same codon (p.C1733Y and p.C1733F) were associated with different phenotypes (GD and AD, respectively). However, the mutations p.C1748F and p.C1748R were associated with WMS. Our data support the importance of TGFbeta-binding protein-like domain 5 of FBN1 protein in pathogenicity of acromelic dysplasia, and expands the genotype/phenotype relations of these rare forms of fibrilliopathies. PMID- 25142511 TI - Sequential processing of quantitative phase images for the study of cell behaviour in real-time digital holographic microscopy. AB - Transmitted light holographic microscopy is particularly used for quantitative phase imaging of transparent microscopic objects such as living cells. The study of the cell is based on extraction of the dynamic data on cell behaviour from the time-lapse sequence of the phase images. However, the phase images are affected by the phase aberrations that make the analysis particularly difficult. This is because the phase deformation is prone to change during long-term experiments. Here, we present a novel algorithm for sequential processing of living cells phase images in a time-lapse sequence. The algorithm compensates for the deformation of a phase image using weighted least-squares surface fitting. Moreover, it identifies and segments the individual cells in the phase image. All these procedures are performed automatically and applied immediately after obtaining every single phase image. This property of the algorithm is important for real-time cell quantitative phase imaging and instantaneous control of the course of the experiment by playback of the recorded sequence up to actual time. Such operator's intervention is a forerunner of process automation derived from image analysis. The efficiency of the propounded algorithm is demonstrated on images of rat fibrosarcoma cells using an off-axis holographic microscope. PMID- 25142512 TI - Vimentin is necessary for colony growth of human diploid keratinocytes. AB - The role of vimentin (Vim) in diploid epithelial cells is not well known. To understand its biological function, we cultured human epidermal keratinocytes under conditions that support migration, proliferation, stratification and terminal differentiation. We identified a keratinocyte subpopulation that shows a p63(+)/alpha5beta1(bright) phenotype and displays Vim intermediate filaments (IFs) besides their keratin IF network. These cells were mainly located at the proliferative/migratory rim of the growing colonies; but also, they were scarce and scattered or formed small groups of basal cells in confluent stratified epithelia. Stimulation of cells with EGF and wounding experiments in confluent arrested epithelia increased the number of Vim(+) keratinocytes in an extent higher to the expected for a cell population doubling. BrdU labeling demonstrated that most of the proliferative cells located at the migratory border of the colony have Vim, in contrast with proliferative cells located at the basal layer at the center of big colonies which lacked of Vim IFs, suggesting that Vim expression was not solely linked to proliferation. Therefore, we silenced Vim mRNA in the cultured keratinocytes and observed an inhibition of colony growth. Such results, together with long-term cultivation assays which showed that Vim might be associated to pattern formation in cultured epithelia, suggest that Vim expression is essential for a highly motile phenotype, which is necessary for keratinocyte colony growth and possibly for development and wound healing. Vim(+)/p63(+)/alpha5beta1(bright) epithelial cells may play a significant physiological role in embryonic morphogenetic movements; wound healing and other pathologies such as carcinomas and hyperproliferative diseases. PMID- 25142513 TI - DNA G-segment bending is not the sole determinant of topology simplification by type II DNA topoisomerases. AB - DNA topoisomerases control the topology of DNA. Type II topoisomerases exhibit topology simplification, whereby products of their reactions are simplified beyond that expected based on thermodynamic equilibrium. The molecular basis for this process is unknown, although DNA bending has been implicated. To investigate the role of bending in topology simplification, the DNA bend angles of four enzymes of different types (IIA and IIB) were measured using atomic force microscopy (AFM). The enzymes tested were Escherichia coli topo IV and yeast topo II (type IIA enzymes that exhibit topology simplification), and Methanosarcina mazei topo VI and Sulfolobus shibatae topo VI (type IIB enzymes, which do not). Bend angles were measured using the manual tangent method from topographical AFM images taken with a novel amplitude-modulated imaging mode: small amplitude small set-point (SASS), which optimises resolution for a given AFM tip size and minimises tip convolution with the sample. This gave improved accuracy and reliability and revealed that all 4 topoisomerases bend DNA by a similar amount: ~120 degrees between the DNA entering and exiting the enzyme complex. These data indicate that DNA bending alone is insufficient to explain topology simplification and that the 'exit gate' may be an important determinant of this process. PMID- 25142514 TI - Ultraslow recombination in AOT-capped TiO2 nanoparticles sensitized by protoporphyrin IX. AB - Aerosol OT (AOT) capped TiO2 nanoparticles have been prepared by a phase transfer mechanism. The TiO2 nanoparticles have a diameter of 5-10 nm, are highly crystalline (anatase) and show high photoluminescence. They are effectively sensitized by protoporphyrin IX (PPIX) and show high electron injection rates while the rate of back recombination is much slower than those reported previously. Thus the AOT capped TiO2 nanoparticles synthesized in this work are highly effective not only in promoting ultrafast electron injection from PPIX to TiO2 but more importantly they lead to extremely slow back recombination rates. The significance of this work is in the synthesis of highly photoluminescent TiO2 nanoparticles which can be easily sensitized by a porphyrin dye, whereby ultraslow recombination is observed. PMID- 25142515 TI - The life and times of Ferruccio Ritossa. AB - Ferruccio Ritossa wrote these lines only a few months before he died, as a preface to a book he wanted to write and that, unfortunately, we will never be able to read. It was to be the story of his life, an amazing story indeed. With this article, we want to take a picture of Ferruccio's life, a mosaic of events, facts, ideas, hopes, and memories linked in a way that they will not go away, even after "a stroll in our brain." PMID- 25142516 TI - The interplay between cooperativity and diversity in model threshold ensembles. AB - The interplay between cooperativity and diversity is crucial for biological ensembles because single molecule experiments show a significant degree of heterogeneity and also for artificial nanostructures because of the high individual variability characteristic of nanoscale units. We study the cross effects between cooperativity and diversity in model threshold ensembles composed of individually different units that show a cooperative behaviour. The units are modelled as statistical distributions of parameters (the individual threshold potentials here) characterized by central and width distribution values. The simulations show that the interplay between cooperativity and diversity results in ensemble-averaged responses of interest for the understanding of electrical transduction in cell membranes, the experimental characterization of heterogeneous groups of biomolecules and the development of biologically inspired engineering designs with individually different building blocks. PMID- 25142517 TI - Pattern selection and hysteresis in the Rietkerk model for banded vegetation in semi-arid environments. AB - Banded vegetation is a characteristic feature of semi-arid environments. It occurs on gentle slopes, with alternating stripes of vegetation and bare ground running parallel to the contours. A number of mathematical models have been proposed to investigate the mechanisms underlying these patterns, and how they might be affected by changes in environmental conditions. One of the most widely used models is due to Rietkerk and co-workers, and is based on a water redistribution hypothesis, with the key feedback being that the rate of rainwater infiltration into the soil is an increasing function of plant biomass. Here, for the first time, we present a detailed study of the existence and stability of pattern solutions of the Rietkerk model on slopes, using the software package wavetrain (www.ma.hw.ac.uk/wavetrain). Specifically, we calculate the region of the rainfall-migration speed parameter plane in which patterns exist, and the sub region in which these patterns are stable as solutions of the model partial differential equations. We then perform a detailed simulation-based study of the way in which patterns evolve when the rainfall parameter is slowly varied. This reveals complex behaviour, with sudden jumps in pattern wavelength, and hysteresis; we show that these jumps occur when the contours of constant pattern wavelength leave the parameter region giving stable patterns. Finally, we extend our results to the case in which a diffusion term for surface water is added to the model equations. The parameter regions for pattern existence and stability are relatively insensitive to small or moderate levels of surface water diffusion, but larger diffusion coefficients significantly change the subdivision into stable and unstable patterns. PMID- 25142518 TI - Crowdsourcing contest dilemma. AB - Crowdsourcing offers unprecedented potential for solving tasks efficiently by tapping into the skills of large groups of people. A salient feature of crowdsourcing--its openness of entry--makes it vulnerable to malicious behaviour. Such behaviour took place in a number of recent popular crowdsourcing competitions. We provide game-theoretic analysis of a fundamental trade-off between the potential for increased productivity and the possibility of being set back by malicious behaviour. Our results show that in crowdsourcing competitions malicious behaviour is the norm, not the anomaly--a result contrary to the conventional wisdom in the area. Counterintuitively, making the attacks more costly does not deter them but leads to a less desirable outcome. These findings have cautionary implications for the design of crowdsourcing competitions. PMID- 25142519 TI - Progressive promoter element combinations classify conserved orthogonal plant circadian gene expression modules. AB - We aimed to test the proposal that progressive combinations of multiple promoter elements acting in concert may be responsible for the full range of phases observed in plant circadian output genes. In order to allow reliable selection of informative phase groupings of genes for our purpose, intrinsic cyclic patterns of expression were identified using a novel, non-biased method for the identification of circadian genes. Our non-biased approach identified two dominant, inherent orthogonal circadian trends underlying publicly available microarray data from plants maintained under constant conditions. Furthermore, these trends were highly conserved across several plant species. Four phase specific modules of circadian genes were generated by projection onto these trends and, in order to identify potential combinatorial promoter elements that might classify genes into these groups, we used a Random Forest pipeline which merged data from multiple decision trees to look for the presence of element combinations. We identified a number of regulatory motifs which aggregated into coherent clusters capable of predicting the inclusion of genes within each phase module with very high fidelity and these motif combinations changed in a consistent, progressive manner from one phase module group to the next, providing strong support for our hypothesis. PMID- 25142520 TI - A mathematical model of collagen lattice contraction. AB - Two mathematical models for fibroblast-collagen interaction are proposed which reproduce qualitative features of fibroblast-populated collagen lattice contraction. Both models are force based and model the cells as individual entities with discrete attachment sites; however, the collagen lattice is modelled differently in each model. In the collagen lattice model, the lattice is more interconnected and formed by triangulating nodes to form the fibrous structure. In the collagen fibre model, the nodes are not triangulated, are less interconnected, and the collagen fibres are modelled as a string of nodes. Both models suggest that the overall increase in stress of the lattice as it contracts is not the cause of the reduced rate of contraction, but that the reduced rate of contraction is due to inactivation of the fibroblasts. PMID- 25142521 TI - Counterintuitive properties of the fixation time in network-structured populations. AB - Evolutionary dynamics on graphs can lead to many interesting and counterintuitive findings. We study the Moran process, a discrete time birth-death process, that describes the invasion of a mutant type into a population of wild-type individuals. Remarkably, the fixation probability of a single mutant is the same on all regular networks. But non-regular networks can increase or decrease the fixation probability. While the time until fixation formally depends on the same transition probabilities as the fixation probabilities, there is no obvious relation between them. For example, an amplifier of selection, which increases the fixation probability and thus decreases the number of mutations needed until one of them is successful, can at the same time slow down the process of fixation. Based on small networks, we show analytically that (i) the time to fixation can decrease when links are removed from the network and (ii) the node providing the best starting conditions in terms of the shortest fixation time depends on the fitness of the mutant. Our results are obtained analytically on small networks, but numerical simulations show that they are qualitatively valid even in much larger populations. PMID- 25142522 TI - The effect of glass-forming sugars on vesicle morphology and water distribution during drying. AB - Cryopreservation requires that stored materials be kept at extremely low temperatures and uses cryoprotectants that are toxic to cells at high concentrations. Lyopreservation is a potential alternative where stored materials can remain at room temperatures. That storage process involves desiccating cells filled with special glass-forming sugars. However, current desiccation techniques fail to produce viable cells, and researchers suspect that incomplete vitrification of the cells is to blame. To explore this hypothesis, a cell is modelled as a lipid vesicle to monitor the water content and membrane deformation during desiccation. The vesicle is represented as a moving, bending-resistant, inextensible interface and is tracked by a level set method. The vesicle is placed in a fluid containing a spatially varying sugar concentration field. The glass-forming nature is modelled through a concentration-dependent diffusivity and viscosity. It is found that there are optimal regimes for the values of the osmotic flow parameter and of the concentration dependence of the diffusivity to limit water trapping in the vesicle. Furthermore, it is found that the concentration dependencies of the diffusivity and viscosity can have profound effects on membrane deformations, which may have significant implications for vesicle damage during the desiccation process. PMID- 25142523 TI - Mapping the stereotyped behaviour of freely moving fruit flies. AB - A frequent assumption in behavioural science is that most of an animal's activities can be described in terms of a small set of stereotyped motifs. Here, we introduce a method for mapping an animal's actions, relying only upon the underlying structure of postural movement data to organize and classify behaviours. Applying this method to the ground-based behaviour of the fruit fly, Drosophila melanogaster, we find that flies perform stereotyped actions roughly 50% of the time, discovering over 100 distinguishable, stereotyped behavioural states. These include multiple modes of locomotion and grooming. We use the resulting measurements as the basis for identifying subtle sex-specific behavioural differences and revealing the low-dimensional nature of animal motions. PMID- 25142524 TI - Modelling biological behaviours with the unified modelling language: an immunological case study and critique. AB - We present a framework to assist the diagrammatic modelling of complex biological systems using the unified modelling language (UML). The framework comprises three levels of modelling, ranging in scope from the dynamics of individual model entities to system-level emergent properties. By way of an immunological case study of the mouse disease experimental autoimmune encephalomyelitis, we show how the framework can be used to produce models that capture and communicate the biological system, detailing how biological entities, interactions and behaviours lead to higher-level emergent properties observed in the real world. We demonstrate how the UML can be successfully applied within our framework, and provide a critique of UML's ability to capture concepts fundamental to immunology and biology more generally. We show how specialized, well-explained diagrams with less formal semantics can be used where no suitable UML formalism exists. We highlight UML's lack of expressive ability concerning cyclic feedbacks in cellular networks, and the compounding concurrency arising from huge numbers of stochastic, interacting agents. To compensate for this, we propose several additional relationships for expressing these concepts in UML's activity diagram. We also demonstrate the ambiguous nature of class diagrams when applied to complex biology, and question their utility in modelling such dynamic systems. Models created through our framework are non-executable, and expressly free of simulation implementation concerns. They are a valuable complement and precursor to simulation specifications and implementations, focusing purely on thoroughly exploring the biology, recording hypotheses and assumptions, and serve as a communication medium detailing exactly how a simulation relates to the real biology. PMID- 25142525 TI - Actin flow and talin dynamics govern rigidity sensing in actin-integrin linkage through talin extension. AB - At cell-substrate adhesion sites, the linkage between actin filaments and integrin is regulated by mechanical stiffness of the substrate. Of potential molecular regulators, the linker proteins talin and vinculin are of particular interest because mechanical extension of talin induces vinculin binding with talin, which reinforces the actin-integrin linkage. For understanding the molecular and biophysical mechanism of rigidity sensing at cell-substrate adhesion sites, we constructed a simple physical model to examine a role of talin extension in the stiffness-dependent regulation of actin-integrin linkage. We show that talin molecules linking between retrograding actin filaments and substrate-bound integrin are extended in a manner dependent on substrate stiffness. The model predicts that, in adhesion complexes containing ~30 talin links, talin is extended enough for vinculin binding when the substrate is stiffer than 1 kPa. The lifetime of talin links needs to be 2-5 s to achieve an appropriate response of talin extension against substrate stiffness. Furthermore, changes in actin velocity drastically shift the range of substrate stiffness that induces talin-vinculin binding. Our results suggest that talin extension is a key step in sensing and responding to substrate stiffness at cell adhesion sites. PMID- 25142526 TI - What makes an accurate and reliable subject-specific finite element model? A case study of an elephant femur. PMID- 25142527 TI - Comparative study of the fluid viscosity in tarsal hairy attachment systems of flies and beetles. AB - Wet adhesive systems of insects strongly rely for their function on the formation of capillary bridges with the substrate. Studies on the chemical composition and evaporation dynamics of tarsal secretions strongly suggest a difference in chemistry of secretion in beetles and flies, both possessing hairy attachment devices. This difference is assumed to influence the viscosity of the secretion. Here, we applied a microrheological technique, based on the immersion of nanometric beads in the collected tarsal footprints, to estimate secretion viscosity in a beetle (Coccinella septempunctata) and a fly (Calliphora vicina). Both species studied possess distinct differences in viscosity, the median of which was calculated as 21.8 and 10.9 mPa s, respectively. We further present an approximate theoretical model to calculate the contact formation time of spatula like terminal contact elements using the viscosity data of the covering fluid. The estimated contact formation time is proportional to the tarsal secretion viscosity and to the square of the contact radius of the contact element. PMID- 25142528 TI - Theory and data for simulating fine-scale human movement in an urban environment. AB - Individual-based models of infectious disease transmission depend on accurate quantification of fine-scale patterns of human movement. Existing models of movement either pertain to overly coarse scales, simulate some aspects of movement but not others, or were designed specifically for populations in developed countries. Here, we propose a generalizable framework for simulating the locations that an individual visits, time allocation across those locations, and population-level variation therein. As a case study, we fit alternative models for each of five aspects of movement (number, distance from home and types of locations visited; frequency and duration of visits) to interview data from 157 residents of the city of Iquitos, Peru. Comparison of alternative models showed that location type and distance from home were significant determinants of the locations that individuals visited and how much time they spent there. We also found that for most locations, residents of two neighbourhoods displayed indistinguishable preferences for visiting locations at various distances, despite differing distributions of locations around those neighbourhoods. Finally, simulated patterns of time allocation matched the interview data in a number of ways, suggesting that our framework constitutes a sound basis for simulating fine-scale movement and for investigating factors that influence it. PMID- 25142529 TI - No association between NRG1 and ErbB4 genes and psychopathological symptoms of schizophrenia. AB - Neuregulin 1 (NRG1) and v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) have been extensively studied in schizophrenia susceptibility because of their pivotal role in key neurodevelopmental processes. One of the reasons for the inconsistencies in results could be the fact that the phenotype investigated has mostly the diagnosis of schizophrenia per se, which is widely heterogeneous, both clinically and biologically. In the present study we tested, in a large cohort of 461 schizophrenia patients recruited in Scotland, whether several SNPs in NRG1 and/or ErbB4 are associated with schizophrenia symptom dimensions as evaluated by the Positive and Negative Syndrome Scale (PANSS). We then followed up nominally significant results in a second cohort of 439 schizophrenia subjects recruited in Germany. Using linear regression, we observed two different groups of polymorphisms in NRG1 gene: one showing a nominal association with higher scores of the PANSS positive dimension and the other one with higher scores of the PANSS negative dimension. Regarding ErbB4, a small cluster located in the 5' end of the gene was detected, showing nominal association mainly with negative, general and total dimensions of the PANSS. These findings suggest that some regions of NRG1 and ErbB4 are functionally involved in biological processes that underlie some of the phenotypic manifestations of schizophrenia. Because of the lack of significant association after correction for multiple testing, our analyses should be considered as exploratory and hypothesis generating for future studies. PMID- 25142530 TI - Incidence, risk factors, etiology, severity and short-term outcome of non traumatic intracerebral hemorrhage in young adults. AB - BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a common and severe form of stroke but is scarcely studied in young adults. Our aim was to study risk factors, clinical presentation and early mortality of ICH in the young and compare these features with older patients. METHODS: All consecutive patients aged between 16 and 49 diagnosed with a first-ever ICH at the Departments of Neurology or Neurosurgery of the Helsinki University Central Hospital between January 2000 and March 2010 (n = 336) were analyzed retrospectively. Comparisons were performed amongst demographic subgroups and with patients over 49 years of age enrolled between January 2005 and March 2010 (n = 921). RESULTS: In the young patients, median age was 42 years (interquartile range 34-47), 59.5% were male, and annual incidence was 4.9 (95% confidence interval 4.5-5.3) per 100 000. The most prevalent risk factors were hypertension (29.8%) and smoking (22.3%). Compared with older patients hypertensive microangiopathy was less common (25.0% vs. 34.3%, P = 0.002) and structural lesions more common (25.0% vs. 4.9%, P < 0.001) assumed etiologies of ICH. The cause remained elusive in 32.1% of all young patients and in 22.5% of those who underwent magnetic resonance imaging and any angiography (n = 89, P = 0.023). Three-month mortality rate was lower in young patients compared with older ones (17.0% vs. 32.7%, P < 0.001). Hematoma volumes were similar across all ages (P = 0.324) and independently predicted mortality in older patients but not in the young. CONCLUSIONS: Intracerebral hemorrhage (ICH) in the young appears less fatal and has a different spectrum of causes and factors associated with short-term mortality than for the elderly. PMID- 25142531 TI - Leptomeningeal carcinomatosis in esophageal cancer: a case series and systematic review of the literature. AB - The aim of this study was to more clearly define the clinical course of leptomeningeal carcinomatosis due to esophageal cancer. A single institution retrospective case series was conducted. Additionally, a systematic review of the literature was performed. We present a large case series (n = 7) of leptomeningeal carcinomatosis due to esophageal cancer. Our case series and systematic review of the literature report similar findings. In our series, we report a predominance of male patients (86%) with adenocarcinoma histology (77%). Variable onset of leptomeningeal involvement of esophageal cancer in relation to the original diagnosis of the primary disease (5 months to 3 years and 11 weeks) was noted. Disease progresses quickly and overall survival is poor, measured in weeks (2.5-16 weeks) from the diagnosis of leptomeningeal involvement. Four of our patients initiated whole-brain radiation therapy with only two completing the course prior to clinical deterioration. Our patient with the longest survival (16 weeks) received intrathecal topotecan and oral temozolomide. Leptomeningeal carcinomatosis secondary to esophageal cancer has a poor prognosis. A clearly beneficial treatment modality is lacking. PMID- 25142532 TI - Cirrhosis patients have a coagulopathy that is associated with decreased clot formation capacity. AB - BACKGROUND: The coagulopathy in cirrhosis is associated with thrombosis and bleeding. OBJECTIVES: To gain better insights into the coagulopathy in patients with cirrhosis, we evaluated plasma thrombin generation and whole blood clot formation in a cross-sectional study. METHODS: Blood was collected from 73 patients with all-cause cirrhosis (Child-Pugh-A n = 52, B n = 15, C n = 6) and 20 healthy controls. Activity of the coagulation pathways was measured with assays for factor (F) VIIa and FIXa-antithrombin and FXa-antithrombin complexes, respectively. Thrombin generation by calibrated automated thrombography was determined in platelet-poor plasma using a 1 or 5 pm tissue factor trigger with/without thrombomodulin. ROTEM measurements were performed in whole blood triggered with 35 pm tissue factor without/with 175 ng mL(-1) tissue plasminogen activator (the latter refered to as 'tPA-ROTEM'). RESULTS: We observed an increased generation of FVIIa and a moderately elevated amount of FIXa (in complex with antithrombin) without apparent increase in FX activation in patients with cirrhosis. In accordance with this prothrombotic state, markers of thrombin generation potential were also increased upon increasing severity of cirrhosis. In the whole blood clotting assay we observed delayed clot formation and decreased clot strength associated with increased severity of cirrhosis. No significant differences were found for tPA-ROTEM parameters of clot degradation. CONCLUSION: These results indicate that cirrhosis patients have an overall procoagulant plasma milieu but a decreased whole blood clot formation capacity with an apparently unaltered resistance to clot lysis. PMID- 25142533 TI - Knowledge and attitude of Indian clinical dental students towards the dental treatment of patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). AB - OBJECTIVES: Oral health care of patients with human immunodeficiency virus (HIV)/acquired immune-deficiency syndrome (AIDS) is a growing area of concern. Information on HIV- and AIDS-related knowledge among dental students provides a crucial foundation for efforts aimed at developing an appropriate dental curriculum on HIV and AIDS. The purpose of this study was to assess the knowledge and attitude of Indian clinical dental students towards the treatment of patients with HIV/AIDS and perceived sources of information regarding HIV-related issues. MATERIALS AND METHODS: Data were collected from clinical dental students (third year, fourth year and internship) from three dental institutions in Delhi National Capital Region (NCR). The questions assessed the knowledge and attitude towards treatment of patients with HIV and the perceived source of information related to HIV. RESULTS: The willingness to treat HIV-positive patients among dental students was 67.0%, and 74.20% were confident of treating a patient with HIV/AIDS. The potential problems in rendering treatment to these patients were effect on the attitude of other patients (49.90%) and staff fears (52.50%). The correct knowledge regarding the infection-control practice (barrier technique) was found among only 15.50% of respondents. The respondents had sufficient knowledge regarding the oral manifestations of HIV/AIDS. CONCLUSIONS: There was no correlation between the knowledge and attitude score, demonstrating a gap between knowledge and attitude among dental students regarding treatment of HIV infected patients. Appropriate knowledge has to be delivered through the dental education curriculum, which can instil confidence in students about their ability to manage HIV-positive patients. PMID- 25142534 TI - [A case of left hemi-facial metamorphopsia induced by infarction of the right side of the splenium of the corpus callosum]. AB - We describe a patient, 61-year-old left-handed Japanese woman, who presented with left hemi-facial metamorphopsia after infarct that extended from the splenium of the corpus callosum to the major forceps on the right side. Past medical history revealed a right putaminal hemorrhage with amnesic aphasia. She complained that the right side of people's faces, that is, the left side when visualized by her, seemed distorted. When she looked at other people's faces, the right half of the faces looked smaller than the left half, and the eyes, noses, and mouths appeared to be hanging toward the center of their faces. This phenomenon was observed for whomever she visualized. She stated that objects other than the face looked normal. Her visual acuity and visual field were normal. Callosal disconnection syndrome was not presented. Magnetic resonance imaging of the brain on diffusion weighted image revealed a high intensity area that extended from the splenium of the corpus callosum to the major forceps on the right side. Electroencephalography did not show any epileptic discharge. Her visual symptoms improved gradually. The mechanism of hemi-facial metamorphopsia remains obscure. We hypothesized that this patient developed left hemi-facial metamorphopsia because of the disrupted transfer of visual information of the left side of face at the splenium of the corpus callosum and the major forceps, which may be the responsible lesion of hemi-facial metamorphopsia. PMID- 25142535 TI - [A case of 77-year-old male with spinocerebellar ataxia type 31 with left dominant dystonia]. AB - We report on the case of a 77-year-old male with genetically proven spinocerebellar ataxia type 31 (SCA31) who had dystonia. He was referred to our hospital for evaluation following a 6-year history of slowly progressive unsteadiness of his left leg during walking and dysarthria at the age of 62 years old. On the basis of his symptoms, we diagnosed him as spinocerebellar degeneration (SCD), and prescribed taltirelin hydrate. However, his symptoms continued to worsen. He required a cane for walking at the age of 63 years, and a wheelchair at the age of 66 years. He was admitted to our hospital following acute cerebral infarction at the age of 77 years. On examination at admission, right hemiparesis and cerebellar ataxia were detected. And left hallux moved involuntarily toward the top surface of the foot at rest, that is dystonia. The dystonia was not associated with cerebral infarction, because it had been several years with dystonia that he got cerebral infarction. Genetic analysis revealed that this patient harbored a heterozygous SCA31 mutation. Previously there have been no reports of SCA31 associated with dystonia. Our case report support clinical heterogeneity of SCA31, and highlight the importance of considering this type in patients with dystonia and ataxia. Patients with the combination of dystonia and ataxia and a family history of a neurodegenerative disorder should be tested for SCA31. PMID- 25142536 TI - [A case of cerebral fat embolism after artificial bone replacement operation for femoral head fracture]. AB - A 83 years old woman was slipped and injured with right femoral neck fracture. After three days from the fracture, she underwent an artificial head bone replacement operation. Immediately after surgery, she complained of chest discomfort, nausea and dyspnea. A few hours later, she became comatose. Brain CT showed no abnormality and clinical diagnosis of heart failure was made without pulmonary embolism on enhanced chest CT. Magnetic resonance imaging (MRI) of the brain next day showed multiple small patchy hyperintense lesion in bilateral hemispheres on diffusion-weighted images (DWI), producing a "star field pattern''. Based on Criteria of Gurd, this patient had one major criterion and four minor criteria. And according to the Criteria of Schonfeld, this patient had 5 points, consistent with clinical diagnosis of fat embolism. Because of these criteria, she was diagnosed as cerebral fat embolism syndrome. We started supported care and edaravon. Two weeks after surgery, her condition recovered and remaind to stuporous state even six month after surgery. We experienced a typical case of cerebral fat embolism, after bone surgery with diagnostic findings on MRI DWI. Diagnosis of cerebral fat embolism syndrome requires a history of long bone fracture and/or replacing surgery with typical finding on MRI images, such as "star field pattern''. PMID- 25142537 TI - [Hypothermia and memory disturbance as initial manifestations associated with lesions of the diencephalon in a patient with anti-aquaporin 4 antibody associated disorder: a case report]. AB - A 69-year-old woman was admitted due to gradual progression of daytime sleepiness and forgetfulness over a period of approximately 1 month. Bradycardia and hypothermia were observed on admission, and neurological examination revealed memory disturbance, mild dysarthria, and bradykinesia. Fluid-attenuated inversion recovery (FLAIR) images of the brain magnetic resonance imaging (MRI) indicated signal hyperintensity in the region bordering the lateral and third ventricles. Serum anti-aquaporin 4 (AQP4) antibody was detected. The patient had no history or findings of optic neuritis or myelitis, and she was diagnosed as anti-AQP4 antibody-associated disorder. Diencephalon lesion and/or symptoms are rarely observed at the onset of neuromyelitis optica. Differential diagnosis of this disorder is necessary in cases manifesting diencephalon symptoms or involving lesions bordering the third ventricle without evidence of previous optic neuritis or myelitis. PMID- 25142538 TI - [A case of acute limbic encephalitis with cerebral salt wasting syndrome]. AB - A 37-year-old woman presented with psychiatric symptoms. Cerebrospinal fluid analysis revealed pleocytosis and increased protein. The patient was diagnosed with limbic encephalitis on the basis of the clinical course. However, remarkable hyponatremia was noted throughout the clinical course, leading to a diagnosis of cerebral salt wasting syndrome (CSWS). The hyponatremia was alleviated by supplementation with sodium and water. The findings seen in this case indicate that differentiation between syndrome of inappropriate of antidiuretic hormone and CSWS is important in cases of hyponatremia accompanied by central nervous system disease. PMID- 25142539 TI - [Malignant lymphoma in a perineural spreading along trigeminal nerve, which developed as trigeminal neuralgia]. AB - A rare cause of trigeminal neuralgia is malignant lymphoma which spread along the trigeminal nerve. We report a 79-year-old male presented with 4-month history of neuralgic pain in right cheek. He was diagnosed as classical trigeminal neuralgia. It had improved through medication of carbamazepine. Four months later, the dull pain unlike neuralgia complicated on the right cheeks, it was ineffective with the medication. Furthermore, diplopia and facial palsy as the other cranial nerve symptoms appeared. Gadolinium-enhanced magnetic resonance imaging (MRI) revealed contrast-enhanced mass lesion extend both external pterygoid muscle and brainstem through the swelling trigeminal nerve. The patient was pathological diagnosed of diffuse large B cell lymphoma by biopsy. Malignant lymphoma should be considered in the different diagnosis of cases with a minimal single cranial nerve symptom. PMID- 25142540 TI - [IgG4-related disease that presented cranial, cervical, lumbar and sacral hypertrophic pachymeningitis associated with infundibulo-hypophysitis]. AB - We report a patient of 32-year-old female with central IgG4-related disease. She developed headache and visual disturbance. On examination, she revealed diabetes insipidus, retrobulbar neuritis, hyperreflexia and limb weakness. Her laboratory findings showed serum IgG4 elevation, pleocytosis and protein elevation in cerebrospinal fluid. Chest CT showed a nodular lesion in the S8 of the left lung. Cranial and spinal magnetic resonance images with gadolinium contrast material showed cranial, cervical and lumbosacral hypertrophic pachymeningitis associated with infundibulo-hypophysitis. Pathological findings of the left frontal dura mater revealed lymphoplasmacytic inflammatory cell infiltrate with dense fibrosis. IgG4 immunohistochemistry showed no IgG4 + plasma cells within the inflammatory infiltrate. During treatment with intravenous pulse methylprednisolone followed by oral prednisolone, she revealed recovery of visual acuity with improvement of hypertrophic pachymeningitis and normalization of serum IgG4. This is a first report of IgG4-related hypertrophic pachymeningitis which involved cranial, cervical and lumbosacral regions as well as infundibulo hypophysitis in a young female. PMID- 25142541 TI - [A case of rubella encephalitis presenting as clinically mild encephalitis/encephalopathy with a reversible splenial lesion]. AB - A 26-year-old male was admitted because of a fever, headache and disturbance of consciousness with lymph node swelling of the neck two days after developing a rash. A neurological examination revealed restlessness with irritability in response to sensory stimuli, such as an injection. Diffusion-weighted brain magnetic resonance imaging (MRI) revealed a hyperintense ovoid lesion in the splenium of the corpus callosum, which showed a low coefficient in the ADC map: the lesion disappeared after 22 days. An enzyme immunoassay (EIA) of the serum and cerebrospinal IgM were positive for rubella virus. The patient was therefore diagnosed with rubella encephalitis. He recovered gradually and was discharged on day 19 after the onset of symptoms without any sequelae. To our knowledge, this is the first case of rubella encephalitis presenting as clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). Although the exact mechanism underlying the development of rubella encephalitis is not well established, this case indicated that our patient had an immune-mediated secondary encephalitis. According to the survey of the pandemic of rubella from 2012 to April 2013 in Japan, the incidence of rubella encephalitis is thought to be relatively higher than was previously noted. This emphasizes the importance of vaccination for preventing encephalitis. PMID- 25142542 TI - [A case of demyelinating polyneuropathy associated with anti-myelin-associated glycoprotein antibodies with progressive quadriparesis and respiratory failure]. AB - A 79-year-old man was admitted due to progressive weakness of both hands for two and a half years. Neurologically, he presented with weakness of the upper limbs, predominantly in the left distal portion, and hypoactive deep tendon reflexes. Nerve conduction studies were consistent with a motor and sensory demyelinating neuropathy. Sural nerve biopsy revealed a decrease of myelinated fibers with a predominance of larger diameter fibers. Widening of myelin lamellae and uncompacted myelin were detected on electron microscopy. Laboratory examinations showed IgM-kappa-type M-protein and anti-myelin-associated glycoprotein (MAG) antibody. He was diagnosed as having anti-MAG-associated demyelinating neuropathy based on the laboratory, electrophysiological, and pathological findings. While no bulbar symptoms or upper motor neuron signs were shown, the patient developed quadriparesis and respiratory failure after three years. Although anti-MAG associated demyelinating neuropathy is usually characterized by sensory symptoms, particularly sensory ataxia, the present case indicates that motor symptoms such as quadriparesis and respiratory failure can be among the clinical manifestations of antiMAG-associated demyelinating neuropathy. PMID- 25142543 TI - [A case of leptomeningeal melanomatosis presenting with right abducens nerve palsy]. AB - A 39 year-old man was admitted to this hospital because of severe headache and vomiting. He had been suffering from lumbago about one month previously, and diplopia ten days previously. The neurological examination revealed disturbance of right eye abduction, no nuchal rigidity. The cerebrospinal fluid (CSF) at the time of admission included erythrocytes (1,490/MUl), white blood cell (62/MUl) and increased level of protein (531 mg/dl), but no malignant cells were detected. He was treated as meningitis. Cranial magnetic resonance imaging (MRI) demonstrated heterogeneous intensity lesion in the left maxillary sinus and gadolinium enhancement of diffuse meninges and cranial nerves. Spine MRI showed gadolinium enhancement of lumbar spinal meninges and the cauda equina. Biopsy of the lesion in the left maxillary sinus was performed. The pathological findings demonstrated malignant melanoma. Because malignant cells were also observed in CSF, we diagnosed this case as leptomeningeal melanomatosis. Leptomeningeal carcinomatosis should be suspected when headache accompanied with pleomorphic clinical manifestations. PMID- 25142545 TI - [The proceedings of the 2013 Tohoku Regional Post Graduate Education Meeting]. PMID- 25142546 TI - [The proceedings of the 208th Kanto-Koshinetsu Regional Meeting of the Japanese Society of Neurology]. PMID- 25142549 TI - Forever competent: deep-sea bivalves are colonized by their chemosynthetic symbionts throughout their lifetime. AB - Symbiotic bivalves at hydrothermal vents and cold seeps host chemosynthetic bacteria intracellularly in gill cells. In bivalves, the gills grow continuously throughout their lifetime by forming new filaments. We examined how newly developed gill tissues are colonized in bivalves with horizontal and vertical symbiont transmission (Bathymodiolus mussels versus a vesicoymid clam) using fluorescence in situ hybridization and transmission electron microscopy. Symbiont colonization was similar in mussels and clams and was independent of the transmission modes. Symbionts were absent in the growth zones of the gills, indicating that symbionts colonize newly formed gill filaments de novo after they are formed and that gill colonization is a continuous process throughout the host's lifetime. Symbiont abundance and distribution suggested that colonization is shaped by the developmental stage of host cells. Self-infection, in which new gill cells are colonized by symbionts from ontogenetically older gill tissues, may also play a role. In mussels, symbiont infection led to changes in gill cell structure similar to those described from other epithelial cells infected by intracellular pathogens, such as the loss of microvilli. A better understanding of the factors that affect symbiont colonization of bivalve gills could provide new insights into interactions between intracellular bacteria and epithelial tissues. PMID- 25142550 TI - Optically decomposed near-band-edge structure and excitonic transitions in Ga2S3. AB - The band-edge structure and band gap are key parameters for a functional chalcogenide semiconductor to its applications in optoelectronics, nanoelectronics, and photonics devices. Here, we firstly demonstrate the complete study of experimental band-edge structure and excitonic transitions of monoclinic digallium trisulfide (Ga2S3) using photoluminescence (PL), thermoreflectance (TR), and optical absorption measurements at low and room temperatures. According to the experimental results of optical measurements, three band-edge transitions of EA = 3.052 eV, EB = 3.240 eV, and EC = 3.328 eV are respectively determined and they are proven to construct the main band-edge structure of Ga2S3. Distinctly optical-anisotropic behaviors by orientation- and polarization dependent TR measurements are, respectively, relevant to distinguish the origins of the EA, EB, and EC transitions. The results indicated that the three band-edge transitions are coming from different origins. Low-temperature PL results show defect emissions, bound-exciton and free-exciton luminescences in the radiation spectra of Ga2S3. The below-band-edge transitions are respectively characterized. On the basis of experimental analyses, the optical property of near-band-edge structure and excitonic transitions in the monoclinic Ga2S3 crystal is revealed. PMID- 25142555 TI - The clinical presentation of the high-mitotic-rate melanoma. PMID- 25142552 TI - Immunotherapy with B cell epitopes ameliorates inflammatory responses in Balb/c mice. AB - Osmotin, a protein from the pathogenesis-related family (PR-5), has been identified as an allergen based on in-silico and in-vitro studies. In the present study, three B cell epitopes of osmotin with single and double amino acid modifications were studied for immunotherapy in a murine model. The single modification peptides (P-1-1, P-2-1 and P-3-1) and double-modification peptides (P-1-2, P-2-2 and P-3-2) showed significantly lower immunoglobulin (Ig)E binding with patients' sera compared to osmotin (P < 0.01). These peptides showed reduced IgE binding compared to the unmodified peptides (B cell epitopes) P-1, P-2 and P 3. Among the modified peptides, P-2-1, P-3-1, P-2-2 and P-3-2 showed significant reduction in IgE binding and were used for immunotherapy in mice. The sera of mice group treated with peptides showed a significant increase in IgG2a level and a significant decrease in IgE and IgG1 levels (P < 0.05). The mice that received peptide immunotherapy showed a shift from a T helper type 2 (Th2) to Th1 type where interferon (IFN)-gamma and interleukin (IL)-10 levels were elevated, with a significant increase in groups treated with peptides P-3-1 and P-3-2 (P < 0.05). There was a reduction in the IL-4 and IL-5 levels in bronchoalveolar lavage fluid (BALF) in the peptide-treated mice groups. Total cell count and eosinophil count in BALF of the peptide-treated groups was also reduced compared to the phosphate buffered saline (PBS)-treated group. Lung histology showed a significant reduction in cellular infiltrate in mice treated with P-2-2 and P-3-2 compared to PBS. In conclusion, peptides P-2-2 and P-3-2 lowered inflammatory responses and induced a Th1 response in mice. PMID- 25142556 TI - Impact of smoking on response to systemic treatment in patients with psoriasis: a retrospective case-control study. AB - BACKGROUND: Smoking is a well-established risk factor for developing psoriasis and is associated with development of more severe disease. Smoking cessation does not appear to result in clinical improvement of psoriasis. Whether smoking in patients with psoriasis impacts response to systemic therapy is unknown. OBJECTIVES: To determine whether smokers with psoriasis with or without psoriatic arthritis respond to systemic agents as well as nonsmokers do. METHODS: We performed a retrospective review of patients with moderate-to-severe psoriasis with or without psoriatic arthritis seen at our institution, who were either active smokers or nonsmokers, and calculated changes in Physician's Global Assessment (PGA) scores after 3-16 months of systemic treatment. We also calculated the average number of systemic treatments tried per patient. RESULTS: Sixty-six patients (46 nonsmokers, 20 smokers) met our inclusion criteria. Changes in PGA scores between baseline and 3-16 months after initiation of systemic treatment did not significantly differ between smokers and nonsmokers, nor did the average number of systemic treatments tried per patient. We detected a borderline significant trend in the percentage of patients who had significant outcomes after treatment, with a higher percentage of patients smoking < 10 cigarettes daily achieving target PGA scores compared with those smoking > 10 cigarettes daily. Limitations of our study include its retrospective nature and the relatively small number of patients meeting our inclusion criteria. CONCLUSIONS: In our retrospectively studied cohort, smoking did not affect response to systemic treatment in patients with psoriasis. A prospective study examining the complex relationship between smoking, psoriasis and response to systemic therapy is warranted to explore this association better. PMID- 25142551 TI - Influence of gene flow on divergence dating - implications for the speciation history of Takydromus grass lizards. AB - Dating the time of divergence and understanding speciation processes are central to the study of the evolutionary history of organisms but are notoriously difficult. The difficulty is largely rooted in variations in the ancestral population size or in the genealogy variation across loci. To depict the speciation processes and divergence histories of three monophyletic Takydromus species endemic to Taiwan, we sequenced 20 nuclear loci and combined with one mitochondrial locus published in GenBank. They were analysed by a multispecies coalescent approach within a Bayesian framework. Divergence dating based on the gene tree approach showed high variation among loci, and the divergence was estimated at an earlier date than when derived by the species-tree approach. To test whether variations in the ancestral population size accounted for the majority of this variation, we conducted computer inferences using isolation-with migration (IM) and approximate Bayesian computation (ABC) frameworks. The results revealed that gene flow during the early stage of speciation was strongly favoured over the isolation model, and the initiation of the speciation process was far earlier than the dates estimated by gene- and species-based divergence dating. Due to their limited dispersal ability, it is suggested that geographical isolation may have played a major role in the divergence of these Takydromus species. Nevertheless, this study reveals a more complex situation and demonstrates that gene flow during the speciation process cannot be overlooked and may have a great impact on divergence dating. By using multilocus data and incorporating Bayesian coalescence approaches, we provide a more biologically realistic framework for delineating the divergence history of Takydromus. PMID- 25142557 TI - White matter integrity in obstructive sleep apnea before and after treatment. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is commonly associated with cognitive and functional deficits, some of which are resolved after continuous positive airway pressure (CPAP) treatment. The investigation of brain structural changes before and after treatment could provide deep insights into the pathogenesis and the reversibility of this disorder. We hypothesized that severe OSA patients would have altered white matter (WM) integrity and cognition and that treatment would improve both the structural damage and the cognitive impairment. DESIGN: Prospective clinical study. SETTING: The Sleep Disorders Center and the Center of Excellence in High-Field Magnetic Resonance Imaging at Vita-Salute San Raffaele University, Milan, Italy. PARTICIPANTS: Seventeen never treated consecutive OSA patients were evaluated before and after treatment (after 3 and 12 months) and compared to 15 matched healthy controls. INTERVENTION: CPAP. MEASUREMENTS: WM integrity measured by diffusion tensor imaging (DTI) and cognitive performance (measured with neuropsychological testing) before and after 3 and 12 months of CPAP. RESULTS: Results in pre-treatment OSA patients showed impairments in most cognitive areas, mood and sleepiness that were associated with diffuse reduction of WM fiber integrity reflected by diminished fractional anisotropy (FA) and mean diffusivity (MD) in multiple brain areas. After 3 months of CPAP, only limited changes of WM were found. However, over the course of 12 months CPAP treatment, an almost complete reversal of WM abnormalities in all the affected regions was observed in patients who were compliant with treatment. Significant improvements involving memory, attention, and executive-functioning paralleled WM changes after treatment. CONCLUSIONS: Changes of WM DTI "signatures" of brain pathology in OSA patients are appreciable over the course of 12-month treatment with CPAP in most of the regions involved. Recovery of cognitive deficits after treatment is consistent with the presence of a reversible structural neural injury in OSA in patients who were compliant with treatment. PMID- 25142558 TI - Slow sleep spindle activity, declarative memory, and general cognitive abilities in children. AB - STUDY OBJECTIVES: Functional interactions between sleep spindle activity, declarative memory consolidation, and general cognitive abilities in school-aged children. DESIGN: Healthy, prepubertal children (n = 63; mean age 9.56 +/- 0.76 y); ambulatory all-night polysomnography (2 nights); investigating the effect of prior learning (word pair association task; experimental night) versus nonlearning (baseline night) on sleep spindle activity; general cognitive abilities assessed using the Wechsler Intelligence Scale for Children-IV (WISC IV). MEASUREMENTS AND RESULTS: Analysis of spindle activity during nonrapid eye movement sleep (N2 and N3) evidenced predominant peaks in the slow (11-13 Hz) but not in the fast (13-15 Hz) sleep spindle frequency range (baseline and experimental night). Analyses were restricted to slow sleep spindles. Changes in spindle activity from the baseline to the experimental night were not associated with the overnight change in the number of recalled words reflecting declarative memory consolidation. Children with higher sleep spindle activity as measured at frontal, central, parietal, and occipital sites during both baseline and experimental nights exhibited higher general cognitive abilities (WISC-IV) and declarative learning efficiency (i.e., number of recalled words before and after sleep). CONCLUSIONS: Slow sleep spindles (11-13 Hz) in children age 8-11 y are associated with inter-individual differences in general cognitive abilities and learning efficiency. PMID- 25142559 TI - miRNA profiles in plasma from patients with sleep disorders reveal dysregulation of miRNAs in narcolepsy and other central hypersomnias. AB - STUDY OBJECTIVES: MicroRNAs (miRNAs) have been implicated in the pathogenesis of human diseases including neurological disorders. The aim is to address the involvement of miRNAs in the pathophysiology of central hypersomnias including autoimmune narcolepsy with cataplexy and hypocretin deficiency (type 1 narcolepsy), narcolepsy without cataplexy (type 2 narcolepsy), and idiopathic hypersomnia. DESIGN: We conducted high-throughput analysis of miRNA in plasma from three groups of patients-with type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia, respectively-in comparison with healthy controls using quantitative real-time polymerase chain reaction (qPCR) panels. SETTING: University hospital based sleep clinic and research laboratories. PATIENTS: Twelve patients with type 1 narcolepsy, 12 patients with type 2 narcolepsy, 12 patients with idiopathic hypersomnia, and 12 healthy controls. MEASUREMENTS AND RESULTS: By analyzing miRNA in plasma with qPCR we identified 50, 24, and 6 miRNAs that were different in patients with type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia, respectively, compared with healthy controls. Twenty miRNA candidates who fulfilled the criteria of at least two-fold difference and p value < 0.05 were selected to validate the miRNA changes in an independent cohort of patients. Four miRNAs differed significantly between type 1 narcolepsy patients and healthy controls. Levels of miR-30c, let-7f, and miR-26a were higher, whereas the level of miR-130a was lower in type 1 narcolepsy than healthy controls. The miRNA differences were not specific for type 1 narcolepsy, since the levels of the four miRNAs were also altered in patients with type 2 narcolepsy and idiopathic hypersomnia compared with healthy controls. CONCLUSION: The levels of four miRNAs differed in plasma from patients with type 1 narcolepsy, type 2 narcolepsy and idiopathic hypersomnia suggesting that alterations of miRNAs may be involved in the pathophysiology of central hypersomnias. PMID- 25142560 TI - Insomnia and driving ability. PMID- 25142561 TI - The "anti-inflammatory" properties of CBT-I. PMID- 25142562 TI - Is melatonin the next "new" therapy to improve sleep and reduce pain? PMID- 25142563 TI - Working with poor sleep. PMID- 25142564 TI - Impaired driving performance associated with effect of time duration in patients with primary insomnia. AB - STUDY OBJECTIVES: To evaluate driving performance and psychomotor vigilance in patients with primary insomnia. DESIGN: After 1 night of polysomnography, participants performed a 1-h simulated monotonous driving task and a psychomotor vigilance task (PVT). Self-ratings of sleepiness, mood, and driving performance were completed. SETTING: This study was conducted at the CHU of Caen Sleep Unit and the University of Caen. PARTICIPANTS: Twenty-one primary insomnia patients and 16 good sleepers. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: Results revealed a larger standard deviation of lateral position (P = 0.023) and more lane crossings (P = 0.03) in insomnia patients than in good sleepers. Analyses of effect of time on task performance showed that the impairment in patients occurred after 20 min of driving, which was not the case for good sleepers. No difference between groups was found for the PVT, neither for the mean reaction time (RT) (P = 0.43) nor the number of lapses (P = 0.21) and the mean slowest 10% 1/RT (P = 0.81). Patients rated their sleepiness level higher (P = 0.06) and their alertness level lower (P = 0.007) than did good sleepers (P = 0.007). The self-evaluation of the driving performance was not different between groups (P = 0.15). CONCLUSIONS: These findings revealed that primary insomnia is associated with a performance decrement during a simulated monotonous driving task. We also showed that patients are able to drive safely only for a short time. It appears advisable for clinicians to warn patients about their impaired driving performance that could lead to an increased risk of driving accidents. PMID- 25142565 TI - Validation of the Sonomat: a contactless monitoring system used for the diagnosis of sleep disordered breathing. AB - STUDY OBJECTIVES: To evaluate the ability of the Sonomat to diagnose obstructive sleep apnea (OSA). DESIGN: Prospective and randomized. SETTING: Sleep laboratory and home. PARTICIPANTS: 62 subjects; 54 with a clinical history of OSA and 8 normal control subjects. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Simultaneous PSG and Sonomat recordings were made in 62 subjects; 2 were excluded due to a poor nasal flow recording in PSG. There were positive correlations between the two devices for measures of sleep time, respiratory events, and the AHI (all correlations > 0.89). Bland-Altman analysis of the AHI showed positive agreement between devices, particularly at levels around common diagnostic thresholds. The mean difference in AHI values was 1.4 events per hour, and at a diagnostic threshold of 15 events per hour, sensitivity and specificity were 88% and 91%. More than 93% of PSG defined respiratory events were identified by the Sonomat and the absence of respiratory events was correctly identified in 91% of occasions. Gender, obesity, and body position did not influence the accuracy of the Sonomat. PSG snore sensors differed in how much snoring was detected when compared to the Sonomat. CONCLUSION: These data indicate that the Sonomat was reliable and accurate for the diagnosis of OSA. The provision of audible breath sound/snoring replay permits more accurate quantification of snoring. It requires no patient attachment and can be performed in the home with minimal training. PMID- 25142566 TI - A randomized controlled trial of mindfulness meditation for chronic insomnia. AB - STUDY OBJECTIVES: To evaluate the efficacy of mindfulness meditation for the treatment of chronic insomnia. DESIGN: Three-arm, single-site, randomized controlled trial. SETTING: Academic medical center. PARTICIPANTS: Fifty-four adults with chronic insomnia. INTERVENTIONS: Participants were randomized to either mindfulness-based stress reduction (MBSR), mindfulness-based therapy for insomnia (MBTI), or an eight-week self-monitoring (SM) condition. MEASUREMENTS AND RESULTS: Patient-reported outcome measures were total wake time (TWT) from sleep diaries, the pre-sleep arousal scale (PSAS), measuring a prominent waking correlate of insomnia, and the Insomnia Severity Index (ISI) to determine remission and response as clinical endpoints. Objective sleep measures were derived from laboratory polysomnography and wrist actigraphy. Linear mixed models showed that those receiving a meditation-based intervention (MBSR or MBTI) had significantly greater reductions on TWT minutes (43.75 vs 1.09), PSAS (7.13 vs 0.16), and ISI (4.56 vs 0.06) from baseline-to-post compared to SM. Post hoc analyses revealed that each intervention was superior to SM on each of the patient-reported measures, but no significant differences were found when comparing MBSR to MBTI from baseline-to-post. From baseline to 6-month follow-up, MBTI had greater reductions in ISI scores than MBSR (P < 0.05), with the largest difference occurring at the 3-month follow-up. Remission and response rates in MBTI and MBSR were sustained from post-treatment through follow-up, with MBTI showing the highest rates of treatment remission (50%) and response (78.6%) at the 6-month follow-up. CONCLUSIONS: Mindfulness meditation appears to be a viable treatment option for adults with chronic insomnia and could provide an alternative to traditional treatments for insomnia. TRIAL REGISTRATION: Mindfulness-Based Approaches to Insomnia: clinicaltrials.gov, identifier: NCT00768781. PMID- 25142567 TI - Characterization of sleep in Aplysia californica. AB - STUDY OBJECTIVE: To characterize sleep in the marine mollusk, Aplysia californica. DESIGN: Animal behavior and activity were assessed using video recordings to measure activity, resting posture, resting place preference, and behavior after rest deprivation. Latencies for behavioral responses were measured for appetitive and aversive stimuli for animals in the wake and rest states. SETTING: Circadian research laboratory for Aplysia. PATIENTS OR PARTICIPANTS: A. californica from the Pacific Ocean. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Aplysia rest almost exclusively during the night in a semi-contracted body position with preferential resting locations in the upper corners of their tank. Resting animals demonstrate longer latencies in head orientation and biting in response to a seaweed stimulus and less frequent escape response steps following an aversive salt stimulus applied to the tail compared to awake animals at the same time point. Aplysia exhibit rebound rest the day following rest deprivation during the night, but not after similar handling stimulation during the day. CONCLUSIONS: Resting behavior in Aplysia fulfills all invertebrate characteristics of sleep including: (1) a specific sleep body posture, (2) preferred resting location, (3) reversible behavioral quiescence, (4) elevated arousal thresholds for sensory stimuli during sleep, and (5) compensatory sleep rebound after sleep deprivation. PMID- 25142568 TI - Deep conservation of genes required for both Drosphila melanogaster and Caenorhabditis elegans sleep includes a role for dopaminergic signaling. AB - OBJECTIVES: Cross-species conservation of sleep-like behaviors predicts the presence of conserved molecular mechanisms underlying sleep. However, limited experimental evidence of conservation exists. Here, this prediction is tested directly. MEASUREMENTS AND RESULTS: During lethargus, Caenorhabditis elegans spontaneously sleep in short bouts that are interspersed with bouts of spontaneous locomotion. We identified 26 genes required for Drosophila melanogaster sleep. Twenty orthologous C. elegans genes were selected based on similarity. Their effect on C. elegans sleep and arousal during the last larval lethargus was assessed. The 20 most similar genes altered both the quantity of sleep and arousal thresholds. In 18 cases, the direction of change was concordant with Drosophila studies published previously. Additionally, we delineated a conserved genetic pathway by which dopamine regulates sleep and arousal. In C. elegans neurons, G-alpha S, adenylyl cyclase, and protein kinase A act downstream of D1 dopamine receptors to regulate these behaviors. Finally, a quantitative analysis of genes examined herein revealed that C. elegans arousal thresholds were directly correlated with amount of sleep during lethargus. However, bout duration varies little and was not correlated with arousal thresholds. CONCLUSIONS: The comprehensive analysis presented here suggests that conserved genes and pathways are required for sleep in invertebrates and, likely, across the entire animal kingdom. The genetic pathway delineated in this study implicates G-alpha S and previously known genes downstream of dopamine signaling in sleep. Quantitative analysis of various components of quiescence suggests that interdependent or identical cellular and molecular mechanisms are likely to regulate both arousal and sleep entry. PMID- 25142569 TI - Sleep and sickness absence: a nationally representative register-based follow-up study. AB - STUDY OBJECTIVES: We aimed to examine various sleep measures as determinants of sickness absence while considering confounders. DESIGN: Nationally representative Health 2000 Survey linked with sickness absence data from the Finnish Social Insurance Institution. SETTING: Finland. PARTICIPANTS: Working-aged women (n = 1,875) and men (n = 1,885). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Insomnia-related symptoms, early morning awakenings, being more tired during daytime than other people of same age, use of sleeping pills, excessive daytime sleepiness, probable sleep apnea (4 items about snoring/apnea), and reporting that sleep duration varies between different seasons were examined as determinants of sickness absence over a 7.2 year follow-up. Poisson and gamma regression models were fitted. After adjusting age, all examined sleep disturbances except excessive daytime sleepiness were associated with sickness absence among men (RRs 1.3-2.5). Among women, after adjusting for age, insomnia related symptoms, early morning awakenings, being more tired than others, and use of sleeping pills were associated with sickness absence (RRs 1.4-1.8). After further adjustments for education, working conditions, health behaviors, and objectively measured mental and somatic health, the associations somewhat attenuated but mainly remained. The optimal sleep duration with the lowest risk of sickness absence was 7.6 hours for women and 7.8 hours for men. Although persistence of other health problems could affect the estimates, direct costs due to sickness absence could decrease by up to 28% if sleep disturbances could be fully addressed. CONCLUSIONS: This study highlights the need for prevention of sleep disturbances and promotion of optimal sleep length to prevent sickness absence. PMID- 25142570 TI - Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD. AB - STUDY OBJECTIVES: To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS). SETTING: Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research. PATIENTS: Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000 2012). DESIGN AND INTERVENTIONS: A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P < 8.3 * 10(-3)). RLS symptoms were categorized into four groups: likely, possible, no symptoms, and unknown based on a mailed survey response. MEASUREMENTS AND RESULTS: Prevalence of PLMI >= 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI > 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5*10(-8); TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 * 10(-5); MEIS1 rs12469063(G) OR = 1.38, P = 2.0 * 10(-4); MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3*10(-2); and PTPRD(A) rs1975197 OR = 1.31, P = 6.3*10(-3). Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations. CONCLUSIONS: Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased PLM as well, although some loci may have more effects on one versus the other phenotype. PMID- 25142571 TI - Cognitive behavioral therapy vs. Tai Chi for late life insomnia and inflammatory risk: a randomized controlled comparative efficacy trial. AB - STUDY OBJECTIVES: To investigate the comparative efficacy of cognitive behavioral therapy (CBT), Tai Chi Chih (TCC), and sleep seminar education control (SS) on the primary outcome of insomnia diagnosis, and secondary outcomes of sleep quality, fatigue, depressive symptoms, and inflammation in older adults with insomnia. DESIGN: Randomized controlled, comparative efficacy trial. SETTING: Los Angeles community. PATIENTS: 123 older adults with chronic and primary insomnia. INTERVENTIONS: Random assignment to CBT, TCC, or SS for 2-hour group sessions weekly over 4 months with follow-up at 7 and 16 months. MEASUREMENTS: Insomnia diagnosis, patient-reported outcomes, polysomnography (PSG), and high-sensitivity C-reactive protein (CRP) levels. RESULTS: CBT performed better than TCC and SS in remission of clinical insomnia as ascertained by a clinician (P < 0.01), and also showed greater and more sustained improvement in sleep quality, sleep parameters, fatigue, and depressive symptoms than TCC and SS (all P values < 0.01). As compared to SS, CBT was associated with a reduced risk of high CRP levels (> 3.0 mg/L) at 16 months (odds ratio [OR], 0.26 [95% CI, 0.07-0.97] P < 0.05). Remission of insomnia was associated with lower levels of CRP (P < 0.05) at 16 months. TCC was associated with improvements in sleep quality, fatigue, and depressive symptoms as compared to SS (all P's < 0.05), but not insomnia remission. PSG measures did not change. CONCLUSIONS: Treatment of late-life insomnia is better achieved and sustained by cognitive behavioral therapies. Insomnia treatment and remission reduces a marker of inflammatory risk, which has implications for cardiovascular morbidity and diabetes observed with sleep disturbance in epidemiologic surveys. PMID- 25142572 TI - Sleep deprivation aggravates median nerve injury-induced neuropathic pain and enhances microglial activation by suppressing melatonin secretion. AB - STUDY OBJECTIVES: Sleep deprivation is common in patients with neuropathic pain, but the effect of sleep deprivation on pathological pain remains uncertain. This study investigated whether sleep deprivation aggravates neuropathic symptoms and enhances microglial activation in the cuneate nucleus (CN) in a median nerve chronic constriction injury (CCI) model. Also, we assessed if melatonin supplements during the sleep deprived period attenuates these effects. DESIGN: Rats were subjected to sleep deprivation for 3 days by the disc-on-water method either before or after CCI. In the melatonin treatment group, CCI rats received melatonin supplements at doses of 37.5, 75, 150, or 300 mg/kg during sleep deprivation. Melatonin was administered at 23:00 once a day. PARTICIPANTS: Male Sprague-Dawley rats, weighing 180-250 g (n = 190), were used. MEASUREMENTS: Seven days after CCI, behavioral testing was conducted, and immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay were used for qualitative and quantitative analyses of microglial activation and measurements of proinflammatory cytokines. RESULTS: In rats who underwent post-CCI sleep deprivation, microglia were more profoundly activated and neuropathic pain was worse than those receiving pre-CCI sleep deprivation. During the sleep deprived period, serum melatonin levels were low over the 24-h period. Administration of melatonin to CCI rats with sleep deprivation significantly attenuated activation of microglia and development of neuropathic pain, and markedly decreased concentrations of proinflammatory cytokines. CONCLUSIONS: Sleep deprivation makes rats more vulnerable to nerve injury-induced neuropathic pain, probably because of associated lower melatonin levels. Melatonin supplements to restore a circadian variation in melatonin concentrations during the sleep deprived period could alleviate nerve injury-induced behavioral hypersensitivity. PMID- 25142573 TI - Genetic rescue of functional senescence in synaptic and behavioral plasticity. AB - STUDY OBJECTIVES: Aging has been linked with decreased neural plasticity and memory formation in humans and in laboratory model species such as the fruit fly, Drosophila melanogaster. Here, we examine plastic responses following social experience in Drosophila as a high-throughput method to identify interventions that prevent these impairments. PATIENTS OR PARTICIPANTS: Wild-type and transgenic Drosophila melanogaster. DESIGN AND INTERVENTIONS: Young (5-day old) or aged (20-day old) adult female Drosophila were housed in socially enriched (n = 35-40) or isolated environments, then assayed for changes in sleep and for structural markers of synaptic terminal growth in the ventral lateral neurons (LNVs) of the circadian clock. MEASUREMENTS AND RESULTS: When young flies are housed in a socially enriched environment, they exhibit synaptic elaboration within a component of the circadian circuitry, the LNVs, which is followed by increased sleep. Aged flies, however, no longer exhibit either of these plastic changes. Because of the tight correlation between neural plasticity and ensuing increases in sleep, we use sleep after enrichment as a high-throughput marker for neural plasticity to identify interventions that prolong youthful plasticity in aged flies. To validate this strategy, we find three independent genetic manipulations that delay age-related losses in plasticity: (1) elevation of dopaminergic signaling, (2) over-expression of the transcription factor blistered (bs) in the LNVs, and (3) reduction of the Imd immune signaling pathway. These findings provide proof-of-principle evidence that measuring changes in sleep in flies after social enrichment may provide a highly scalable assay for the study of age-related deficits in synaptic plasticity. CONCLUSIONS: These studies demonstrate that Drosophila provides a promising model for the study of age related loss of neural plasticity and begin to identify genes that might be manipulated to delay the onset of functional senescence. PMID- 25142575 TI - General practitioners using complementary and alternative medicine differ from general practitioners using conventional medicine in their view of the risks of electromagnetic fields: a postal survey from Germany. AB - OBJECTIVE: General practitioners (GPs) play a key role in consulting patients worried about health effects of electromagnetic fields (EMF). We compared GPs using conventional medicine (COM) with GPs using complementary and alternative medicine (CAM) concerning their perception of EMF risks. Moreover, we assessed whether the kind of alternative medicine has an influence on the results. METHODS: A total of 2795 GPs drawn randomly from lists of German GPs were sent an either long or short self-administered postal questionnaire on EMF-related topics. Adjusted logistic regression models were fitted to assess the association of an education in alternative medicine with various aspects of perceiving EMF risks. RESULTS: Concern about EMF, misconceptions about EMF, and distrust toward scientific organizations are more prevalent in CAM-GPs. CAM-GPs more often falsely believed that mobile phone use can lead to head warming of more than 1 degrees C (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.5-3.3), more often distrusted the Federal Office for Radiation Protection (OR = 2.2, 95% CI = 1.4-3.6), were more often concerned about mobile phone base stations (OR = 2.4, 95% CI = 1.6-3.6), more often attributed own health complaints to EMF (OR = 3.2, 95% CI = 1.8-5.6), and more often reported at least 1 EMF consultation (OR = 2.5, 95% CI = 1.6-3.9). GPs using homeopathy perceived EMF as more risky than GPs using acupuncture or naturopathic treatment. CONCLUSION: Concern about common EMF sources is highly prevalent among German GPs. CAM-GPs perceive stronger associations between EMF and health problems than COM-GPs. There is a need for evidence-based information about EMF risks for GPs and particularly for CAM-GPs. This is the precondition that GPs can inform patients about EMF and health in line with current scientific knowledge. PMID- 25142574 TI - In utero exposure to valproic acid changes sleep in juvenile rats: a model for sleep disturbances in autism. AB - STUDY OBJECTIVES: To determine whether sleep disturbances are found in the valproic acid model of autism spectrum disorders (ASD). DESIGN: Comparative study for sleep behavior, sleep architecture, electroencephalogram (EEG) spectral analysis, and glutamic acid decarboxylase (GAD) 65/67 protein expression in juvenile rats exposed to valproic acid (VPA), sodium salt, or saline in utero. SETTING: N/A. PARTICIPANTS: Juvenile (postnatal day 32) male and female Sprague Dawley rats. INTERVENTIONS: In utero exposure to either saline or 400 mg/kg VPA administered intraperitoneally to the dams on gestational day 12.5. On postnatal days 22-24, all rats were implanted with transmitters to record EEG and electromyogram (EMG) activity. MEASUREMENTS AND RESULTS: During the light phase, when nocturnal animals are typically quiescent, the VPA-exposed animals spent significantly more time in wake (~35 min) and significantly less time in non rapid eye movement (NREM) sleep (~26 min) compared to the saline controls. Furthermore, spectral analysis of the EEG revelled that VPA-exposed animals exhibited increased high-frequency activity during wake and rapid eye movement (REM) sleep and reduced theta power across all vigilance states. Interestingly, the gamma-aminobutyric acid (GABA)-ergic system, which modulates the induction and maintenance of sleep states, was also disrupted, with reduced levels of both GAD 65 and GAD67 in the cortical tissue of VPA-exposed animals compared to saline controls. CONCLUSIONS: To date, the current animal models of ASD have been underutilized in the investigation of associated sleep disturbances. The VPA animal model recapitulates aspects of sleep disruptions reported clinically, providing a tool to investigate cellular and molecular dysregulation contributing to sleep disruptions in ASD. PMID- 25142576 TI - Which adenomas are detected by fecal occult blood testing? A state-wide analysis from Bavaria, Germany. AB - Guaiac-based fecal occult blood tests (gFOBTs) are the most widely used noninvasive tests for colorectal cancer screening. While it is well known that they detect only a minority of colorectal adenomas, evidence for the characteristics of adenomas associated with detection is sparse. We derived estimates of the positive likelihood ratio (LR+), a summary measure of diagnostic performance, according to adenoma characteristics by comparing findings at colonoscopy among 19,208 and 181,128 participants who underwent colonoscopy to follow-up a positive gFOBT and as a primary screening examination, respectively, in Bavaria, Germany, in 2007-2009. Age and sex-adjusted estimates of LR+ (95% confidence intervals, 95% CI) ranged from 1.09 (1.05-1.13) for adenomas <1 cm to 2.52 (2.30-2.75) for adenomas >2 cm, and were much higher for pedunculated adenomas (1.96, 95% CI 1.85-2.08) than for flat or sessile adenomas (1.11, 95% CI 1.02-1.21 and 1.12, 95% CI 1.08-1.16, respectively). Villous or tubulovillous structure and dysplasia were likewise associated with a higher chance to be detected by gFOBT. Diagnostic performance was worse for proximal than for distal adenomas (age and sex adjusted LR+:1.16, 95% CI 1.09-1.23 and 1.35, 95% CI 1.29 1.41, respectively) which was explained by the lower proportions of large, pedunculated and nontubular adenomas in the proximal colon. Size, pedunculated shape, and nontubular histology are the key determinants of detection which also explain lower detection rates of adenomas located in the proximal colon. PMID- 25142577 TI - Indication criteria and outcomes with the Bonebridge transcutaneous bone conduction implant. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to evaluate functional hearing gain, speech understanding, and preoperative bone-conduction thresholds with the bone-conduction implant Bonebridge. STUDY DESIGN: Retrospective study at a tertiary referral center. METHODS: Twenty-four consecutive Bonebridge patients were identified. Nine patients suffered from combined hearing loss (HL), 12 from atresia of the external auditory canal and three from single-sided deafness. One patient was lost to follow-up. Twenty-three patients were therefore analyzed. RESULTS: The overall average functional hearing gain of all patients (n = 23) was 28.8 dB (+/-16.1 standard deviation [SD]). Monosyllabic word scores at 65 dB sound pressure level in quiet increased statistically significantly from 4.6 (+/ 7.4 SD) percentage points to 53.7 (+/-23.0 SD) percentage points. Evaluation of preoperative bone-conduction thresholds revealed three patients with thresholds higher than 45 dB HL in the high frequencies starting at 2 kHz. These three patients had a very limited benefit of their bone-conduction implants. CONCLUSIONS: The Bonebridge bone-conduction implant provides satisfactory results concerning functional gain and speech perception if preoperative bone conduction lies within 45 dB HL. LEVEL OF EVIDENCE: 4. PMID- 25142578 TI - Chlorovirus PBCV-1 encodes an active copper-zinc superoxide dismutase. AB - Superoxide dismutases (SODs) are metalloproteins that protect organisms from toxic reactive oxygen species by catalyzing the conversion of superoxide anion to hydrogen peroxide and molecular oxygen. Chlorovirus PBCV-1 encodes a 187-amino acid protein that resembles a Cu-Zn SOD with all of the conserved amino acid residues for binding copper and zinc (named cvSOD). cvSOD has an internal Met that results in a 165-amino-acid protein (named tcvSOD). Both cvSOD and tcvSOD recombinant proteins inhibited nitroblue tetrazolium reduction of superoxide anion generated in a xanthine-xanthine oxidase system in solution. tcvSOD was chosen for further characterization because it was easier to produce. Recombinant tcvSOD also inhibited a riboflavin photochemical reduction system in a polyacrylamide gel assay, which was blocked by the Cu-Zn SOD inhibitor cyanide but not by azide, which inhibits Fe and Mn SODs. A k(cat)/K(m) value for cvSOD was determined by stop-flow spectrophotometry as 1.28 * 10(8) M(-1) s(-1), suggesting that cvSOD-catalyzed O2 (-) dismutation was not a diffusion controlled encounter. The cvsod gene was expressed as a late gene, and cvSOD activity was detected in purified virions. Superoxide accumulated rapidly during virus infection, and circumstantial evidence indicates that cvSOD aids its decomposition to benefit virus replication. Cu-Zn SOD homologs have been described to occur in 3 other families of large DNA viruses, poxviruses, baculoviruses, and mimiviruses, which group as a clade. Interestingly, cvSOD does not group in the same clade as the other virus SODs but instead groups in an expanded clade that includes Cu-Zn SODs from many cellular organisms. IMPORTANCE: Virus infection often leads to an increase in toxic reactive oxygen species in the host, which can be detrimental to virus replication. Viruses have developed various ways to overcome this barrier. As reported in this article, the chloroviruses often encode and package a functional Cu-Zn superoxide dismutase in the virion that presumably lowers the concentration of reactive oxygen induced early during virus infection. PMID- 25142579 TI - Influenza A virus polymerase is a site for adaptive changes during experimental evolution in bat cells. AB - The recent identification of highly divergent influenza A viruses in bats revealed a new, geographically dispersed viral reservoir. To investigate the molecular mechanisms of host-restricted viral tropism and the potential for transmission of viruses between humans and bats, we exposed a panel of cell lines from bats of diverse species to a prototypical human-origin influenza A virus. All of the tested bat cell lines were susceptible to influenza A virus infection. Experimental evolution of human and avian-like viruses in bat cells resulted in efficient replication and created highly cytopathic variants. Deep sequencing of adapted human influenza A virus revealed a mutation in the PA polymerase subunit not previously described, M285K. Recombinant virus with the PA M285K mutation completely phenocopied the adapted virus. Adaptation of an avian virus-like virus resulted in the canonical PB2 E627K mutation that is required for efficient replication in other mammals. None of the adaptive mutations occurred in the gene for viral hemagglutinin, a gene that frequently acquires changes to recognize host-specific variations in sialic acid receptors. We showed that human influenza A virus uses canonical sialic acid receptors to infect bat cells, even though bat influenza A viruses do not appear to use these receptors for virus entry. Our results demonstrate that bats are unique hosts that select for both a novel mutation and a well-known adaptive mutation in the viral polymerase to support replication. IMPORTANCE: Bats constitute well-known reservoirs for viruses that may be transferred into human populations, sometimes with fatal consequences. Influenza A viruses have recently been identified in bats, dramatically expanding the known host range of this virus. Here we investigated the replication of human influenza A virus in bat cell lines and the barriers that the virus faces in this new host. Human influenza A and B viruses infected cells from geographically and evolutionarily diverse New and Old World bats. Viruses mutated during infections in bat cells, resulting in increased replication and cytopathic effects. These mutations were mapped to the viral polymerase and shown to be solely responsible for adaptation to bat cells. Our data suggest that replication of human influenza A viruses in a nonnative host drives the evolution of new variants and may be an important source of genetic diversity. PMID- 25142580 TI - Recombinant adeno-associated virus utilizes cell-specific infectious entry mechanisms. AB - Understanding the entry and trafficking mechanism(s) of recombinant adeno associated virus (rAAV) into host cells can lead to evolution in capsid and vector design and delivery methods, resulting in enhanced transduction and therapeutic gene expression. Variability of findings regarding the early entry pathway of rAAV supports the possibility that rAAV, like other viruses, can utilize more than one infectious entry pathway. We tested whether inhibition of macropinocytosis impacted rAAV transduction of HeLa cells compared to hepatocellular carcinoma cell lines. We found that macropinocytosis inhibitor cytochalasin D blocked rAAV transduction of HeLa cells (>2-fold) but enhanced (10 fold) transduction in HepG2 and Huh7 lines. Similar results were obtained with another macropinocytosis inhibitor, 5-(N-ethyl-N-isopropyl) amiloride (EIPA). The augmented transduction was due to neither viral binding nor promoter activity, affected multiple rAAV serotypes (rAAV2, rAAV2-R585E, and rAAV8), and influenced single-stranded and self-complementary virions to comparable extents. Follow-up studies using CDC42 inhibitor ML141 and p21-activated kinase 1 (PAK1) siRNA knockdown also resulted in enhanced HepG2 transduction. Microscopy revealed that macropinocytosis inhibition correlated with expedited nuclear entry of the rAAV virions into HepG2 cells. Enhancement of hepatocellular rAAV transduction extended to the mouse liver in vivo (4-fold enhancement) but inversely blocked heart tissue transduction (13-fold). This evidence of host cell-specific rAAV entry pathways confers a potent means for controlling and enhancing vector delivery and could help unify the divergent accounts of rAAV cellular entry mechanisms. IMPORTANCE: There is a recognized need for improved rAAV vector targeting strategies that result in delivery of fewer total particles, averting untoward toxicity and/or an immune response against the vector. A critical step in rAAV transduction is entry and early trafficking through the host cellular machinery, the mechanisms of which are under continued study. However, should the early entry and trafficking mechanisms of rAAV differ across virus serotype or be dependent on host cell environment, this could expand our ability to target particular cells and tissue for selective transduction. Thus, the observation that inhibiting macropinocytosis leads to cell-specific enhancement or inhibition of rAAV transduction that extends to the organismic level exposes a new means of modulating vector targeting. PMID- 25142581 TI - Immunogenicity studies of proteins forming the T4 phage head surface. AB - Advances in phage therapy and novel applications of phages in biotechnology encourage interest in phage impact on human and animal immunity. Here we present comparative studies of immunogenic properties of T4 phage head surface proteins gp23*, gp24*, Hoc, and Soc, both as elements of the phage capsid and as isolated agents. Studies comprise evaluation of specific antibodies in the human population, analysis of the proteins' impact on the primary and secondary responses in mice, and the effect of specific antibodies on phage antibacterial activity in vitro and in vivo in mice. In humans, natural antibodies specific to T4-like phages were abundant (81% of investigated sera). Among those, significantly elevated levels of IgG antibodies only against major head protein (gp23*) were found, which probably reflected cross-reactions of T4 with antibodies induced by other T4-like phages. Both IgM and IgG antibodies were induced mostly by gp23* and Hoc, while weak (gp24*) and very weak (Soc) reactivities of other head proteins were noticed. Thus, T4 head proteins that markedly contribute to immunological memory to the phage are highly antigenic outer capsid protein (Hoc) and major capsid protein (gp23*). Specific anti-gp23* and anti-Hoc antibodies substantially decreased T4 phage activity in vitro and to some extent in vivo. Cooperating with antibodies, the immune complement system also contributed to annihilating phages. IMPORTANCE: Current descriptions of phage immunogenicity and its biological consequences are still vague and incomplete; thus, the central problem of this work is timely and may have strong practical implications. Here is presented the very first description of the contribution of bacteriophage proteins to immunological memory of the phage. Understanding of interactions between phages and mammalian immunology may help in biotechnological adaptations of phages for therapeutic requirements as well as for better appreciation of phage ecology and their role in the biosphere. PMID- 25142582 TI - Catalytic function and substrate specificity of the papain-like protease domain of nsp3 from the Middle East respiratory syndrome coronavirus. AB - The papain-like protease (PLpro) domain from the deadly Middle East respiratory syndrome coronavirus (MERS-CoV) was overexpressed and purified. MERS-CoV PLpro constructs with and without the putative ubiquitin-like (UBL) domain at the N terminus were found to possess protease, deubiquitinating, deISGylating, and interferon antagonism activities in transfected HEK293T cells. The quaternary structure and substrate preferences of MERS-CoV PLpro were determined and compared to those of severe acute respiratory syndrome coronavirus (SARS-CoV) PLpro, revealing prominent differences between these closely related enzymes. Steady-state kinetic analyses of purified MERS-CoV and SARS-CoV PLpros uncovered significant differences in their rates of hydrolysis of 5-aminomethyl coumarin (AMC) from C-terminally labeled peptide, ubiquitin, and ISG15 substrates, as well as in their rates of isopeptide bond cleavage of K48- and K63-linked polyubiquitin chains. MERS-CoV PLpro was found to have 8-fold and 3,500-fold higher catalytic efficiencies for hydrolysis of ISG15-AMC than for hydrolysis of the Ub-AMC and Z-RLRGG-AMC substrates, respectively. A similar trend was observed for SARS-CoV PLpro, although it was much more efficient than MERS-CoV PLpro toward ISG15-AMC and peptide-AMC substrates. MERS-CoV PLpro was found to process K48- and K63-linked polyubiquitin chains at similar rates and with similar debranching patterns, producing monoubiquitin species. However, SARS-CoV PLpro much preferred K48-linked polyubiquitin chains to K63-linked chains, and it rapidly produced di-ubiquitin molecules from K48-linked chains. Finally, potent inhibitors of SARS-CoV PLpro were found to have no effect on MERS-CoV PLpro. A homology model of the MERS-CoV PLpro structure was generated and compared to the X-ray structure of SARS-CoV PLpro to provide plausible explanations for differences in substrate and inhibitor recognition. IMPORTANCE: Unlocking the secrets of how coronavirus (CoV) papain-like proteases (PLpros) perform their multifunctional roles during viral replication entails a complete mechanistic understanding of their substrate recognition and enzymatic activities. We show that the PLpro domains from the MERS and SARS coronaviruses can recognize and process the same substrates, but with different catalytic efficiencies. The differences in substrate recognition between these closely related PLpros suggest that neither enzyme can be used as a generalized model to explain the kinetic behavior of all CoV PLpros. As a consequence, decoding the mechanisms of PLpro mediated antagonism of the host innate immune response and the development of anti-CoV PLpro enzyme inhibitors will be a challenging undertaking. The results from this study provide valuable information for understanding how MERS-CoV PLpro mediated antagonism of the host innate immune response is orchestrated, as well as insight into the design of inhibitors against MERS-CoV PLpro. PMID- 25142583 TI - Cellular requirements for bovine immunodeficiency virus Vif-mediated inactivation of bovine APOBEC3 proteins. AB - Human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) viral infectivity factor (Vif) form a CRL5 E3 ubiquitin ligase complex to suppress virus restriction by host APOBEC3 (A3) proteins. The primate lentiviral Vif complex is composed of the unique cofactor core binding factor beta (CBF beta) and canonical ligase components Cullin 5 (CUL5), Elongin B/C (ELOB/C), and RBX2. However, the mechanism by which the Vif protein of the related lentivirus bovine immunodeficiency virus (BIV) overcomes its host A3 proteins is less clear. In this study, we show that BIV Vif interacts with Cullin 2 (CUL2), ELOB/C, and RBX1, but not with CBF-beta or CUL5, to form a CRL2 E3 ubiquitin ligase and degrade the restrictive bovine A3 proteins (A3Z2Z3 and A3Z3). RNA interference mediated knockdown of ELOB or CUL2 inhibited BIV Vif-mediated degradation of these A3 proteins, whereas knockdown of CUL5 or CBF-beta did not. BIV Vif with mutations in the BC box (Vif SLQ-AAA) or putative VHL box (Vif YI-AA), which cannot interact with ELOB/C or CUL2, respectively, lost the ability to counteract bovine A3 proteins. Moreover, CUL2 and UBE2M dominant negative mutants competitively inhibited the BIV Vif-mediated degradation mechanism. Thus, although the general strategy for inhibiting A3 proteins is conserved between HIV 1/SIV and BIV, the precise mechanisms can differ substantially, with only the HIV 1/SIV Vif proteins requiring CBF-beta as a cofactor, HIV-1/SIV Vif using CUL5 RBX2, and BIV Vif using CUL2-RBX1. IMPORTANCE: Primate lentivirus HIV-1 and SIV Vif proteins form a ubiquitin ligase complex to target host antiviral APOBEC3 proteins for degradation. However, the mechanism by which the nonprimate lentivirus BIV Vif inhibits bovine APOBEC3 proteins is unclear. In the present study, we determined the mechanism for BIV Vif-mediated degradation of bovine APOBEC3 proteins and found that it differs from the mechanism of HIV-1/SIV Vif by being CBF-beta independent and requiring different ubiquitin ligase scaffolding proteins (CUL2-RBX1 instead of CUL5-RBX2). BIV Vif is the only known retroviral protein that can interact with CUL2. This information broadens our understanding of the distinct mechanisms by which the Vif proteins of different lentiviruses facilitate viral infection. This novel mechanism for assembly of the BIV Vif APOBEC3 ubiquitin ligase complex advances our understanding of viral hijacking of host E3 ubiquitin ligases and illustrates the evolutionary flexibility of lentiviruses. PMID- 25142584 TI - Sapovirus translation requires an interaction between VPg and the cap binding protein eIF4E. AB - Sapoviruses of the Caliciviridae family of small RNA viruses are emerging pathogens that cause gastroenteritis in humans and animals. Molecular studies on human sapovirus have been hampered due to the lack of a cell culture system. In contrast, porcine sapovirus (PSaV) can be grown in cell culture, making it a suitable model for understanding the infectious cycle of sapoviruses and the related enteric caliciviruses. Caliciviruses are known to use a novel mechanism of protein synthesis that relies on the interaction of cellular translation initiation factors with the virus genome-encoded viral protein genome (VPg) protein, which is covalently linked to the 5' end of the viral genome. Using PSaV as a representative member of the Sapovirus genus, we characterized the role of the viral VPg protein in sapovirus translation. As observed for other caliciviruses, the PSaV genome was found to be covalently linked to VPg, and this linkage was required for the translation and the infectivity of viral RNA. The PSaV VPg protein was associated with the 4F subunit of the eukaryotic translation initiation factor (eIF4F) complex in infected cells and bound directly to the eIF4E protein. As has been previously demonstrated for feline calicivirus, a member of the Vesivirus genus, PSaV translation required eIF4E and the interaction between eIF4E and eIF4G. Overall, our study provides new insights into the novel mechanism of sapovirus translation, suggesting that sapovirus VPg can hijack the cellular translation initiation mechanism by recruiting the eIF4F complex through a direct eIF4E interaction. IMPORTANCE: Sapoviruses, which are members of the Caliciviridae family, are one of the causative agents of viral gastroenteritis in humans. However, human sapovirus remains noncultivable in cell culture, hampering the ability to characterize the virus infectious cycle. Here, we show that the VPg protein from porcine sapovirus, the only cultivatable sapovirus, is essential for viral translation and functions via a direct interaction with the cellular translation initiation factor eIF4E. This work provides new insights into the novel protein-primed mechanism of calicivirus VPg dependent translation initiation. PMID- 25142585 TI - Multiple groups of endogenous epsilon-like retroviruses conserved across primates. AB - Several types of cancer in fish are caused by retroviruses, including those responsible for major outbreaks of disease, such as walleye dermal sarcoma virus and salmon swim bladder sarcoma virus. These viruses form a phylogenetic group often described as the epsilonretrovirus genus. Epsilon-like retroviruses have become endogenous retroviruses (ERVs) on several occasions, integrating into germ line cells to become part of the host genome, and sections of fish and amphibian genomes are derived from epsilon-like retroviruses. However, epsilon-like ERVs have been identified in very few mammals. We have developed a pipeline to screen full genomes for ERVs, and using this pipeline, we have located over 800 endogenous epsilon-like ERV fragments in primate genomes. Genomes from 32 species of mammals and birds were screened, and epsilon-like ERV fragments were found in all primate and tree shrew genomes but no others. These viruses appear to have entered the genome of a common ancestor of Old and New World monkeys between 42 million and 65 million years ago. Based on these results, there is an ancient evolutionary relationship between epsilon-like retroviruses and primates. Clearly, these viruses had the potential to infect the ancestors of primates and were at some point a common pathogen in these hosts. Therefore, this result raises questions about the potential of epsilonretroviruses to infect humans and other primates and about the evolutionary history of these retroviruses. IMPORTANCE: Epsilonretroviruses are a group of retroviruses that cause several important diseases in fish. Retroviruses have the ability to become a permanent part of the DNA of their host by entering the germ line as endogenous retroviruses (ERVs), where they lose their infectivity over time but can be recognized as retroviruses for millions of years. Very few mammals are known to have epsilon-like ERVs; however, we have identified over 800 fragments of endogenous epsilon-like ERVs in the genomes of all major groups of primates, including humans. These viruses seem to have circulated and infected primate ancestors 42 to 65 million years ago. We are now interested in how these viruses have evolved and whether they have the potential to infect modern humans or other primates. PMID- 25142586 TI - Gammaherpesvirus latency differentially impacts the generation of primary versus secondary memory CD8+ T cells during subsequent infection. AB - Unlike laboratory animals, humans are infected with multiple pathogens, including the highly prevalent herpesviruses. The purpose of these studies was to determine the effect of gammaherpesvirus latency on T cell number and differentiation during subsequent heterologous viral infections. Mice were first infected with murine gammaherpesvirus 68 (MHV68), a model of Epstein-Barr virus (EBV) infection, and then after latency was established, they were challenged with the Armstrong strain of lymphocytic choriomeningitis virus (LCMV). The initial replication of LCMV was lower in latently infected mice, and the maturation of dendritic cells was abated. Although the number of LCMV-specific effector CD8(+) T cells was not altered, they were skewed to a memory phenotype. In contrast, LCMV-specific effector CD4(+) T cells were increased in latently infected mice compared to those in mice infected solely with LCMV. When the memory phase was reached, latently infected mice had an LCMV-specific memory T cell pool that was increased relative to that found in singly infected mice. Importantly, LCMV specific memory CD8(+) T cells had decreased CD27 and increased killer cell lectin-like receptor G1 (KLRG1) expression. Upon secondary challenge, LCMV specific secondary effector CD8(+) T cells expanded and cleared the infection. However, the LCMV-specific secondary memory CD8(+) T cell pool was decreased in latently infected animals, abrogating the boosting effect normally observed following rechallenge. Taken together, these results demonstrate that ongoing gammaherpesvirus latency affects the number and phenotype of primary versus secondary memory CD8(+) T cells during acute infection. IMPORTANCE: CD8(+) T cells are critical for the clearance of intracellular pathogens, including viruses, certain bacteria, and tumors. However, current models for memory CD8(+) T cell differentiation are derived from pathogen-free laboratory mice challenged with a single pathogen or vaccine vector. Unlike laboratory animals, all humans are infected with multiple acute and chronic pathogens, including the highly prevalent herpesviruses Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex viruses (HSV), and varicella-zoster virus (VZV). The purpose of these studies was to determine the effect of gammaherpesvirus latency on T cell number and differentiation during subsequent heterologous viral infections. We observed that ongoing gammaherpesvirus latency affects the number and phenotype of primary versus secondary memory CD8(+) T cells during acute infection. These results suggest that unlike pathogen-free laboratory mice, infection or immunization of latently infected humans may result in the generation of T cells with limited potential for long-term protection. PMID- 25142587 TI - Human papillomavirus type 1 E1^E4 protein is a potent inhibitor of the serine arginine (SR) protein kinase SRPK1 and inhibits phosphorylation of host SR proteins and of the viral transcription and replication regulator E2. AB - The serine-arginine-specific protein kinase SRPK1 is a common binding partner of the E1^E4 protein of diverse human papillomavirus types. We show here for the first time that the interaction between HPV1 E1^E4 and SRPK1 leads to potent inhibition of SRPK1 phosphorylation of host serine-arginine (SR) proteins that have critical roles in mRNA metabolism, including pre-mRNA processing, mRNA export, and translation. Furthermore, we show that SRPK1 phosphorylates serine residues of SR/RS dipeptides in the hinge region of the HPV1 E2 protein in in vitro kinase assays and that HPV1 E1^E4 inhibits this phosphorylation. After mutation of the putative phosphoacceptor serine residues, the localization of the E2 protein was altered in primary human keratinocytes; with a significant increase in the cell population showing intense E2 staining of the nucleolus. A similar effect was observed following coexpression of E2 and E1^E4 that is competent for inhibition of SRPK1 activity, suggesting that the nuclear localization of E2 is sensitive to E1^E4-mediated SRPK1 inhibition. Collectively, these data suggest that E1^E4-mediated inhibition of SRPK1 could affect the functions of host SR proteins and those of the virus transcription/replication regulator E2. We speculate that the novel E4 function identified here is involved in the regulation of E2 and SR protein function in posttranscriptional processing of viral transcripts. IMPORTANCE: The HPV life cycle is tightly linked to the epithelial terminal differentiation program, with the virion-producing phase restricted to differentiating cells. While the most abundant HPV protein expressed in this phase is the E4 protein, we do not fully understand the role of this protein. Few E4 interaction partners have been identified, but we had previously shown that E4 proteins from diverse papillomaviruses interact with the serine-arginine-specific protein kinase SRPK1, a kinase important in the replication cycles of a diverse range of DNA and RNA viruses. We show that HPV1 E4 is a potent inhibitor of this host cell kinase. We show that E4 inhibits SRPK1 phosphorylation, not only of cellular SR proteins involved in regulating alternative splicing of RNA but also the viral transcription/replication regulator E2. Our findings reveal a potential E4 function in regulation of viral late gene expression through the inhibition of a host cell kinase. PMID- 25142588 TI - APOBEC3F determinants of HIV-1 Vif sensitivity. AB - HIV-1 Vif counteracts restrictive APOBEC3 proteins by targeting them for proteasomal degradation. To determine the regions mediating sensitivity to Vif, we compared human APOBEC3F, which is HIV-1 Vif sensitive, with rhesus APOBEC3F, which is HIV-1 Vif resistant. Rhesus-human APOBEC3F chimeras and amino acid substitution mutants were tested for sensitivity to HIV-1 Vif. This approach identified the alpha3 and alpha4 helices of human APOBEC3F as important determinants of the interaction with HIV-1 Vif. PMID- 25142589 TI - Trafficking of bluetongue virus visualized by recovery of tetracysteine-tagged virion particles. AB - Bluetongue virus (BTV), a member of the Orbivirus genus in the Reoviridae family, is a double-capsid insect-borne virus enclosing a genome of 10 double-stranded RNA segments. Like those of other members of the family, BTV virions are nonenveloped particles containing two architecturally complex capsids. The two proteins of the outer capsid, VP2 and VP5, are involved in BTV entry and in the delivery of the transcriptionally active core to the cell cytoplasm. Although the importance of the endocytic pathway in BTV entry has been reported, detailed analyses of entry and the role of each protein in virus trafficking have not been possible due to the lack of availability of a tagged virus. Here, for the first time, we report on the successful manipulation of a segmented genome of a nonenveloped capsid virus by the introduction of tags that were subsequently fluorescently visualized in infected cells. The genetically engineered fluorescent BTV particles were observed to enter live cells immediately after virus adsorption. Further, we showed the separation of VP2 from VP5 during virus entry and confirmed that while VP2 is shed from virions in early endosomes, virus particles still consisting of VP5 were trafficked sequentially from early to late endosomes. Since BTV infects both mammalian and insect cells, the generation of tagged viruses will allow visualization of the trafficking of BTV farther downstream in different host cells. In addition, the tagging technology has potential for transferable application to other nonenveloped complex viruses. IMPORTANCE: Live-virus trafficking in host cells has been highly informative on the interactions between virus and host cells. Although the insertion of fluorescent markers into viral genomes has made it possible to study the trafficking of enveloped viruses, the physical constraints of architecturally complex capsid viruses have imposed practical limitations. In this study, we have successfully genetically engineered the segmented RNA genome of bluetongue virus (BTV), a complex nonenveloped virus belonging to the Reoviridae family. The resulting fluorescent virus particles could be visualized in virus entry studies of both live and fixed cells. This is the first time a structurally complex capsid virus has been successfully genetically manipulated to generate virus particles that could be visualized in infected cells. PMID- 25142590 TI - Organization of capsid-associated tegument components in Kaposi's sarcoma associated herpesvirus. AB - Capsid-associated tegument proteins have been identified in alpha- and betaherpesviruses to play an essential role in viral DNA packaging. Whether and how such tegument proteins exist in gammaherpesviruses have been mysteries. Here, we report a 6-A-resolution cryo-electron microscopy (cryo-EM) structure of Kaposi's sarcoma-associated herpesvirus (KSHV) virion, a member of the oncogenic gammaherpesvirus subfamily. The KSHV virion structure reveals, for the first time, how capsid-associated tegument proteins are organized in a gammaherpesvirus, with five tegument densities capping each penton vertex, a pattern highly similar to that in alphaherpesvirus but completely different from that in betaherpesvirus. Each KSHV tegument density can be divided into three prominent regions: a penton-binding globular region, a helix-bundle stalk region, and a beta-sheet-rich triplex-binding region. Fitting of the crystal structure of the truncated HSV-1 UL25 protein (the KSHV ORF19 homolog) and secondary structure analysis of the full-length ORF19 established that ORF19 constitutes the globular region with an N-terminal, 60-amino-acid-long helix extending into the stalk region. Matching secondary structural features resolved in the cryo-EM density with secondary structures predicted by sequence analysis identifies the triplex binding region to be ORF32, a homolog of alphaherpesvirus UL17. Despite the high level of tegument structural similarities between KSHV and alphaherpesvirus, an ORF19 monomer in KSHV, in contrast to a UL25 dimer in alphaherpesviruses, binds each penton subunit, an observation that correlates with conformational differences in their pentons. This newly discovered organization of triplex-ORF32 ORF19 also resolves a long-standing mystery surrounding the virion location and conformation of alphaherpesvirus UL25 protein. IMPORTANCE: Several capsid associated tegument proteins have been identified in the alpha- and betaherpesvirus subfamilies of the Herpesviridae. These tegument proteins play essential roles in viral propagation and are potential drug targets for curbing herpesvirus infections. However, no such tegument proteins have been identified for gammaherpesviruses, the third herpesvirus subfamily, which contains members causing several human cancers. Here, by high-resolution cryo-EM, we show the three-dimensional structure of the capsid-associated tegument proteins in the prototypical member of gammaherpesviruses, KSHV. The cryo-EM structure reveals that the organization of KSHV capsid-associated tegument proteins is highly similar to that in alphaherpesvirus but completely different from that in betaherpesvirus. Structural analyses further localize ORF19 and ORF32 proteins (the alphaherpesvirus UL25 and UL17 homologs in KSHV, respectively) in the KSHV capsid-associated tegument cryo-EM structure. These findings also resolve a long standing mystery regarding the location and conformation of alphaherpesvirus UL25 protein inside the virion. PMID- 25142591 TI - Impact of clade, geography, and age of the epidemic on HIV-1 neutralization by antibodies. AB - Neutralizing antibodies (nAbs) are a high priority for vaccines that aim to prevent the acquisition of HIV-1 infection. Vaccine effectiveness will depend on the extent to which induced antibodies neutralize the global diversity of circulating HIV-1 variants. Using large panels of genetically and geographically diverse HIV-1 Env-pseudotyped viruses and chronic infection plasma samples, we unambiguously show that cross-clade nAb responses are commonly induced in response to infection by any virus clade. Nonetheless, neutralization was significantly greater when the plasma clade matched the clade of the virus being tested. This within-clade advantage was diminished in older, more-diverse epidemics in southern Africa, the United States, and Europe compared to more recent epidemics in Asia. It was most pronounced for circulating recombinant form (CRF) 07_BC, which is common in China and is the least-divergent lineage studied; this was followed by the slightly more diverse Asian CRF01_AE. We found no evidence that transmitted/founder viruses are generally more susceptible to neutralization and are therefore easier targets for vaccination than chronic viruses. Features of the gp120 V1V2 loop, in particular, length, net charge, and number of N-linked glycans, were associated with Env susceptibility and plasma neutralization potency in a manner consistent with neutralization escape being a force that drives viral diversification and plasma neutralization breadth. The overall susceptibility of Envs and potencies of plasma samples were highly predictive of the neutralization outcome of any single virus-plasma combination. These findings highlight important considerations for the design and testing of candidate HIV-1 vaccines that aim to elicit effective nAbs. IMPORTANCE: An effective HIV-1 vaccine will need to overcome the extraordinary variability of the virus, which is most pronounced in the envelope glycoproteins (Env), which are the sole targets for neutralizing antibodies (nAbs). Distinct genetic lineages, or clades, of HIV-1 occur in different locales that may require special consideration when designing and testing vaccines candidates. We show that nAb responses to HIV-1 infection are generally active across clades but are most potent within clades. Because effective vaccine-induced nAbs are likely to share these properties, optimal coverage of a particular clade or combination of clades may require clade-matched immunogens. Optimal within-clade coverage might be easier to achieve in regions such as China and Thailand, where the epidemic is more recent and the virus less diverse than in southern Africa, the United States, and Europe. Finally, features of the first and second hypervariable regions of gp120 (V1V2) may be critical for optimal vaccine design. PMID- 25142592 TI - The endoplasmic reticulum stress sensor IRE1alpha protects cells from apoptosis induced by the coronavirus infectious bronchitis virus. AB - The unfolded-protein response (UPR) is a signal transduction cascade triggered by perturbation of the homeostasis of the endoplasmic reticulum (ER). UPR resolves ER stress by activating a cascade of cellular responses, including the induction of molecular chaperones, translational attenuation, ER-associated degradation, and other mechanisms. Under prolonged and irremediable ER stress, however, the UPR can also trigger apoptosis. Here, we report that in cells infected with the avian coronavirus infectious bronchitis virus (IBV), ER stress was induced and the IRE1alpha-XBP1 pathway of UPR was activated. Knockdown and overexpression experiments demonstrated that IRE1alpha protects infected cells from IBV-induced apoptosis, which required both its kinase and RNase activities. Our data also suggest that splicing of XBP1 mRNA by IRE1alpha appears to convert XBP1 from a proapoptotic XBP1u protein to a prosurvival XBP1s protein. Moreover, IRE1alpha antagonized IBV-induced apoptosis by modulating the phosphorylation status of the proapoptotic c-Jun N-terminal kinase (JNK) and the prosurvival RAC-alpha serine/threonine-protein kinase (Akt). Taken together, the data indicate that the ER stress sensor IRE1alpha is activated in IBV-infected cells and serves as a survival factor during coronavirus infection. IMPORTANCE: Animal coronaviruses are important veterinary viruses, which could cross the species barrier, becoming severe human pathogens. Molecular characterization of the interactions between coronaviruses and host cells is pivotal to understanding the pathogenicity and species specificity of coronavirus infection. It has been well established that the endoplasmic reticulum (ER) is closely associated with coronavirus replication. Here, we report that inositol-requiring protein 1 alpha (IRE1alpha), a key sensor of ER stress, is activated in cells infected with the avian coronavirus infectious bronchitis virus (IBV). Moreover, IRE1alpha is shown to protect the infected cells from apoptosis by modulating the unfolded-protein response (UPR) and two kinases related to cell survival. This study demonstrates that UPR activation constitutes a major aspect of coronavirus-host interactions. Manipulations of the coronavirus-induced UPR may provide novel therapeutic targets for the control of coronavirus infection and pathogenesis. PMID- 25142593 TI - Epstein-Barr virus glycoprotein gB and gHgL can mediate fusion and entry in trans, and heat can act as a partial surrogate for gHgL and trigger a conformational change in gB. AB - Epstein-Barr virus (EBV) fusion with an epithelial cell requires virus glycoproteins gHgL and gB and is triggered by an interaction between gHgL and integrin alphavbeta5, alphavbeta6, or alphavbeta8. Fusion with a B cell requires gHgL, gp42, and gB and is triggered by an interaction between gp42 and human leukocyte antigen class II. We report here that, like alpha- and betaherpesviruses, EBV, a gammaherpesvirus, can mediate cell fusion if gB and gHgL are expressed in trans. Entry of a gH-null virus into an epithelial cell is possible if the epithelial cell expresses gHgL, and entry of the same virus, which phenotypically lacks gHgL and gp42, into a B cell expressing gHgL is possible in the presence of a soluble integrin. Heat is capable of inducing the fusion of cells expressing only gB, and the proteolytic digestion pattern of gB in virions changes in the same way following the exposure of virus to heat or to soluble integrins. It is suggested that the Gibbs free energy released as a result of the high-affinity interaction of gHgL with an integrin contributes to the activation energy required to cause the refolding of gB from a prefusion to a postfusion conformation. IMPORTANCE: The core fusion machinery of herpesviruses consists of glycoproteins gB and gHgL. We demonstrate that as in alpha- and betaherpesvirus, gB and gHgL of the gammaherpesvirus EBV can mediate fusion and entry when expressed in trans in opposing membranes, implicating interactions between the ectodomains of the proteins in the activation of fusion. We further show that heat and exposure to a soluble integrin, both of which activate fusion, result in the same changes in the proteolytic digestion pattern of gB, possibly representing the refolding of gB from its prefusion to its postfusion conformation. PMID- 25142594 TI - Naturally arising strains of polyomaviruses with severely attenuated microRNA expression. AB - Several different polyomaviruses (PyVs) encode microRNAs (miRNAs) that regulate viral as well as host gene expression. However, the functions of polyomaviral miRNAs, particularly during in vivo infection, remain poorly understood. Here we identify rare naturally arising PyVs that are severely attenuated or null for miRNA expression. We identify hypomorphic or null strains for miRNA expression from rhesus macaque simian virus 40 (SV40) and human JC virus. These strains were isolated from immunocompromised hosts and derive from insertions or deletions in the viral DNA that preserve the amino acid reading frame of opposing-strand large T antigen gene. Characterization of the SV40 miRNA hypomorph, K661, shows that it is inhibited at the early miRNA biogenesis step of Drosha-mediated processing. Despite having a nonrearranged enhancer, which a previous study has shown renders some PyVs more susceptible to the autoregulatory activities of the miRNA, restoring miRNA expression to K661 has little effect on virus growth in either immortalized or primary monkey kidney cells. Thus, in addition to any effect of accompanying genomic elements, these results suggest that the cellular context also determines susceptibility to PyV miRNA-mediated effects. Combined, these results demonstrate that polyomaviruses lacking miRNAs can arise infrequently and that the functional importance of polyomaviral miRNAs is context dependent, consistent with an activity connected to the immune status of the host. IMPORTANCE: Diverse virus families encode miRNAs, yet much remains unknown about viral miRNA function and contribution to the infectious cycle. Polyomaviruses (PyVs) are small DNA viruses, long known to be important as etiological agents of rare diseases and valuable models of DNA virus infection. Here, in immunosuppressed hosts, we uncover rare naturally arising variants of different PyVs that have lost the ability to express miRNAs. This represents some of the only known natural viruses to have lost miRNA expression. By probing the biogenesis pathways of these variants, we uncover that miRNA expression is lost via small insertions or deletions that render the transcripts resistant to early steps of miRNA biogenesis while preserving the reading frame of the opposing T antigen transcripts. Overall, our study informs how miRNA genes evolve/devolve in viruses and suggests that miRNA function is exquisitely dependent not only on viral genomic context but also on the cellular and host environment. PMID- 25142595 TI - Role of hypervariable region 1 for the interplay of hepatitis C virus with entry factors and lipoproteins. AB - Hepatitis C virus (HCV) particles associate with lipoproteins and infect cells by using at least four cell entry factors. These factors include scavenger receptor class B type I (SR-BI), CD81, claudin 1 (CLDN1), and occludin (OCLN). Little is known about specific functions of individual host factors during HCV cell entry and viral domains that mediate interactions with these factors. Hypervariable region 1 (HVR1) within viral envelope protein 2 (E2) is involved in the usage of SR-BI and conceals the viral CD81 binding site. Moreover, deletion of this domain alters the density of virions. We compared lipoprotein interaction, surface attachment, receptor usage, and cell entry between wild-type HCV and a viral mutant lacking this domain. Deletion of HVR1 did not affect CD81, CLDN1, and OCLN usage. However, unlike wild-type HCV, HVR1-deleted viruses were not neutralized by antibodies and small molecules targeting SR-BI. Nevertheless, modulation of SR BI cell surface expression altered the infection efficiencies of both viruses to similar levels. Analysis of affinity-purified virions revealed comparable levels of apolipoprotein E (ApoE) incorporation into viruses with or without HVR1. However, ApoE incorporated into these viruses was differentially recognized by ApoE-specific antibodies. Thus, SR-BI has at least two functions during cell entry. One of them can be neutralized by SR-BI-targeting molecules, and it is critical only for wild-type HCV. The other one is important for both viruses but apparently is not inactivated by the SR-BI binding antibodies and small molecules evaluated here. In addition, HVR1 modulates the conformation and/or epitope exposure of virus particle-associated ApoE. IMPORTANCE: HCV cell entry is SR-BI dependent irrespective of the presence or absence of HVR1. Moreover, this domain modulates the properties of ApoE on the surface of virus particles. These findings have implications for the development of SR-BI-targeting antivirals. Furthermore, these findings highlight separable functions of SR-BI during HCV cell entry and reveal a novel role of HVR1 for the properties of virus-associated lipoproteins. PMID- 25142596 TI - Comprehensive analysis of herpes simplex virus 1 (HSV-1) entry mediated by zebrafish 3-O-Sulfotransferase isoforms: implications for the development of a zebrafish model of HSV-1 infection. AB - Binding of herpes simplex virus 1 (HSV-1) envelope glycoprotein D (gD) to the receptor 3-O-sulfated heparan sulfate (3-OS HS) mediates viral entry. 3-O Sulfation of HS is catalyzed by the 3-O-sulfotransferase (3-OST) enzyme. Multiple isoforms of 3-OST are differentially expressed in tissues of zebrafish (ZF) embryos. Here, we performed a comprehensive analysis of the role of ZF 3-OST isoforms (3-OST-1, 3-OST-5, 3-OST-6, and 3-OST-7) in HSV-1 entry. We found that a group of 3-OST gene family isoforms (3-OST-2, -3, -4, and -6) with conserved catalytic and substrate-binding residues of the enzyme mediates HSV-1 entry and spread, while the other group (3-OST-1, -5, and -7) lacks these properties. These results demonstrate that HSV-1 entry can be recapitulated by certain ZF 3-OST enzymes, a significant step toward the establishment of a ZF model of HSV-1 infection and tissue-specific tropism. PMID- 25142597 TI - The herpes simplex virus 2 virion-associated ribonuclease vhs interferes with stress granule formation. AB - In a previous study, it was observed that cells infected with herpes simplex virus 2 (HSV-2) failed to accumulate stress granules (SGs) in response to oxidative stress induced by arsenite treatment. As a follow-up to this observation, we demonstrate here that disruption of arsenite-induced SG formation by HSV-2 is mediated by a virion component. Through studies on SG formation in cells infected with HSV-2 strains carrying defective forms of UL41, the gene that encodes vhs, we identify vhs as a virion component required for this disruption. Cells infected with HSV-2 strains producing defective forms of vhs form SGs spontaneously late in infection. In addition to core SG components, these spontaneous SGs contain the viral immediate early protein ICP27 as well as the viral serine/threonine kinase Us3. As part of these studies, we reexamined the frameshift mutation known to reside within the UL41 gene of HSV-2 strain HG52. We demonstrate that this mutation is unstable and can rapidly revert to restore wild type UL41 following low-multiplicity passaging. Identification of the involvement of virion-associated vhs in the disruption of SG formation will enable mechanistic studies on how HSV-2 is able to counteract antiviral stress responses early in infection. In addition, the ability of Us3 to localize to stress granules may indicate novel roles for this viral kinase in the regulation of translation. IMPORTANCE: Eukaryotic cells respond to stress by rapidly shutting down protein synthesis and storing mRNAs in cytoplasmic stress granules (SGs). Stoppages in protein synthesis are problematic for all viruses as they rely on host cell machinery to synthesize viral proteins. Thus, many viruses target SGs for disruption or modification. Infection by herpes simplex virus 2 (HSV-2) was previously observed to disrupt SG formation induced by oxidative stress. In this follow-up study, we identify virion host shutoff protein (vhs) as a viral protein involved in this disruption. The identification of a specific viral protein involved in disrupting SG formation is a key step toward understanding how HSV-2 interacts with these antiviral structures. Additionally, this understanding may provide insights into the biology of SGs that may find application in studies on human motor neuron degenerative diseases, like amyotrophic lateral sclerosis (ALS), which may arise as a result of dysregulation of SG formation. PMID- 25142598 TI - Residue 82 of the Chikungunya virus E2 attachment protein modulates viral dissemination and arthritis in mice. AB - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has reemerged to cause profound epidemics of fever, rash, and arthralgia throughout sub-Saharan Africa, Southeast Asia, and the Caribbean. Like other arthritogenic alphaviruses, mechanisms of CHIKV pathogenesis are not well defined. Using the attenuated CHIKV strain 181/25 and virulent strain AF15561, we identified a residue in the E2 viral attachment protein that is a critical determinant of viral replication in cultured cells and pathogenesis in vivo. Viruses containing an arginine at E2 residue 82 displayed enhanced infectivity in mammalian cells but reduced infectivity in mosquito cells and diminished virulence in a mouse model of CHIKV disease. Mice inoculated with virus containing an arginine at this position exhibited reduced swelling at the site of inoculation with a concomitant decrease in the severity of necrosis in joint-associated tissues. Viruses containing a glycine at E2 residue 82 produced higher titers in the spleen and serum at early times postinfection. Using wild-type and glycosaminoglycan (GAG)-deficient Chinese hamster ovary (CHO) cell lines and soluble GAGs, we found that an arginine at residue 82 conferred greater dependence on GAGs for infection of mammalian cells. These data suggest that CHIKV E2 interactions with GAGs diminish dissemination to lymphoid tissue, establishment of viremia, and activation of inflammatory responses early in infection. Collectively, these results suggest a function for GAG utilization in regulating CHIKV tropism and host responses that contribute to arthritis. IMPORTANCE: CHIKV is a reemerging alphavirus of global significance with high potential to spread into new, immunologically naive populations. The severity of CHIKV disease, particularly its propensity for chronic musculoskeletal manifestations, emphasizes the need for identification of genetic determinants that dictate CHIKV virulence in the host. To better understand mechanisms of CHIKV pathogenesis, we probed the function of an amino acid polymorphism in the E2 viral attachment protein using a mouse model of CHIKV musculoskeletal disease. In addition to influencing glycosaminoglycan utilization, we identified roles for this polymorphism in differential infection of mammalian and mosquito cells and targeting of CHIKV to specific tissues within infected mice. These studies demonstrate a correlation between CHIKV tissue tropism and virus-induced pathology modulated by a single polymorphism in E2, which in turn illuminates potential targets for vaccine and antiviral drug development. PMID- 25142599 TI - Dissection of the antibody response against herpes simplex virus glycoproteins in naturally infected humans. AB - Relatively little is known about the extent of the polyclonal antibody (PAb) repertoire elicited by herpes simplex virus (HSV) glycoproteins during natural infection and how these antibodies affect virus neutralization. Here, we examined IgGs from 10 HSV-seropositive individuals originally classified as high or low virus shedders. All PAbs neutralized virus to various extents. We determined which HSV entry glycoproteins these PAbs were directed against: glycoproteins gB, gD, and gC were recognized by all sera, but fewer sera reacted against gH/gL. We previously characterized multiple mouse monoclonal antibodies (MAbs) and mapped those with high neutralizing activity to the crystal structures of gD, gB, and gH/gL. We used a biosensor competition assay to determine whether there were corresponding human antibodies to those epitopes. All 10 samples had neutralizing IgGs to gD epitopes, but there were variations in which epitopes were seen in individual samples. Surprisingly, only three samples contained neutralizing IgGs to gB epitopes. To further dissect the nature of these IgGs, we developed a method to select out gD- and gB-specific IgGs from four representative sera via affinity chromatography, allowing us to determine the contribution of antibodies against each glycoprotein to the overall neutralization capacity of the serum. In two cases, gD and gB accounted for all of the neutralizing activity against HSV 2, with a modest amount of HSV-1 neutralization directed against gC. In the other two samples, the dominant response was to gD. IMPORTANCE: Antibodies targeting functional epitopes on HSV entry glycoproteins mediate HSV neutralization. Virus neutralizing epitopes have been defined and characterized using murine monoclonal antibodies. However, it is largely unknown whether these same epitopes are targeted by the humoral response to HSV infection in humans. We have shown that during natural infection, virus-neutralizing antibodies are principally directed against gD, gB, and, to a lesser extent, gC. While several key HSV-neutralizing epitopes within gD and gB are commonly targeted by human serum IgG, others fail to induce consistent responses. These data are particularly relevant to the design of future HSV vaccines. PMID- 25142600 TI - Analysis of the highly diverse gene borders in Ebola virus reveals a distinct mechanism of transcriptional regulation. AB - Ebola virus (EBOV) belongs to the group of nonsegmented negative-sense RNA viruses. The seven EBOV genes are separated by variable gene borders, including short (4- or 5-nucleotide) intergenic regions (IRs), a single long (144 nucleotide) IR, and gene overlaps, where the neighboring gene end and start signals share five conserved nucleotides. The unique structure of the gene overlaps and the presence of a single long IR are conserved among all filoviruses. Here, we sought to determine the impact of the EBOV gene borders during viral transcription. We show that readthrough mRNA synthesis occurs in EBOV-infected cells irrespective of the structure of the gene border, indicating that the gene overlaps do not promote recognition of the gene end signal. However, two consecutive gene end signals at the VP24 gene might improve termination at the VP24-L gene border, ensuring efficient L gene expression. We further demonstrate that the long IR is not essential for but regulates transcription reinitiation in a length-dependent but sequence-independent manner. Mutational analysis of bicistronic minigenomes and recombinant EBOVs showed no direct correlation between IR length and reinitiation rates but demonstrated that specific IR lengths not found naturally in filoviruses profoundly inhibit downstream gene expression. Intriguingly, although truncation of the 144 nucleotide-long IR to 5 nucleotides did not substantially affect EBOV transcription, it led to a significant reduction of viral growth. IMPORTANCE: Our current understanding of EBOV transcription regulation is limited due to the requirement for high-containment conditions to study this highly pathogenic virus. EBOV is thought to share many mechanistic features with well-analyzed prototype nonsegmented negative-sense RNA viruses. A single polymerase entry site at the 3' end of the genome determines that transcription of the genes is mainly controlled by gene order and cis-acting signals found at the gene borders. Here, we examined the regulatory role of the structurally unique EBOV gene borders during viral transcription. Our data suggest that transcriptional regulation in EBOV is highly complex and differs from that in prototype viruses and further the understanding of this most fundamental process in the filovirus replication cycle. Moreover, our results with recombinant EBOVs suggest a novel role of the long IR found in all filovirus genomes during the viral replication cycle. PMID- 25142601 TI - Molecular basis for ebolavirus VP35 suppression of human dendritic cell maturation. AB - Zaire ebolavirus (EBOV) VP35 is a double-stranded RNA (dsRNA)-binding protein that inhibits RIG-I signaling and alpha/beta interferon (IFN-alpha/beta) responses by both dsRNA-binding-dependent and -independent mechanisms. VP35 also suppresses dendritic cell (DC) maturation. Here, we define the pathways and mechanisms through which VP35 impairs DC maturation. Wild-type VP35 (VP35-WT) and two well-characterized VP35 mutants (F239A and R322A) that independently ablate dsRNA binding and RIG-I inhibition were delivered to primary human monocyte derived DCs (MDDCs) using a lentivirus-based expression system. VP35-WT suppressed not only IFN-alpha/beta but also proinflammatory responses following stimulation of MDDCs with activators of RIG-I-like receptor (RLR) signaling, including RIG-I activators such as Sendai virus (SeV) or 5'-triphosphate RNA, or MDA5 activators such as encephalomyocarditis virus (EMCV) or poly(I . C). The F239A and R322A mutants exhibited greatly reduced suppression of IFN-alpha/beta and proinflammatory cytokine production following treatment of DCs with RLR agonists. VP35-WT also blocked the upregulation of DC maturation markers and the stimulation of allogeneic T cell responses upon SeV infection, whereas the mutants did not. In contrast to the RLR activators, VP35-WT and the VP35 mutants impaired IFN-beta production induced by Toll-like receptor 3 (TLR3) or TLR4 agonists but failed to inhibit proinflammatory cytokine production induced by TLR2, TLR3, or TLR4 agonists. Furthermore, VP35 did not prevent lipopolysaccharide (LPS)-induced upregulation of surface markers of MDDC maturation and did not prevent LPS-triggered allogeneic T cell stimulation. Therefore, VP35 is a general antagonist of DC responses to RLR activation. However, TLR agonists can circumvent many of the inhibitory effects of VP35. Therefore, it may be possible to counteract EBOV immune evasion by using treatments that bypass the VP35-imposed block to DC maturation. IMPORTANCE: The VP35 protein, which is an inhibitor of RIG-I signaling and alpha/beta interferon (IFN-alpha/beta) responses, has been implicated as an EBOV-encoded factor that contributes to suppression of dendritic cell (DC) function. We used wild-type VP35 and previously characterized VP35 mutants to clarify VP35-DC interactions. Our data demonstrate that VP35 is a general inhibitor of RIG-I-like receptor (RLR) signaling that blocks not only RIG-I- but also MDA5-mediated induction of IFN-alpha/beta responses. Furthermore, in DCs, VP35 also impairs the RLR-mediated induction of proinflammatory cytokine production, upregulation of costimulatory markers, and activation of T cells. These inhibitory activities require VP35 dsRNA-binding activity, an activity previously correlated to VP35 RIG-I inhibitory function. In contrast, while VP35 can inhibit IFN-alpha/beta production induced by TLR3 or TLR4 agonists, this occurs in a dsRNA-independent fashion, and VP35 does not inhibit TLR-mediated expression of proinflammatory cytokines. These data suggest strategies to overcome VP35 inhibition of DC function. PMID- 25142602 TI - Epstein-barr virus blocks the autophagic flux and appropriates the autophagic machinery to enhance viral replication. AB - Autophagy is a catabolic pathway that helps cells to survive under stressful conditions. Cells also use autophagy to clear microbiological infections, but microbes have learned how to manipulate the autophagic pathway for their own benefit. The experimental evidence obtained in this study suggests that the autophagic flux is blocked at the final steps during the reactivation of Epstein Barr virus (EBV) from latency. This is indicated by the level of the lipidated form of LC3 that does not increase in the presence of bafilomycin and by the lack of colocalization of autophagosomes with lysosomes, which correlates with reduced Rab7 expression. Since the inhibition of the early phases of autophagy impaired EBV replication and viral particles were observed in autophagic vesicles in the cytoplasm of producing cells, we suggest that EBV exploits the autophagic machinery for its transportation in order to enhance viral production. The autophagic block was not mediated by ZEBRA, an immediate-early EBV lytic gene, whose transfection in Ramos, Akata, and 293 cells promoted a complete autophagic flux. The block occurred only when the complete set of EBV lytic genes was expressed. We suggest that the inhibition of the early autophagic steps or finding strategies to overcome the autophagic block, allowing viral degradation into the lysosomes, can be exploited to manipulate EBV replication. IMPORTANCE: This study shows, for the first time, that autophagy is blocked at the final degradative steps during EBV replication in several cell types. Through this block, EBV hijacks the autophagic vesicles for its intracellular transportation and enhances viral production. A better understanding of virus-host interactions could help in the design of new therapeutic approaches against EBV-associated malignancies. PMID- 25142603 TI - Immunodeficient mouse models with different disease profiles by in vivo infection with the same clinical isolate of enterovirus 71. AB - Like poliovirus infection, severe infection with enterovirus 71 (EV71) can cause neuropathology. Unlike poliovirus, EV71 is often associated with hand-foot-and mouth disease (HFMD). Here we established three mouse models for experimental infection with the same clinical isolate of EV71. The NOD/SCID mouse model is unique for the development of skin rash, an HFMD-like symptom. While the NOD/SCID mice developed limb paralysis and death at near-100% efficiency, the gamma interferon receptor knockout (ifngr KO) and stat-1 knockout mice exhibited paralysis and death rates near 78% and 30%, respectively. Productive infection with EV71 depends on the viral dose, host age, and inoculation route. Levels of infectious EV71, and levels of VP1-specific RNA and protein in muscle, brain, and spinal cord, were compared side by side between the NOD/SCID and stat-1 knockout models before, during, and after disease onset. Spleen fibrosis and muscle degeneration are common in the NOD/SCID and stat-1 knockout models. The main differences between these two models include their disease manifestations and cytokine/chemokine profiles. The pathology of the NOD/SCID model includes (i) inflammation and expression of viral VP1 antigen in muscle, (ii) increased neutrophil levels and decreased eosinophil and lymphocyte levels, and (iii) hair loss and skin rash. The characteristic pathology of the stat-1 knockout model includes (i) a strong tropism of EV71 for the central nervous system, (ii) detection of VP1 protein in the Purkinje layer of cerebellar cortex, pons, brain stem, and spinal cord, (iii) amplification of microglial cells, and (iv) dystrophy of intestinal villi. Our comparative studies on these new models with oral or intraperitoneal (i.p.) infection underscored the contribution of host immunity, including the gamma interferon receptor, to EV71 pathogenesis. IMPORTANCE: In the past decade, enterovirus 71 (EV71) has emerged as a major threat to public health in the Asia-Pacific region. Disease manifestations include subclinical infection, common-cold-like syndromes, hand-foot-and-mouth disease (HFMD), uncomplicated brain stem encephalitis, severe dysregulation of the autonomic nerve system, fatal pulmonary edema, and cardiopulmonary collapse. To date, no effective vaccine or treatment is available. A user-friendly and widely accessible animal model for researching EV71 infection and pathogenesis is urgently needed by the global community, both in academia and in industry. PMID- 25142604 TI - Intrabronchial infection of rhesus macaques with simian varicella virus results in a robust immune response in the lungs. AB - Varicella-zoster virus (VZV) is the etiological agent of varicella (chickenpox) and herpes zoster (shingles). Primary VZV infection is believed to occur via the inhalation of virus either in respiratory droplets or from shedding varicella lesions or by direct contact with infectious vesicular fluid. However, the ensuing immune response in the lungs remains incompletely understood. We have shown that intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, recapitulates the hallmarks of acute and latent VZV infection in humans. In this study, we performed an in-depth analysis of the host immune response to acute SVV infection in the lungs and peripheral blood. We report that acute SVV infection results in a robust innate immune response in the lungs, characterized by the production of inflammatory cytokines, chemokines, and growth factors as well as an increased frequency of plasmacytoid dendritic cells (DCs) that corresponded with alpha interferon (IFN-alpha) production and a rapid decrease in viral loads in the lungs. This is followed by T and B cell proliferation, antibody production, T cell differentiation, and cytokine production, which correlate with the complete cessation of viral replication. Although terminally differentiated CD8 T cells became the predominant T cell population in bronchoalveolar lavage cells, a higher percentage of CD4 T cells were SVV specific, which suggests a critical role for these cells in the resolution of primary SVV infection in the lungs. Given the homology between SVV and VZV, our data provide insight into the immune response to VZV within the lung. IMPORTANCE: Although primary VZV infection occurs primarily via the respiratory route, the host response in the lungs and its contribution to the cessation of viral replication and establishment of latency remain poorly understood. The difficulty in accessing lung tissue and washes from individuals infected with VZV has hampered efforts to address this knowledge gap. SVV infection of rhesus macaques is an important model of VZV infection of humans; therefore, we utilized this animal model to gain a comprehensive view of the kinetics of the immune response to SVV in the lung and its relationship to the resolution of acute infection in respiratory tissues. These data not only advance our understanding of host immunity to VZV, a critical step in developing new vaccines, but also provide additional insight into immunity to respiratory pathogens. PMID- 25142605 TI - Novel Denisovan and Neanderthal retroviruses. AB - Following the recent availability of high-coverage genomes for Denisovan and Neanderthal hominids, we conducted a screen for endogenized retroviruses, identifying six novel, previously unreported HERV-K(HML2) elements (HERV-K is human endogenous retrovirus K). These elements are absent from the human genome (hg38) and appear to be unique to archaic hominids. These findings provide further evidence supporting the recent activity of the HERV-K(HML2) group, which has been implicated in human disease. They will also provide insights into the evolution of archaic hominids. PMID- 25142606 TI - Lysine 63-linked TANK-binding kinase 1 ubiquitination by mindbomb E3 ubiquitin protein ligase 2 is mediated by the mitochondrial antiviral signaling protein. AB - Beta interferon (IFN-beta) is involved in a wide range of cellular functions, and its secretion must be tightly controlled to inhibit viral spreading while minimizing cellular damage. Intracellular viral replication triggers cellular signaling cascades leading to the activation of the transcription factors NF kappaB and interferon regulatory factor 3 (IRF3) and IRF7 (IRF3/7), which synergistically bind to the IFN-beta gene promoter to induce its expression. The mitochondrial antiviral signaling protein (MAVS) is a governing adaptor protein that mediates signaling communications between virus-sensing proteins and transcription factors. The activity of MAVS in the regulation of IFN-beta secretion is affected by many cellular factors. However, the mechanism of MAVS mediated IRF3/7 activation is not completely understood. Here, we identified a highly conserved DLAIS motif at amino acid positions 438 to 442 of MAVS that is indispensable for IRF3/7 activation. Specifically, the L439S and A440R mutations suppress IRF3/7 activation. Pulldown experiments using wild-type and mutant MAVS showed that mindbomb E3 ubiquitin protein ligase 2 (MIB2) binds to the DLAIS motif. Furthermore, the DLAIS motif was found to be critical for MIB2 binding, the ligation of K63-linked ubiquitin to TANK-binding kinase 1, and phosphorylation-mediated IRF3/7 activation. Our results suggest that MIB2 plays a putative role in MAVS-mediated interferon signaling. IMPORTANCE: Mitochondrial antiviral signaling protein (MAVS) mediates signaling from virus-sensing proteins to transcription factors for the induction of beta interferon. However, the mechanism underlying activation of MAVS-mediated interferon regulatory factors 3 and 7 (IRF3/7) is not completely understood. We found a highly conserved DLAIS motif in MAVS that is indispensable for IRF3/7 activation through TANK-binding kinase 1 (TBK1) and identified it as the binding site for mindbomb E3 ubiquitin protein ligase 2 (MIB2). The mutations that targeted the DLAIS motif abolished MIB2 binding, attenuated the K63-linked ubiquitination of TBK1, and decreased the phosphorylation-mediated activation of IRF3/7. PMID- 25142608 TI - Establishment and characterization of a lethal mouse model for the Angola strain of Marburg virus. AB - Infections with Marburg virus (MARV) and Ebola virus (EBOV) cause severe hemorrhagic fever in humans and nonhuman primates (NHPs) with fatality rates up to 90%. A number of experimental vaccine and treatment platforms have previously been shown to be protective against EBOV infection. However, the rate of development for prophylactics and therapeutics against MARV has been lower in comparison, possibly because a small-animal model is not widely available. Here we report the development of a mouse model for studying the pathogenesis of MARV Angola (MARV/Ang), the most virulent strain of MARV. Infection with the wild-type virus does not cause disease in mice, but the adapted virus (MARV/Ang-MA) recovered from liver homogenates after 24 serial passages in severe combined immunodeficient (SCID) mice caused severe disease when administered intranasally (i.n.) or intraperitoneally (i.p.). The median lethal dose (LD50) was determined to be 0.015 50% TCID50 (tissue culture infective dose) of MARV/Ang-MA in SCID mice, and i.p. infection at a dose of 1,000* LD50 resulted in death between 6 and 8 days postinfection in SCID mice. Similar results were obtained with immunocompetent BALB/c and C57BL/6 mice challenged i.p. with 2,000* LD50 of MARV/Ang-MA. Virological and pathological analyses of MARV/Ang-MA-infected BALB/c mice revealed that the associated pathology was reminiscent of observations made in NHPs with MARV/Ang. MARV/Ang-MA-infected mice showed most of the clinical hallmarks observed with Marburg hemorrhagic fever, including lymphopenia, thrombocytopenia, marked liver damage, and uncontrolled viremia. Virus titers reached 10(8) TCID50/ml in the blood and between 10(6) and 10(10) TCID50/g tissue in the intestines, kidney, lungs, brain, spleen, and liver. This model provides an important tool to screen candidate vaccines and therapeutics against MARV infections. IMPORTANCE: The Angola strain of Marburg virus (MARV/Ang) was responsible for the largest outbreak ever documented for Marburg viruses. With a 90% fatality rate, it is similar to Ebola virus, which makes it one of the most lethal viruses known to humans. There are currently no approved interventions for Marburg virus, in part because a small-animal model that is vulnerable to MARV/Ang infection is not available to screen and test potential vaccines and therapeutics in a quick and economical manner. To address this need, we have adapted MARV/Ang so that it causes illness in mice resulting in death. The signs of disease in these mice are reminiscent of wild-type MARV/Ang infections in humans and nonhuman primates. We believe that this will be of help in accelerating the development of life-saving measures against Marburg virus infections. PMID- 25142607 TI - Enhanced potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo. AB - Over the past 5 years, a new generation of highly potent and broadly neutralizing HIV-1 antibodies has been identified. These antibodies can protect against lentiviral infection in nonhuman primates (NHPs), suggesting that passive antibody transfer would prevent HIV-1 transmission in humans. To increase the protective efficacy of such monoclonal antibodies, we employed next-generation sequencing, computational bioinformatics, and structure-guided design to enhance the neutralization potency and breadth of VRC01, an antibody that targets the CD4 binding site of the HIV-1 envelope. One variant, VRC07-523, was 5- to 8-fold more potent than VRC01, neutralized 96% of viruses tested, and displayed minimal autoreactivity. To compare its protective efficacy to that of VRC01 in vivo, we performed a series of simian-human immunodeficiency virus (SHIV) challenge experiments in nonhuman primates and calculated the doses of VRC07-523 and VRC01 that provide 50% protection (EC50). VRC07-523 prevented infection in NHPs at a 5 fold lower concentration than VRC01. These results suggest that increased neutralization potency in vitro correlates with improved protection against infection in vivo, documenting the improved functional efficacy of VRC07-523 and its potential clinical relevance for protecting against HIV-1 infection in humans. IMPORTANCE: In the absence of an effective HIV-1 vaccine, alternative strategies are needed to block HIV-1 transmission. Direct administration of HIV-1 neutralizing antibodies may be able to prevent HIV-1 infections in humans. This approach could be especially useful in individuals at high risk for contracting HIV-1 and could be used together with antiretroviral drugs to prevent infection. To optimize the chance of success, such antibodies can be modified to improve their potency, breadth, and in vivo half-life. Here, knowledge of the structure of a potent neutralizing antibody, VRC01, that targets the CD4-binding site of the HIV-1 envelope protein was used to engineer a next-generation antibody with 5 to 8-fold increased potency in vitro. When administered to nonhuman primates, this antibody conferred protection at a 5-fold lower concentration than the original antibody. Our studies demonstrate an important correlation between in vitro assays used to evaluate the therapeutic potential of antibodies and their in vivo effectiveness. PMID- 25142609 TI - Autographa californica multiple nucleopolyhedrovirus orf132 encodes a nucleocapsid-associated protein required for budded-virus and multiply enveloped occlusion-derived virus production. AB - Autographa californica multiple nucleopolyhedrovirus orf132 (named ac132) has homologs in all genome-sequenced group I nucleopolyhedroviruses. Its role in the viral replication cycle is unknown. In this study, ac132 was shown to express a protein of around 28 kDa, which was determined to be associated with the nucleocapsids of both occlusion-derived virus and budded virus. Confocal microscopy showed that AC132 protein appeared in central region of the nucleus as early as 12 h postinfection with the virus. It formed a ring zone at the periphery of the nucleus by 24 h postinfection. To investigate its role in virus replication, ac132 was deleted from the viral genome by using a bacmid system. In the Sf9 cell culture transfected by the ac132 knockout bacmid, infection was restricted to single cells, and the titer of infectious budded virus was reduced to an undetectable level. However, viral DNA replication and the expression of late genes vp39 and odv-e25 and a reporter gene under the control of the very late gene p10 promoter were unaffected. Electron microscopy showed that nucleocapsids, virions, and occlusion bodies were synthesized in the cells transfected by an ac132 knockout bacmid, but the formation of the virogenic stroma and occlusion bodies was delayed, the numbers of enveloped nucleocapsids were reduced, and the occlusion bodies contained mainly singly enveloped nucleocapsids. AC132 was found to interact with envelope protein ODV-E18 and the viral DNA-binding protein P6.9. The data from this study suggest that ac132 possibly plays an important role in the assembly and envelopment of nucleocapsids. IMPORTANCE: To our knowledge, this is the first report on a functional analysis of ac132. The data presented here demonstrate that ac132 is required for production of the budded virus and multiply enveloped occlusion derived virus of Autographa californica multiple nucleopolyhedrovirus. This article reveals unique phenotypic changes induced by ac132 deletion on the virus and multiple new findings on ac132. PMID- 25142611 TI - Kinetics of radical-molecule reactions in aqueous solution: a benchmark study of the performance of density functional methods. AB - The performance of 18 density functional approximations has been tested for a very challenging task, the calculations of rate constants for radical-molecule reactions in aqueous solution. Despite of the many difficulties involved in such an enterprise, six of them provide high quality results, and are recommended to that purpose. They are LC-omegaPBE, M06-2X, BMK, B2PLYP, M05-2X, and MN12SX, in that order. This trend was obtained using experimental data as reference. The other relevant aspects used in this benchmark are: (i) the SMD model for mimicking the solvent; (ii) the conventional transition state, the zero-curvature tunneling correction, and the limit imposed by diffusion for the calculation of the rate constants. Even though changing any of these aspects might alter the trend in performance, at least, when using them, the aforementioned functionals can be successfully used to obtain high quality kinetic data for the kind of reactions investigated in this work. PMID- 25142610 TI - A synthetic biology approach for a vaccine platform against known and newly emerging serotypes of bluetongue virus. AB - Bluetongue is one of the major infectious diseases of ruminants and is caused by bluetongue virus (BTV), an arbovirus existing in nature in at least 26 distinct serotypes. Here, we describe the development of a vaccine platform for BTV. The advent of synthetic biology approaches and the development of reverse genetics systems has allowed the rapid and reliable design and production of pathogen genomes which can be subsequently manipulated for vaccine production. We describe BTV vaccines based on "synthetic" viruses in which the outer core proteins of different BTV serotypes are incorporated into a common tissue-culture-adapted backbone. As a means of validation for this approach, we selected two BTV-8 synthetic reassortants and demonstrated their ability to protect sheep against virulent BTV-8 challenge. In addition to further highlight the possibilities of genome manipulation for vaccine production, we also designed and rescued a synthetic BTV chimera containing a VP2 protein, including regions derived from both BTV-1 and BTV-8. Interestingly, while the parental viruses were neutralized only by homologous antisera, the chimeric proteins could be neutralized by both BTV-1 and BTV-8 antisera. These data suggest that neutralizing epitopes are present in different areas of the BTV VP2 and likely "bivalent" strains eliciting neutralizing antibodies for multiple strains can be obtained. IMPORTANCE: Overall, this vaccine platform can significantly reduce the time taken from the identification of new BTV strains to the development and production of new vaccines, since the viral genomes of these viruses can be entirely synthesized in vitro. In addition, these vaccines can be brought quickly into the market because they alter the approach, but not the final product, of existing commercial products. PMID- 25142612 TI - Apoptotic effects of two COX-2 inhibitors on breast adenocarcinoma cells through COX-2 independent pathway. AB - Recently, much effort has been directed toward the search for compounds that influence apoptosis and to understand their mechanisms of action. Cyclooxygenase (COX)-2 inhibitors may induce apoptosis through the COX-2-independent mechanism via a mitochondrial pathway. In view of the reported antiproliferative activities of two COX-2 inhibitor derivatives (1, 2) in breast cancer cells (MCF-7), the present study was undertaken to evaluate the potential of these compounds to induce apoptosis and unravel the associated mechanisms. The apoptotic activities of the two compounds were assessed using flow cytometry, fluorescence microscope, and Western blot analysis. Compounds 1 and 2-treated MCF-7 cells revealed the apoptotic cell death, as confirmed by the changes in nuclear morphology and the increased annexin-V/PI staining. Elevation of Bax to Bcl-2 ratio and activation of caspase-3 were found to be associated with the initiation of apoptosis induced by compound 1. Further investigation showed that compounds 1 and 2 inhibited NF kappaB, FHC, and ERK activation, while no dramatic change was revealed in c-Myc and EGR-1 levels. Our data suggest that induction of apoptosis by compounds 1 and 2 is not associated with COX-2 expression and occurs through the NF-kappaB pathway, which sequentially inhibits P-ERK and FHC expression. PMID- 25142613 TI - Introductory paragraph--Volume 28, Issue 9. PMID- 25142614 TI - Controlling and monitoring stem cell safety in vivo in an experimental rodent model. AB - Adult stem cells have been investigated increasingly over the past years for multiple applications. Although they have a more favorable safety profile compared to pluripotent stem cells, they are still capable of self-renewal and differentiate into several cell types. We investigated the behavior of Oct4 positive (Oct4(+)) and Oct4-negative (Oct4(-) ) murine or rat bone marrow (BM) derived stem cells in the healthy brain of syngeneic mice and rats. Engraftment of mouse and rat Oct4-positive BM-derived hypoblast-like stem cells (m/rOct4(+) BM-HypoSCs) resulted in yolk-sac tumor formation in the healthy brain which was monitored longitudinally using magnetic resonance imaging (MRI) and bioluminescence imaging (BLI). Contrast enhanced MRI confirmed the disruption of the blood brain barrier. In contrast, m/r Oct4-negative BM-derived multipotent adult progenitor cells (m/rOct4(-) BM-MAPCs) did not result in mass formation after engraftment into the brain. mOct4(+) BM-HypoSCs and mOct4(-) BM-MAPCs were transduced to express enhanced green fluorescent protein, firefly luciferase (fLuc), and herpes simplex virus-thymidine kinase to follow up suicide gene expression as a potential "safety switch" for tumor-forming stem cells by multimodal imaging. Both cell lines were eradicated efficiently in vivo by ganciclovir administration indicating successful suicide gene expression in vivo, as assessed by MRI, BLI, and histology. The use of suicide genes to prevent tumor formation is in particular of interest for therapeutic approaches where stem cells are used as vehicles to deliver therapeutic genes. PMID- 25142615 TI - Prevalence of retinopathy among adults with self-reported diabetes mellitus: the Sri Lanka diabetes and Cardiovascular Study. AB - BACKGROUND: At present there are no large scale nationally-representative studies from Sri Lanka on the prevalence and associations of Diabetic Retinopathy (DR). The present study aims to evaluate the prevalence and risk factors for DR in a community-based nationally-representative sample of adults with self-reported diabetes mellitus from Sri Lanka. METHODS: A cross-sectional community-based national study among 5,000 adults (>=18 years) was conducted in Sri Lanka, using a multi-stage stratified cluster sampling technique. An interviewer-administered questionnaire was used to collect data. Ophthalmological evaluation of patients with 'known' diabetes (previously diagnosed at a government hospital or by a registered medical practitioner) was done using indirect ophthalmoscopy. A binary logistic regression analysis was performed with 'presence of DR' as the dichotomous dependent variable and other independent covariates. RESULTS: Crude prevalence of diabetes was 12.0% (n = 536), of which 344 were patients with 'known' diabetes. Mean age was 56.4 +/- 10.9 years and 37.3% were males. Prevalence of any degree of DR was 27.4% (Males-30.5%, Females-25.6%; p = 0.41). In patients with DR, majority had NPDR (93.4%), while 5.3% had maculopathy. Patients with DR had a significantly longer duration of diabetes than those without. In the binary-logistic regression analysis in all adults duration of diabetes (OR:1.07), current smoking (OR:1.67) and peripheral neuropathy (OR:1.72) all were significantly associated with DR. CONCLUSIONS: Nearly 1/3rd of Sri Lankan adults with self-reported diabetes are having retinopathy. DR was associated with diabetes duration, cigarette smoking and peripheral neuropathy. However, further prospective follow up studies are required to establish causality for identified risk factors. PMID- 25142616 TI - Onset of Huntington's disease: can it be purely cognitive? AB - Knowledge of the cognitive manifestation of Huntington's disease has burgeoned over the past two decades. Many studies from independent datasets have shown that cognitive impairment is evident before motor diagnosis, and annual cognitive decline is a robust marker of disease progression. Additionally, cognition is a critical concern to patients and families and is associated with meaningful outcomes, including functional capacity, driving, loss of accustomed work, and quality of life. In the past few years, Huntington's disease animal models of cognition have increased, preparing for preclinical experimental therapeutics with cognitive endpoints. A longitudinal analysis of cognitive variables was conducted with 559 gene-positive cases and 233 controls showing no signs of motor abnormalities over approximately a 3-year period. Results show statistically significant differences in rate of annual change for some cognitive variables, such that the cases group had worsening performance over time. These findings show that cognitive deterioration can be seen in persons with the Huntington's disease gene expansion with no overt motor signs or symptoms, suggesting that cognitive onset of Huntington's disease may precede motor. PMID- 25142617 TI - Circadian (about 24-hour) variation in malondialdehyde content and catalase activity of mouse erythrocytes. AB - Lipid peroxidation is a part of normal metabolism that may cause biological molecule damage leading to the formation of several specific metabolites that include aldehydes of variable chains, such as malondialdehyde (MDA). These biological effects are controlled in vivo by a wide spectrum of enzymatic and non enzymatic defense mechanisms among which catalase (CAT) is considered as an important regulator of oxidative stress. The present study aimed to investigate the possible relationship between the temporal patterns of the formation of MDA and the activity of CAT in the erythrocytes of mice. Twenty-four-hour studies were performed on male Swiss albino mice, 12 weeks old, synchronized to a 12:12 light: dark cycle for 3 weeks. Different and comparable groups of animals (n = 10) were sacrificed at an interval of 4 hours (1, 5, 9, 13, 17, and 21 hours after light onset (HALO)). The levels of erythrocyte MDA concentration and CAT activity both significantly (analysis of variance: F = 6.4, P < 0.002) varied according to the time of sampling under non-stressed conditions. The characteristics of the waveform describing the temporal patterns differed between the two studied variables, e.g. MDA content showing one peak (?21 HALO) and CAT activity showing three peaks (?9, 17, and 21 HALO). Cosinor analysis revealed a significant (adjusted Cosinor: P <= 0.018) circadian (tau ? 24 hours) rhythm in MDA level and no statistically significant rhythmicity in CAT activity. The differences and the absence of correlation between the curve patterns of erythrocyte MDA content and CAT activity under physiological conditions are hypothesized to explain that variation in lipid peroxidation may depend on several factors. Moreover, the identification of peak/trough levels of MDA accumulation in erythrocytes may reflect the degree of oxidative stress in these blood cells. In addition, the observed significant time-of-day effect suggests that, in both clinical and scientific settings, appropriate comparison of MDA production and CAT activity levels can only be achieved on data obtained at the same time of day. PMID- 25142618 TI - Hemicarceplex formation allows ready identification of the isomers of the metallofullerene Sc3N@C80 using (1)H and (13)C NMR spectroscopy. AB - A cyclotriveratrylene-based molecular cage forms hemicarceplexes that significantly increase the solubility of commercially available Sc3N@C80 in CDCl3. When incarcerated within the molecular cage, the two structural isomers of this metallofullerene, Sc3N@D5h-C80 and Sc3N@Ih-C80, displayed characteristic signals in both (1)H and (13)C NMR spectra, allowing direct identification of each isomer without the need to enrich the sample with (13)C atoms. PMID- 25142619 TI - Development and evaluation of a treatment fidelity instrument for family-based treatment of adolescent anorexia nervosa. AB - OBJECTIVE: This study provides data on the psychometric properties of a newly developed measure of treatment fidelity in Family-Based Treatment (FBT) for adolescent anorexia nervosa (AN). The Family Therapy Fidelity and Adherence Check (FBT-FACT) was created to evaluate therapist adherence and competency on the core interventions in FBT. METHOD: Participants were 45 adolescents and their families sampled from three randomized clinical trials evaluating treatment for AN. Trained fidelity raters evaluated 19 therapists across 90 early session recordings using the FBT-FACT. They also rated an additional 15 session 1 recordings of an alternate form of family therapy-Systemic Family Therapy for the purpose of evaluating discriminant validity of the FBT-FACT. The process of development and the psychometric properties of the FBT-FACT are presented. RESULTS: Overall fidelity ratings for each session demonstrated moderate to strong inter-rater agreement. Internal consistency of the measure was strong for sessions 1 and 2 and poor for session 3. Principal components analysis suggests sessions 1 and 2 are distinct interventions. DISCUSSION: The FBT-FACT demonstrates good reliability and validity as a measure of treatment fidelity in the early phase of FBT. PMID- 25142620 TI - Performance of a low cost magnifying device, Magnivisualizer, versus colposcope for detection of pre-cancer and cancerous lesions of uterine cervix. AB - OBJECTIVE: To assess the performance of a low cost magnifying device (Magnivisualizer) compared to a standard optical colposcope for detection of precancerous and cancerous lesions of the uterine cervix. METHODS: A total of 659 consecutive symptomatic women attending a gynecologic outpatient clinic underwent unaided visual inspection followed by cytology, visual inspection of the cervix using 5% acetic acid (VIA), and VIA under magnification (VIAM) with the Magnivisualizer. All women, independently of test results, were referred for colposcopic examination. Colposcopic-directed biopsies were obtained from all positive lesions and compared to positive VIAM cases. RESULTS: The detection rate for VIA positive lesions was 12% (134/659), while it was 29% for VIAM positive lesions (191/659). The sensitivities of detection of cervical intraepithelial neoplasia (CIN) 2 and higher lesions were 61.7% for VIA, 88.3% for VIAM, and 86.7% for colposcopy, with a specificity of 58.5% for VIA, 55.8% for VIAM, and 90.4% for colposcopy. The performance of colposcopy and VIAM was moderate (kappa, 0.48; 95% confidence interval [CI], 0.41 to 0.54) for detection of CIN 1 and higher lesions and excellent (kappa, 0.87; 95% CI, 0.82 to 0.94) for detection of CIN 2 and higher lesions. CONCLUSION: In low resource settings, where colposcopic facilities are not available at the community level, a simple low-cost, handheld Magnivisualizer can be considered a valid option for detection of cervical precancerous and cancerous lesions. However, it cannot replace traditional colposcopy because it has a low specificity that results in many unnecessary biopsies. PMID- 25142621 TI - Fertility sparing surgery in early stage epithelial ovarian cancer. AB - OBJECTIVE: Fertility sparing surgery (FSS) is a strategy often considered in young patients with early epithelial ovarian cancer. We investigated the role and the outcomes of FSS in eEOC patients who underwent comprehensive surgery. METHODS: From January 2003 to January 2011, 24 patients underwent fertility sparing surgery. Eighteen were one-to-one matched and balanced for stage, histologic type and grading with a group of patients who underwent radical comprehensive staging (n=18). Demographics, surgical procedures, morbidities, pathologic findings, recurrence-rate, pregnancy-rate and correlations with disease-free survival were assessed. RESULTS: A total of 36 patients had a complete surgical staging including lymphadenectomy and were therefore analyzed. Seven patients experienced a recurrence: four (22%) in the fertility sparing surgery group and three (16%) in the control group (p=not significant). Sites of recurrence were: residual ovary (two), abdominal wall and peritoneal carcinomatosis in the fertility sparing surgery group; pelvic (two) and abdominal wall in the control group. Recurrences in the fertility sparing surgery group appeared earlier (mean, 10.3 months) than in radical comprehensive staging group (mean, 53.3 months) p<0.001. Disease-free survival were comparable between the two groups (p=0.422). No deaths were reported. All the patients in fertility sparing surgery group recovered a regular period. Thirteen out of 18 (72.2%) attempted to have a pregnancy. Five (38%) achieved a spontaneous pregnancy with a full term delivery. CONCLUSION: Fertility sparing surgery in early epithelial ovarian cancer submitted to a comprehensive surgical staging could be considered safe with oncological results comparable to radical surgery group. PMID- 25142622 TI - Analysis of treatment modalities and prognosis on microinvasive cervical cancer: a 10-year cohort study in China. AB - OBJECTIVE: To explore appropriate treatment modality of microinvasive cervical cancer (MIC) and to analyze prognosis and risk factors of recurrence. METHODS: A cohort of 324 Chinese patients with MIC diagnosed and treated at Peking Union Medical College Hospital was retrospectively reviewed. Demographic features, treatment modalities, pathologic parameters, risk factors of residual disease, survival and risk factors of recurrence were analyzed. RESULTS: Of all patients, 280 cases were staged IA1 and 44 cases staged IA2 MIC. Twenty-five cases (7.7%) were found to have lympho-vascular space involvement (LVSI), but no parametrial involvement or ovarian metastasis was detected. Only one staged IA2 patient with LVSI was found to have lymph node metastasis. 32.4% patients (82/253) had residual diseases after conization. No significant difference of LVSI, lymph node metastasis and residual disease after coniztion was found between stage IA1 and IA2 MIC patients. Multivariate logistic analysis showed positive margin was the only independent risk factor of residual disease after conization (odds ratio [OR], 4.18; p<0.001). Recurrence occurred in five cases, but no mortality was found. Progression-free survival for stage IA1 patients treated by conization or hysterectomy was similar (92.3% and 98.8%, p=0.07). Cox regression analysis revealed LVSI as an independent risk factor for recurrence in stage IA1 patients (OR, 12.14; p=0.01). CONCLUSION: For stage IA1 patients with negative resection margin and no LVSI, conization can be an ideal treatment modality. For stage IA2 patients, more conservative surgery such as simple hysterectomy may be considered. LVSI is an independent risk factor for recurrence in patients with stage IA1 cervical cancer. PMID- 25142623 TI - Lymphadenectomy can be omitted for low-risk endometrial cancer based on preoperative assessments. AB - OBJECTIVE: According to the International Federation of Gynecology and Obstetrics staging, some surgeons perform lymphadenectomy in all patients with early stage endometrial cancer to enable the accurate staging. However, there are some risks to lymphadenectomy such as lower limb lymphedema. The aim of this study was to investigate whether preoperative assessment is useful to select the patients in whom lymphadenectomy can be safely omitted. METHODS: We evaluated the risk of lymph node metastasis (LNM) using LNM score (histological grade, tumor volume measured in magnetic resonance imaging [MRI], and serum CA-125), myometrial invasion and extrautrerine spread assessed by MRI. Fifty-six patients of which LNM score was 0 and myometrial invasion was less than 50% were consecutively enrolled in the study in which a lymphadenectomy was initially intended not to perform. We analyzed several histological findings and investigated the recurrence rate and overall survival. RESULTS: Fifty-one patients underwent surgery without lymphadenectomy. Five (8.9%) who had obvious myometrial invasion intraoperatively underwent systematic lymphadenectomy. One (1.8%) with endometrial cancer which was considered to arise from adenomyosis had para-aortic LNM. Negative predictive value of deep myometrial invasion was 96.4% (54/56). During the mean follow-up period of 55 months, one patient with deep myometrial invasion who refused an adjuvant therapy had tumor recurrence. The overall survival rate was 100% during the study period. CONCLUSION: This preoperative assessment is useful to select the early stage endometrial cancer patients without risk of LNM and to safely omit lymphadenectomy. PMID- 25142624 TI - Granulocyte-colony stimulating factor decreases the extent of ovarian damage caused by cisplatin in an experimental rat model. AB - OBJECTIVE: To investigate whether granulocyte-colony stimulating factor (G-CSF) can decrease the extent of ovarian follicle loss caused by cisplatin treatment. METHODS: Twenty-one adult female Sprague-Dawley rats were used. Fourteen rats were administered 2 mg/kg/day cisplatin by intraperitoneal injection twice per week for five weeks (total of 20 mg/kg). Half of the rats (n=7) were treated with 1 mL/kg/day physiological saline, and the other half (n=7) were treated with 100 MUg/kg/day G-CSF. The remaining rats (n=7, control group) received no therapy. The animals were then euthanized, and both ovaries were obtained from all animals, fixed in 10% formalin, and stored at 4 degrees C for paraffin sectioning. Blood samples were collected by cardiac puncture and stored at -30 degrees C for hormone assays. RESULTS: All follicle counts (primordial, primary, secondary, and tertiary) and serum anti-Mullerian hormone levels were significantly increased in the cisplatin+G-CSF group compared to the cisplatin+physiological saline group. CONCLUSION: G-CSF was beneficial in decreasing the severity of follicle loss in an experimental rat model of cisplatin chemotherapy. PMID- 25142625 TI - The clinical performance of APTIMA human papillomavirus and Hybrid Capture 2 assays in the triage of lesser abnormal cervical cytologies. AB - OBJECTIVE: This study was performed to evaluate the clinical performance of APTIMA human papillomavirus (AHPV) assay and Hybrid Capture 2 (HC2) assay in screening for cervical disease, especially in women with atypical squamous cell of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL). METHODS: A total of 411 women diagnosed with ASC-US or LSIL were referred and further triaged by HC2 test. Prior to colposcopy, liquid-based cytology specimens were collected for the AHPV assay. Sensitivity and specificity were established based on the histological findings of cervical intraepithelial neoplasia (CIN). RESULTS: In all 411 subjects, the positive detection rate of AHPV assay was 70.8% (95% confidence interval [CI], 66.4 to 75.2), which was significantly lower than the positive detection rate of 94.9% obtained using HC2 test (95% CI, 92.3 to 96.8). Only one CIN 3-positive case was detected among the 120 AHPV-negative women, which was then confirmed by Pap smear test to be LSIL. The sensitivities of AHPV and HC2 for CIN 3 were similar (94.1% and 100%, respectively). However, AHPV showed a significantly higher specificity than HC2 test (30.2% and 5.3%, respectively; p<0.001). CONCLUSION: AHPV assay is effective in identifying CIN 3-positive cases because of its high specificity and lower false-negative rate. The use of AHPV for the triage of ASC-US and LSIL might help to reduce the referral rate of colposcopy during cervical cancer screening. PMID- 25142626 TI - Defining the concept of locally advanced squamous cell carcinoma of the vulva: a new perspective based on standardization of criteria and current evidence. AB - The phrase "locally advanced carcinoma of the vulva" has often been mentioned in the literature, though not accurately defined, or even leading to the interpretation overlapping. Grounded on cervical cancer experience, we are able to state that designing a tailored primary strategy based on clinically measurable adverse prognostic factors represents the cornerstone of therapy. This fact urged us to rethink about the real usefulness of the concept of locally advanced squamous cell carcinoma of the vulva. We will refer to this concept as a clinical entity emerging from a rigorous workup which is a valuable guiding tool in the context of a thorough debate about the best primary treatment approach to be used. Furthermore, bulky tumors of the vulva have been associated with a worse prognosis on several occasions. Some authors have questioned the fact that tumor size has not been considered in the staging system. Finally, a standardized definition will help us compare the results obtained, which is extremely necessary given the worldwide low prevalence of this disease. PMID- 25142627 TI - High expression of epidermal growth factor-like domain 7 is correlated with poor differentiation and poor prognosis in patients with epithelial ovarian cancer. AB - OBJECTIVE: The purpose of this study was to evaluate the expression of epidermal growth factor-like domain 7 (EGFL7) in epithelial ovarian cancer, and to assess its relevance to clinicopathological characteristics and patients' survival. METHODS: A total of 177 patients with epithelial ovarian cancer were enrolled in the current study. For each patient, a retrospective review of medical records was conducted. Immunohistochemical staining for EGFL7 was performed using tissue microarrays made with paraffin-embedded tissue block. EGFL7 expression levels were graded on a grade of 0 to 3 based on the percentage of positive cancer cells. We analyzed the correlations between the expression of EGFL7 and various clinical parameters, and also analyzed the survival outcome according to the EGFL7 expression. RESULTS: The expression of EGFL7 in ovarian cancer tissues was observed in 98 patients (55.4%). High expression of EGFL7 (grade 2 or 3) was significantly correlated with pathologic type, differentiation, stage, residual tumor after debulking surgery, lymphovascular space involvement, lymph node metastasis, high cancer antigen 125, peritoneal cytology, and ascites. Among these clinicopathologic factors, differentiation was significantly correlated with EGFL7 expression in multivariate analysis (p<0.05). Survival analysis showed that the patients with high EGFL7 expression had a poorer disease free survival than those with low EGFL7 expression (p=0.002). CONCLUSION: Our data suggest that EGFL7 expression is a novel predictive factor for the clinical progression of epithelial ovarian cancer, and may constitute a therapeutic target for antiangiogenesis therapy in patients with epithelial ovarian cancer. PMID- 25142628 TI - Completeness of pedigree and family cancer history for ovarian cancer patients. AB - OBJECTIVE: To investigate the completeness of pedigree and of number of pedigree analysis to know the acceptable familial history in Korean women with ovarian cancer. METHODS: Interview was conducted in 50 ovarian cancer patients for obtaining familial history three times over the 6 weeks. The completeness of pedigree is estimated in terms of familial history of disease (cancer), health status (health living, disease and death), and onset age of disease and death. RESULTS: The completion of pedigree was 79.3, 85.1, and 85.6% at the 1st, 2nd, and 3rd time of interview and the time for pedigree analysis was 34.3, 10.8, and 3.1 minutes, respectively. The factors limiting pedigree analysis were as follows: out of contact with their relatives (38%), no living ancestors who know the family history (34%), dispersed family member because of the Korean War (16%), unknown cause of death (12%), reluctance to ask medical history of relatives (10%), and concealing their ovarian cancer (10%). The percentage of cancers revealed in 1st (2%) and 2nd degree (8%) relatives were increasing through surveys, especially colorectal cancer related with Lynch syndrome (4%). CONCLUSION: Analysis of pedigree at least two times is acceptable in Korean woman with ovarian cancer from the first study. The completion of pedigree is increasing, while time to take family history is decreasing during three time survey. PMID- 25142629 TI - The survival outcome and patterns of failure in node positive endometrial cancer patients treated with surgery and adjuvant radiotherapy with curative intent. AB - OBJECTIVE: The purpose of this study was to evaluate the patterns of failure, overall survival (OS), disease-free survival (DFS) and factors influencing outcome in endometrial cancer patients who presented with metastatic lymph nodes and were treated with curative intent. METHODS: One hundred and twenty-six patients treated between January 1996 to December 2008 with surgery and adjuvant radiotherapy were identified from our service's prospective database. Radiotherapy consisted of 45 Gy in 1.8 Gy fractions to the whole pelvis. The involved nodal sites were boosted to a total dose of 50.4 to 54 Gy. RESULTS: The 5-year OS rate was 61% and the 5-year DFS rate was 59%. Grade 3 endometrioid, serous, and clear cell histologies and involvement of upper para-aortic nodes had lower OS and DFS. The number of positive nodes did not influence survival. Among the histological groups, serous histology had the worst survival. Among the 54 patients relapsed, only three (6%) failed exclusively in the pelvis and the rest of the 94% failed in extrapelvic nodal or distant sites. Patients with grade 3 endometrioid, serous and clear cell histologies did not influence pelvic failure but had significant extrapelvic failures (p<0.001). CONCLUSION: Majority of node positive endometrial cancer patients fail at extrapelvic sites. The most important factors influencing survival and extrapelvic failure are grade 3 endometrioid, clear cell and serous histologies and involvement of upper para aortic nodes. PMID- 25142630 TI - Metastatic pattern of uterine leiomyosarcoma: retrospective analysis of the predictors and outcome in 113 patients. AB - OBJECTIVE: To describe metastatic pattern of uterine leiomyosarcomas (ULMS) and correlate it with clinical and histopathologic parameters. METHODS: We included 113 women (mean age, 53 years; range, 29 to 72 years) with histopathology confirmed ULMS from 2000 to 2012. Distribution of metastases was noted from imaging by two radiologists in consensus. Predictors of development of metastases were analyzed with univariate and multivariate analysis. Impact of various clinical and histopathologic parameters on survival was compared using Log-rank test and Cox proportional hazard regression model. RESULTS: Distant metastases were seen in 81.4% (92/113) of the patients after median interval of 7 months (interquartile range, 1 to 21). Lung was most common site of metastases (74%) followed by peritoneum (41%), bones (33%), and liver (27%). Local tumor recurrence was noted in 57 patients (50%), 51 of whom had distant metastases. Statistically significant correlation was noted between local recurrence and peritoneal metastases (p<0.001) and between lung and other common sites of hematogeneous metastases (p<0.05). Age, serosal involvement, local recurrence, and the International Federation of Gynecology and Obstetrics (FIGO) stage were predictive factors for metastases. At the time of reporting, 65% (74/113) of the patients have died; median survival was 45 months. Stage, local recurrence, and age were poor prognostic factors. CONCLUSION: ULMS metastasizes most frequently to lung, peritoneum, bone, and liver. Local recurrence was associated with peritoneal spread and lung metastases with other sites of hematogeneous metastases. Age, FIGO stage and local recurrence predicted metastatic disease and advanced stage, older age and local recurrence predicted poor outcome. PMID- 25142631 TI - Solvent isotope effects on alkane formation by cyanobacterial aldehyde deformylating oxygenase and their mechanistic implications. AB - The reaction catalyzed by cyanobacterial aldehyde deformylating oxygenase is of interest both because of its potential application to the production of biofuels and because of the highly unusual nature of the deformylation reaction it catalyzes. Whereas the proton in the product alkane derives ultimately from the solvent, the identity of the proton donor in the active site remains unclear. To investigate the proton transfer step, solvent isotope effect (SIE) studies were undertaken. The rate of alkane formation was found to be maximal at pH 6.8 and to be the same in D2O or H2O within experimental error, implying that proton transfer is not a kinetically significant step. However, when the ratio of protium to deuterium in the product alkane was measured as a function of the mole fraction of D2O, a (D2O)SIEobs of 2.19 +/- 0.02 was observed. The SIE was invariant with the mole fraction of D2O, indicating the involvement of a single protic site in the reaction. We interpret this SIE as most likely arising from a reactant state equilibrium isotope effect on a proton donor with an inverse fractionation factor, for which Phi = 0.45. These observations are consistent with an iron-bound water molecule being the proton donor to the alkane in the reaction. PMID- 25142632 TI - Phytochemical and antioxidant profiles of leaves from different Sorbus L. species. AB - Leaves of Sorbus L. have been used in various traditional medicine systems. Phenolic compounds determine the main pharmacological effects of Sorbus L. In this study, phytochemical and antioxidant profiles of Sorbus anglica, Sorbus aria, Sorbus arranensis, Sorbus aucuparia, Sorbus austriaca, Sorbus caucasica, Sorbus commixta, Sorbus discolor, Sorbus gracilis, Sorbus hostii, Sorbus semi incisa and Sorbus tianschanica were determined. Twenty four constituents were identified in Sorbus L. species using ultra high performance liquid chromatography coupled to quadruple and time-of-flight mass spectrometers. Post column FRAP assay identified compounds with reducing activity and revealed significantly greatest total antioxidant activity of 175.30 MUmol TE/g DW, 169.20 MUmol TE/g DW and 148.11 MUmol TE/g DW in S. commixta, S. discolor and S. gracilis leaf samples, respectively, with neochlorogenic and chlorogenic acids being most significant contributors. Characteristic fingerprints of phytochemical and antioxidant profiles could be applied for the quality evaluation of various raw materials of Sorbus L. species. PMID- 25142633 TI - A critical number of workers in a honeybee colony triggers investment in reproduction. AB - Social insect colonies, like individual organisms, must decide as they develop how to allocate optimally their resources among survival, growth, and reproduction. Only when colonies reach a certain state do they switch from investing purely in survival and growth to investing also in reproduction. But how do worker bees within a colony detect that their colony has reached the state where it is adaptive to begin investing in reproduction? Previous work has shown that larger honeybee colonies invest more in reproduction (i.e., the production of drones and queens), however, the term 'larger' encompasses multiple colony parameters including number of adult workers, size of the nest, amount of brood, and size of the honey stores. These colony parameters were independently increased in this study to test which one(s) would increase a colony's investment in reproduction via males. This was assayed by measuring the construction of drone comb, the special type of comb in which drones are reared. Only an increase in the number of workers stimulated construction of drone comb. Colonies with over 4,000 workers began building drone comb, independent of the other colony parameters. These results show that attaining a critical number of workers is the key parameter for honeybee colonies to start to shift resources towards reproduction. These findings are relevant to other social systems in which a group's members must adjust their behavior as a function of the group's size. PMID- 25142634 TI - Torpor at high ambient temperature in a neotropical didelphid, the grey short tailed opossum (Monodelphis domestica). AB - The grey short-tailed opossum, Monodelphis domestica, has been an established research animal for more than five decades, but relatively, little is known about its thermophysiology. Here we studied core body temperature (T b) and metabolic rate (MR) of female adult M. domestica housed in the laboratory at an ambient temperature (T a) of 26 degrees C. In expanding previous reports, the average recorded core T b of M. domestica was 34.3 degrees C. The T b of an individual M. domestica can drop below 30 degrees C (minimal T b: 28.6 degrees C) accompanied by a reduction in MR of up to 52 % even while having ad libitum access to food. These findings demonstrate for the first time the presence of spontaneous torpor in M. domestica. Metabolic suppression at relatively high T a and T b furthermore broadens our perspective on the use of torpor as a metabolic strategy not just restricted to cold climates. PMID- 25142635 TI - Elevation of circulating fatty acid-binding protein 4 is independently associated with left ventricular diastolic dysfunction in a general population. AB - BACKGROUND: Fatty acid-binding protein 4 (FABP4) is expressed in both adipocytes and macrophages. Recent studies have shown secretion of FABP4 from adipocytes and association of elevated serum FABP4 level with obesity, insulin resistance, hypertension, and atherosclerosis. However, little is known about role of FABP4 in cardiac function. METHODS: From the database of the Tanno-Sobetsu Study, data for 190 subjects (male/female: 82/108) who were not treated with any medication and underwent echocardiography in 2011 or 2012 were retrieved for analyses of relationships between serum FABP4 concentration, metabolic markers and parameters of echocardiography. RESULTS: Serum FABP4 level was positively correlated with age, body mass index (BMI), blood pressure (BP), LDL cholesterol, HOMA-R and mean left ventricular (LV) wall thickness (LVWT, males: r = 0.315, females: r = 0.401, p < 0.01) and was negatively correlated with HDL cholesterol, estimated glomerular filtration rate (eGFR) and peak myocardial velocity during early diastole (e'; males: r = -0.434, females: r = -0.353, p < 0.01), an index of LV diastolic function. However, no significant correlation was found between FABP4 level and LV end-diastolic dimension, LV ejection fraction or LV mass index. There were significant correlations of e' with age, BMI, BP, eGFR, brain natriuretic peptide (BNP), FABP4, metabolic markers and LVWT. Multivariate regression analysis adjusted by HOMA-R, BMI, eGFR, BNP or LVWT in addition to age, gender and BP revealed that serum FABP4 concentration was independently correlated with e'. CONCLUSIONS: Elevation of circulating FABP4 may contribute to LV diastolic dysfunction in a general population. PMID- 25142636 TI - A simple technique for the excision of cutaneous carcinoma: the round block purse string suture. AB - BACKGROUND: Purse-string suture is a simple technique that can be used to reduce the surface area of circular wounds in an effort to obtain minimal scarring. In this report, we provide evidence of the effectiveness of the purse-string suture as a stand-alone procedure that allows a permanent primary complete closure of small to moderate skin defects. The procedure is used primarily for the repair of skin defects due to cutaneous tumor excision in older patients. METHODS: The purse-string suture is executed by using a 1-0 absorbable suture, always by exiting and reentering intradermally and never penetrating the epidermis, in a circumferential fashion. RESULTS: The immediate postoperative folds flatten in about a 4-week postoperative time span, and the resulting scar is the smallest obtainable. CONCLUSIONS: The round block purse-string suture is a simple technique which allows complete closure of skin defects without importing tissue from a distance, and it can be particularly suitable for older patients because of their skin laxity. PMID- 25142637 TI - Population access to rotavirus vaccination in industrialized countries: lessons learnt from current experience. AB - BACKGROUND: Four steps are usually necessary before population access to vaccination programmes. Marketing authorization, appropriation by national agencies of the data, recommendation and policy-decision steps on funding and implementation. Using rotavirus vaccination as an illustrative case, this study aims at better understanding picture of population access, and identifying lessons learnt from current experience. METHODS: Systematic review of national vaccination policies in 20 countries. RESULTS: 12 countries have included rotavirus vaccination in their childhood national vaccination programme, two decided not to include it, decision is pending in three countries, while it has not started in the three remaining countries. Published evaluations and/or advice were available in 16 countries. Many differences in content and outcomes were identified. CONCLUSION: Rotavirus vaccination implementation across industrialized countries was disparate, leading to unequal population access over time. Comparative analyses of the decision-making process suggest different interpretations of available evidence, raising the need for a similar decision integrated framework, using a structured and systematic approach. PMID- 25142638 TI - Need to evaluate the performance of real-time PCR assays for the quantitation of cytomegalovirus DNA load in lower respiratory tract specimens. PMID- 25142682 TI - Women performing repetitive work: is there a difference in the prevalence of shoulder pain and pathology in supermarket cashiers compared to the general female population? AB - OBJECTIVES: Shoulder disorders in the occupational environment have been widely studied, but the quality of research and methodology applied vary. Little has been done to ascertain whether shoulder pain in female repetitive workers is due to any verifiable pathology, or to compare findings with the general population. Therefore, we decided to evaluate the prevalence of self-reported shoulder pain in a group of female supermarket cashiers and in the general female population using a standardized questionnaire. Shoulder pain prevalence was then compared to imaging findings in order to assess specific and non-specific pain prevalence. MATERIAL AND METHODS: 196 cashiers and 302 controls filled in a standardized shoulder questionnaire and underwent an imaging examination of a shoulder. RESULTS: The prevalence of shoulder pain was significantly higher in the group of cashiers (46.4%) than in the general population (25.5%) (OR = 1.821; 95% CI: 1.426-2.325). Specific pain prevalence was higher among the controls (19.5%) than among the cashiers (13.2%). CONCLUSIONS: The more frequent reports of shoulder pain in the supermarket cashiers are not correlated with a higher prevalence of imaging abnormalities. The causes of these more frequent complaints should be probably sought in the psycho-social and occupational environment. PMID- 25142683 TI - Shiitake mushroom (Lentinus edodes): a poorly known allergen in Western countries responsible for severe work-related asthma. AB - OBJECTIVES: The aim of this study was to investigate the IgE-mediated pathogenesis of severe asthma presented by a patient only after handling shiitake (Lentinus edodes) mushrooms (SM). MATERIAL AND METHODS: Skin tests were performed using in-house extracts from mushrooms that the patient usually handled, i.e., shiitake, porcini, oyster and black fungus mushroom varieties. Specific IgE to champignons and various molds were determined. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) immunoblotting was performed to detect IgE-binding components. Four negative controls were included in the study. RESULTS: Skin prick tests performed with in-house mushroom extracts from varieties other than shiitake were completely negative, in contrast to the positive test obtained for shiitake mushrooms. Serum specific IgE levels for common molds and champignons were all negative. SDS-PAGE revealed many protein bands in the four mushroom extracts. Immunoblotting using the patient's serum showed allergenic bands at about 15 and 24 kDa exclusively for SM that were not shared with negative controls. Another faint band was detectable at approximately 37 kDa for SM and porcini varieties. CONCLUSIONS: Here, we present the first European case of SM-induced occupational asthma, a disease more frequently occurring in Asia. Asthma attacks stopped when the patient avoided contact with shiitake mushrooms. No skin reactions and no IgE-binding proteins by immunoblotting were detectable with the other mushrooms tested. The positive skin test with shiitake mushrooms and IgE-binding components in the shiitake extract confirmed the IgE-mediated etiology of the reaction. PMID- 25142684 TI - Chlorambucil-induced cytomegalovirus infection: a case report. AB - INTRODUCTION: Chlorambucil is an alkylating agent used in combination with prednisolone for the treatment of idiopathic membranous nephropathy. Although chlorambucil is generally well-tolerated, it is a myelosuppresive drug that can cause several infections. CASE PRESENTATION: We report the case of an 81-year-old Caucasian male presenting with idiopathic membranous nephropathy who developed fever, cough, dyspnea, pulmonary infiltrates, and abdominal pain shortly after the initiation of treatment with chlorambucil and corticosteroids for nephropathy. Virology tests for infectious diseases revealed a recent cytomegalovirus infection. Antiviral treatment (ganciclovir) resulted in full remission. CONCLUSIONS: Cytomegalovirus infection should be considered in the differential diagnosis of respiratory symptoms and pulmonary infiltrates in patients treated with chlorambucil for nephrotic syndrome. PMID- 25142685 TI - The use of data from national and other large-scale user experience surveys in local quality work: a systematic review. AB - PURPOSE: An important goal for national and large-scale surveys of user experiences is quality improvement. However, large-scale surveys are normally conducted by a professional external surveyor, creating an institutionalized division between the measurement of user experiences and the quality work that is performed locally. The aim of this study was to identify and describe scientific studies related to the use of national and large-scale surveys of user experiences in local quality work. DATA SOURCES: Ovid EMBASE, Ovid MEDLINE, Ovid PsycINFO and the Cochrane Database of Systematic Reviews. STUDY SELECTION: Scientific publications about user experiences and satisfaction about the extent to which data from national and other large-scale user experience surveys are used for local quality work in the health services. DATA EXTRACTION: Themes of interest were identified and a narrative analysis was undertaken. RESULTS OF DATA SYNTHESIS: Thirteen publications were included, all differed substantially in several characteristics. The results show that large-scale surveys of user experiences are used in local quality work. The types of follow-up activity varied considerably from conducting a follow-up analysis of user experience survey data to information sharing and more-systematic efforts to use the data as a basis for improving the quality of care. CONCLUSION: This review shows that large-scale surveys of user experiences are used in local quality work. However, there is a need for more, better and standardized research in this field. The considerable variation in follow-up activities points to the need for systematic guidance on how to use data in local quality work. PMID- 25142686 TI - Comment to the paper "The response and survival of children with recurrent diffuse intrinsic pontine glioma based on phase II study of antineoplastons A10 and AS2-1 in patients with brain stem glioma" by Burzynski et al. PMID- 25142687 TI - Highly unstable cervical spine injury in an infant: a case report. AB - Although the rate of surgical intervention for pediatric cervical spine injuries has risen, none of these instrumentation techniques has been reported in children less than 1 year of age. Additional consideration with placement of wires or cables is not safe because of the presence of cartilaginous bone and poor bone strength. The authors report a technique of internal fixation without fusion using nonabsorbable synthetic suture in an infant with unstable cervical injury. METHODS: A 5-month-old girl was transported to emergency department and computed tomography showed severe distraction injury at the C6-7 level with total disruption of the facet joints bilaterally. To improve her general condition, she was placed in a customized occipito-cervical brace until surgical stabilization could be performed. After 1 month, surgical fixation was performed. After removing all soft tissues at the appropriate level, a hole was made in the center of the superior articular process of C6. A nonabsorbable suture (2-0 Ethibond; Ethicon, Somerville, NJ, USA) was passed from the superior articular process to the facet joint. The suture was passed into the spinous process of the lower level, and it was progressively tightened and radiographs were taken until anatomic reduction was achieved. RESULTS: After surgery, solid fusion was achieved. She was able to sit up in a stroller after 6 months. CONCLUSION: As surgical treatment of pediatric cervical spine injuries is unsuitable for infants, the Ethibond sutures are strong enough to hold and stabilize the spine. This suturing technique can be used as an alternative treatment for cervical injury in infants. PMID- 25142688 TI - Clinical features and long-term outcomes of intraspinal ependymomas in pediatric patients. AB - PURPOSE: The aim of this study was to discuss the clinical manifestations, radiological features, treatment, and long-term outcomes of intraspinal ependymomas (Word Health Organization grade II) in pediatric patients. METHODS: The data of 15 pediatric patients who underwent microsurgery for intraspinal grade II ependymomas were retrospectively reviewed. Pre- and postoperative magnetic resonance imaging was performed in all patients. The diagnosis of grade II ependymomas was based on pathology. All the follow-up data were obtained during office visits. RESULTS: There were ten males and five females, with a mean age of 13.7 +/- 3.4 years. Four tumors were located in the cervical cord, six in the cervicothoracic cord, four in the thoracic cord, and one in the conus-cauda region, respectively. The most common symptom was motor deficits. Gross total resection (GTR) of the tumor was achieved in 12 cases, and subtotal resection (STR) was achieved in three cases. Regrowth of the residual tumor was observed in two STR cases during a mean follow-up period of 44.8 months. STR was performed again in one case due to clinical progression. At the last follow-up, 12 patients experienced an improvement in the neurological function and three patients maintained their preoperative status. CONCLUSIONS: Pediatric intraspinal grade II ependymomas are amenable to surgical resection before neurological deficits deteriorate. GTR is the best treatment of choice, and the outcome is favorable. Due to uncertain therapeutic efficacy and possible radiation-induced toxicity, postoperative radiotherapy should be considered carefully for cases of STR. PMID- 25142689 TI - Microsurgical fenestration and cystoperitoneal shunt through preauricular subtemporal keyhole craniotomy for the treatment of symptomatic middle fossa arachnoid cysts in children. AB - INTRODUCTION: The optimal surgical treatment for symptomatic middle fossa arachnoid cyst is still controversial. The most leading therapeutic options include cyst shunting and fenestration (endoscopic, microsurgical). We present our experience on surgical treatments of arachnoid cysts. PATIENTS AND METHODS: A retrospective data review of 16 children who underwent keyhole craniotomy for microsurgical fenestration and shunting of middle fossa arachnoid cysts between 1999 and 2012 was performed after institutional review board approval. The average patient age was 6.1 years. The average follow-up period was 36.5 months. There were ten male and six female patients in the series. Indications for surgery included intractable headaches (50%), increasing in cyst size (18.75%), and seizures (31.25%). All patient records were reviewed for their clinical presentation, classification, cyst resolution, symptom resolution, and cyst outcomes. After surgery, all patients underwent assessments of clinical and radiological improvement. RESULTS: Postoperative complications were observed in two cases: progressively resolving monoparesia in one case and resolving epileptic seizure with monotherapy in the other. All patients had a satisfactory clinical outcome, and in 87.5%, there was either a decrease in the size or a complete disappearance of the MFAC. Nevertheless, three (18.75%) of all patients needed shunt revision because of shunt dysfunction. Complication related to surgical technique was cerebrospinal fluid leak which spontaneously resolved in one patient. CONCLUSION: Microsurgical fenestration with keyhole craniotomy to provide passage between cysts to basal cisterns together with cystoperitoneal shunting during the same operation is still an effective and safe method in cases with symptomatic middle fossa arachnoid cysts in children. PMID- 25142690 TI - Delayed post-traumatic large subgaleal hematoma caused by diastasis of rhomboid skull suture on the transverse sinus. AB - PURPOSE: This study aimed to consider an appropriate treatment for large subgaleal hematoma with skull fracture and epidural hematoma (EDH). CASE REPORT: A 6-year-old boy presented at our hospital with head trauma, and computed tomography (CT) showed a thin EDH in the right temporo-occipital area and cranial diastasis in the right lambdoidal suture. However, no neurological deficits were identified in the patient. One week after trauma, he visited our hospital again with a massive fluctuant watery mass extending from the forehead to the right temporoparietal areas, and laboratory data revealed that he was anemic. CT showed a massive subgaleal hematoma with extremely high density around the cranial diastasis. Damage of the transverse sinus was suspected, and emergent sinus repair surgery was performed. The surgery disclosed that bleeding from the transverse sinus was flowing out extracranially through the cranial diastasis. The subgaleal and epidural hematomas were removed, and bleeding from the sinus was stopped by dural tacking sutures along the transverse sinus. Postoperative CT demonstrated complete disappearance of epidural and subgaleal hematomas. The patient recovered from general fatigue without blood transfusion and was discharged 9 days after surgery. CONCLUSIONS: The therapeutic strategy for massive subgaleal hematoma is individualized. However, treatment for massive subgaleal hematoma with skull fracture should not be considered the same as for hematoma without skull fracture. Emergent surgery is recommended before neurological deterioration is recognized in the patient if damage to the dural sinus is suspected. PMID- 25142691 TI - Intracerebellar malignant nerve sheath tumor in a child: case report and review of literature. AB - PURPOSE: Intracerebellar malignant nerve sheath tumor (ICMNST) is an extremely rare entity, only two cases have been reported previously, and this is the first case to be reported in a child. The histogenesis, diagnosis, and management of this entity are very ambiguous, and natural history in a child is unknown. METHODS: The authors report a 7-year-old girl who presented with ataxia and signs of raised intracranial pressure and discuss the challenges in diagnosis, surgical strategy, and treatment. RESULTS: Following gross total resection and radiation to tumor bed, the patient had unremarkable recovery and is recurrence free at 1 year follow-up. CONCLUSION: ICMNSTs are extremely rare tumors of the cerebellum. Preoperative radiological diagnosis is not possible due to its close radiological resemblance to other common posterior fossa tumors. Immunohistochemistry plays a pivotal role in clinching the diagnosis. Though the reported adult counterparts have shown dismal prognosis, the pediatric counterparts may fare better with good surgical resection followed by radiotherapy. PMID- 25142692 TI - Anorexia: an early sign of fourth ventricle astrocytoma in children. AB - INTRODUCTION: Paediatric low-grade astrocytomas of the fourth ventricle are rare tumours, generally revealed by hydrocephalus. However, some patients present with a history of severe anorexia. It might be a harbinger, which if recognized, could lead to earlier diagnosis. We decided to examine our database in order to evaluate the incidence and signification of anorexia in this context. METHODS: Retrospective monocentric study of cases of low-grade astrocytomas of the fourth ventricle operated between 1991 and 2012 in our paediatric neurosurgery department. We particularly observed the clinical presentation and long-term clinical, oncological and radiological evolution. Non-parametrical tests were used (Mann-Whitney, Fisher). RESULTS: We reviewed 34 cases, 31 pilocytic astrocytomas and 3 diffuse astrocytomas, 16 boys and 18 girls, (M/F ratio 0.89). Mean age at diagnosis was 8 years old. Seven presented with notable anorexia, the average BMI in this group was <=2 standard deviation (SD); with clinical signs evolving for 11.5 months. Twenty-seven children had no anorexia; average BMI in this group was +1 SD, with clinical evolution for 6 months on an average of p < 0.05. We found no significant difference regarding hydrocephalus or tumour location. In all children with anorexia, body mass index improved markedly in the postoperative follow-up, which lasted, on average, for 6 years. CONCLUSION: Anorexia with stunted body weight curve is a non-exceptional presentation in children with low-grade astrocytomas of the fourth ventricle. Unexplained or atypical anorexia with negative etiologic assessment should prompt cerebral imaging. Clinical improvement after surgical resection, could suggest a possible interaction between tumour tissue and appetite-suppressing peptide secretion. PMID- 25142693 TI - Diversity analysis of the bacterial community in tobacco waste extract during reconstituted tobacco process. AB - Reconstituted tobacco sheet process has been developed to treat and reuse tobacco wastes in the industry. During this process, microorganisms in original and concentrated tobacco waste extract (TWE) might play important roles in the final quality of the reconstituted tobacco. However, microbial communities in TWE remain largely unknown. In the present study, the Roche 454 bar-coded pyrosequencing was applied to analyze the bacterial community structure in samples. Comparison based on 16S rRNA gene sequences showed that the original and concentrated solutions of TWE harbored abundant bacteria probably resistant to the acid, high nicotine concentration, and high osmotic pressure environment. The dominant phyla were Firmicutes and Proteobacteria. Lactobacillus and Lysinibacillus were the dominant genera of Firmicutes. The most interesting genus of Proteobacteria was Pseudomonas. It is the first time to reveal the bacterial diversities on the TWE samples from the process of reconstituted tobacco sheets. PMID- 25142694 TI - Implications of new research and technologies for malolactic fermentation in wine. AB - The initial conversion of grape must to wine is an alcoholic fermentation (AF) largely carried out by one or more strains of yeast, typically Saccharomyces cerevisiae. After the AF, a secondary or malolactic fermentation (MLF) which is carried out by lactic acid bacteria (LAB) is often undertaken. The MLF involves the bioconversion of malic acid to lactic acid and carbon dioxide. The ability to metabolise L-malic acid is strain specific, and both individual Oenococcus oeni strains and other LAB strains vary in their ability to efficiently carry out MLF. Aside from impacts on acidity, LAB can also metabolise other precursors present in wine during fermentation and, therefore, alter the chemical composition of the wine resulting in an increased complexity of wine aroma and flavour. Recent research has focused on three main areas: enzymatic changes during MLF, safety of the final product and mechanisms of stress resistance. This review summarises the latest research and technological advances in the rapidly evolving study of MLF and investigates the directions that future research may take. PMID- 25142695 TI - Manipulation of fungal development as source of novel secondary metabolites for biotechnology. AB - Fungal genomics revealed a large potential of yet-unexplored secondary metabolites, which are not produced during vegetative growth. The discovery of novel bioactive compounds is increasingly gaining importance. The high number of resistances against established antibiotics requires novel drugs to counteract increasing human and animal mortality rates. In addition, growth of plant pathogens has to be controlled to minimize harvest losses. An additional critical issue is the post-harvest production of deleterious mycotoxins. Fungal development and secondary metabolite production are linked processes. Therefore, molecular regulators of development might be suitable to discover new bioactive fungal molecules or to serve as targets to control fungal growth, development, or secondary metabolite production. The fungal impact is relevant as well for our healthcare systems as for agriculture. We propose here to use the knowledge about mutant strains discovered in fungal model systems for a broader application to detect and explore new fungal drugs or toxins. As examples, mutant strains impaired in two conserved eukaryotic regulatory complexes are discussed. The COP9 signalosome (CSN) and the velvet complex act at the interface between development and secondary metabolism. The CSN is a multi-protein complex of up to eight subunits and controls the activation of CULLIN-RING E3 ubiquitin ligases, which mark substrates with ubiquitin chains for protein degradation by the proteasome. The nuclear velvet complex consists of the velvet-domain proteins VeA and VelB and the putative methyltransferase LaeA acting as a global regulator for secondary metabolism. Defects in both complexes disturb fungal development, light perception, and the control of secondary metabolism. The potential biotechnological relevance of these developmental fungal mutant strains for drug discovery, agriculture, food safety, and human healthcare is discussed. PMID- 25142696 TI - The essential role of nitrogen limitation in expression of xplA and degradation of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in Gordonia sp. strain KTR9. AB - Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a widely used explosive and a major soil and groundwater contaminant. Organisms such as Gordonia sp. KTR9, capable of degrading RDX and using it as an N source, may prove useful for bioremediation of contaminated sites. XplA is a cytochrome P450 monooxygenase responsible for RDX degradation. Expression of xplA in KTR9 was not induced by RDX but was strongly induced (50-fold) during N-limited growth. When glnR, encoding a regulatory protein affecting N assimilation in diverse Actinobacteria, was deleted from KTR9, the bacterium lost the ability to use nitrate, nitrite, and RDX as N sources. Deletion of glnR also abolished the inhibition of xplA expression by nitrite. Our results confirm the essential role of GlnR in regulating assimilation of nitrite, but there was no evidence for a direct role of GlnR in regulating XplA expression. Rather, the general availability of nitrogen repressed XplA expression. We conclude that the inability of the glnR mutant to use RDX as an N source was due to its inability to assimilate nitrite, an intermediate in the assimilation of nitrogen from RDX. Regulation of XplA does not seem adaptive for KTR9, but it is important for RDX bioremediation with KTR9 or similar bacteria. PMID- 25142697 TI - Rapid detection of bacteriophages in starter culture using water-in-oil-in-water emulsion microdroplets. AB - Bacteriophage contamination of starter culture and raw material poses a major problem in the fermentation industry. In this study, a rapid detection of lytic phage contamination in starter culture using water-in-oil-in-water (W/O/W) emulsion microdroplets was described. A model bacteria with varying concentrations of lytic phages were encapsulated in W/O/W emulsion microdroplets using a simple needle-in-tube setup. The detection of lytic phage contamination was accomplished in 1 h using the propidium iodide labeling of the phage-infected bacteria inside the W/O/W emulsion microdroplets. Using this approach, a detection limit of 10(2) PFU/mL of phages was achieved quantitatively, while 10(4) PFU/mL of phages could be detected qualitatively based on visual comparison of the fluorescence images. Given the simplicity and sensitivity of this approach, it is anticipated that this method can be adapted to any strains of bacteria and lytic phages that are commonly used for fermentation, and has potential for a rapid detection of lytic phage contamination in the fermentation industry. PMID- 25142698 TI - TAT-RhoGDI2, a novel tumor metastasis suppressor fusion protein: expression, purification and functional evaluation. AB - Rho GDP dissociation inhibitor 2 (RhoGDI2) was identified as a functional metastasis suppressor in human bladder cancer, suggesting that increasing the RhoGDI2 level may represent a promising therapeutic strategy. It has been shown that the transactivator of transcription (TAT) protein from HIV-1 is able to efficiently deliver various biological molecules into several cell types. In this study, TAT peptide was fused with the N-terminus of RhoGDI2, and the resulting TAT-RhoGDI2 fragment was inserted into the pGEX-6p-1 plasmid and expressed as a glutathione S-transferase (GST)/TAT-RhoGDI2 fusion protein in Escherichia coli BL21(DE3) cells. A two-step purification strategy involving glutathione sepharose chromatography and PreScission protease cleavage was developed to purify TAT RhoGDI2; subsequently, the identification of the involved macromolecules was achieved by Western blot. The final product, TAT-RhoGDI2, was obtained at a concentration of 112 mg/L. This is the first report on the efficient production of bioactive TAT-RhoGDI2 through a gene-engineering approach in E. coli. Using flow cytometry, we found that the TAT-RhoGDI2 fusion proteins could penetrate into bladder cancer cells with an extremely high efficiency. In vitro scratch and transwell assay and the migration/invasion behavior of UMUC3 cells were strongly reduced by the treatment with TAT-RhoGDI2. These studies support the use of the TAT-RhoGDI2 protein in tumor metastasis therapy. PMID- 25142699 TI - Rapid, de novo development of isolated intracranial rosai-dorfman disease: A case report. AB - Isolated intracranial Rosai-Dorfman Disease is rare. Here, we describe a patient who developed an asymptomatic, right parietal RDD lesion over 18 months while being followed radiographically for another brain lesion. To our knowledge, rapid, de novo radiographic formation of isolated intracranial RDD has never been reported in an asymptomatic patient. PMID- 25142701 TI - An investigation into the clinical impacts of lowering shunt opening pressure in idiopathic normal pressure hydrocephalus: A case series. AB - Introduction. Idiopathic normal pressure hydrocephalus (iNPH) is a shunt- reversible syndrome of the elderly. Shunt management is aimed at achieving a balance between clinical improvement and the complications associated with overdrainage. Although clinical improvement occurs at low pressure, these benefits may be negated by the increase in complication rates observed at lower pressures. The addition of gravity-switch devices has been shown to reduce over drainage problems even at a low valve pressure setting. At our centre the Miethke proGAV is used and commonly lowered below 5 cmH2O to gain further clinical improvement. Object. To determine whether lowering the opening pressure to below 5cmH2O using the proGAV valve in iNPH patients results in a) improved clinical features; and b) no significant increase in complication rates. Methods. A retrospective case series of iNPH patients was undertaken with 24 patients who had the proGAV shunt system inserted with an initial opening pressure of 5cmH2O. Exclusion criteria were secondary NPH, shunt system other than proGAV inserted, no valve adjustment to below 5cmH2O and inadequate follow-up. Outcome measures were clinical improvement (gait, cognition and urinary continence) and complications (subdural haematoma, low-pressure symptoms and valve damage). Results. Patients underwent a total of 29 adjustments to below 5cmH2O. The mean valve opening pressure after the first adjustment was 2.5cmH2O and the mean opening pressure after the second adjustment was 1cmH2O. Overall, outcome after adjustment included 26% no change, 48% improvement and 26% deterioration clinically. One patient (4%) suffered traumatic subdural haematoma that resolved with increasing valve pressure to 20cmH2O. There was no valve damage or low pressure symptoms after adjustment. Conclusion. This study found that lowering the opening pressure of the proGAV shunt system to below 5cmH2O results in clinical improvement and does not significantly increase the complication rate in iNPH patients. PMID- 25142702 TI - Impact of CINV in earlier cycles on CINV and chemotherapy regimen modification in subsequent cycles in Asia Pacific clinical practice. AB - PURPOSE: We sought to describe the impact of chemotherapy-induced nausea and vomiting (CINV) in prior cycles on CINV and chemotherapy regimen modification in subsequent cycles. METHODS: Eligible patients in this multinational prospective observational study were adults (>=18 years old) receiving their first single-day highly or moderately emetogenic chemotherapy (HEC or MEC). Multivariate logistic regression was used to assess the impact of CINV in prior cycles on CINV in subsequent cycles. Other independent variables included in the model were the cycle number, age, sex, and emetogenicity of regimen. RESULTS: There were 598 evaluable patients in cycle 2 and 533 in cycle 3, half receiving HEC and half MEC. Patients who experienced complete response (no emesis or rescue antiemetics) in earlier cycles, relative to those with no complete response, had an adjusted odds ratio (OR) of 5.9 (95% confidence interval (CI), 4.14-8.50) for experiencing complete response in subsequent cycles. Prior CINV was a significant and consistent predictor of subsequent CINV for all CINV endpoints: for emesis, OR 12.7 (95% CI, 8.47-18.9), for clinically significant nausea, OR 7.9 (95% CI, 5.66 10.9), and for clinically significant nausea and/or vomiting, OR 7.2 (5.17-10.1). Modifications to chemotherapy were recorded for 26-29% of patients in cycles 2 and 3, with CINV as the major reason for the modification for 5-9% of these patients. CONCLUSIONS: CINV in prior cycles was a strong and consistent predictor of CINV in subsequent cycles, while the incidence of chemotherapy regimen modification due to CINV was low in individual cycles. PMID- 25142703 TI - Systematic review of the multidimensional fatigue symptom inventory-short form. AB - PURPOSE: Fatigue is a subjective complaint that is believed to be multifactorial in its etiology and multidimensional in its expression. Fatigue may be experienced by individuals in different dimensions as physical, mental, and emotional tiredness. The purposes of this study were to review and characterize the use of the 30-item Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) in published studies and to evaluate the available evidence for its psychometric properties. METHODS: A systematic review was conducted to identify published articles reporting results for the MFSI-SF. Data were analyzed to characterize internal consistency reliability of multi-item MFSI-SF scales and test-retest reliability. Correlation coefficients were summarized to characterize concurrent, convergent, and divergent validity. Standardized effect sizes were calculated to characterize the discriminative validity of the MFSI-SF and its sensitivity to change. RESULTS: Seventy articles were identified. Sample sizes reported ranged from 10 to 529 and nearly half consisted exclusively of females. More than half the samples were composed of cancer patients; of those, 59% were breast cancer patients. Mean alpha coefficients for MFSI-SF fatigue subscales ranged from 0.84 for physical fatigue to 0.93 for general fatigue. The MFSI-SF demonstrated moderate test-retest reliability in a small number of studies. Correlations with other fatigue and vitality measures were moderate to large in size and in the expected direction. The MFSI-SF fatigue subscales were positively correlated with measures of distress, depressive, and anxious symptoms. Effect sizes for discriminative validity ranged from medium to large, while effect sizes for sensitivity to change ranged from small to large. CONCLUSIONS: Findings demonstrate the positive psychometric properties of the MFSI-SF, provide evidence for its usefulness in medically ill and nonmedically ill individuals, and support its use in future studies. PMID- 25142704 TI - Care trajectories and survival after discharge from specialized inpatient palliative care--results from an observational follow-up study. AB - BACKGROUND: Little is known about the patients' individual care trajectories after discharge or transfer from inpatient palliative care units (PCU) to other care settings. This study aims to survey the further care trajectory and overall survival from the time of discharge of patients in a palliative care situation. Patient groups from either the PCU or the palliative care mobile support team (PCMT) are compared in order to analyze the demographic data, discharge settings, frequency of changes of care settings, overall survival from the time of discharge and place of death. METHODS: In a mono-centre prospective observational study, patients discharged or transferred from a German inpatient PCU or from other hospital wards with support of the PCMT were invited to participate in this study. After discharge, the central care provider, such as inpatient hospices, nursing homes or general practitioners, was asked for information on the care trajectory and on readmissions to hospital in four weekly follow-up phone calls until the patients' death. Place of death and overall survival from the time of discharge were noted. RESULTS: During the study period, 467 inpatients from the PCU and 554 inpatients from the PCMT were treated. Ultimately, 418 were discharged. Two hundred forty-five patients agreed to participate in the study, and the majority of them were either discharged home (60.8 %), to inpatient hospices (20.0 %) or to nursing homes (11.0 %). More than half of all of them (55.9 %) stayed continuously in their discharge setting. The remaining 44.1 % experienced a mean number of 3.1 +/- 4.1 changes of care setting. Most frequently, patients changed their care setting from private home to hospital (N = 110; 32.4 %) and from hospital back to private home (N = 82; 24.4 %). Patients' mean overall survival from the time of discharge was 51.7 days (median 24.0 days, range 1-488 days). Most patients died in their private home (35.9 %), inpatient hospices (23.3 %) or inpatient PCUs (22.4 %). CONCLUSIONS: The results show a high percentage of stable care trajectories at the end of life with few or no changes of care setting. To achieve this, well-considered discharge planning and an adequately chosen network of care providers are necessary. PMID- 25142705 TI - Length of home hospice care, family-perceived timing of referrals, perceived quality of care, and quality of death and dying in terminally ill cancer patients who died at home. AB - PURPOSE: This study aims to clarify the length of home hospice care, family perceived timing of referrals, and their effects on the family-perceived quality of care and quality of death and dying of terminally ill cancer patients who died at home and identify the determinants of perceived late referrals. METHODS: A multicenter questionnaire survey was conducted involving 1,052 family members of cancer patients who died at home supported by 15 home-based hospice services throughout Japan. RESULTS: A total of 693 responses were analyzed (effective response rate, 66 %). Patients received home-based hospice care for a median of 35.0 days, and 8.0 % received home hospice care for less than 1 week. While 1.5 % of the families reported the timing of referrals as early, 42 % reported the timing as late or too late. The families of patients with a length of care of less than 4 weeks were more likely to regard the timing of referrals as late or too late. The patients of family members who regarded the timing of referrals as late or too late had a significantly lower perceived quality of care (effect size, 0.18; P = 0.039) and lower quality of death and dying (effect size, 0.15, P = 0.063). Independent determinants of higher likelihoods of perceived late referrals included: frequent visits to emergency departments, patient being unprepared for worsening condition, and patient having concerns about relationship with new doctor. Discharge nurse availability was independently associated with lower likelihoods of perceived late referrals. CONCLUSIONS: A significant number of bereaved families regarded the timing of referrals to home hospices as late, and the perceived timing was associated with the family perceived quality of care and quality of death and dying. Systematic strategies to overcome the barriers related to perceived late referrals are necessary. PMID- 25142706 TI - Hyponatraemia is a predictor of clinical outcome for malignant pleural mesothelioma. AB - PURPOSE: Hyponatraemia is one of the most common tumour-related electrolyte disorders. Several clinical, histological and serum factors have been found to influence prognosis, but, to date, there are no studies focusing on the prognostic role of hyponatraemia in mesothelioma. The aim of this study was to assess the prognostic role of hyponatraemia in malignant pleural mesothelioma. METHODS: We analysed 62 consecutive patients with histologically or cytologically proven advanced malignant pleural mesothelioma undergoing chemotherapy at our institution between January 2003 and September 2013. RESULTS: All patients received a first-line pemetrexed-based chemotherapy. A second-line chemotherapy was administered to 29 patients. The onset of hyponatraemia (serum sodium <135 mEq/L) during the treatment was significantly related to a worsened median overall survival (7.93 vs 13.48 months; p = 0.0069). The occurrence of hyponatraemia during first-line chemotherapy (cutoff 135 and 130 mEq/L) was significantly associated to a shorter median progression-free survival (p = 0.0214). Results were also similar in the subgroup receiving a second-line treatment. At the multivariate analysis, including haemoglobin and sodium level at the beginning of first-line chemotherapy, age, gender, smoking habit, job exposure and performance status, only hyponatraemia was found to be an independent factor (p = 0.029). Hyponatraemia was also found to be a predictive factor for both first-line chemotherapy, being related to poorer response to pemetrexed-based chemotherapy (p = 0.047) and second-line chemotherapy (p = 0.044). CONCLUSION: Our results show that hyponatraemia might be considered a negative prognostic parameter in malignant pleural mesothelioma patients. To our knowledge, this is the first study to evaluate the association of hyponatraemia with the outcome of malignant pleural mesothelioma patients. PMID- 25142707 TI - Model-driven meta-analyses for informing health care: a diabetes meta-analysis as an exemplar. AB - A relatively novel type of meta-analysis, a model-driven meta-analysis, involves the quantitative synthesis of descriptive, correlational data and is useful for identifying key predictors of health outcomes and informing clinical guidelines. Few such meta-analyses have been conducted and thus, large bodies of research remain unsynthesized and uninterpreted for application in health care. We describe the unique challenges of conducting a model-driven meta-analysis, focusing primarily on issues related to locating a sample of published and unpublished primary studies, extracting and verifying descriptive and correlational data, and conducting analyses. A current meta-analysis of the research on predictors of key health outcomes in diabetes is used to illustrate our main points. PMID- 25142709 TI - Do we need to know whether nitrous oxide harms patients? PMID- 25142708 TI - The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): a randomised, single blind trial. AB - BACKGROUND: Nitrous oxide is commonly used in general anaesthesia but concerns exist that it might increase perioperative cardiovascular risk. We aimed to gather evidence to establish whether nitrous oxide affects perioperative cardiovascular risk. METHODS: We did an international, randomised, assessor blinded trial in patients aged at least 45 years with known or suspected coronary artery disease having major non-cardiac surgery. Patients were randomly assigned via automated telephone service, stratified by site, to receive a general anaesthetic with or without nitrous oxide. Attending anaesthetists were aware of patients' group assignments, but patients and assessors were not. The primary outcome measure was a composite of death and cardiovascular complications (non fatal myocardial infarction, stroke, pulmonary embolism, or cardiac arrest) within 30 days of surgery. Our modified intention-to-treat population included all patients randomly assigned to groups and undergoing induction of general anaesthesia for surgery. This trial is registered at ClinicalTrials.gov, number NCT00430989. FINDINGS: Of 10,102 eligible patients, we enrolled 7112 patients between May 30, 2008, and Sept 28, 2013. 3543 were assigned to receive nitrous oxide and 3569 were assigned not to receive nitrous oxide. 3483 patients receiving nitrous oxide and 3509 not receiving nitrous oxide were assessed for the primary outcome. The primary outcome occurred in 283 (8%) patients receiving nitrous oxide and in 296 (8%) patients not receiving nitrous oxide (relative risk 0.96, 95% CI 0.83-1.12; p=0.64). Surgical site infection occurred in 321 (9%) patients assigned to nitrous oxide, and in 311 (9%) patients in the no-nitrous oxide group (p=0.61), and severe nausea and vomiting occurred in 506 patients (15%) assigned to nitrous oxide and 378 patients (11%) not assigned to nitrous oxide (p<0.0001). INTERPRETATION: Our findings support the safety profile of nitrous oxide use in major non-cardiac surgery. Nitrous oxide did not increase the risk of death and cardiovascular complications or surgical-site infection, the emetogenic effect of nitrous oxide can be controlled with antiemetic prophylaxis, and a desired effect of reduced volatile agent use was shown. FUNDING: Australian National Health and Medical Research Council; Australian and New Zealand College of Anaesthetists; Heart and Stroke Foundation of Quebec, Heart and Stroke Foundation of Ontario, Canada; General Research Fund of the Research Grant Council, Hong Kong Special Administrative Region, China. PMID- 25142711 TI - Elective splenectomy for hematologic diseases: can we predict complications? PMID- 25142710 TI - The diversity of small non-coding RNAs in the diatom Phaeodactylum tricornutum. AB - BACKGROUND: Marine diatoms constitute a major component of eukaryotic phytoplankton and stand at the crossroads of several evolutionary lineages. These microalgae possess peculiar genomic features and novel combinations of genes acquired from bacterial, animal and plant ancestors. Furthermore, they display both DNA methylation and gene silencing activities. Yet, the biogenesis and regulatory function of small RNAs (sRNAs) remain ill defined in diatoms. RESULTS: Here we report the first comprehensive characterization of the sRNA landscape and its correlation with genomic and epigenomic information in Phaeodactylum tricornutum. The majority of sRNAs is 25 to 30 nt-long and maps to repetitive and silenced Transposable Elements marked by DNA methylation. A subset of this population also targets DNA methylated protein-coding genes, suggesting that gene body methylation might be sRNA-driven in diatoms. Remarkably, 25-30 nt sRNAs display a well-defined and unprecedented 180 nt-long periodic distribution at several highly methylated regions that awaits characterization. While canonical miRNAs are not detectable, other 21-25 nt sRNAs of unknown origin are highly expressed. Besides, non-coding RNAs with well-described function, namely tRNAs and U2 snRNA, constitute a major source of 21-25 nt sRNAs and likely play important roles under stressful environmental conditions. CONCLUSIONS: P. tricornutum has evolved diversified sRNA pathways, likely implicated in the regulation of largely still uncharacterized genetic and epigenetic processes. These results uncover an unexpected complexity of diatom sRNA population and previously unappreciated features, providing new insights into the diversification of sRNA-based processes in eukaryotes. PMID- 25142713 TI - Editorial: Impact of alcohol on HIV related issues in human population or model system. PMID- 25142712 TI - Genes and gene networks implicated in aggression related behaviour. AB - Aggressive behaviour is a major cause of mortality and morbidity. Despite of moderate heritability estimates, progress in identifying the genetic factors underlying aggressive behaviour has been limited. There are currently three genetic mouse models of high and low aggression created using selective breeding. This is the first study to offer a global transcriptomic characterization of the prefrontal cortex across all three genetic mouse models of aggression. A systems biology approach has been applied to transcriptomic data across the three pairs of selected inbred mouse strains (Turku Aggressive (TA) and Turku Non-Aggressive (TNA), Short Attack Latency (SAL) and Long Attack Latency (LAL) mice and North Carolina Aggressive (NC900) and North Carolina Non-Aggressive (NC100)), providing novel insight into the neurobiological mechanisms and genetics underlying aggression. First, weighted gene co-expression network analysis (WGCNA) was performed to identify modules of highly correlated genes associated with aggression. Probe sets belonging to gene modules uncovered by WGCNA were carried forward for network analysis using ingenuity pathway analysis (IPA). The RankProd non-parametric algorithm was then used to statistically evaluate expression differences across the genes belonging to modules significantly associated with aggression. IPA uncovered two pathways, involving NF-kB and MAPKs. The secondary RankProd analysis yielded 14 differentially expressed genes, some of which have previously been implicated in pathways associated with aggressive behaviour, such as Adrbk2. The results highlighted plausible candidate genes and gene networks implicated in aggression-related behaviour. PMID- 25142714 TI - Non-proteinuric diabetic nephropathy. PMID- 25142715 TI - New insight on human type 1 diabetes biology: nPOD and nPOD-transplantation. AB - The Juvenile Diabetes Research Foundation (JDRF) Network for Pancreatic Organ Donors with Diabetes (JDRF nPOD) was established to obtain human pancreata and other tissues from organ donors with type 1 diabetes (T1D) in support of research focused on disease pathogenesis. Since 2007, nPOD has recovered tissues from over 100 T1D donors and distributed specimens to approximately 130 projects led by investigators worldwide. More recently, nPOD established a programmatic expansion that further links the transplantation world to nPOD, nPOD-Transplantation; this effort is pioneering novel approaches to extend the study of islet autoimmunity to the transplanted pancreas and to consent patients for postmortem organ donation directed towards diabetes research. Finally, nPOD actively fosters and coordinates collaborative research among nPOD investigators, with the formation of working groups and the application of team science approaches. Exciting findings are emerging from the collective work of nPOD investigators, which covers multiple aspects of islet autoimmunity and beta cell biology. PMID- 25142716 TI - Motivational interviewing to promote adherence behaviors in pediatric type 1 diabetes. AB - Suboptimal regimen adherence among youth with type 1 diabetes (T1D) is a common challenge for patients, families, and providers. Motivational interviewing (MI) is a brief communication style designed to elicit intrinsic motivation and strengthen commitment to behavior change goals. As pediatric MI research expands, a critical review of its evidence base and applicability to promote adherence behaviors for youth with T1D is needed. This review introduces the core tenets of MI and clinical applications in T1D, synthesizes the existing MI research in T1D, and discusses the next steps in MI research. Overall, mixed results for MI interventions in T1D reflect variations in research study design and clinical implementation. Targeting adherence rather than glycemic outcomes typically demonstrates greater results, highlighting the promise of MI to facilitate meaningful and enduring improvements in youths' T1D adherence behaviors. PMID- 25142717 TI - Executive function, adherence, and glycemic control in adolescents with type 1 diabetes: a literature review. AB - The aim of the present review was to examine and report findings from published research to date that has examined associations between executive function (EF), adherence, and glycemic control in youth with type 1 diabetes. A review of the published research is presented with the objectives of reporting the following: (1) the associations between EF and adherence, (2) the associations between EF and glycemic control, (3) proposed methodological considerations needed to advance related research, (4) recommendations for future research, and (5) clinical recommendations. The major conclusions of this review support the presence of an association between EF, adherence, and glycemic control. Additional prospective and controlled studies are necessary to fully understand the impact of EF on the ability of youth to independently manage type 1 diabetes. PMID- 25142718 TI - Neurocognitive outcomes in pediatric diabetes: a developmental perspective. AB - The impact of diabetes on the developing brain is well-accepted. Effects on neurocognitive functioning are moderate but have larger functional implications, especially when considered through a developmental lens. Pathophysiological factors such as severe hypoglycemia and chronic hyperglycemia can alter developmental trajectories in early childhood and perhaps at later periods. In this paper, we selectively review neurocognitive outcomes in pediatric diabetes (largely type 1), integrating recent research from developmental neuroscience and neuroimaging. We examine the effects of diabetes at different stages and place findings within a neurodevelopmental diathesis/stress framework. Early-onset diabetes is associated with specific effects on memory and more global cognitive late-effects, but less is known about cognitive outcomes of diabetes in later childhood and in adolescence, a time of increased neurobehavioral vulnerability that has received relatively limited empirical attention. Studies are also needed to better elucidate risk and protective factors that may moderate neurodevelopmental outcomes in youth with diabetes. PMID- 25142719 TI - Is there an association between diabetic neuropathy and low vitamin D levels? AB - In the past few years, the effects of vitamin D that go beyond its relationship with bone metabolism have come into the focus of scientific attention. Research concerning diabetes and its complications has become a public health priority. An increasing number of reports link vitamin D deficiency to diabetes; however, so far, there has only been limited and contradictory data available on the correlation between diabetic peripheral neuropathy and vitamin D. Studies of people with type 2 diabetes confirmed the relationship between vitamin D deficiency and neuropathy incidence as well as the severity of the symptoms caused by neuropathy. The latest studies are also suggesting a relationship between the incidence of plantar ulcers and vitamin D deficiency. PMID- 25142720 TI - The role of sodium channels in painful diabetic and idiopathic neuropathy. AB - Painful neuropathies are frequently encountered in clinical practice as an early or late complication of several systemic disorders. Among them, diabetes is one of the most important due to its epidemiology and the relevance for regulatory agencies in the assessment of efficacy of new analgesics. However, the presentation and course of painful neuropathies, as well as the response to available drugs, are highly variable and unpredictable, posing significant challenges in the management of patients. Experimental and clinical studies have suggested that polymorphisms and mutations in pain-related genes are involved in the facilitation or inhibition of nociception, and might modulate neuropathic pain and the response to analgesics in patients. Voltage-gated sodium channel genes are among the most relevant, due to the key role of these membrane proteins in the physiology of nociception and their involvement in the pathogenesis of idiopathic painful small fiber neuropathies. These compelling features make sodium channel candidate targets for a novel approach to painful diabetic and idiopathic neuropathies, which will hopefully allow a new classification of patients and more effective targeted treatments. PMID- 25142722 TI - Clinical applicability of the Thy3a cytological category in thyroid nodules aspirates. Our experience in one hundred and fifty-seven patients with Thy3 cytology. PMID- 25142723 TI - Effects of ventilation rate per person and per floor area on perceived air quality, sick building syndrome symptoms, and decision-making. AB - Ventilation rates (VRs) in buildings must adequately control indoor levels of pollutants; however, VRs are constrained by the energy costs. Experiments in a simulated office assessed the effects of VR per occupant on perceived air quality (PAQ), Sick Building Syndrome (SBS) symptoms, and decision-making performance. A parallel set of experiments assessed the effects of VR per unit floor area on the same outcomes. Sixteen blinded healthy young adult subjects participated in each study. Each exposure lasted four hours and each subject experienced two conditions in a within-subject study design. The order of presentation of test conditions, day of testing, and gender were balanced. Temperature, relative humidity, VRs, and concentrations of pollutants were monitored. Online surveys assessed PAQ and SBS symptoms and a validated computer-based tool measured decision-making performance. Neither changing the VR per person nor changing the VR per floor area, had consistent statistically significant effects on PAQ or SBS symptoms. However, reductions in either occupant-based VR or floor-area-based VR had a significant and independent negative impact on most decision-making measures. These results indicate that the changes in VR employed in the study influence performance of healthy young adults even when PAQ and SBS symptoms are unaffected. PRACTICAL IMPLICATIONS: The study results indicate the importance of avoiding low VRs per person and low VRs per floor area to minimize decrements in cognitive performance. PMID- 25142721 TI - Lifestyle management for enhancing outcomes after bariatric surgery. AB - Bariatric surgery has been safe and effective for treatment of severe obesity and comorbidities like type 2 diabetes mellitus (T2D). Nonetheless, weight loss and health outcomes vary considerably across individuals. Although the factors associated with outcomes are not fully understood, postoperative weight loss following any type of bariatric surgery is largely dependent on the extent to which patients can make and sustain changes in eating and activity. Therefore, lifestyle management including diet, exercise, and behavior modification is critical to helping patients achieve long-term weight loss. Pharmacotherapy and reoperation may also play a role after bariatric surgery. In this article, we highlight recent research findings in all of these areas to provide suggestions for how to enhance outcomes following bariatric surgery. Research on the mechanisms for weight loss and improvements in T2D following the different surgical procedures is needed to support the development of more personalized approaches to the multidisciplinary management of severe obesity. PMID- 25142724 TI - Combined vascular resection and reconstruction during hepatobiliary and pancreatic cancer surgery. PMID- 25142725 TI - Extracellular matrix remodeling of the testes through the male reproductive cycle in Teleostei fish. AB - During the fish reproductive cycle, testes undergo morphological changes related to germinal epithelium and remodeling of extracellular matrix components (ECM). ECM is degraded mainly by action of matrix metalloproteinases (MMPs). Due to the natural renewal of ECM in fish testes, we choose Pimelodus maculatus to study remodeling of ECM throughout reproductive cycle, using picrosirius (to identify type I, II, III collagen) and reticulin (type III collagen), and to immunolocalize MT1-MMP (membrane type 1-matrix metalloproteinase) and MMP-2 in testis cells. Testes were classified in four reproductive phases: regenerating, development, spawning capable and regressing. Picrosirius and reticulin demonstrated a differential distribution of total collagen fibers during the reproductive cycle. Immunohistochemistry showed MT1-MMP only in acidophilic granulocyte cells mainly inside blood vessels, in connective tissue of capsule close to the germinal compartment, and also infiltrated in interstitial connective tissue. MMP-2 was detected in fibroblast and endothelial cells of interstitial and capsule blood vessels, in epithelial cells of capsule, and in acidophilic granulocyte cells at same description for MT1-MMP. The fish testes ECM were remodeled throughout reproductive cycle in according to morphophysiological alterations. During reproductive season (spawning capable), the interstitium increased in total collagen fibers (type I, II, III). After spermiation period (regression and regenerating), the amount of collagen fibers decreased in response to action of MMPs on collagen degradation and other interstitial components (not assessed in this study). MMPs seem to be indispensable components for natural cyclic events of ECM remodeling of fish testes and for guarantee tissue homeostasis throughout reproductive cycle. PMID- 25142726 TI - Sub-inhibitory concentrations of antifungals suppress hemolysin activity of oral Candida albicans and Candida tropicalis isolates from HIV-infected individuals. AB - Secretion of hydrolytic enzymes such as hemolysin is considered an important virulence attribute of the opportunistic pathogenic fungus Candida. It is known that Candida spp. isolated from HIV-infected patients produce copious hemolysins. As common antifungal agents may perturb the production of extracellular enzymes, we evaluated the effect of three antifungals nystatin, amphotericin B and fluconazole on the hemolytic activity of Candida albicans and Candida tropicalis isolates from HIV-infected individuals. The impact of antimycotics on hemolytic activity was assessed by a previously described in vitro plate assay, after exposing ten isolates each of C. albicans and C. tropicalis recovered from HIV infected individuals to sub-minimum inhibitory concentrations (sub-MIC) of nystatin, amphotericin B and fluconazole. All Candida isolates showed a significant reduction in hemolytic activity. The reduction was highest for amphotericin B-exposed C. albicans and C. tropicalis followed by nystatin and fluconazole. The effect of antimycotics was more pronounced on the hemolytic activity of C. tropicalis compared to that of C. albicans. Commonly used antifungal agents significantly suppress hemolysin activity of Candida species. This implies that the antifungals, in addition to their lethality, may modulate key virulence attributes of the yeast. The clinical relevance of this phenomenon in HIV disease and other similar pathologies remains to be determined. PMID- 25142727 TI - Occurrence of methicillin-resistant Staphylococcus aureus in farm workers and the livestock environment in Mecklenburg-Western Pomerania, Germany. AB - BACKGROUND: Livestock-associated methicillin-resistant Staphylococcus aureus (LA MRSA) has a wide host range and is transmissible to humans, especially to those with close contact to colonized animals. This study presents the first data on the occurrence of MRSA in farm workers and livestock farms (pig, cattle and poultry) in the federal state of Mecklenburg-Western Pomerania in northeast Germany. 78 farm workers at pig farms, cattle farms and poultry farms were tested for MRSA via pooled nasal and pharyngeal swabs. Additionally, from each of the 34 participating farms (17 pig farms, 11 cattle farms, 6 poultry farms) five dust samples were taken from the direct surroundings of the animals. Furthermore, oropharyngeal swabs were additionally taken from 10 animals per poultry farm. Isolated MRSA strains were characterized and confirmed using PCR and spa typing. Resistance patterns were obtained using the broth microdilution assay. RESULTS: In total, 20 of 78 (25.6%; 95% CI:17.3-36.3) farm workers were positive for MRSA. All MRSA-positive workers were employed at pig farms. Six of 17 (35.3%; 95% CI:17.3-58.7) pooled dust samples from pig farms were also positive. Overall, six spa types were identified, of which t034 predominated. All strains belonged to LA MRSA CC398 and were resistant to tetracycline. Resistance to lincosamides, macrolides, fluoroquinolones and aminoglycosides was present in some strains. Three farm workers harbored the identical spa type and antimicrobial resistance pattern found in the corresponding dust sample. Neither workers, dust samples from cattle and poultry farms, nor oropharyngeal poultry swabs tested positive for MRSA. CONCLUSIONS: The present study emphasizes the importance of MRSA on pig farms and pig-farm workers in the rural region of Mecklenburg-Western Pomerania, whereas LA-MRSA could not be isolated from cattle and poultry farms. PMID- 25142728 TI - Surface Al leached Ti3AlC2 as a substitute for carbon for use as a catalyst support in a harsh corrosive electrochemical system. AB - Surface Al leached Ti3AlC2 particles (e-TAC) with high corrosion resistance and excellent electrical conductivity were developed as an advanced support material for Pt catalysts. Electrochemical measurements confirm that the supported Pt/e TAC electrocatalyst shows much improved activity and enhanced durability toward the oxygen reduction reaction when compared with the commercial Pt/C catalyst. PMID- 25142729 TI - Effects of rapid intravenous 100% L-isomer lactated Ringer's administration on plasma lactate concentrations in healthy dogs. AB - OBJECTIVE: To determine if rapid intravenous administration of lactated Ringer's solution containing 28 mmol/L of l-lactate (L-LRS) can result in an increase in plasma lactate concentration in healthy dogs. DESIGN: Prospective cross over study with a 4-week washout period. SETTING: Veterinary teaching hospital. ANIMALS: Six healthy adult Beagles. INTERVENTIONS: Dogs received 180 mL/kg/h of L LRS over 60 minutes, followed by a 4-week washout period, then 180 mL/kg/h of 0.9% sodium chloride (NaCl) over 60 minutes. MEASUREMENTS AND MAIN RESULTS: Blood samples were drawn at baseline (T0), every 10 minutes during fluid administration (T10 to T60), and 60 minutes after fluid administration (T120). Samples were measured in duplicate at all time points with a handheld meter and at T0, T60, and T120 with a blood gas analyzer. Data were analyzed with 1-way or 2-way ANOVA for repeated measures and post hoc tests with Dunnett's or Bonferroni's correction for within-group and between group analyses, respectively. P values < 0.05 were considered significant. Results are mean +/- SD. There was no difference between groups at T0 (L-LRS = 1.1 +/- 0.6 mmol/L, NaCl = 1.2 +/- 0.9 mmol/L). Within the L-LRS group, T0 was significantly lower than all other time points except T120. At T50 and T60, the L-LRS group was higher than the NaCl group. There was a statistical significance between the 2 groups over time. CONCLUSIONS: The rapid administration of intravenous L-LRS to healthy dogs significantly increases plasma lactate concentration within 10 minutes and returns to baseline values within 60 minutes after cessation of administration. This could have implications in how plasma lactate concentration is interpreted with respect to prognosis, particularly in patients receiving resuscitative rates of L-LRS. Interpretation of plasma lactate concentrations should be considered in light of the rate, quantity and type of fluid administered, and timing of blood samples. PMID- 25142730 TI - Persistence of anti-desmoglein 3 IgG(+) B-cell clones in pemphigus patients over years. AB - Pemphigus vulgaris (PV) is a prototypic tissue-specific autoantibody-mediated disease, in which anti-desmoglein 3 (Dsg3) IgG autoantibodies cause life threatening blistering. We characterized the autoimmune B-cell response over 14 patient years in two patients with active and relapsing disease, then in one of these patients after long-term remission induced by multiple courses of rituximab (anti-CD20 antibody). Characterization of the anti-Dsg3 IgG(+) repertoire by antibody phage display (APD) and PCR indicated that six clonal lines persisted in patient 1 (PV3) over 5.5 years, with only one new clone detected. Six clonal lines persisted in patient 2 (PV1) for 4 years, of which five persisted for another 4.5 years without any new clones detected. However, after long-term clinical and serologic remission, ~11 years after initial characterization, we could no longer detect any anti-Dsg3 clones in PV1 by APD. Similarly, in another PV patient, ~4.5 years after a course of rituximab that induced long-term remission, anti-Dsg3 B-cell clones were undetectable. These data suggest that in PV a given set of non-tolerant B-cell lineages causes autoimmune diseases and that new sets do not frequently or continually escape tolerance. Therapy such as rituximab, aimed at eliminating these aberrant sets of lineages, may be effective for disease because new ones are unlikely to develop. PMID- 25142733 TI - The role of level anti-crossings in nuclear spin hyperpolarization. AB - Nuclear spin hyperpolarization is an important resource for increasing the sensitivity of NMR spectroscopy and MRI. Signal enhancements can be as large as 3 4 orders of magnitude. In hyperpolarization experiments, it is often desirable to transfer the initial polarization to other nuclei of choice, either protons or insensitive nuclei such as (13)C and (15)N. This situation arises primarily in Chemically Induced Dynamic Nuclear Polarization (CIDNP), Para-Hydrogen Induced Polarization (PHIP), and the related Signal Amplification By Reversible Exchange (SABRE). Here we review the recent literature on polarization transfer mechanisms, in particular focusing on the role of Level Anti-Crossings (LACs) therein. So-called "spontaneous" polarization transfer may occur both at low and high magnetic fields. In addition, transfer of spin polarization can be accomplished by using especially designed pulse sequences. It is now clear that at low field spontaneous polarization transfer is primarily due to coherent spin state mixing under strong coupling conditions. However, thus far the important role of LACs in this process has not received much attention. At high magnetic field, polarization may be transferred by cross-relaxation effects. Another promising high-field technique is to generate the strong coupling condition by spin locking using strong radio-frequency fields. Here, an analysis of polarization transfer in terms of LACs in the rotating frame is very useful to predict which spin orders are transferred depending on the strength and frequency of the B1 field. Finally, we will examine the role of strong coupling and LACs in magnetic-field dependent nuclear spin relaxation and the related topic of long lived spin-states. PMID- 25142731 TI - Pro-survival role of MITF in melanoma. AB - Melanoma is a therapy-resistant skin cancer due to numerous mechanisms supporting cell survival. Although components of melanoma cytoprotective mechanisms are overexpressed in many types of tumors, some of their regulators are characteristic for melanoma. Several genes mediating pro-survival functions have been identified as direct targets of microphthalmia-associated transcription factor (MITF), a melanocyte-specific modulator also recognized as a lineage addiction oncogene in melanoma. BRAF(V600E) and other proteins deregulated in melanoma influence MITF expression and activity, or they are the partners of MITF in melanoma response to radiotherapy and chemotherapeutics. In this review, the pro-survival activity of MITF is discussed. PMID- 25142734 TI - A review of blind source separation in NMR spectroscopy. AB - Fourier transform is the data processing naturally associated to most NMR experiments. Notable exceptions are Pulse Field Gradient and relaxation analysis, the structure of which is only partially suitable for FT. With the revamp of NMR of complex mixtures, fueled by analytical challenges such as metabolomics, alternative and more apt mathematical methods for data processing have been sought, with the aim of decomposing the NMR signal into simpler bits. Blind source separation is a very broad definition regrouping several classes of mathematical methods for complex signal decomposition that use no hypothesis on the form of the data. Developed outside NMR, these algorithms have been increasingly tested on spectra of mixtures. In this review, we shall provide an historical overview of the application of blind source separation methodologies to NMR, including methods specifically designed for the specificity of this spectroscopy. PMID- 25142735 TI - Metabolites in safety testing assessment in early clinical development: a case study with a glucokinase activator. AB - The present article summarizes Metabolites in Safety Testing (MIST) studies on a glucokinase activator, N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2 yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (PF-04937319), which is under development for the treatment of type 2 diametes mellitus. Metabolic profiling in rat, dog, and human hepatocytes revealed that PF-04937319 is metabolized via oxidative (major) and hydrolytic pathways (minor). N Demethylation to metabolite M1 [N-methyl-5-((2-methyl-6-((5-methylpyrazin-2 yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide] was the major metabolic fate of PF-04937319 in human (but not rat or dog) hepatocytes, and was catalyzed by CYP3A and CYP2C isoforms. Qualitative examination of circulating metabolites in humans at the 100- and 300-mg doses from a 14-day multiple dose study revealed unchanged parent drug and M1 as principal components. Because M1 accounted for 65% of the drug-related material at steady state, an authentic standard was synthesized and used for comparison of steady-state exposures in humans and the 3-month safety studies in rats and dogs at the no-observed-adverse effect level. Although circulating levels of M1 were very low in beagle dogs and female rats, adequate coverage was obtained in terms of total maximal plasma concentration (~7.7* and 1.8*) and area under the plasma concentration-time curve (AUC; 3.6* and 0.8* AUC) relative to the 100- and 300-mg doses, respectively, in male rats. Examination of primary pharmacology revealed M1 was less potent as a glucokinase activator than the parent drug (compound PF-04937319: EC50 = 0.17 MUM; M1: EC50 = 4.69 MUM). Furthermore, M1 did not inhibit major human P450 enzymes (IC50 > 30 MUM), and was negative in the Salmonella Ames assay, with minimal off-target pharmacology, based on CEREP broad ligand profiling. Insights gained from this analysis should lead to a more efficient and focused development plan for fulfilling MIST requirements with PF-04937319. PMID- 25142736 TI - Activity-limiting role of molecular size: size-dependency of maximum activity for P450 inhibition as revealed by qHTS data. AB - Analysis of a large number of data on cytochrome P450 (P450) inhibition obtained from quantitative high-throughput screening assays from the PubChem BioAssay Database clearly indicates that molecular size has an important activity-limiting role for datasets focused on drug-like compounds (PubChem BioAssay Identifier [AID] 1851) as well as for datasets also incorporating a wider range of environmental chemicals (AIDs 410, 899, 883, 891, and 884). Maximum inhibitory activity increases with size for small enough structures then plateaus and begins to show a decreasing trend for larger structures. Log-scaled maximum median inhibitory concentration (pIC50) as a function of molecular size could be fitted well with a bilinear model (LinBiExp), and the shape of the curve is quite similar across five P450 isozymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4) with a turning-point of maximum inhibition around 300-500 Da. While the present size based approach cannot account for the variability of activity in general, using data for a very large number of compounds, it still provides an intuitive interpretation of the maximum P450-inhibitory activity obtainable for a given molecular size and highlights the presence of an "optimum" size range. PMID- 25142737 TI - Effects of cytochrome P450 2C9 polymorphism on bosentan metabolism. AB - Cytochrome P450 (P450) 2C9 is an important member of the P450 enzyme superfamily, with 58 CYP2C9 allelic variants previously reported. Genetic polymorphisms of CYP2C9 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. The aim of this study was to assess the catalytic activities of 38 human CYP2C9 alleles, including 24 novel alleles (*36-*60) found in the Han Chinese population, toward bosentan (BOS) in vitro. Insect microsomes expressing the 38 CYP2C9 alleles were incubated with 10 625 MUM bosentan for 30 minutes at 37 degrees C and terminated by cooling to -80 degrees C immediately. BOS and hydroxyl bosentan, the major metabolite of BOS, were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry system. Thirty-eight defective alleles can be classified into three categories according to the relative clearance value compared with wild type: nine alleles exhibited significantly increased intrinsic clearance values (Vmax/Km) compared with the wild type (1.5-fold-~4.9-fold relative clearance); nine alleles exhibited significantly reduced intrinsic clearance values compared with the wild type (0.6-28.9% relative clearance). The remaining 20 alleles exhibited no significant difference (1-fold) in enzyme activity compared with the wild type. These findings suggest that more attention should be directed to subjects carrying these infrequent CYP2C9 alleles when administering BOS in the clinic. This is the first report of all these rare alleles for BOS metabolism, providing fundamental data for further clinical studies on CYP2C9 alleles. PMID- 25142738 TI - Heterogeneity of shale documented by micro-FTIR and image analysis. AB - In this study, four New Albany Shale Devonian and Mississippian samples, with vitrinite reflectance [Ro ] values ranging from 0.55% to 1.41%, were analyzed by micro-FTIR mapping of chemical and mineralogical properties. One additional postmature shale sample from the Haynesville Shale (Kimmeridgian, Ro = 3.0%) was included to test the limitation of the method for more mature substrates. Relative abundances of organic matter and mineral groups (carbonates, quartz and clays) were mapped across selected microscale regions based on characteristic infrared peaks and demonstrated to be consistent with corresponding bulk compositional percentages. Mapped distributions of organic matter provide information on the organic matter abundance and the connectivity of organic matter within the overall shale matrix. The pervasive distribution of organic matter mapped in the New Albany Shale sample MM4 is in agreement with this shale's high total organic carbon abundance relative to other samples. Mapped interconnectivity of organic matter domains in New Albany Shale samples is excellent in two early mature shale samples having Ro values from 0.55% to 0.65%, then dramatically decreases in a late mature sample having an intermediate Ro of 1.15% and finally increases again in the postmature sample, which has a Ro of 1.41%. Swanson permeabilities, derived from independent mercury intrusion capillary pressure porosimetry measurements, follow the same trend among the four New Albany Shale samples, suggesting that micro-FTIR, in combination with complementary porosimetric techniques, strengthens our understanding of porosity networks. In addition, image processing and analysis software (e.g. ImageJ) have the capability to quantify organic matter and total organic carbon - valuable parameters for highly mature rocks, because they cannot be analyzed by micro-FTIR owing to the weakness of the aliphatic carbon-hydrogen signal. PMID- 25142740 TI - Accurate evaluation of para-Hisian pacing in a patient with fasciculoventricular bypass. PMID- 25142739 TI - Whole-body vibration and the risk of low back pain and sciatica: a systematic review and meta-analysis. AB - PURPOSE: The aim of this systematic literature review was to evaluate the association between whole-body vibration (WBV) and low back pain (LBP) and sciatica with special attention given to exposure estimates. Moreover, the aim was to estimate the magnitude of such an association using meta-analysis and to compare our findings with previous reviews. METHODS: The authors systematically searched the PubMed (National Library of Medicine, Bethesda), Nioshtic2 (National Institute for Occupational Safety and Health (NIOSH, Morgantown), and ScienceDirect (Elsevier, Amsterdam) databases for records up to December 31, 2013. Two of the authors independently assessed studies to determine their eligibility, validity, and possible risk of bias. RESULTS: The literature search gave a total of 306 references out of which 28 studies were reviewed and 20 were included in the meta-analysis. Exposure to WBV was associated with increased prevalence of LBP and sciatica [pooled odds ratio (OR) = 2.17, 95% confidence interval (CI) 1.61-2.91 and OR 1.92, 95% CI 1.38-2.67, respectively]. Workers exposed to high vibration levels had a pooled risk estimate of 1.5 for both outcomes when compared with workers exposed to low levels of vibration. The results also indicate that some publication bias could have occurred especially for sciatica. CONCLUSIONS: This review shows that there is scientific evidence that exposure to WBV increases the risk of LBP and sciatica. PMID- 25142741 TI - Ventricular pre-excitation: symptomatic and asymptomatic children have the same potential risk of sudden cardiac death. AB - AIMS: Children and adolescents with ventricular pre-excitation (VPE) are at increased risk for sudden cardiac death (SCD). Although antiarrhythmic therapy and catheter ablation are well established temporary or definitive treatments for patients with Wolff-Parkinson-White (WPW) syndrome, the optimal management of children with asymptomatic VPE remains to be clearly defined. On the basis of the most recent guidelines and recommendations, the aim of this study was to determine the electrophysiological characteristics of young patients with VPE and WPW syndrome to assess and compare their potential risk of SCD. METHODS AND RESULTS: We retrospectively investigated 124 consecutive young patients with VPE (51 with WPW syndrome and 73 asymptomatic) who underwent transoesophageal electrophysiological study. At baseline, atrioventricular reentrant tachycardia (AVRT) was induced in 13 WPW vs. 10 asymptomatic patients (25.5 vs. 13.7%, P = NS). Atrial fibrillation (AF) was induced in 13 WPW vs. 15 asymptomatic patients (25.5 vs. 20.5%, P = NS). A shortest pre-excited R-R interval (SPERRI) <=250 ms during AF was found in four WPW vs. six asymptomatic patients (30.8 vs. 40%, P = NS). During isoproterenol infusion or stress testing, AVRT was induced in 31 of 44 WPW vs. 33 of 69 asymptomatic patients (70.4 vs. 47.8%, P = 0.018). Atrial fibrillation was induced in 12 of 44 WPW vs. 21 of 69 asymptomatic patients (27.3 vs. 30.4%, P = NS). A SPERRI <= 210 ms was found in 6 of 12 WPW vs. 10 of 21 asymptomatic patients (50 vs. 47.6%, P = NS). No statistically significant correlation was observed between accessory pathway location and symptoms, AVRT/AF inducibility, or mean APERP/SPERRI values. CONCLUSION: Children and adolescents with WPW syndrome have a higher rate of AVRT inducibility than asymptomatic patients. However, no differences between the two groups were found in atrial vulnerability and parameters related to the risk of SCD. PMID- 25142742 TI - Sinus rhythm restoration affects collagen turnover in patients with persistent atrial fibrillation. AB - AIMS: Collagen turnover and atrial fibrosis have been implicated in the generation and perpetuation of atrial fibrillation (AF). We evaluated the importance of serum markers of collagen turnover in predicting the outcome of electrical cardioversion (CV) of persistent AF and the relationship between AF and fibrosis. METHODS AND RESULTS: Serum C-terminal pro-peptide of collagen type I (CICP) and C-terminal telopeptide of collagen type-I (CITP) were measured in 164 patients with AF before and 2 months after CV. All the patients were successfully cardioverted to sinus rhythm (SR) although in 38 of them AF recurred. Baseline CICP levels were comparable in patients in SR 60 days after CV and in those who experienced a relapse of AF (85.08 +/- 16.99 vs. 87.55 +/- 10.43 ng/mL, respectively, P = ns). Baseline CITP levels were significantly higher in patients with AF recurrence compared with those who remained in SR (0.48 +/- 0.16 vs. 0.32 +/- 0.17 ng/mL, respectively, P < 0.0001). In the 126 patients who maintained the SR, CICP levels were significantly lower at the end of the study as compared with the baseline (63.74 +/- 15.92 vs. 85.08 +/- 16.99 ng/mL P = 0.003), while there was a mild increase in plasma CITP levels (0.36 +/- 0.21 vs. 0.32 +/- 0.17 ng/mL, respectively, P = 0.03). CONCLUSION: Atrial fibrillation can result in alterations in atrial structure and architecture that make the atrial myocardium more susceptible to the maintenance of the arrhythmia. Sinus rhythm restoration could affect the fibrotic process occurring or exacerbating during AF course. PMID- 25142743 TI - Modulation transfer function measurement of CT images by use of a circular edge method with a logistic curve-fitting technique. AB - We propose a method for measuring the modulation transfer function (MTF) of a computed tomography (CT) system by use of a circular edge method with a logistic curve-fitting technique. An American College of Radiology (ACR) phantom was scanned by a Philips Brilliance system, and axial images were reconstructed by the filtered back projection algorithm with a standard reconstruction filter. The radial MTF was measured from a disk image of a rod or cylinder in the ACR phantom by use of the circular edge method. In this study, we applied a logistic curve fitting technique to an edge-spread function (ESF) to eliminate noise because the edge method is very susceptible to noise in the ESF in a CT image. The circular edge method with the logistic curve-fitting technique provided the MTF without fluctuations due to noise for the entire spatial frequency range. The MTF was not affected by the tube current, the slice thickness, or the disk contrast, which were factors related to the amount of noise in the CT image. However, the MTF was affected by the location of the disk and by the disk size, depending on the average distance from the isocenter to the disk edge. Our results indicated that the MTF measured by the circular edge method with the logistic curve-fitting technique was not susceptible to noise in CT images. Therefore, this method is useful for MTF measurement for not only high-contrast objects, but also low contrast objects with a large amount of noise. PMID- 25142744 TI - Self-sustained oscillations in blood flow through a honeycomb capillary network. AB - Numerical simulations of unsteady blood flow through a honeycomb network originating at multiple inlets and terminating at multiple outlets are presented and discussed under the assumption that blood behaves as a continuum with variable constitution. Unlike a tree network, the honeycomb network exhibits both diverging and converging bifurcations between branching capillary segments. Numerical results based on a finite difference method demonstrate that as in the case of tree networks considered in previous studies, the cell partitioning law at diverging bifurcations is an important parameter in both steady and unsteady flow. Specifically, a steady flow may spontaneously develop self-sustained oscillations at critical conditions by way of a Hopf bifurcation. Contrary to tree-like networks comprised entirely of diverging bifurcations, the critical parameters for instability in honeycomb networks depend weakly on the system size. The blockage of one or more network segments due to the presence of large cells or the occurrence of capillary constriction may cause flow reversal or trigger a transition to unsteady flow. PMID- 25142745 TI - Theoretical description of metabolism using queueing theory. AB - A theoretical description of the process of metabolism has been developed on the basis of the Pachinko model (see Nicholson and Wilson in Nat Rev Drug Discov 2:668-676, 2003) and the queueing theory. The suggested approach relies on the probabilistic nature of the metabolic events and the Poisson distribution of the incoming flow of substrate molecules. The main focus of the work is an output flow of metabolites or the effectiveness of metabolism process. Two simplest models have been analyzed: short- and long-living complexes of the source molecules with a metabolizing point (Hole) without queuing. It has been concluded that the approach based on queueing theory enables a very broad range of metabolic events to be described theoretically from a single probabilistic point of view. PMID- 25142746 TI - A model for genome size evolution. AB - We present a model for genome size evolution that takes into account both local mutations such as small insertions and small deletions, and large chromosomal rearrangements such as duplications and large deletions. We introduce the possibility of undergoing several mutations within one generation. The model, albeit minimalist, reveals a non-trivial spontaneous dynamics of genome size: in the absence of selection, an arbitrary large part of genomes remains beneath a finite size, even for a duplication rate 2.6-fold higher than the rate of large deletions, and even if there is also a systematic bias toward small insertions compared to small deletions. Specifically, we show that the condition of existence of an asymptotic stationary distribution for genome size non-trivially depends on the rates and mean sizes of the different mutation types. We also give upper bounds for the median and other quantiles of the genome size distribution, and argue that these bounds cannot be overcome by selection. Taken together, our results show that the spontaneous dynamics of genome size naturally prevents it from growing infinitely, even in cases where intuition would suggest an infinite growth. Using quantitative numerical examples, we show that, in practice, a shrinkage bias appears very quickly in genomes undergoing mutation accumulation, even though DNA gains and losses appear to be perfectly symmetrical at first sight. We discuss this spontaneous dynamics in the light of the other evolutionary forces proposed in the literature and argue that it provides them a stability-related size limit below which they can act. PMID- 25142747 TI - Adipokines and biochemical changes in Egyptian obese subjects: possible variation with sex and degree of obesity. AB - The purpose of this study was firstly to evaluate the adipokines and biochemical changes in obese subjects in relation to different grades of obesity and in relation to gender difference (males versus females) and secondly to evaluate the role of TNF-alpha in obesity. From January 2013 to February 2014, a total number of 120 non-diabetic subjects of both sexes were recruited and randomly selected from Dr. Abd-Elhamid Elsheikh center for physiotherapy and weight control, El menofia-Egypt. Those subjects were classified according to their sex into two main groups; the female group and the male group. The female group (60 women) was distributed according to BMI into group 1 (15 lean women), group 2 (15 class I obese women), group 3 (15 class II obese women), and group 4 (15 class III obese women). The male group (60 men) was also distributed according to the BMI into group 1 (15 lean men), group 2 (15 class I obese men), group 3 (15 class II obese men), and group 4 (15 class III obese men). All individuals enrolled in the study were submitted to weight and height measurements with subsequent calculation of body mass index. Fasting blood samples were collected from all participants for quantitative determination of blood glucose, serum lipid, TNF-alpha, leptin, and adiponectin levels. One-way analysis of variance followed by LSD post hoc test was used for comparison of variables. In obese subjects of both sexes, it was found that circulating leptin and TNF-alpha levels were significantly high (P<0.05) and positively correlated to BMI. In contrast to leptin, adiponectin concentrations were significantly low (P<0.05) and inversely correlated to BMI. Regarding gender difference, although serum leptin and adiponectin levels were higher in women than men, men showed higher atherogenic parameters. We conclude that leptin, TNF-alpha, and adiponectin were related to both BMI and grades of obesity. Furthermore, TNF-alpha may play a role in obesity. PMID- 25142748 TI - Restless legs syndrome is associated with cardio/cerebrovascular events and mortality in end-stage renal disease. AB - BACKGROUND AND PURPOSE: Earlier studies suggested an association between idiopathic restless legs syndrome (RLS) and cardiovascular diseases. However, the risk of cardiovascular events in patients with secondary RLS due to end-stage renal disease (ESRD) is unclear. Our aim was to examine whether ESRD patients with RLS had an increased risk of cardio/cerebrovascular events and mortality. METHODS: In all, 1093 ESRD patients were recruited between 2009 and 2010. The diagnosis and severity of RLS were assessed in a face-to-face interview. The occurrence of cardio/cerebrovascular events and death were confirmed by medical record review. The association between RLS and the outcomes of interest was examined using an adjusted multivariate Cox regression model. RESULTS: After a mean follow-up period of 3.7 +/- 0.8 years, ESRD patients with RLS had a significantly higher risk of developing cardiovascular events and strokes [adjusted hazard ratio (aHR) 2.82, 95% confidence interval (CI) 2.02-4.11, and aHR 2.41, 95% CI 1.55-3.75, respectively] compared with patients without RLS. Increasing RLS severity was associated with an increasing likelihood of cardiovascular events [mild RLS severity, aHR 1.71 (95% CI 1.02-2.87); moderate, 2.79 (1.64-4.66); severe, 2.85 (1.99-4.46)] and strokes [mild, 1.89 (0.87-4.16); moderate, 2.42 (1.50-3.90); severe, 2.64 (1.49-4.91)] in a dose-dependent manner. RLS also increased the risk of total mortality in patients with ESRD [aHR 1.53 (95% CI 1.07-2.18), P = 0.02]; this association attenuated slightly after stratification by individual RLS severity category [mild RLS severity, aHR 1.44 (95% CI 0.78-2.67); moderate, 1.49 (0.98-2.55); severe, 2.03 (0.93-4.45)]. CONCLUSIONS: ESRD patients with RLS demonstrated an increased likelihood of cardio/cerebrovascular events and mortality. PMID- 25142749 TI - Synthesis and reactivity of coordinatively unsaturated halocarbonyl molybdenum PNP pincer complexes. AB - In the present study a series of six-coordinate neutral 16e halocarbonyl Mo(ii) complexes of the type [Mo(PNP(Me)-iPr)(CO)X2] (X = I, Br, Cl), featuring the PNP pincer ligand N,N'-bis(diisopropylphosphino)-N,N'-dimethyl-2,6-diaminopyridine (PNP(Me)-iPr), were prepared and fully characterized. The synthesis of these complexes was accomplished by different methodologies depending on the halide ligands. For X = I and Br, [Mo(PNP(Me)-iPr)(CO)I2] and [Mo(PNP(Me)-iPr)(CO)Br2] were obtained by reacting [Mo(PNP(Me)-iPr)(CO)3] with stoichiometric amounts of I2 and Br2, respectively. In the case of X = Cl, [Mo(PNP(Me)-iPr)(CO)Cl2] was afforded by the reaction of [Mo(CO)4(MU-Cl)Cl]2 with 1 equiv. of PNP(Me)-iPr. The equivalent procedure also worked for X = Br. The modification of the 2,6 diaminopyridine scaffold by introducing NMe instead of NH spacers between the aromatic pyridine ring and the phosphine moieties changed the steric properties of the PNP-iPr ligand significantly. While in the present case exclusively neutral six-coordinate complexes of the type [Mo(PNP(Me)-iPr)(CO)X2] were obtained, with the parent PNP-iPr ligand, i.e. featuring NH spacers, cationic seven-coordinate complexes of the type [Mo(PNP-iPr)(CO)3X]X were afforded. Upon treatment of [Mo(PNP(Me)-iPr)(CO)X2] (X = Br, Cl) with Ag(+) in CH3CN, the cationic complexes [Mo(PNP(Me)-iPr)(CO)(CH3CN)X](+) were formed. Halide abstraction from [Mo(PNP(Me)-iPr)(CO)Cl2] in THF-CH2Cl2 afforded [Mo(PNP(Me) iPr)(CO)(THF)Cl](+). In keeping with the facile synthesis of monocationic complexes preliminary ESI-MS and DFT/B3LYP studies revealed that one halide ligand in complexes [Mo(PNP(Me)-iPr)(CO)X2] is labile forming cationic fragments [Mo(PNP(Me)-iPr)(CO)X](+) which react with molecular oxygen in parallel pathways to yield mono and dioxo Mo(iv) and Mo(vi) species. Structures of representative complexes were determined by X-ray single crystal analyses. PMID- 25142750 TI - Immunoglobulin A nephropathy in horseshoe kidney: case reports and literature review. AB - Horseshoe kidney is the most common congenital renal fusion anomaly. Immunoglobulin A nephropathy is a common glomerulonephritis worldwide. However, the co-occurrence of these diseases had not been reported in the literature. We report the first two cases with the occurrence of immunoglobulin A nephropathy in horseshoe kidney. The first case was a 26-year-old male with hypertension and proteinuria (1.4 g/24 h), his pathological finding was primary immunoglobulin A nephropathy. The second case was a 15-year-old female who presented with recurrent peliosis on bilateral lower extremities, haematuria and proteinuria (1.7 g/24 h). Her renal biopsy finding was Henoch-Schonlein purpura nephritis (secondary immunoglobulin A nephropathy). In both cases, renal biopsy was performed by experienced doctors under ultrasonic guidance at the renal upper pole and no postoperative complications were observed. After they were treated based on the renal pathological findings for 6 months, urine protein excretion decreased significantly and blood pressure and serum creatinine stabilized. It is possible that immunoglobulin A nephropathy occurs in a horseshoe kidney patient. Renal biopsy may be valuable and viable for horseshoe kidney patients with heavy proteinuria to identify pathologic type of glomerulopathy and to guide treatment, if renal biopsy is performed by experienced doctors at the renal upper pole under renal ultrasonic guidance. PMID- 25142751 TI - Multiplication of microbes below 0.690 water activity: implications for terrestrial and extraterrestrial life. AB - Since a key requirement of known life forms is available water (water activity; aw ), recent searches for signatures of past life in terrestrial and extraterrestrial environments have targeted places known to have contained significant quantities of biologically available water. However, early life on Earth inhabited high-salt environments, suggesting an ability to withstand low water-activity. The lower limit of water activity that enables cell division appears to be ~ 0.605 which, until now, was only known to be exhibited by a single eukaryote, the sugar-tolerant, fungal xerophile Xeromyces bisporus. The first forms of life on Earth were, though, prokaryotic. Recent evidence now indicates that some halophilic Archaea and Bacteria have water-activity limits more or less equal to those of X. bisporus. We discuss water activity in relation to the limits of Earth's present-day biosphere; the possibility of microbial multiplication by utilizing water from thin, aqueous films or non-liquid sources; whether prokaryotes were the first organisms able to multiply close to the 0.605 aw limit; and whether extraterrestrial aqueous milieux of >= 0.605 aw can resemble fertile microbial habitats found on Earth. PMID- 25142752 TI - School-based oral health-education program using experiential learning or traditional lecturing in adolescents: a clinical trial. AB - The aim of this project was to compare the effectiveness of experiential learning (EL) and traditional lecturing (TL) school-based oral health education on the oral health knowledge, attitude, habits, oral hygiene, gingival health and caries incidence of 13-year-old Greek children. Eighty-seven children for the EL group and 80 for the TL group were selected from two areas of Greece. Information on oral health knowledge, attitude and behaviours were obtained using a questionnaire. Dental plaque was recorded using a modified hygiene index, gingivitis was assessed using the simplified gingival index and dental caries was measured by recording the number of Decayed, Missing and Filled teeth (DMFT) using the British Association for the Study of Community Dentistry (BASCD) criteria. All children were examined by two calibrated dentists, using a World Health Organisation (WHO) periodontal probe and artificial light. Questionnaires were delivered and clinical examinations were performed at baseline and at 6 and 18 months post-intervention. The EL oral health educational programme was implemented by teachers using the programme's manual. Oral health knowledge had improved significantly (P < 0.001) in both groups at 6 and 18 months post intervention. Oral health behaviour (P < 0.001) and attitude (P < 0.05) had improved significantly at 6 months, and oral hygiene and gingival health had improved significantly at both 6 (P < 0.001) and 18 (P < 0.05) months for the EL group. Lower caries incidence was recorded for the EL group, 18 months post intervention (P < 0.05). School-based oral health EL for adolescents was found to be more effective than TL in improving oral health attitude and behaviour at 6 months, in improving oral hygiene and gingival health at both 6 and 18 months and in reducing caries incidence 18 months post-intervention. PMID- 25142753 TI - The effect of corn trypsin inhibitor and inhibiting antibodies for FXIa and FXIIa on coagulation of plasma and whole blood. AB - BACKGROUND: Corn trypsin inhibitor (CTI), an inhibitor of FXIIa, is used to prevent plasma coagulation by contact activation, to specifically investigate tissue factor (TF)-initiated coagulation. OBJECTIVE: In the present work the specificity of CTI for factor (F) XIIa is questioned. METHODS AND RESULTS: In the commercial available plasma coagulation assays CTI was found to double activated partial thromboplastin time (APTT) at a plasma concentration of 7.3 +/- 1.5 MUm CTI (assay concentration 2.4 MUm). No effect was found on the prothrombin time (PT) when high TF concentrations were used. Also, with specific antibodies for FXIIa and for FXIa only APTT was found to be extended but not PT. With specific enzyme assays using chromogenic substrates CTI was shown to be a strong inhibitor of FXIIa and a competitive inhibitor of FXIa with Ki = 8.1 +/- 0.3 MUm, without effect on the coagulation factors FVIIa, FIXa, FXa and thrombin. In thrombin generation and coagulation (free oscillation rheometry, FOR) assays, initiated with low TF concentrations, no effect of CTI (plasma concentrations of 4.4 and 13.6 MUm CTI, 25 resp. 100 mg L(-1) in blood) was found with >= 1 pm TF. At <= 0.1 pm TF in the FOR whole blood assay the coagulation time (CT) concentration dependently increased while the plasma CT became longer than the observation time. CONCLUSION: To avoid inhibition of FXIa and the thrombin feedback loop we recommend that for coagulation assays the concentration of CTI in blood should be below 20 mg L(-1) (1.6 MUm) and in plasma below 3 MUm. PMID- 25142754 TI - The role of beta-blockers in cardiac perioperative management. PMID- 25142755 TI - Redo valve surgery--current status and future perspectives. AB - Surgeons are now facing the challenge of redo valve surgery because of the increasing number of elderly individuals in Japan. The incidence of bioprosthesis dysfunction has increased among the various surgical indications of redo valve surgery due to the preference of patients and a paradigm shift in prostheses from mechanical valves to bioprostheses. Previous studies reported that the clinical outcomes of reoperative valvular surgery have markedly improved due to the maneuver of myocardial protection, cardiopulmonary bypass strategies, and appropriate safer surgical approach. The general surgical outcomes of redo valve surgery have been reported as being similar to those of primary valve surgery; however, this is still controversial and has not yet been confirmed in some developed countries. Although the unique surgical technique of transcatheter valve-in-valve implantation for bioprosthetic dysfunction is promising, redo valve surgery may become more prevalent in the future. We here reviewed the current status of reoperative valve surgery and future perspectives including catheter-based surgical interventions. PMID- 25142756 TI - Measurement biases explain discrepancies between the observed and simulated decadal variability of surface incident solar radiation. AB - Observations have reported a widespread dimming of surface incident solar radiation (Rs) from the 1950s to the 1980s and a brightening afterwards. However, none of the state-of-the-art earth system models, including those from the Coupled Model Intercomparison Project phase 5 (CMIP5), could successfully reproduce the dimming/brightening rates over China. We find that the decadal variability of observed Rs may have important errors due to instrument sensitivity drifting and instrument replacement. While sunshine duration (SunDu), which is a robust measurement related to Rs, is nearly free from these problems. We estimate Rs from SunDu with a method calibrated by the observed Rs at each station. SunDu-derived Rs declined over China by -2.8 (with a 95% confidence interval of -1.9 to -3.7) W m(-2) per decade from 1960 to 1989, while the observed Rs declined by -8.5 (with a 95% confidence interval of -7.3 to -9.8) W m(-2) per decade. The former trend was duplicated by some high-quality CMIP5 models, but none reproduced the latter trend. PMID- 25142758 TI - The impact dermatologists can have on misdiagnosis of cellulitis and overuse of antibiotics: closing the gap. PMID- 25142757 TI - Outcomes of human immunodeficiency virus-infected children after anti-retroviral therapy in Malaysia. AB - AIMS: To describe outcome and examine factors associated with mortality among human immunodeficiency virus (HIV)-infected children in Malaysia after anti retroviral therapy (ART). METHODS: Retrospective and prospective data collected through March 2009 from children in four different states in Malaysia enrolled in TREAT Asia's Pediatric HIV Observational Database were analysed. RESULTS: Of 347 children in the cohort, only 278 (80.1%) were commenced on ART. The median CD4 count and median age at baseline prior to ART was 272 cells/MUL and 4.2 years (interquartile range (IQR): 1.4, 7.4 years), respectively. The median duration of follow-up was 3.7 years (IQR: 1.8, 6.0) with 32 deaths giving a crude mortality rate of 2.86 per 100 child-years. The mortality rate highest in the first 6 months of ART was 10.62 per 100 child-years and declined to 1.83 per 100 child years thereafter. On univariate analyses, only baseline median CD4 percentage, weight for age z score, height for age z score and anaemia were significantly associated with mortality. Upon including all four of these predictors into a single multivariate model, only weight for age z score remained statistically significantly predictive of mortality. CONCLUSIONS: Children commenced on ART had high mortality in the first 6 months especially in those with low CD4 percentage, wasting and anaemia. Poor nutritional status is an important independent predictor of mortality in this study. Besides initiating ART therapy, nutritional support and intervention must receive the utmost attention. PMID- 25142759 TI - Darier disease can be complicated by generalized cutaneous candidiasis: a case report. PMID- 25142760 TI - Stress-related sleep vulnerability and maladaptive sleep beliefs predict insomnia at long-term follow-up. AB - INTRODUCTION: Vulnerability to stress-related sleep disturbances and maladaptive sleep beliefs has been proposed to be predisposing factors for insomnia. Yet previous studies addressing these factors have been cross-sectional in nature and could not be used to infer the time sequences of the association. The current study used a six-year follow-up to examine the predisposing roles of these two factors and their interactions with major life stressors in the development of insomnia. METHODS: One hundred seventeen college students recruited for a survey in 2006 participated in this follow-up survey in 2012. In 2006, they completed a packet of questionnaires including the Dysfunctional Beliefs and Attitudes about Sleep Questionnaire, 10-item version (DBAS-10), the Ford Insomnia Response to Stress Test (FIRST), and the Pittsburgh Sleep Quality Index (PSQI); in 2012 they completed the Insomnia Severity Index (ISI) and the modified Life Experiences Survey (LES). RESULTS: Fourteen of the participants were found to suffer from insomnia as measured by the ISI. Logistic regression showed that scores on both DBAS-10 and FIRST could predict insomnia at follow-up. When the interaction of DBAS-10 and LES and that of FIRST and LES were added, both DBAS-10 and FIRST remained significant predictors, while the interaction of FIRST and LES showed a near-significant trend in predicting insomnia. CONCLUSIONS: The results showed that both vulnerability to stress-related sleep disturbances and maladaptive sleep beliefs are predisposing factors for insomnia. The hypothesized interaction effect between sleep vulnerability and major life stressors was found to be marginal. The maladaptive sleep beliefs, on the other hand, showed a predisposing effect independent from the influences of negative life events. PMID- 25142761 TI - Sleep measures predict next-day symptoms in women with irritable bowel syndrome. AB - STUDY OBJECTIVES: Patients with irritable bowel syndrome (IBS) often report sleep disturbances. Previously, we have shown that self-reported sleep difficulties predicted exacerbations of next-day IBS symptoms, mood disturbance, and fatigue. The purpose of this study was to explore whether objectively measured sleep using actigraphy, as well as self-report, predicts next-day symptoms in women with IBS and to explore whether or not symptoms also predict self-report and objective sleep. METHODS: Women aged 18-45 years with IBS were community-recruited (n = 24, mean age = 32 +/- 8 years). Participants completed sleep and IBS symptom diaries for one menstrual cycle and wore Actiwatch-64 actigraphs for 7 days at home. Statistical analyses used generalized estimating equation (GEE) models. RESULTS: Poorer self-reported sleep quality significantly (p < 0.05) predicted higher next day abdominal pain, anxiety, and fatigue, but was not significant for gastrointestinal (GI) symptoms or depressed mood. Actigraphic sleep efficiency (SEF) significantly predicted worsening next-day anxiety and fatigue, but not abdominal pain, GI symptoms, or depressed mood. On temporally reversed analyses, none of the symptoms significantly predicted subsequent sleep, except that GI symptoms significantly predicted higher actigraphic sleep efficiency. CONCLUSION: This small exploratory study supports previous findings that self-reported sleep disturbance predicted exacerbation of next-day symptoms in women with IBS and extends this relationship using an objective sleep measure. The study adds further evidence that sleep quality predicts subsequent IBS symptoms, but not the converse. The findings from this small study support the importance of additional longitudinal research to further understand the relationships between sleep and IBS. PMID- 25142762 TI - Psychomotor vigilance task demonstrates impaired vigilance in disorders with excessive daytime sleepiness. AB - STUDY OBJECTIVE: The Psychomotor Vigilance Task (PVT) is one of the leading assays of sustained vigilant attention in sleep research and highly sensitive to the effects of sleep loss. Even though PVT is widely used in sleep deprivation studies, little is known about PVT performance in patients suffering from sleep wake disorders. We aimed to quantify the impact of sleep-wake disorders on PVT outcome measures and examine whether PVT can distinguish between healthy controls and patients with sleep-wake disorders and whether PVT can distinguish between three different disorders that express excessive daytime sleepiness. METHODS: We compared PVT data of 143 patients and 67 age- and gender-matched healthy controls. Patients were diagnosed with one of the following sleep-wake disorders: narcolepsy with cataplexy (n = 20), insufficient sleep syndrome (ISS, n = 67) and hypersomnia (HS, n = 56). Several PVT outcomes were analyzed: reciprocal mean reaction time, response variability, number of lapses, number of false reaction time, slowest and fastest 10% of reaction time, and duration of lapses. RESULTS: PVT performance was generally better in healthy controls than in patients with any of the sleep-wake disorders analyzed. Patients with narcolepsy and HS performed worse on PVT than subjects with ISS. In controls, but not in patients, older subjects had slower reactions times and higher response variability in PVT. CONCLUSIONS: PVT performance shows different patterns in patients with different sleep-wake disorders and control subjects and may add useful information to the diagnostic work-up of sleep-wake disorders. PMID- 25142763 TI - The underdiagnosis of sleep disorders in patients with multiple sclerosis. AB - STUDY OBJECTIVES: To report at a population level the prevalence of restless legs syndrome, insomnia, and the risk of obstructive sleep apnea in multiple sclerosis patients. Sleep patterns and associations with fatigue and daytime sleepiness were identified. METHODS: A cross-sectional study was performed using a written survey that was mailed to 11,400 individuals from the Northern California Chapter of the National Multiple Sclerosis (MS) Society Database who self-identified as having MS. The survey included individual questions relating to demographics as well as several standard validated questionnaires related to primary sleep disorders, sleepiness, fatigue severity, and sleep patterns. RESULTS: Among the 11,400 surveys mailed out, 2,810 (24.6%) were returned. Of these, 2,375 (84.5%) met the inclusion criteria. Among the completed surveys, 898 (37.8%) screened positive for obstructive sleep apnea, 746 (31.6%) for moderate to severe insomnia, and 866 (36.8%) for restless legs syndrome. In contrast, only 4%, 11%, and 12% of the cohort reported being diagnosed by a health care provider with obstructive sleep apnea, insomnia, and restless legs syndrome, respectively. Excessive daytime sleepiness was noted in 30% of respondents based on the Epworth Sleepiness Scale. More than 60% of the respondents reported an abnormal level of fatigue based on the Fatigue Severity Scale. Both abnormal fatigue and sleepiness scores were associated with screening positive for obstructive sleep apnea, insomnia, and restless legs syndrome. CONCLUSION: A significant percentage of MS subjects in our sample screened positive for one or more sleep disorders. The vast majority of these sleep disorders were undiagnosed. Greater attention to sleep problems in this population is warranted, especially in view of fatigue being the most common and disabling symptom of MS. PMID- 25142764 TI - Mallampati score and pediatric obstructive sleep apnea. AB - RATIONALE: Pediatric obstructive sleep apnea (OSA) is common, and a delay in diagnosis can lead to significant morbidity. Polysomnography (PSG) is the gold standard for the diagnosis of OSA. However, difficulty accessing PSG due to the relative shortage of sleep centers with pediatric expertise can lead to a delay in the diagnosis and management of OSA. OBJECTIVES: To assess the utility of Mallampati score (sitting and supine) in predicting the presence and severity of OSA in children. METHODS: A retrospective study of 158 children from a single pediatric sleep center. All patients had a PSG and a physical examination documenting Mallampati score. The Mallampati score, tonsillar size, age, sex, and apnea hypopnea index (AHI) were analyzed. Odds ratio of having pediatric OSA (AHI > 1) with increase in Mallampati score and tonsillar size were calculated. MEASUREMENTS AND MAIN RESULTS: A significant correlation was found between Mallampati score, tonsillar size, and AHI. For every point increase in the Mallampati score, the odds ratio of having OSA increased by more than 6-fold. For every point increase in tonsillar size, the odds ratio of having OSA increased by more than 2-fold. CONCLUSIONS: Mallampati score and tonsillar size are independent predictors of OSA. Oral examination including Mallampati score and tonsillar size should be considered when evaluating a patient for OSA. They can be used to prioritize children who may need PSG. PMID- 25142765 TI - Expediting peer review: just say no. PMID- 25142766 TI - Prevalence and clinical significance of supine-dependent obstructive sleep apnea in patients using oral appliance therapy. AB - STUDY OBJECTIVE: The prevalence of supine-dependent obstructive sleep apnea (sdOSA) in a general population ranges from 20% to 60%, depending on the criteria used. Currently, the prevalence and evolution of sdOSA once oral appliance therapy with a mandibular advancement device (OAm) has started is unknown. In addition, literature on the correlation between sdOSA and treatment success with OAm is not unequivocal. The first purpose of this study was to assess the prevalence of sdOSA before and under OAm therapy. Second, the conversion rate from non-sdOSA to sdOSA during OAm therapy was evaluated. The third and final goal was to analyze the correlation between sdOSA and treatment success with OAm therapy in the patient population. METHODS: Two hundred thirty-seven consecutive patients (age 48 +/- 9 years; male/female ratio 173/64; AHI 20.1 +/- 14.7 events/h; BMI 27.2 +/- 4.3 kg/m(2)) starting OAm therapy were included. RESULTS: The prevalence of sdOSA before the start of OAm therapy, ranged from 27.0% to 67.5%. The prevalence of residual sdOSA under OAm therapy in this study ranged from 17.5% to 33.9%. Second, the conversion rate from non-sdOSA to sdOSA ranged from 23.0% to 37.5%. Third, the presence of sdOSA at baseline was not a significant factor for treatment success with OAm therapy. CONCLUSIONS: The results of this study indicate that the prevalence of sdOSA before and under OAm therapy is relatively high. One-third of patients shift from non-sdOSA to sdOSA. Finally, treatment success for OAm therapy was not significantly correlated with the presence of sdOSA at baseline. PMID- 25142767 TI - Alternative scoring models of STOP-bang questionnaire improve specificity to detect undiagnosed obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is common among surgical patients. The STOP-Bang questionnaire is a validated screening tool with a high sensitivity. However, its moderate specificity may yield fairly high false positive rate. We hypothesized that the specific combinations of predicting factors in the STOP Bang questionnaire would improve its specificity. METHODS: After research ethics approval, consented patients were asked to complete the STOP-Bang questionnaire and then underwent sleep studies. The predictive performance of the STOP-Bang alternative scoring models was evaluated. Five hundred sixteen patients with complete data on the STOP-Bang questionnaire and polysomnography were reported. RESULTS: When the STOP-Bang score was >= 3 (any 3 positive items), the sensitivity and specificity for identifying moderate-severe OSA was 87% and 31%, respectively. The specificity for any 2 positive items from the 4 STOP questions plus BMI > 35 kg/m(2), male gender, or neck circumference > 40 cm for identifying moderate-severe OSA was 85%, 77%, and 79%, respectively. Compared with STOP-Bang score >= 3, the predicted probability for severe OSA of the specific combinations of STOP score >= 2 + male and STOP score >= 2 + BMI increased by 36% and 42%, respectively. For severe OSA, the specific combination of STOP score >= 2 + BMI + male demonstrated a specificity of 97% and 86% increase in predicted probability versus any 4 positive items of STOP-Bang questionnaire. CONCLUSIONS: The specific constellations of predictive factors improved the specificity of STOP-Bang questionnaire. For patients with STOP score >= 2, male gender, and BMI > 35 kg/m(2) were more predictive than age >= 50 and neck circumference > 40 cm. PMID- 25142768 TI - Evaluation of a new pediatric positive airway pressure mask. AB - STUDY OBJECTIVES: The choice and variety of pediatric masks for continuous positive airway pressure (CPAP) is limited in the US. Therefore, clinicians often prescribe modified adult masks. Until recently a mask for children aged < 7 years was not available. This study evaluated apnea-hypopnea index (AHI) equivalence and acceptability of a new pediatric CPAP mask for children aged 2-7 years (Pixi; ResMed Ltd, Sydney, Australia). METHODS: Patients aged 2-7 years were enrolled and underwent in-lab baseline polysomnography (PSG) using their previous mask, then used their previous mask and the VPAP III ST-A flow generator for >= 10 nights at home. Thereafter, patients switched to the Pixi mask for >= 2 nights before returning for a PSG during PAP therapy via the Pixi mask. Patients then used the Pixi mask at home for >= 21 nights. Patients and their parents/guardians returned to the clinic for follow-up and provided feedback on the Pixi mask versus their previous mask. RESULTS: AHI with the Pixi mask was 1.1 +/- 1.5/h vs 2.6 +/- 5.4/h with the previous mask (p = 0.3538). Parents rated the Pixi mask positively for: restfulness of the child's sleep, trouble in getting the child to sleep, and trouble in having the child stay asleep. The Pixi mask was also rated highly for leaving fewer or no marks on the upper lip and under the child's ears, and being easy to remove. CONCLUSIONS: The Pixi mask is suitable for children aged 2-7 years and provides an alternative to other masks available for PAP therapy in this age group. PMID- 25142769 TI - Average heart rates of hispanic and caucasian adolescents during sleep: longitudinal analysis from the TuCASA cohort. AB - OBJECTIVE: The current study describes sleeping heart rate patterns in an adolescent cohort of Hispanic and Caucasian children over approximately a 5-year period to determine how sex, ethnicity, and body mass index (BMI) contribute to sleeping heart rate patterns over time. METHODS: Participants were recruited from a large urban school district in the southwest United States as part of the Tucson Children's Assessment of Sleep Apnea Study (TuCASA). Heart rate data was obtained through electrocardiogram (ECG) recordings during in-home polysomnography, approximately 5 years apart. Second-wave cohort data were analyzed to determine how age, sex, ethnicity, physical activity, and BMI contribute to average sleeping heart rates. The same variables were used to investigate how sleeping heart rate patterns change longitudinally from school age (6-11 years) to adolescence (10-17 years) during sleep. RESULTS: Female adolescents had significantly faster average heart rates during sleep. Sleeping heart rate decreased significantly with increasing age in the adolescent cohort. Although the Hispanic group had a statistically significant higher body mass index than Caucasians, there were no significant differences in heart rate observed between ethnicities or in those who were classified as obese (BMI >= 95(th) percentile for age). Longitudinal analysis between the school-aged and adolescent cohort revealed a significant overall decrease in heart rate across a 5-year period. CONCLUSIONS: Hispanic and Caucasian adolescents experience a similar decrease in sleeping heart rate with age. Female adolescents had significantly faster heart rates than males, and no significant differences were observed between Caucasians and Hispanics, or obese vs. nonobese adolescents. PMID- 25142770 TI - Association of self-reported sleep and hypertension in non-insomniac elderly subjects. AB - OBJECTIVES: Sleep duration and sleep quality play important roles in the development of hypertension (HT) in middle-aged subjects, with controversial data in elderly. In this study, we investigated the link between HT and self-reported sleep in non-insomniac elderly subjects. METHODS: We examined 500 participants without insomnia complaints aged 72 +/- 1 years. An extensive instrumental evaluation was carried out, including 24-h blood pressure (BP) monitoring and an assessment of nocturnal BP dipping. Sleep duration and quality were evaluated by the Pittsburgh Sleep Quality Index (PSQI). The subjects were stratified into three groups according to sleep duration: short (< 6 h), normal (> 6h to < 8 h), and long (> 8 h) sleepers. A PSQI < 5 defined good sleepers (GS, n = 252), and a PSQI > 5 (n = 248) defined poor sleepers (PS). RESULTS: PS represented 50% of the subjects, more frequently females. Compared to GS, PS did not differ in terms of HT, BP, baroreflex sensitivity (BRS), and BP dipping. Short, normal, and long sleepers accounted for 28%, 42%, and 30% of subjects, with HT, BP values, BRS, and gender not differing between groups. No relationship was found between nocturnal BP values and self-reported sleep measures. Logistic regression analysis indicated that neither sleep duration nor sleep quality predicts the prevalence of HT, the body mass index being the only factor affecting this association. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT00759304 and NCT00766584. CONCLUSIONS: In a sample of non-insomniac elderly subjects, neither sleep duration nor sleep quality affected the prevalence of HT. These data argue against a relationship between self-reported sleep duration and quality and HT in elderly without insomnia. PMID- 25142771 TI - Upper airway obstruction during noninvasive ventilation induced by the use of an oronasal mask. AB - In patients with neuromuscular disorders, no randomized studies have been performed whether nasal or oronasal masks should be preferred. Oronasal masks are often used in acute respiratory failure, while nasal masks are preferred in patients with chronic respiratory failure. However, the use of nasal masks can result in mouth leaks with implications on sleep quality. To reduce these leaks, oronasal masks have been applied during home noninvasive ventilation (NIV). Until now, upper airway obstruction during NIV has been thought to be induced by nasal obstruction, pharyngeal collapse, and/or glottis closure. We report a case indicating another cause of upper airway obstruction: use of an oronasal mask can induce obstructive events in the upper airways, possibly resulting in sleep fragmentation and decreased efficiency of NIV. PMID- 25142772 TI - Dual cases of type 1 narcolepsy with schizophrenia and other psychotic disorders. AB - OBJECTIVE: Cases of narcolepsy in association with psychotic features have been reported but never fully characterized. These patients present diagnostic and treatment challenges and may shed new light on immune associations in schizophrenia. METHOD: Our case series was gathered at two narcolepsy specialty centers over a 9-year period. A questionnaire was created to improve diagnosis of schizophrenia or another psychotic disorder in patients with narcolepsy. Pathophysiological investigations included full HLA Class I and II typing, testing for known systemic and intracellular/synaptic neuronal antibodies, recently described neuronal surface antibodies, and immunocytochemistry on brain sections to detect new antigens. RESULTS: Ten cases were identified, one with schizoaffective disorder, one with delusional disorder, two with schizophreniform disorder, and 6 with schizophrenia. In all cases, narcolepsy manifested first in childhood or adolescence, followed by psychotic symptoms after a variable interval. These patients had auditory hallucinations, which was the most differentiating clinical feature in comparison to narcolepsy patients without psychosis. Narcolepsy therapy may have played a role in triggering psychotic symptoms but these did not reverse with changes in narcolepsy medications. Response to antipsychotic treatment was variable. Pathophysiological studies did not reveal any known autoantibodies or unusual brain immunostaining pattern. No strong HLA association outside of HLA DQB1*06:02 was found, although increased DRB3*03 and DPA1*02:01 was notable. CONCLUSION: Narcolepsy can occur in association with schizophrenia, with significant diagnostic and therapeutic challenges. Dual cases maybe under diagnosed, as onset is unusually early, often in childhood. Narcolepsy and psychosis may share an autoimmune pathology; thus, further investigations in larger samples are warranted. PMID- 25142773 TI - CPAP pressure for prediction of oral appliance treatment response in obstructive sleep apnea. AB - STUDY OBJECTIVES: Mandibular advancement splints (MAS) are often preferred to CPAP treatment for OSA but are not always equally efficacious. High therapeutic CPAP pressure has been associated with MAS treatment failure in a Japanese population. We sought to assess the relationship between CPAP pressure and MAS treatment response in an Australian population. METHODS: Therapeutic CPAP pressure and MAS treatment response were obtained from a one-month crossover trial of both treatments. Predictive utility of CPAP pressure to identify MAS treatment response was assessed. RESULTS: Seventy-eight OSA patients were included (age 49.3 +/- 11.1 years, BMI 29.1 +/- 5.8 kg/m(2)) with predominantly moderate-severe OSA (AHI 30.0 +/- 12.7/h). CPAP pressure was lower in MAS responders (MAS AHI < 10/h) 9.7 +/- 1.6 vs. 11.7 +/- 2.4 cm H O, p < 0.01, with area under ROC curve of 0.74 (95% CI 0.63-0.86), p < 0.01. The best cutoff value of 10.5 cm H O useful for discriminating MAS responders and non-responders in the previous Japanese population, was inadequate for prediction in the current population (0.47 negative predictive value [NPV]). However a cutoff of 13 cm H O identified MAS non-responders (1.0 NPV). Multivariate regression identified CPAP pressure (odds ratio [95% confidence interval] 0.53 [0.33-0.87], age (0.93 [0.87 0.99]) and AHI (0.92 [0.86-0.97]) as predictors of MAS treatment response (model r(2) = 0.54, p < 0.001). CONCLUSIONS: In Australian patients, the majority of whom are Caucasian, a higher therapeutic CPAP pressure requirement in conjunction with age and OSA severity characteristics may be useful to indicate likelihood of success with MAS as an alternative therapy. PMID- 25142775 TI - Restless legs syndrome as a first manifestation of a cerebral infarct. AB - The onset of restless legs syndrome (RLS) is usually progressive and the neural substrates underlying its pathophysiology remain to be identified. Here we report on a patient presenting with acute-onset RLS that was symptomatic of a right anteromedial pontine infarction. This case is exceptional because RLS appeared several hours before the occurrence of a regressive dysarthria clumsy-hand syndrome. Additionally, millimetric MRI sections showed that the structures possibly involved in RLS pathogenesis were the corticospinal tract, the pontine nuclei, and the pontocerebellar fibers. Although this is uncommon, clinicians should be aware that RLS characterized by a sudden onset can be a clinical manifestation related to stroke. PMID- 25142774 TI - Craniofacial contribution to residual obstructive sleep apnea after adenotonsillectomy in children: a preliminary study. AB - STUDY OBJECTIVES: Pediatric obstructive sleep apnea (OSA) is frequently associated with adenotonsillar hypertrophy, and the fact that about 30% of affected children continue to show OSA after adenotonsillectomy (AT) suggests the presence of some other predisposing factor(s). We hypothesized that abnormal maxillofacial morphology may be a predisposing factor for residual OSA in pediatric patients. METHODS: A total of 13 pediatric OSA patients (9 boys and 4 girls, age [median (interquartile range)] = 4.7 (4.0, 6.4) y, body mass index (BMI) z score = -0.3 (-0.8, 0.5)) who had undergone AT were recruited for this study. Maxillomandibular size was measured using an upright lateral cephalogram, and correlations between size and the apnea hypopnea index (AHI) values obtained before (pre AT AHI) and about 6 months after AT (post AT AHI) were analyzed. RESULTS: AHI decreased from 12.3 (8.9, 26.5)/h to 3.0 (1.5, 4.6)/h after AT (p < 0.05). Residual OSA was seen in 11 of the 13 patients (84.6%) and their AHI after AT was 3.1 (2.7, 4.7)/h. The mandible was smaller than the Japanese standard value, and a significant negative correlation was seen between maxillomandibular size and post AT AHI (p < 0.05). CONCLUSIONS: These findings suggest that the persistence of OSA after AT may be partly due to the smaller sizes of the mandible in pediatric patients. We propose that the maxillomandibular morphology should be carefully examined when a treatment plan is developed for OSA children. PMID- 25142776 TI - Comprehensive screening for mutations associated with colorectal cancer in unselected cases reveals penetrant and nonpenetrant mutations. AB - Germline mutation testing in patients with colorectal cancer (CRC) is offered only to a subset of patients with a clinical presentation or tumor histology suggestive of familial CRC syndromes, probably underestimating familial CRC predisposition. The aim of our study was to determine whether unbiased screening of newly diagnosed CRC cases with next generation sequencing (NGS) increases the overall detection rate of germline mutations. We analyzed 152 consecutive CRC patients for germline mutations in 18 CRC-associated genes using NGS. All patients were also evaluated for Bethesda criteria and all tumors were investigated for microsatellite instability, immunohistochemistry for mismatch repair proteins and the BRAF*V600E somatic mutation. NGS based sequencing identified 27 variants in 9 genes in 23 out of 152 patients studied (18%). Three of them were already reported as pathogenic and 12 were class 3 germline variants with an uncertain prediction of pathogenicity. Only 1 of these patients fulfilled Bethesda criteria and had a microsatellite instable tumor and an MLH1 germline mutation. The others would have been missed with current approaches: 2 with a MSH6 premature termination mutation and 12 uncertain, potentially pathogenic class 3 variants in APC, MLH1, MSH2, MSH6, MSH3 and MLH3. The higher NGS mutation detection rate compared with current testing strategies based on clinicopathological criteria is probably due to the large genetic heterogeneity and overlapping clinical presentation of the various CRC syndromes. It can also identify apparently nonpenetrant germline mutations complicating the clinical management of the patients and their families. PMID- 25142777 TI - Adamts1 mediates ethanol-induced alterations in collagen and elastin via a FoxO1 sestrin3-AMPK signaling cascade in myocytes. AB - A variety of stressors including alcohol (EtOH) are known to induce collagen production and fibrotic diseases. Matrix metalloproteinases (MMP) play an important role in regulating fibrosis, but little is known regarding the relationship between EtOH and MMPs. In addition, the signaling cascades involved in this process have not been elucidated. We have identified the MMP Adamts1 as a target of EtOH regulation. To characterize the function of Adamts1, we examined EtOH-induced alterations in collagen I and elastin protein levels in C2C12 myocytes. Incubation of myocytes with 100 mM EtOH decreased elastin and increased collagen content, respectively, and these changes were associated with increased O-GLcNAc modification of Adamts1. Conversely, silencing of Adamts1 by siRNA blocked the adverse effects of EtOH on collagen and elastin levels. Similar results were obtained after treatment with a pharmacological inhibitor of MMP. Changes in collagen were due, at least in part, to a decreased interaction of Adamts1 with its endogenous inhibitor TIMP3. The AMPK inhibitor compound C blocked the EtOH-induced stimulation of collagen and O-GLcNAc Adamts1 protein. Changes in AMPK appear linked to FoxO1, since inhibition of FoxO1 blocked the effects of EtOH on AMPK phosphorylation and O-GLcNAc levels. These FoxO-dependent modifications were associated with an upregulation of the FoxO1 transcription target sestrin 3, as well as increased binding of sestrin 3 with AMPK. Collectively, these data indicate that EtOH regulates the collagen I and elastin content in an Adamts1-dependent manner in myocytes. Furthermore, Adamts1 appears to be controlled by the FoxO1-sestrin 3-AMPK signaling cascade. PMID- 25142778 TI - Non-obligatory role of prostaglandin D2 receptor subtype 1 in rosacea: laropiprant in comparison to a placebo did not alleviate the symptoms of erythematoelangiectaic rosacea. AB - Erythematotelangiectatic rosacea shares facial flushing features with those seen after niacin. This study was performed to test the hypothesis whether prostaglandin D2 (PGD2) receptor subtype 1 antagonist (laropiprant) will improve the symptoms of rosacea. The purpose of this study was to evaluate the effect of laropiprant 100 mg administered once daily for 4 weeks on the signs and symptoms of erythematotelangiectatic rosacea. Subjects received laropiprant 100 mg once daily (n = 30) or placebo (n = 30) for 4 weeks. The primary pharmacodynamics endpoint was change in Clinician's Erythema Assessment (CEA) score from baseline to week 4. The patient self-assessment (PSA) was a secondary endpoint. Laropiprant was generally well tolerated in this study for the primary endpoint of change in CEA score from Baseline to Week 4, the least-squares mean of change from baseline to visit 4/week 4 was -3.7 and -3.4 for placebo and laropiprant (100 mg), respectively. The least-squares mean difference (placebo minus laropiprant) with 90% confidence interval of change in CEA score from baseline to visit 4/week 4 was estimated as -0.3 (-1.6, 1.0). For the secondary endpoint, the least-squares mean difference (placebo minus laropiprant) with 90% confidence interval of change from baseline to visit 4/week 4 was estimated as -0.7 (-7.7, 6.4) for PSA total score, -4.5 (-14.2, 5.3) for PSA emotion score, -1.3 (-7.8, 5.3) for PSA symptoms score, and 3.6 (-4.3, 11.4) for PSA functioning score. Laropiprant administered once daily for 4 weeks was generally well tolerated in this population of subjects with rosacea. However, there were no clinically meaningful changes in the primary endpoint of CEA given that the response to laropiprant could not be differentiated from that to placebo. There was also no clinically meaningful change in the secondary endpoint, PSA. A DP1 antagonist is not likely to be effective in rosacea. PMID- 25142780 TI - Dynamic response of ultrathin highly dense ZIF-8 nanofilms. AB - Ultrathin ZIF-8 nanofilms are prepared by facile step-by-step dip coating. A critical withdrawal speed allows for films with a very uniform minimum thickness. The high refractive index of the films denotes the absence of mesopores. The dynamic response of the films to CO2 exposure resembles behaviour observed for non-equilibrium organic polymers. PMID- 25142779 TI - Retinal vein occlusion in retinal racemose hemangioma: a case report and literature review of ocular complications in this rare retinal vascular disorder. AB - BACKGROUD: Retinal racemose hemangioma (RRH) is a rare congenital disorder that often co-occurs with other ocular complications. In this study, we present a case of RRH complicated with retinal vein obstruction in three branches and provide a review of ocular complications and associations with RRH. CASE PRESENTATION: One case of RRH is presented. Fundus examination, fluorescein angiography (FFA) and optical coherence tomography (OCT) of the patient identified Group 3 RRH complicated with retinal vein occlusions in the superotemporal, inferotemporal, and inferonasal branches. Macular edema, which causes visual impairment, was detected. A brief literature review was also presented. The PubMed database was searched for RRH or related keywords to find reports of ocular complications or associations published on or before Dec. 31, 2013. A total of 140 papers describing167 RRH cases were found. The mean age of diagnosis was 22.97 years. Ocular complications were mentioned in 32 (19.16%) cases. Retinal vein occlusion (46.88%) was the major ocular complication in RRH, followed by hemorrhage (34.38%). Eight (4.79%) cases were associated with other ocular diseases such as Sturge-Weber syndrome , Morning glory disc anomaly and macroaneurysm. CONCLUSIONS: Although RRH is a relatively non-progressive condition, its complications may lead to vision loss and should be treated in time. PMID- 25142781 TI - Abstracts of the 33rd European Peptide Symposium, August 31-September 5, 2014, Sofia, Bulgaria. PMID- 25142782 TI - Effective discrimination between biologically relevant contacts and crystal packing contacts using new determinants. AB - In the structural models determined by X-ray crystallography, contacts between molecules can be divided into two categories: biologically relevant contacts and crystal packing contacts. With the growth in the number and quality of available large crystal packing contacts structures, distinguishing crystal packing contacts from biologically relevant contacts remains a difficult task, which can lead to wrong interpretation of structural models. In this study, we performed a systematic analysis on the biologically relevant contacts and crystal packing contacts. The analysis results reveal that biologically contacts are more tightly packed than crystal packing contacts. This property of biologically contacts may contribute to the formation of their interfacial core region. Meanwhile, the differences between the core and surface region of biologically contacts in amino acid composition and evolutionary measure are more dramatic than crystal packing contacts and these differences appear to be useful in distinguishing these two categories of contacts. On the basis of the features derived from our analysis, we developed a random forest model to classify biological relevant contacts and crystal packing contacts. Our method can achieve a high receiver operating curve of 0.923 in the 5-fold cross-validation and accuracies of 91.4% and 91.7% for two different test sets. Moreover, in a comparison study, our model outperforms other existing methods, such as DiMoVo, Pita, Pisa, and Eppic. We believe that this study will provide useful help in the validation of oligomeric proteins and protein complexes. The model and all data used in this paper are freely available at http://cic.scu.edu.cn/bioinformatics/bio-cry.zip. PMID- 25142783 TI - Assessing what generates precompetitive emotions: development of the precompetitive appraisal measure. AB - Athletes' precompetitive appraisal determines which emotion they experience with regard to an upcoming competition. Such precompetitive emotions have powerful and potentially destructive consequences for performance. To control and optimise these consequences, it is important to examine precompetitive appraisal. Currently, such efforts are hampered by the lack of a valid measurement tool. The present study aimed to develop a novel measure of precompetitive appraisal. Specifically, the Precompetitive Appraisal Measure (PAM) was constructed by adapting an existing self-report scale. Female and male intercollegiate team sport athletes (N = 384) completed the PAM, along with a measure of intensity and interpretation of precompetitive anxiety symptoms (CSAI-2D) prior to competition. On these responses, (a) a Principal Component Analysis and a Confirmatory Factor Analysis supported the PAM's suggested two-factor structure (Primary and Secondary Appraisal), (b) cluster analyses indicated the measure's ability to distinguish theoretically congruent appraisal profiles (Threat and Challenge) and (c) a MANOVA and multiple regression analyses demonstrated that PAM-responses predicted precompetitive symptom intensity and interpretation. Further, analyses revealed that the majority of athletes appraised the upcoming competition as a challenge. PMID- 25142784 TI - Prevalence of DSM-5 avoidant/restrictive food intake disorder in a pediatric gastroenterology healthcare network. AB - OBJECTIVE: Few published studies have evaluated the clinical utility of new diagnostic criteria for avoidant/restrictive food intake disorder (ARFID), a DSM 5 reformulation of feeding and eating disorder of infancy or early childhood. We examined the prevalence of ARFID and inter-rater reliability of its diagnostic criteria in a pediatric gastrointestinal sample. METHOD: We conducted a retrospective chart review of 2,231 consecutive new referrals (ages 8-18 years) to 19 Boston-area pediatric gastroenterology clinics for evidence of DSM-5 ARFID. RESULTS: We identified 33 (1.5%) ARFID cases; 22 of whom (67%) were male. Most were characterized by insufficient intake/little interest in feeding (n = 19) or limited diet due to sensory features of the food (n = 7). An additional 54 cases (2.4%) met one or more ARFID criteria but there was insufficient information in the medical record to confer or exclude the diagnosis. Diagnostic agreement between coders was adequate (kappa = 0.72). Common challenges were (i) distinguishing between diagnoses of ARFID and anorexia nervosa or anxiety disorders; (ii) determination of whether the severity of the eating/feeding disturbance was sufficient to warrant diagnosis in the presence of another medical or psychiatric disorder; and (iii) assessment of psychosocial impairment related to eating/feeding problems. DISCUSSION: In a pediatric treatment-seeking sample where ARFID features were common, cases meeting full criteria were rare, suggesting that the diagnosis is not over-inclusive even in a population where eating/feeding difficulties are expected. PMID- 25142785 TI - Molecular description of the LCST behavior of an elastin-like polypeptide. AB - Elastin-like polypeptides (ELPs) with the repeat sequence of VPGVG are widely used as a model system for investigation of lower critical solution temperature (LCST) transition behavior. In this paper, the effect of temperature on the structure, dynamics and association of (VPGVG)18 in aqueous solution is investigated using atomistic molecular dynamics simulations. Our simulations show that as the temperature increases the ELP backbones undergo gradual conformational changes, which are attributed to the formation of more ordered secondary structures such as beta-strands. In addition, increasing temperature changes the hydrophobicity of the ELP by exposure of hydrophobic valine-side chains to the solvent and hiding of proline residues. Based on our simulations, we conclude that the transition behavior of (VPGVG)18 can be attributed to a combination of thermal disruption of the water network that surrounds the polypeptide, reduction of solvent accessible surface area of the polypeptide, and increase in its hydrophobicity. Simulations of the association of two (VPGVG)18 molecules demonstrated that the observed gradual changes in the structural properties of the single polypeptide chain are enough to cause the aggregation of polypeptides above the LCST. These results lead us to propose that the LCST phase behavior of poly(VPGVG) is a collective phenomenon that originates from the correlated gradual changes in single polypeptide structure and the abrupt change in properties of hydration water around the peptide and is a result of a competition between peptide-peptide and peptide-water interactions. This is a computational study of an important intrinsically disordered peptide system that provides an atomic-level description of structural features and interactions that are relevant in the LCST phase behavior. PMID- 25142786 TI - A new meroterpenoid tatenoic acid from the fungus Neosartorya tatenoi KKU-2NK23. AB - A new meroterpenoid, named tatenoic acid (1), was isolated from the fungus Neosartorya tatenoi KKU-2NK23, together with five known compounds, aszonapyrones A and B (2 and 3), aszonalenin (4), ergosterol (5) and D-mannitol (6). Their structures were established on the basis of spectroscopic methods. Aszonapyrones A (2) exhibited antimalarial activity against Plasmodium falciparum, and it also exhibited cytotoxicity against two cancer cell lines, NCI-H187 and KB. PMID- 25142787 TI - [Organ-sparing therapy for testicular cancer]. AB - BACKGROUND: The therapy of malignant testicular neoplasms has always been characterized by a high degree of radicality. Thanks to a number of medical achievements the cure rate of testicular cancer has notably increased through the last decades. In the meanwhile the main focus is on reducing therapy load, scrutinizing radical orchiectomy as the only adequate therapy for the primary tumour. OBJECTIVES: This article discusses the question, if and under which conditions an organ-sparing approach can be used appropriately in clinical practice. MATERIALS AND METHODS: A selective literature search was performed in PubMed. RESULTS: A set of data suggest that endocrine and exocrine function of the testis can be preserved using an organ-sparing approach and many patients could benefit regarding their quality of life, e.g., preserving the ability to father a child at least temporarily and avoiding the need for hormone substitution. Different from kidney tumors, precancerous lesions (testicular intraepithelia neoplasia, TIN) can almost inevitably be found in the surrounding tissue of testicular tumors. This has to be considered when making a decision in favor of an organ-sparing approach, because radiation therapy on the affected testis has to be performed after tumor resection. Despite the absence of prospective data, organ-sparing surgical tumor resection can be recommended in carefully selected patients. CONCLUSION: After careful selection of patients, particularly young men can profit from an organ-sparing therapy regimen. Therefore, organ preservation should always be considered in the surgical treatment of testicular masses. PMID- 25142789 TI - [Caudal migration of the verumontanum and enlargement of the utricle in hypospadias]. AB - Hypospadias is one of the morphological and functional alterations of the internal urogenital organs under the influence of androgen deficiency. In the time period 1974-1998 a total of 823 cases of hypospadias were surgically treated and the findings of the preoperative X-ray diagnostics with micturating cystourethrogram (MCU) and urethrocystogram (UCG) as well as urethrocystoscopy were analyzed. A caudal migration of the verumontanum could be detected in 55% of cases with hypospadias (453/823) and in 79% (322/403) of middle grade (penoscrotal) and high grade (scrotoperineal) cases of hypospadias. Enlargement of the utricle was present in 31.5% (259/823) cases of hypospadias and in 46.2% (186/423) of middle grade (penoscrotal) and high grade (scrotoperineal) cases of hypospadias. PMID- 25142788 TI - [Organ and kidney function preservation in renal cell carcinoma]. AB - BACKGROUND: The organ-preserving partial nephrectomy has increasingly established itself in small unilateral renal tumours (<4 cm) with contralateral healthy kidney and counter gained in recent years in importance. There was found a significantly increased cardiovascular mortality rate and deteriorated quality of life, the more intact kidney tissue has been removed. OBJECTIVES: In the present study, the influence of pre- and perioperative factors on direct postoperative course was examined, including 5-year survival rate and relapse behaviour after open organ-preserving partial nephrectomy in our own collective. MATERIALS AND METHODS: In this retrospective study of 1657 patients were collected, who underwent surgery between 2007 and 2013 in the Department of Urology at the University Hospital Essen because of a renal tumour. 38 % of these operations (n = 636) were performed organ-preserving. In this trial there are factors identified that have an impact on need of blood transfusion and length of hospitalization in organ-preserving operation method. RESULTS: No independent parameter can be determined for the need of blood transfusion. Tumour size and thus time of resection procedure does not affect the need of erythrocytes administration. In addition, the tumour size influences neither the postoperative serum-haemoglobin nor serum-creatinine. Increased patient age and female gender are identified as non-modifiable factors, which cause a longer hospitalisation. Postoperative pain therapy can be considered as a variable size, which does not affect the length of hospital stay. Modifiable factors that increase the overall length of stay, however, are the type of direct postoperative monitoring (ICU vs. anaesthetic recovery room) and the administration of blood transfusions. CONCLUSIONS: There are constant factors, which can be associated with a longer residence time in the framework of an organ-preserving partial nephrectomy. Further there is shown evidence of the independence of the tumour size - in addition to proven good oncological results - of an extension of indication of organ-preserving nephrectomy of tumours > 4 cm. PMID- 25142790 TI - [Residents' schedule for the 2014 Congress of the German Society for Urology]. PMID- 25142791 TI - Effects of the Multidisciplinary Risk Assessment and Management Program for Patients with Diabetes Mellitus (RAMP-DM) on biomedical outcomes, observed cardiovascular events and cardiovascular risks in primary care: a longitudinal comparative study. AB - BACKGROUND: To assess whether the Multidisciplinary Risk Assessment and Management Program for Patients with Diabetes Mellitus (RAMP-DM) led to improvements in biomedical outcomes, observed cardiovascular events and predicted cardiovascular risks after 12-month intervention in the primary care setting. METHODS: A random sample of 1,248 people with diabetes enrolled to RAMP-DM for at least 12 months was selected and 1,248 people with diabetes under the usual primary care were matched by age, sex, and HbA1c level at baseline as the usual care group. Biomedical and cardiovascular outcomes were measured at baseline and at 12-month after the enrollment. Difference-in-differences approach was employed to measure the effect of RAMP-DM on the changes in biomedical outcomes, proportion of subjects reaching treatment targets, observed and predicted cardiovascular risks. RESULTS: Compared to the usual care group, RAMP-DM group had lower cardiovascular events incidence (1.21% vs 2.89%, P = 0.003), and net decrease in HbA1c (-0.20%, P < 0.01), SBP (-3.62 mmHg, P < 0.01) and 10-year cardiovascular disease (CVD) risks (total CVD risk, -2.06%, P < 0.01; coronary heart disease (CHD) risk, -1.43%, P < 0.01; stroke risk, -0.71%, P < 0.01). The RAMP-DM subjects witnessed significant rises in the proportion of reaching treatment targets of HbA1c, and SBP/DBP. After adjusting for confounding variables, the significance remained for HbA1c, predicted CHD and stroke risks. CONCLUSIONS: The RAMP-DM resulted in greater improvements in HbA1c and reduction in observed and predicted cardiovascular risks at 12 months follow-up, which indicated a risk-stratification multidisciplinary intervention was an effective strategy for managing Chinese people with diabetes in the primary care setting. TRIAL REGISTRY: ClinicalTrials.gov, NCT02034695. PMID- 25142792 TI - Fatal outcome of posterior "reversible" encephalopathy syndrome in metastatic colorectal carcinoma after irinotecan and fluoropyrimidine chemotherapy regimen. AB - Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic entity characterized by headaches, altered mental status, seizures, and visual disturbances. It can occur in many different clinical entities such as severe hypertension and pre-eclampsia, or due to cytotoxic or immunosuppressive therapies. The pathogenesis of PRES is unclear, with dysregulated cerebral auto regulation and endothelial dysfunction as important mechanisms proposed. Endothelial dysfunction is important especially in cases associated with cytotoxic therapies. Herein, we describe a patient with PRES with fatal outcome, who presented 5 days after the infusion of cycle 1 of irinotecan hydrochloride, leucovorin calcium, and fluorouracil (FOLFIRI) regimen chemotherapy, without prior hypertension and other comorbidity, suggesting a link between PRES and FOLFIRI regimen. To our knowledge, this case report is the first describing PRES after FOLFIRI regimen, although others have described PRES after FOLFIRI with bevacizumab in colonic cancer patients. PMID- 25142793 TI - DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors. AB - Malignant brain tumors, which are the leading cause of cancer-related morbidity and mortality in children, span a wide spectrum of diseases with distinct clinical phenotypes but may share remarkably similar morphologic features. Until recently, few molecular markers of childhood brain tumors have been identified, which has limited therapeutic advances. Recent global genomic studies have enabled robust molecular classification of childhood brain tumors and the identification and consolidation of rare, seemingly disparate clinical entities. It is now increasingly evident that deregulation of epigenetic processes contributes substantially to heterogeneity in tumor phenotypes and comprise significant drivers of cancer initiation and progression. Specifically, DNA hypermethylation and silencing of critical tumor suppressor genes by DNA methyltransferases (DNMT) has emerged as an important and fundamental mechanism in brain tumor pathogenesis. These observations have been underscored by the recent discovery of TTYH1-C19MC gene fusions in an aggressive pediatric embryonal brain tumor, which results in deregulation and increased expression of a neural specific DNMT3B isoform in C19MC-associated brain tumors. Our observations that pharmacological inhibitors of DNMTs and histone deacetylases significantly inhibit growth of cells derived from C19MC-associated tumors indicate targeting of epigenomic modifiers as a novel therapeutic approach for these highly treatment-resistant tumors. PMID- 25142794 TI - Robust meta-analysis shows that glioma transcriptional subtyping complements traditional approaches. AB - BACKGROUND: Gliomas traditionally have been sub-classified based on histopathological observations. However, this approach is subject to inter observer variability, and histopathological features may not reflect the biological mechanisms that drive tumor growth. High-throughput transcriptional profiling has shown promise in objectively and reproducibly identifying glioma subtypes. Most prior studies have typically used only modest sample sizes and have sometimes overlooked important data-processing steps to ensure sample quality and to evaluate the robustness of quantitative findings. The purpose of our study was to define robust glioma subtypes by applying rigorous preprocessing and validation steps to 1,952 microarray samples aggregated from 16 prior studies. This data set is the most comprehensive collection of glioma microarray samples compiled to date. METHODS AND RESULTS: We evaluated each sample for quality-control issues, corrected for probe-composition biases, and adjusted for intra- and inter-study batch effects. Using a training/testing validation design that simulates a "bench-to-bedside process," we identified six transcriptional subtypes that contained a heterogeneous mix of histopathological subtypes and tumor grades. Similar to prior studies, age, survival and treatment patterns differed significantly across the transcriptional subtypes. However, due to our large sample size, we also observed that within a given histopathological subtype, our transcriptional subtypes provided additional prognostic value. Lastly, we used a pathway-based approach to elucidate the biological mechanisms associated with each subtype. CONCLUSIONS: Our findings provide clinical and biological insights that may not be apparent with alternative approaches or smaller data sets, and our approach serves as an example for meta-analyses that can be applied to other complex diseases. PMID- 25142795 TI - Ants as vectors of pathogenic microorganisms in a hospital in Sao Paulo county, Brazil. AB - BACKGROUND: The present study aimed to identify and characterize the presence of bacteria carried by ants, and check the distribution of these ants in the physical confines of a medium-sized hospital in Sao Paulo county, Brazil. METHODS: The ants were collected from March 2012 to February 2013. Attractive non toxic baits were used to catch the ants, and the sectors considered for the study were medical wards, outdoor areas, obstetric unit, reception area, kitchen, surgical centres, paediatric clinic and intensive care unit. Captured ants were classified using taxonomic keys and subsequently immersed in Brain Heart Infusion broth. RESULTS: Paratrechina spp. and Monomorium floricola ants were found most frequently in the hospital. Ants had a high capacity for carrying bacteria, and the isolates comprised 68.8% Gram-positive, spore-producing bacilli (Bacillus spp. and Listeria spp.); 14.7% Gram-negative bacilli (Pseudomonas aeruginosa and Klebsiella spp.); and 16.4% Gram-positive cocci (Streptococcus spp. and Staphylococcus aureus). Among the areas being evaluated, the medical wards had the largest number of ants captured, and therefore the most bacteria. CONCLUSIONS: Ants in hospitals may carry both Gram-positive and Gram-negative bacteria, and methods of controlling urban ants should be adopted and strictly adhered to, to minimize the risk of infection in hospital patients. PMID- 25142796 TI - SIX1 promotes tumor lymphangiogenesis by coordinating TGFbeta signals that increase expression of VEGF-C. AB - Lymphatic vessels are one of the major routes for the dissemination of cancer cells. Malignant tumors release growth factors such as VEGF-C to induce lymphangiogenesis, thereby promoting lymph node metastasis. Here, we report that sine oculis homeobox homolog 1 (SIX1), expressed in tumor cells, can promote tumor lymphangiogenesis and lymph node metastasis by coordinating with TGFbeta to increase the expression of VEGF-C. Lymphangiogenesis and lymph node metastasis in cervical cancer were closely correlated with higher expression of SIX1 in tumor cells. By enhancing VEGF-C expression in tumor cells, SIX1 could augment the promoting effect of tumor cells on the migration and tube formation of lymphatic endothelial cells (LEC) in vitro and lymphangiogenesis in vivo. SIX1 enhanced TGFbeta-induced activation of SMAD2/3 and coordinated with the SMAD pathway to modulate VEGF-C expression. Together, SIX1 and TGFbeta induced much higher expression of VEGF-C in tumor cells than each of them alone. Despite its effect in promoting VEGF-C expression, TGFbeta could inhibit lymphangiogenesis by directly inhibiting tube formation by LECs. However, the increased production of VEGF-C not only directly promoted migration and tube formation of LECs but also thwarted the inhibitory effect of TGFbeta on LECs. That is, tumor cells that expressed high levels of SIX1 could promote lymphangiogenesis and counteract the negative effects of TGFbeta on lymphangiogenesis by increasing the expression of VEGF-C. These findings provide new insights into tumor lymphangiogenesis and the various roles of TGFbeta signaling in tumor regulation. Our results also suggest that SIX1/TGFbeta might be a potential therapeutic target for preventing lymph node metastasis of tumor. PMID- 25142797 TI - Do prehospital criteria optimally assign injured children to the appropriate level of trauma team activation and emergency department disposition at a level I pediatric trauma center? AB - PURPOSE: To examine the association of prehospital criteria with the appropriate level of trauma team activation (TTA) and emergency department (ED) disposition among injured children at a level I pediatric trauma center. METHODS: Injured children younger than 15 years and transported by emergency medical services (EMS) from the scene of injury between January 1, 2008 and December 31, 2011 were identified using the institution's trauma registry. Logistic regression was used to study the main outcomes of interest, full TTA (FTTA) and ED disposition. RESULTS: Out of 3,213 children, 1,991 were eligible and analyzed. Only 279 children initiated the FTTA and 73.9% were admitted. Having a chest injury, abnormal heart rate or Glasgow Coma Scale less than 9 (GCSLT9) in the field was associated with higher odds of initiating the FTTA (odds ratio [OR] = 3.33, 95% confidence interval [CI] 1.54-7.20; OR = 2.59, CI 1.15-5.79 and OR = 2.67, CI 1.14-6.22, respectively). Children with the criteria above in addition to abdominal injury were more likely to be discharged to the ICU, OR or morgue compared to those without them. CONCLUSION: Children with GCSLT9, abnormal heart rate, chest and abdominal injury showed a strong association with FTTA and higher resource utilization. PMID- 25142798 TI - Coronary CT angiography in clinical practice: experiences from Denmark. PMID- 25142799 TI - Does the WHO 2010 classification of pancreatic neuroendocrine neoplasms accurately characterize pancreatic neuroendocrine carcinomas? AB - BACKGROUND: The WHO classified pancreatic neuroendocrine neoplasms in 2010 as G1, G2, and neuroendocrine carcinoma (NEC), according to the Ki67 labeling index (LI). However, the clinical behavior of NEC is still not fully studied. We aimed to clarify the clinicopathological and molecular characteristics of NECs. METHODS: We retrospectively evaluated the clinicopathological characteristics, KRAS mutation status, treatment response, and the overall survival of eleven pNEC patients diagnosed between 2001 and 2014 according to the WHO 2010. We subclassified WHO-NECs into well-differentiated NEC (WDNEC) and poorly differentiated NEC (PDNEC). The latter was further subdivided into large-cell and small-cell subtypes. RESULTS: The median Ki67 LI was 69.1% (range 40-95%). Eleven WHO-NECs were subclassified into 4 WDNECs and 7 PDNECs. The latter was further separated into 3 large-cell and 4 small-cell subtypes. Comparisons of WDNEC vs. PDNEC revealed the following traits: hypervascularity on CT, 50% (2/4) vs. 0% (0/7) (P = 0.109); median Ki67 LI, 46.3% (40-53%) vs. 85% (54-95%) (P = 0.001); Rb immunopositivity, 100% (4/4) vs. 14% (1/7) (P = 0.015); KRAS mutations, 0% (0/4) vs. 86% (6/7) (P = 0.015); response rates to platinum-based chemotherapy, 0% (0/2) vs. 100% (4/4) (P = 0.067), and median survival, 227 vs. 186 days (P = 0.227). CONCLUSIONS: The WHO-NEC category may be composed of heterogeneous disease entities, namely WDNEC and PDNEC. These subgroups tended to exhibit differing profiles of Ki67 LI, Rb immunopositivity and KRAS mutation, and distinct response to chemotherapy. Further studies for the reevaluation of the current WHO 2010 classification are warranted. PMID- 25142800 TI - Clinical significance of a papillary adenocarcinoma component in early gastric cancer: a single-center retrospective analysis of 628 surgically resected early gastric cancers. AB - BACKGROUND: We recently reported that the presence of a papillary adenocarcinoma (pap) component was an independent risk factor for lymphatic involvement in endoscopically resected early gastric cancer (EGC). This study aimed to investigate the potential association between the presence of a pap component in EGC and lymph node metastasis (LNM). METHODS: In order to evaluate the association between LNM and clinicopathological features, including a pap component, we reviewed 628 surgically resected EGCs at our institution between 2009 and 2012. Clinicopathological features included age, gender, tumor location, macroscopic type, tumor size, histological type, depth, ulcerative findings, and lymphatic and venous involvement. In addition, the association between clinicopathological features and lymphatic involvement was also evaluated. RESULTS: LNM was observed in 52 cases (8.3%). Univariate analyses revealed a significant correlation between a pap component and LNM as well as tumor size, depth, macroscopic type, a poorly differentiated adenocarcinoma component, and lymphatic and venous involvement. The percentage of positive LNM among the EGC cases with a pap component was significantly higher than in those without the component (18.2 vs. 7.3%, P = 0.010). Via multivariate analyses lymphatic involvement was identified as the strongest risk factor for LNM [odds ratio (OR) 14.1] and a pap component was revealed as an independent risk factor for lymphatic involvement (OR 3.1). CONCLUSION: Our study revealed that EGC cases with a pap component were at higher risk of lymphatic involvement and showed a higher percentage of positive LNM. More attention should be paid to a pap component in EGC. PMID- 25142801 TI - Performance comparison of second- and third-generation sequencers using a bacterial genome with two chromosomes. AB - BACKGROUND: The availability of diverse second- and third-generation sequencing technologies enables the rapid determination of the sequences of bacterial genomes. However, identifying the sequencing technology most suitable for producing a finished genome with multiple chromosomes remains a challenge. We evaluated the abilities of the following three second-generation sequencers: Roche 454 GS Junior (GS Jr), Life Technologies Ion PGM (Ion PGM), and Illumina MiSeq (MiSeq) and a third-generation sequencer, the Pacific Biosciences RS sequencer (PacBio), by sequencing and assembling the genome of Vibrio parahaemolyticus, which consists of a 5-Mb genome comprising two circular chromosomes. RESULTS: We sequenced the genome of V. parahaemolyticus with GS Jr, Ion PGM, MiSeq, and PacBio and performed de novo assembly with several genome assemblers. Although GS Jr generated the longest mean read length of 418 bp among the second-generation sequencers, the maximum contig length of the best assembly from GS Jr was 165 kbp, and the number of contigs was 309. Single runs of Ion PGM and MiSeq produced data of considerably greater sequencing coverage, 279* and 1,927*, respectively. The optimized result for Ion PGM contained 61 contigs assembled from reads of 77* coverage, and the longest contig was 895 kbp in size. Those for MiSeq were 34 contigs, 58* coverage, and 733 kbp, respectively. These results suggest that higher coverage depth is unnecessary for a better assembly result. We observed that multiple rRNA coding regions were fragmented in the assemblies from the second-generation sequencers, whereas PacBio generated two exceptionally long contigs of 3,288,561 and 1,875,537 bps, each of which was from a single chromosome, with 73* coverage and mean read length 3,119 bp, allowing us to determine the absolute positions of all rRNA operons. CONCLUSIONS: PacBio outperformed the other sequencers in terms of the length of contigs and reconstructed the greatest portion of the genome, achieving a genome assembly of "finished grade" because of its long reads. It showed the potential to assemble more complex genomes with multiple chromosomes containing more repetitive sequences. PMID- 25142802 TI - Is a minimally invasive approach the solution for reducing surgical site infections? PMID- 25142803 TI - Surgical treatment for pyogenic vertebral osteomyelitis using iodine-supported spinal instruments: initial case series of 14 patients. AB - Reports have detailed the increasing use of spinal instrumentation in the treatment of pyogenic vertebral osteomyelitis, with the aims of achieving a lower pseudoarthrosis rate and restoring spinal alignment. However, controversy remains over the use of instrumentation in the presence of active infection because of concerns about increased bacterial adherence and biofilm formation on the metallic implant surface. Fourteen consecutive patients were followed who were diagnosed as having pyogenic vertebral osteomyelitis and underwent surgery with spinal instrumentation with iodine-containing surfaces that could be directly supported to existing titanium implants. Bone-cage interfaces and implant-related complications after surgery were evaluated. The white blood cell (WBC) count and C-reactive protein (CRP) level were analyzed during the follow-up period. To confirm the influence of iodine release from the implant, thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were also examined. The infection subsided in all 14 patients. Both WBC counts and CRP levels returned to normal ranges by the final follow-up. One patient showed a lucent area around the screw and two patients showed lucencies inside the cage. However, no cage dislocations, cage migrations, or screw pull-outs were noted, and all patients' FT3, FT4, and TSH levels were within normal ranges during the follow-up period. We demonstrated the efficacy of iodine-supported titanium implants in the management of pyogenic vertebral osteomyelitis. No cytotoxicity or adverse effects were noted in this series. PMID- 25142804 TI - High levels of CD4+ CTLA-4+ Treg cells and CCR5 density in HIV-1-infected patients with visceral leishmaniasis. AB - Visceral leishmaniasis (VL) in HIV-1-infected patients has been associated with poor immunological recovery and frequent disease relapses. The aim of this study was to analyse the role of T cell populations, Treg cells and CCR5 density in patients with VL compared to HIV-1-infected patients without leishmaniasis. A cross-sectional study of nine Leishmania-HIV-1-coinfected (LH) patients with VL receiving suppressive cART for at least 1 year were compared to 16 HIV-1-infected patients with non-immunological response (NIR, CD4 count below 250 cells/mm(3)) and 26 HIV-1-infected patients with immunological response (IR, CD4 count above 500 cells/mm(3)) without leishmaniasis. LH patients had a deep depletion of naive T cells (p = 0.002), despite similar levels of effector T cells compared to NIR patients. CD4 Treg cells were similar compared to NIR patients, but higher compared to IR patients (p < 0.001). Interestingly, CD4 Treg CTLA-4(+) cells were higher in LH patients compared to either NIR or IR patients (p = 0.022 and p < 0.001, respectively), and the CD4 Treg/TEM ratio was similar to NIR patients, but higher compared to IR patients (p = 0.017). CCR5(+) T cell levels were higher compared to IR patients (p < 0.001), while CCR5 density on T cells were higher compared to both NIR and IR patients (p < 0.005 in both cases). Higher levels of CD4(+) CTLA-4(+) Treg cells and CCR5 density on CD8(+) T cells are strongly associated with VL in HIV-1-infected patients. Also, these patients have a poor immunological profile that might explain the persistence and relapse of the pathogen. PMID- 25142805 TI - Suicide tourism may change attitudes to assisted suicide, but not through the courts. PMID- 25142806 TI - Suicide tourism: a pilot study on the Swiss phenomenon. AB - While assisted suicide (AS) is strictly restricted in many countries, it is not clearly regulated by law in Switzerland. This imbalance leads to an influx of people-'suicide tourists'-coming to Switzerland, mainly to the Canton of Zurich, for the sole purpose of committing suicide. Political debate regarding 'suicide tourism' is taking place in many countries. Swiss medicolegal experts are confronted with these cases almost daily, which prompted our scientific investigation of the phenomenon. The present study has three aims: (1) to determine selected details about AS in the study group (age, gender and country of residence of the suicide tourists, the organisation involved, the ingested substance leading to death and any diseases that were the main reason for AS); (2) to find out the countries from which suicide tourists come and to review existing laws in the top three in order to test the hypothesis that suicide tourism leads to the amendment of existing regulations in foreign countries; and (3) to compare our results with those of earlier studies in Zurich. We did a retrospective data analysis of the Zurich Institute of Legal Medicine database on AS of non-Swiss residents in the last 5 years (2008-2012), and internet research for current legislation and political debate in the three foreign countries most concerned. We analysed 611 cases from 31 countries all over the world. Non terminal conditions such as neurological and rheumatic diseases are increasing among suicide tourists. The unique phenomenon of suicide tourism in Switzerland may indeed result in the amendment or supplementary guidelines to existing regulations in foreign countries. PMID- 25142807 TI - Autoantibodies and cardiovascular dysfunction: cause or consequence? AB - There has been a long history of the exploration into autoimmunity as a possible pathogenic factor of cardiovascular diseases from unknown cause represented by dilated cardiomyopathy (DCM). Autoantibodies (AAbs) have emerged either as humoral responses provoked by the release of "self-antigens" due to tissue damage or dysregulated humoral immunity itself. The pathogenic roles of some AAbs have been suggested by the findings from basic research using in vitro and in vivo disease models as well as clinical studies including immunoadsorption studies removing AAbs from patients with DCM. In this context, the importance of AAbs belonging to IgG3 subclass has also been implicated. In this review article, we summarize the findings accumulated to date regarding AAbs which have been considered to be involved in the pathology of DCM or pregnancy-related cardiovascular disease. Furthermore, we discuss the significance of AAbs as a possible cause of DCM and their potential roles as a novel therapeutic target. PMID- 25142808 TI - Growth-promoting Sphingomonas paucimobilis ZJSH1 associated with Dendrobium officinale through phytohormone production and nitrogen fixation. AB - Growth-promoting Sphingomonas paucimobilis ZJSH1, associated with Dendrobium officinale, a traditional Chinese medicinal plant, was characterized. At 90 days post-inoculation, strain ZJSH1 significantly promoted the growth of D. officinale seedlings, with increases of stems by 8.6% and fresh weight by 7.5%. Interestingly, the polysaccharide content extracted from the inoculated seedlings was 0.6% higher than that of the control. Similar growth promotion was observed with the transplants inoculated with strain ZJSH1. The mechanism of growth promotion was attributed to a combination of phytohormones and nitrogen fixation. Strain ZJSH1 was found using the Kjeldahl method to have a nitrogen fixation activity of 1.15 mg l(-1) , which was confirmed by sequencing of the nifH gene. Using high-performance liquid chromatography-mass spectrometry, strain ZJSH1 was found to produce various phytohormones, including salicylic acid (SA), indole-3 acetic acid (IAA), Zeatin and abscisic acid (ABA). The growth curve showed that strain ZJSH1 grew well in the seedlings, especially in the roots. Accordingly, much higher contents of SA, ABA, IAA and c-ZR were detected in the inoculated seedlings, which may play roles as both phytohormones and 'Systemic Acquired Resistance' drivers. Nitrogen fixation and secretion of plant growth regulators (SA, IAA, Zeatin and ABA) endow S. paucimobilis ZJSH1 with growth-promoting properties, which provides a potential for application in the commercial growth of D. officinale. PMID- 25142809 TI - Test chamber investigation of the volatilization from source materials of brominated flame retardants and their subsequent deposition to indoor dust. AB - Numerous studies have reported elevated concentrations of brominated flame retardants (BFRs) in dust from indoor micro-environments. Limited information is available, however, on the pathways via which BFRs in source materials transfer to indoor dust. The most likely hypothesized pathways are (a) volatilization from the source with subsequent partitioning to dust, (b) abrasion of the treated product, transferring microscopic fibers or particles to the dust (c) direct uptake to dust via contact between source and dust. This study reports the development and application of an in-house test chamber for investigating BFR volatilization from source materials and subsequent partitioning to dust. The performance of the chamber was evaluated against that of a commercially available chamber, and inherent issues with such chambers were investigated, such as loss due to sorption of BFRs to chamber surfaces (so-called sink effects). The partitioning of polybrominated diphenyl ethers to dust, post-volatilization from an artificial source was demonstrated, while analysis in the test chamber of a fabric curtain treated with the hexabromocyclododecane formulation, resulted in dust concentrations exceeding substantially those detected in the dust pre experiment. These results provide the first experimental evidence of BFR volatilization followed by deposition to dust. PRACTICAL IMPLICATIONS: Brominated flame retardants (BFRs) are ubiquitous in indoor air and dust, leading to human exposure and resultant concerns about their adverse impact on health. Indoor dust has been demonstrated to constitute an important vector of human exposure to BFRs, especially for toddlers. Despite the greater importance of dust contamination in the context of human exposure to BFRs, the mechanisms via which BFRs transfer from source materials to dust have hitherto been subject to only limited research. In this study, a test chamber is utilized to simulate the migration of BFRs to dust via volatilization from source materials and subsequent deposition to dust. PMID- 25142810 TI - Effect of hospital volume on quality of care and outcome after rectal cancer surgery. AB - BACKGROUND: Research on the relationship between hospital volume and quality of care in the treatment of rectal cancer is limited. METHODS: Process and outcome indicators were assessed in patients with rectal adenocarcinoma who underwent total mesorectal excision, registered on a voluntary basis in the PROCARE clinical database. Volume was derived from an administrative database and analysed as a continuous variable. Sphincter preservation, 30-day mortality and survival rates were cross-checked against population-based data. RESULTS: A total of 1469 patients registered in PROCARE between 2006 and 2011 were included in this study. A volume effect was observed regarding neoadjuvant therapy for stage II-III disease, reporting of the circumferential resection margin, R0 resection rate, sphincter preservation rate, and number of nodes examined after chemoradiotherapy. The global estimate of quality of care was highly variable, but surgery was the single domain in which quality correlated with volume. No volume effect was observed for recurrence and overall survival rates. In the population-based data set (5869 patients), volume was associated with 30-day mortality adjusted for age (odds ratio 0.99, 95 per cent confidence interval (c.i.) 0.98 to 1.00; P = 0.014) and adjusted overall survival (HR 0.99 (95 per cent c.i. 0.99 to 1.00) per additional procedure; P = 0.001), but not with the sphincter preservation rate. Because of incomplete and biased registration on a voluntary basis, results from a clinical database could not be extrapolated to the population. CONCLUSION: Some volume effects were observed, but their effect size was limited. PMID- 25142811 TI - Overexpression of alpha2,3sialyl T-antigen in breast cancer determined by miniaturized glycosyltransferase assays and confirmed using tissue microarray immunohistochemical analysis. AB - Glycan structure alterations during cancer regulate disease progression and represent clinical biomarkers. The study determined the degree to which changes in glycosyltransferase activities during cancer can be related to aberrant cell surface tumor associated carbohydrate structures (TACA). To this end, changes in sialyltransferase (sialylT), fucosyltransferase (fucT) and galactosyltransferase (galT) activity were measured in normal and tumor tissue using a miniaturized enzyme activity assay and synthetic glycoconjugates bearing terminal LacNAc Type I (Galbeta1-3GlcNAc), LacNAc Type-II (Galbeta1-4GlcNAc), and mucin core-1/Type III (Galbeta1-3GalNAc) structures. These data were related to TACA using tissue microarrays containing 115 breast and 26 colon cancer specimen. The results show that primary human breast and colon tumors, but not adjacent normal tissue, express elevated beta1,3GalT and alpha2,3SialylT activity that can form alpha2,3SialylatedType-IIIglycans (Siaalpha2-3Galbeta1-3GalNAc). Prostate tumors did not exhibit such elevated enzymatic activities. alpha1,3/4FucT activity was higher in breast, but not in colon tissue. The enzymology based prediction of enhanced alpha2,3sialylated Type-III structures in breast tumors was verified using histochemical analysis of tissue sections and tissue microarrays. Here, the binding of two markers that recognize Galbeta1-3GalNAc (peanut lectin and mAb A78 G/A7) was elevated in breast tumor, but not in normal control, only upon sialidase treatment. These antigens were also upregulated in colon tumors though to a lesser extent. alpha2,3sialylatedType-III expression correlated inversely with patient HER2 expression and breast metastatic potential. Overall, enzymology measurements of glycoT activity predict truncated O-glycan structures in tumors. High expression of the alpha2,3sialylated T-antigen O-glycans occur in breast tumors. A transformation from linear core-1 glycan to other epitopes may accompany metastasis. PMID- 25142812 TI - Antitumor effect of sinoporphyrin sodium-mediated photodynamic therapy on human esophageal cancer Eca-109 cells. AB - The aim of this study was to evaluate the photodynamic effect of Sinoporphyrin sodium (DVDMS). In this study, Eca-109 cells were treated with DVDMS (5 MUg mL( 1)) and subjected to photodynamic therapy (PDT). The uptake and subcellular localization of DVDMS were monitored by flow cytometry and confocal microscopy. The phototoxicity of DVDMS was studied by MTT assay. The morphological changes were observed by scanning electron microscopy (SEM). DNA damage, reactive oxygen species (ROS) generation and mitochondria membrane potential (MMP) changes were analyzed by flow cytometry. Studies demonstrated maximal uptake of DVDMS occurred within 3 h, with a mitochondrial subcellular localization. MTT assays displayed that DVDMS could be effectively activated by light and the phototoxicity was much higher than photofrin under the same conditions. In addition, SEM observation indicated that cells were seriously damaged after PDT treatment. Furthermore, activation of DVDMS resulted in significant increases in ROS production. The generated ROS played an important role in the phototoxicity of DVDMS. DVDMS mediated PDT (DVDMS-PDT) also induced DNA damage and MMP loss. It is demonstrated that DVDMS-mediated PDT is an effective approach on cell proliferation inhibition of Eca-109 cells. PMID- 25142814 TI - Shape-directional growth of Pt and Pd nanoparticles. AB - The design and synthesis of shape-directed nanoscale noble metal particles have attracted much attention due to their enhanced catalytic properties and the opportunities to study fundamental aspects of nanoscale systems. As such, numerous methods have been developed to synthesize crystals with tunable shapes, sizes, and facets by adding foreign species that promote or restrict growth on specific sites. Many hypotheses regarding how and why certain species direct growth have been put forward, however there has been no consensus on a unifying mechanism of nanocrystal growth. Herein, we develop and demonstrate the capabilities of a mathematical growth model for predicting metal nanoparticle shapes by studying a well known procedure that employs AgNO3 to produce {111} faceted Pt nanocrystals. The insight gained about the role of auxiliary species is then utilized to predict the shape of Pd nanocrystals and to corroborate other shape-directing syntheses reported in literature. The fundamental understanding obtained herein by combining modeling with experimentation is a step toward computationally guided syntheses and, in principle, applicable to predictive design of the growth of crystalline solids at all length scales (nano to bulk). PMID- 25142813 TI - Effect of edaravone on radiation-induced brain necrosis in patients with nasopharyngeal carcinoma after radiotherapy: a randomized controlled trial. AB - Excessive generation of free radicals plays a critical role in the pathogenesis of radiation-induced brain injury. This study was designed to evaluate the protective effect of edaravone, a free radical scavenger, on radiation-induced brain necrosis in patients with nasopharyngeal carcinoma. Eligible patients were randomized 1:1 to the control group and the edaravone group (intravenous 30 mg twice per day for 2 weeks). Both groups received intravenous conventional steroid therapy and were monitored by brain MRI and LENT/SOMA scales prior to the entry of the trial and at 3-months after completing the trial. The primary end point was a 3-month response rate of the proportional changes determined by MRI. The trial is registered at Clinicaltrials.gov Identifier: NCT01865201. Between 2009 and 2012, we enrolled 154 patients. Of whom 137 were eligible for analysis. The volumes of necrosis estimated on T(2)-weighted image showed that 55.6 % edaravone treated patients (40 out of 72) showed edema decreases >=25 %, which was significantly higher than that in the control group (35.4 %, 23 out of 65, p = 0.025). Forty-four patients treated with edaravone (61.1 %) reported improvement in neurologic symptoms and signs evaluated by LENT/SOMA scales, while the rate was 38.5 % in the control group (p = 0.006). MRI of the edaravone group showed a significant decrease in area of T(1)-weighted contrast enhancement (1.67 +/- 4.69 cm(2), p = 0.004) and the T(2)-weighted edema (5.08 +/- 10.32 cm(2), p = 0.000). Moreover, compared with those in control group, patients with edaravone exhibited significantly better radiological improvement measured by T(2)-weighted image (p = 0.042). Administration of edaravone, in adjunct to steroid regimen, might provide a better outcome in patients with radiation-induced brain necrosis. PMID- 25142815 TI - Plant secondary metabolites- potent inhibitors of monoamine oxidase isoforms. AB - Target of monoamine oxidase inhibitions are considered as the treatment of depressive states and neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. Many medicinal chemistry research groups are actively working in this area for the development of most promising selective MAO inhibitors. Many plant isolates also showed remarkable MAO inhibition in recent years. The objective of this review is to identify the major MAO inhibitors secondary metabolites from plants like flavonoids, alkaloids and xanthones class of compounds. PMID- 25142816 TI - A comparison of traditional and quantitative analysis of acid-base imbalances in hypoalbuminemic dogs. AB - OBJECTIVE: To compare the traditional (HH) and quantitative approaches used for the evaluation of the acid-base balance in hypoalbuminemic dogs. DESIGN: Prospective observational study. SETTING: ICU of a veterinary teaching hospital. ANIMALS: One hundred and five client-owned dogs. MEASUREMENTS AND MAIN RESULTS: Jugular venous blood samples were collected from each patient on admission to determine: total plasma protein (TP), albumin (Alb), blood urea nitrogen (BUN), glucose (Glu), hematocrit (HCT), Na(+) , Cl(-) , K(+) , phosphate (Pi ), pH, PvCO2, bicarbonate (HCO3 (-) ), anion gap (AG), adjusted anion gap for albumin (AGalb ) or phosphate (AGalb-phos ), standardized base excess (SBE), strong ion difference (SID), concentration of nonvolatile weak buffers (Atot ), and strong ion gap (SIG). Patients were divided in 2 groups according to the severity of the hypoalbuminemia: mild (Alb = 21-25 g/L) and severe (Alb <=20 g/L). All parameters were compared among groups. Patients with severe hypoalbuminemia showed significant decrease in TP (P = 0.011), Atot (P = 0.050), and a significant increase in adjusted AG (P = 0.048) and the magnitude of SIG (P = 0.011) compared to animals with mild hypoalbuminemia. According to the HH approach, the most frequent imbalances were simple disorders (51.4%), primarily metabolic acidosis (84.7%) associated with a high AG acidosis. However, when using the quantitative method, 58.1% of patients had complex disorders, with SIG acidosis (74.3%) and Atot alkalosis (33.3%) as the most frequent acid-base imbalances. Agreement between methods only matched in 32 cases (kappa < 0.20). CONCLUSIONS: The agreement between the HH and quantitative methods for interpretation of acid-base balance was poor and many imbalances detected using the quantitative approach were missed using the HH approach. Further studies are necessary to confirm the clinical utility of using the quantitative approach in the decision-making process of the severely ill hypoalbuminemic patients. PMID- 25142818 TI - Early death in acute promyelocytic leukemia (APL) in French centers: a multicenter study in 399 patients. PMID- 25142817 TI - Novel drugs for older patients with acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is the second most common form of leukemia and the most frequent cause of leukemia-related deaths in the United States. The incidence of AML increases with advancing age and the prognosis for patients with AML worsens substantially with increasing age. Many older patients are ineligible for intensive treatment and require other therapeutic approaches to optimize clinical outcome. To address this treatment gap, novel agents with varying mechanisms of action targeting different cellular processes are currently in development. Hypomethylating agents (azacitidine, decitabine, SGI-110), histone deacetylase inhibitors (vorinostat, pracinostat, panobinostat), FMS-like tyrosine kinase receptor-3 inhibitors (quizartinib, sorafenib, midostaurin, crenolanib), cytotoxic agents (clofarabine, sapacitabine, vosaroxin), cell cycle inhibitors (barasertib, volasertib, rigosertib) and monoclonal antibodies (gentuzumab ozogamicin, lintuzumab-Ac225) represent some of these promising new treatments. This review provides an overview of novel agents that have either completed or are currently in ongoing phase III trials in patients with previously untreated AML for whom intensive treatment is not an option. Other potential drugs in earlier stages of development will also be addressed in this review. PMID- 25142819 TI - Sex differences in ventricular-vascular coupling following endurance training. AB - INTRODUCTION: Ventricular and vascular coupling is defined as the ratio of arterial elastance (Ea) to ventricular elastance (Elv) and describes the interaction between the heart and arterial system. There are sex differences in both arterial and ventricular function in response to both acute exercise and aerobic exercise training. PURPOSE: To examine the effects of aerobic exercise training on elastances and the coupling ratio in young adult men and women. We hypothesized a reduction in the coupling ratio in both sexes due to a decrease in Ea that would be more pronounced in men and an increase in Elv that would be larger in women. METHODS: Fifty-three healthy, young adults completed the study. Central pulse wave velocity and heart volumes were measured before and after an 8 week aerobic training intervention. Elastances were calculated as Ea = end systolic pressure/stroke volume and Elv = end-systolic pressure/end-systolic volume and indexed to body surface area. RESULTS: After the intervention, women augmented indexed and un-indexed Elv from 2.09 +/- 0.61 to 2.52 +/- 0.80 mmHg/ml, p < 0.05, and reduced the coupling ratio from 0.72 +/- 18 to 0.62 +/- 15, p < 0.05, while men maintained their pre-training ratio (from 0.66 +/- 0.20 to 0.74 +/- 0.21, p > 0.05). Women also reduced end-systolic pressure (from 91 +/- 10 to 87 +/- 10 mmHg), and both groups reduced central pulse wave velocity (from 6.0 +/ 1.0 to 5.6 +/- 0.6 m/s, p < 0.05). CONCLUSION: We conclude that after 8 weeks of aerobic training, only women reduced their coupling ratio due to an increase in Elv. This suggests that aerobic exercise training elicits sex-dependent changes in the coupling ratio in young, healthy individuals. PMID- 25142820 TI - Pharmaceutical and pharmacokinetic evaluation of a novel fast dissolving film formulation of flupentixol dihydrochloride. AB - The objective of the present study was to develop fast dissolving oral film of the antipsychotic drug, flupentixol dihydrochloride, to enhance its bioavailability, optimize its therapeutic effect when used to treat depression with anxiety, and increase the convenience and compliance by the mentally ill, developmentally disable, elderly, and pediatric patients. Six formulae were prepared with different concentrations of water-soluble polymers vis. hydroxypropyl methylcellulose (HPMC E5) and carboxymethyl cellulose (CMC) by solvent casting technique. The prepared films were subjected to characterization for folding endurance, weight variations, thickness, disintegration time, drug release pattern, and drug content. Physical compatibility between the drug and excipients was guaranteed in the selected formulation (2% HPMC) by means of differential scanning calorimetry analysis and Fourier-transform infrared spectroscopy. This formulation revealed high stability after testing according to the International Conference on Harmonisation guidelines. In vivo studies based on single phase parallel design were carried out for the optimized formulation in healthy human volunteers. The concentration of flupentixol dihydrochloride in plasma samples was analyzed by a developed validated LC-MS/MS assay method and the pharmacokinetic parameters of the established formulation were compared with the commercially available oral tablets. Faster rate of absorption of flupentixol could be obtained from the oral film formulation and the relative bioavailability was found to be 151.06% compared to the marketed product. PMID- 25142821 TI - Intranasal drug delivery of olanzapine-loaded chitosan nanoparticles. AB - The aim of this study was to investigate olanzapine (OZ) systemic absolute bioavailability after intranasal (i.n.) administration in vivo to conscious rabbits. Furthermore, the study investigated the potential use of chitosan nanoparticles as a delivery system to enhance the systemic bioavailability of olanzapine following intranasal administration. Olanzapine-loaded chitosan nanoparticles were prepared through ionotropic gelation of chitosan with tripolyphosphate anions and studied in terms of their size, drug loading, and in vitro release. The OZ nanoparticles were administered i.n. to rabbits, and OZ plasma concentration at predetermined time points was compared to i.n. administration of OZ in solution. The concentrations of OZ in plasma were analyzed by ultra performance liquid chromatography mass spectroscopy (UPLC/MS). OZ-loaded chitosan nanoparticles significantly (p < 0.05) enhanced systemic absorption with 51 +/- 11.2% absolute bioavailability as compared to 28 +/- 6.7% after i.n. administration of OZ solution. The results of the present study suggest that intranasal administration of OZ-loaded chitosan nanoparticles formulation could be an attractive modality for delivery of OZ systemically. PMID- 25142822 TI - Regulatory considerations for the classification of video monitoring in dissolution testing. AB - The goal of this article is to discuss the classification of video recordings and images when applied to dissolution testing in USP apparatus 1 and 2. Three use cases are presented. The first case presents the use and classification of video as RBE (review by exception) data under GAMP 5. The second case presents the use of video in formulation development in a research and development environment. The third case presents a feasibility study using readily available computer vision software to recognize and measure objects in the dissolution vessel, setting the groundwork for the use of image analysis as a quantitative tool. The classification of video as "electronic data", requiring 21 CFR part 11 compliance, versus its classification as a RBE data under GAMP 5, likely depends upon its use case. Another goal of this article is to establish a position on the use of video monitoring technology as a tool for dissolution testing that is fit for purpose and compliant with regulations regarding video data management and information. PMID- 25142824 TI - Direct synthesis of the Janus-head ligand ((Me)Py)3Sn-Sn((Me)Py)3 using an unusual pyridyl-transfer reaction ((Me)Py = 6-methyl-2-pyridyl). AB - The in situ reaction of the tripodal anion [EtAl((Me)Py)3](-) ((Me)Py = 6-Me-2 py) with SnCl2 gives the Janus-head ligand ((Me)Py)3Sn-Sn((Me)Py)3, containing a Sn-Sn bond, through a novel, one-pot reaction involving a combination of pyridyl transfer and metal-oxidation. PMID- 25142823 TI - Effect of arginine on pre-nucleus stage of interferon beta-1b aggregation. AB - Understanding the mechanism of aggregation of a therapeutic protein would not only ease the manufacturing processing but could also lead to a more stable finished product. Aggregation of recombinant interferon (IFNbeta-1b) was studied by heating, oxidizing, or seeding of unformulated monomeric solution. The formation of aggregates was monitored by dynamic light scattering (DLS) and UV spectroscopy. The autocatalytic monomer loss model was used to fit the data on aggregation rates. The influence of pre-nucleation on aggregation step was demonstrated by inducing the liquid samples containing a monomer form of folded IFNbeta-1b by heat and also an oxidizing agent. Results tend to suggest that the nucleus includes a single protein molecule which has been probably deformed. Seeding tests showed that aggregation of IFNbeta-1b was probably initiated when 1.0% (w/w) of monomers converted to nucleus form. Chemiluminescence spectroscopy analysis of the sample indicated the generation of 3.0 MUM of hydrogen peroxide (H2O2) during nucleation stage of IFNbeta-1b aggregation. Arginine with a concentration of 200 mM was sufficient to suppress aggregation of IFNbeta-1b by decreasing the rate of pre-nucleation step. We proposed the formation of pre nucleus structures prior to nucleation as the mechanism of aggregation of IFNbeta 1b. Furthermore, we have showed the positive anti-aggregation effect of arginine on pre-nucleation step. PMID- 25142825 TI - Clusters of cortical spreading depolarizations in a patient with intracerebral hemorrhage: a multimodal neuromonitoring study. AB - BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is associated with high morbidity and mortality. Cortical spreading depolarizations (CSDs) increase brain matrix metalloproteinase (MMP)-9 activity leading to perihematomal edema expansion in experimental ICH. METHODS: The purpose of this report is to describe cerebral metabolic changes and brain extracellular MMP-9 levels in a patient with CSDs and perihematomal edema expansion after ICH. RESULTS: We present a 66-year old male patient with ICH who underwent craniotomy for hematoma evacuation. Multimodal neuromonitoring data of the perihematomal region revealed metabolic distress and increased MMP-9 levels in the brain extracellular fluid during perihematomal edema progression. At the same time, subdural electrocorticography showed clusters of CSDs, which disappeared after ketamine anesthesia on day six. Perihematomal edema regression was associated with decreasing cerebral MMP-9 levels. CONCLUSIONS: This novel association between clusters of CSDs, brain metabolic distress, and increased MMP-9 levels expands our knowledge about secondary brain injury after ICH. The role of ketamine after this devastating disorder needs further studies. PMID- 25142826 TI - Bedside evaluation of cerebral energy metabolism in severe community-acquired bacterial meningitis. AB - BACKGROUND: Mortality and morbidity have remained high in bacterial meningitis. Impairment of cerebral energy metabolism probably contributes to unfavorable outcome. Intracerebral microdialysis is routinely used to monitor cerebral energy metabolism, and recent experimental studies indicate that this technique may separate ischemia and non-ischemic mitochondrial dysfunction. The present study is a retrospective interpretation of biochemical data obtained in a series of patients with severe community-acquired meningitis. METHODS: Cerebral energy metabolism was monitored in 15 patients with severe community-acquired meningitis utilizing intracerebral microdialysis and bedside biochemical analysis. According to previous studies, cerebral ischemia was defined as lactate/pyruvate (LP) ratio > 30 with intracerebral pyruvate level < 70 umol L(-1). Non-ischemic mitochondrial dysfunction was defined as LP-ratio > 30 at a normal or increased interstitial concentration of pyruvate (>= 70 MUmol L(-1)). Patients with LP ratios < 30 were classified as no mitochondrial dysfunction. RESULTS: The biochemical pattern was in 8 patients (10 microdialysis catheters) classified as no mitochondrial dysfunction, in 5 patients classified as non-ischemic mitochondrial dysfunction, and in 2 patients (3 catheters) classified as ischemia. CONCLUSIONS: In patients with severe community-acquired meningitis, compromised cerebral energy metabolism occurs frequently and was diagnosed in 7 out of 15 cases. A biochemical pattern of non-ischemic mitochondrial dysfunction appears to be a more common underlying condition than cerebral ischemia. PMID- 25142827 TI - Characterization of the relationship between intracranial pressure and electroencephalographic monitoring in burst-suppressed patients. AB - BACKGROUND: The objective of this study is to characterize the relationship between ICP and EEG METHODS: Simultaneous ICP and EEG data were obtained from burst-suppressed patients and segmented by EEG bursts. Segments were categorized as increasing/decreasing and peak/valley to investigate relationship between ICP changes and EEG burst duration. A generalized ICP response was obtained by averaging all segments time-aligned at burst onsets. A vasodilatation index (VDI) was derived from the ICP pulse waveform and calculated on a sliding interval to investigate cerebrovascular changes post-burst. RESULTS: Data from two patients contained 309 bursts. 246 ICP segments initially increased, of which 154 peaked. 63 ICP segments decreased, and zero reached a valley. The change in ICP (0.54 +/- 0.85 mmHg) was significantly correlated with the burst duration (p < 0.001). Characterization of the ICP segments showed a peak at 8.1 s and a return to baseline at 14.7 s. The VDI for increasing segments was significantly elevated (median 0.56, IQR 0.31, p < 0.001) and correlated with burst duration (p < 0.001). CONCLUSIONS: Changes in the ICP and pulse waveform shape after EEG burst suggest that these signals can be related within the context of neurovascular coupling. SIGNIFICANCE: Existence of a physiological relationship between ICP and EEG may allow the study of neurovascular coupling in acute brain injury patients. PMID- 25142828 TI - Assessment of circulating blood volume with fluid administration targeting euvolemia or hypervolemia. AB - BACKGROUND: The occurrence of hypovolemia in the setting of cerebral vasospasm reportedly increases the risk for delayed ischemic neurologic deficits. Few studies have objectively assessed blood volume (BV) in response to fluid administration targeting normovolemia (NV) or hypervolemia (HV) and none have done so with crystalloids alone. The primary purpose was to evaluate the BV of patients with SAH receiving crystalloid fluid administration targeting NV or HV. METHODS: The University of Washington IRB approved the study. Prospectively collected data was obtained from patients enrolled in a clinical trial and a concurrent group of patients who received IV fluids during the ICU stay. We defined a normovolemia (NV) and hypervolemia (HV) group based on the cumulative amount of IV fluid administered in mL/kg from ICU admission to day 5; >=30-60 mL/kg/day (NV) and >=60 mL/kg/day (HV), respectively. In a subgroup of patients, BV was measured on day 5 post ictus using iodinated (131)I-labeled albumin injection and the BVA-100 (Daxor Corp, New York, NY). Differences between the NV and HV groups were compared using Student's t-test with assumption for unequal variance. RESULTS: Twenty patients in the NV and 19 in the HV groups were included. The HV group received more fluid and had a higher fluid balance than the NV group. The subgroup of patients in whom BV was measured on day 5 (n = 19) was not different from the remainder of the cohort with respect to the total amount of administered fluid and net cumulative fluid balance by day 5. BV was not different between the two groups and varied widely. CONCLUSIONS: Routinely targeting prophylactic HV using crystalloids does not result in a higher circulating BV compared to targeting NV, but the possibility of clinically unrecognized hypovolemia remains. PMID- 25142829 TI - Association between white matter hyperintensity and medial temporal atrophy at various stages of Alzheimer's disease. AB - BACKGROUND AND PURPOSE: Whilst there is evidence implicating small vessel cerebrovascular disease in the pathogenesis of Alzheimer's disease (AD), its specific contribution to the pathophysiology of AD remains unclear. The burden of small vessel cerebrovascular disease visualized as white matter hyperintensity (WMH) and its association with medial temporal atrophy (MTA) at different stages of AD was studied. METHODS: One hundred and sixty-five cognitively normal (CN) community controls, 103 mild cognitive impairment (MCI) patients, 141 mild AD patients and 68 moderate-severe AD patients were studied. Clinical, cognitive and risk factor data were collected, and WMH and MTA were quantified by trained raters. The Jonckheere-Terpstra test for ordered alternatives was used to study the association between WMH and MTA in different stages of AD. RESULTS: The burden of total WMH increased significantly with increasing severity of AD, even after correcting for confounders. The proportion of CN, MCI, mild AD and moderate severe AD subjects with severe burden of WMH was 6.7%, 9.7%, 28.4%, and 39.7%, respectively. A strong positive association between WMH severity and MTA was evident amongst MCI (P = 0.011) and mild AD (P = 0.003) subjects, but not in CN (P = 0.953) and moderate-severe AD subjects (P = 0.301). CONCLUSIONS: The burden of WMH increased significantly from the stage of CN to MCI to AD. The association between WMH and MTA was greatest at the stage of MCI and mild AD. This has implications on the strategy to slow the progression of AD, where measures to reduce WMH, including control of vascular risk factors, need to be optimized at the stage of MCI and mild AD. PMID- 25142830 TI - Diagnostic value of B-type natriuretic peptide for estimating left atrial size and its usefulness for predicting all-cause mortality and cardiovascular events among chronic haemodialysis patients. AB - AIM: Estimating fluid balance in haemodialysis patients is essential when determining dry weight, but limited methods are currently available. B-type natriuretic peptide (BNP) is a useful surrogate marker in patients with congestive heart failure (CHF), but whether its validity could be generalized to haemodialysis patients has not been studied well. METHODS: A total of 457 haemodialysis patients at a dialysis centre were analyzed. Determinants of BNP were assessed in connection with ultrasound cardiography (UCG) records, Kt/V, ultrafiltration rate (UFR), and demographic factors. All-cause death and cardiovascular (CV) events were recorded as the main outcome. RESULTS: Among the UCG records, left atrial diameter (LAD), left ventricular ejection fraction (LVEF), were determinants of log-transformed (ln) BNP; UFR, age and sex were also significant. There was a positive correlation between BNP and LAD (r = 0.285, P < 0.001). Receiver operating characteristic (ROC) analysis revealed that BNP had 90% and 80% sensitivity to predict the presence of LA enlargement of 77.9 pg/mL and 133.2 pg/mL, respectively. Higher BNP and lower LVEF were associated with higher risk for developing all-cause death and CVD. In the adjusted model, patients with BNP higher than 471 pg/mL had hazard ratio of 2.18 (95% confidence interval (CI) 1.20-3.96, P = 0.01), compared to those with BNP <109 pg/mL. CONCLUSION: B-type natriuretic peptide was determined by LAD, LVEF, UFR, age and sex. BNP and LAD had positive correlation and BNP could become a useful tool for estimating the presence of LA enlargement. BNP and LVEF was a strong risk factor for predicting all-cause death and CV events among patients undergoing haemodialysis. PMID- 25142831 TI - Modelling the emergent dynamics and major metabolites of the human colonic microbiota. AB - We present here a first attempt at modelling microbial dynamics in the human colon incorporating both uncertainty and adaptation. This is based on the development of a Monod-equation based, differential equation model, which produces computer simulations of the population dynamics and major metabolites of microbial communities from the human colon. To reduce the complexity of the system, we divide the bacterial community into 10 bacterial functional groups (BFGs) each distinguished by its substrate preferences, metabolic pathways and its preferred pH range. The model simulates the growth of a large number of bacterial strains and incorporates variation in microbiota composition between people, while also allowing succession and enabling adaptation to environmental changes. The model is shown to reproduce many of the observed changes in major phylogenetic groups and key metabolites such as butyrate, acetate and propionate in response to a one unit pH shift in experimental continuous flow fermentors inoculated with human faecal microbiota. Nevertheless, it should be regarded as a learning tool to be updated as our knowledge of bacterial groups and their interactions expands. Given the difficulty of accessing the colon, modelling can play an extremely important role in interpreting experimental data and predicting the consequences of dietary modulation. PMID- 25142832 TI - Genomic insights into the evolution of industrial yeast species Brettanomyces bruxellensis. AB - Brettanomyces bruxellensis, like its wine yeast counterpart Saccharomyces cerevisiae, is intrinsically linked with industrial fermentations. In wine, B. bruxellensis is generally considered to contribute negative influences on wine quality, whereas for some styles of beer, it is an essential contributor. More recently, it has shown some potential for bioethanol production. Our relatively poor understanding of B. bruxellensis biology, at least when compared with S. cerevisiae, is partly due to a lack of laboratory tools. As it is a nonmodel organism, efforts to develop methods for sporulation and transformation have been sporadic and largely unsuccessful. Recent genome sequencing efforts are now providing B. bruxellensis researchers unprecedented access to gene catalogues, the possibility of performing transcriptomic studies and new insights into evolutionary drivers. This review summarises these findings, emphasises the rich data sets already available yet largely unexplored and looks over the horizon at what might be learnt soon through comprehensive population genomics of B. bruxellensis and related species. PMID- 25142833 TI - Legalising assisted suicide: what does the evidence say? PMID- 25142834 TI - Photodynamic diagnoses of malignant pleural diseases using the autofluorescence imaging system. AB - BACKGROUND: We conducted a study on photodynamic diagnosis (PDD) using autofluorescence in video-assisted thoracic surgery for minute intrathoracic small dissemination or early malignant pleural mesothelioma. METHODS: Autofluorescence is the spontaneous emission of light that occurs when mitochondria, lysosomes, and other intracellular organelles absorb light. In normal tissues, green autofluorescence of approximately 520 nm is observed in response to 400-450 nm blue excitation rays. However, in cancer lesions, green autofluorescence is reduced due to thickening of the mucosal epithelium, a decrease in autofluorescent substances, etc., and the color spectrum thus shifts to red-violet. This phenomenon is the basis of PDD. RESULTS: The color spectrum shift was observed in all tumors located on the pleural surface but not in cases with pleural fibrous disease. Among patients with primary lung cancer, those with pleural infiltration (pl) scores of 1 or greater showed color spectrum shifts due to reduced autofluorescence. CONCLUSION: Localization of pleural lesions by autofluorescence imaging was found to be useful. In primary lung cancer cases, differentiation between pl0 and pl1 lesions appears to be useful for determining therapeutic strategies including surgical procedures. PMID- 25142835 TI - Sapodilla plum (Achras sapota) induces apoptosis in cancer cell lines and inhibits tumor progression in mice. AB - Intake of fruits rich in antioxidants in daily diet is suggested to be cancer preventive. Sapota is a tropical fruit grown and consumed extensively in several countries including India and Mexico. Here we show that methanolic extracts of Sapota fruit (MESF) induces cytotoxicity in a dose-dependent manner in cancer cell lines. Cell cycle analysis suggested activation of apoptosis, without arresting cell cycle progression. Annexin V-propidium iodide double-staining demonstrated that Sapota fruit extracts potentiate apoptosis rather than necrosis in cancer cells. Loss of mitochondrial membrane potential, upregulation of proapoptotic proteins, activation of MCL-1, PARP-1, and Caspase 9 suggest that MESF treatment leads to activation of mitochondrial pathway of apoptosis. More importantly, we show that MESF treatment leads to significant inhibition of tumor growth and a 3-fold increase in the life span of tumor bearing animals compared to untreated tumor mice. PMID- 25142837 TI - Progressive widespread cutaneous telangiectasias. PMID- 25142836 TI - Improvement in estimated glomerular filtration rate in patients with chronic kidney disease undergoing catheter ablation for atrial fibrillation. AB - INTRODUCTION: Chronic kidney disease (CKD) and atrial fibrillation (AF) often coexist. We studied the association of CKD with atrial fibrosis and the effect of AF ablation on kidney function. METHODS: AF patients who had a pre- and postablation serum creatinine and who completed a late gadolinium enhancement cardiac magnetic resonance imaging (MRI; LGE-MRI) prior to ablation were included. Estimated glomerular filtration rate (eGFR) was calculated and CKD was staged using the National Kidney Foundation guidelines. Patients with eGFR <30 mL/min/1.73 m(2) were excluded. LGE-MRI was used to quantify atrial fibrosis. Patients were followed for recurrence and change in eGFR. RESULTS: A total of 392 patients were included in the study. A total of 118 (30.2%) had CKD stage 1, 198 (50.4%) CKD stage 2, 56 (14.3%) CKD stage 3A, and 20 (5.1%) CKD stage 3B. Patients with advanced CKD were more likely to be male and to have cardiovascular disease. Atrial fibrosis was not significant different between included CKD stages: 15.8 +/- 8.8%, 16.6 +/- 12.1%, 17.1 +/- 10.4%, and 16.5 +/- 8.4% for CKD stage 1, 2, 3A, and 3B, respectively (P = 0.476). At a median of 115 days following ablation, eGFR increased significantly in CKD stage 2 (74 +/- 9 to 80 +/- 23; P = 0.04), 3A (53 +/- 5 to 69 +/- 24; P < 0.001), and 3B (40 +/- 4 to 71 +/- 28; P < 0.01) and decreased in CKD stage 1 (109 +/- 18 to 82 +/- 28; P < 0.001). Arrhythmia recurrence was associated with atrial fibrosis (hazard ratio [HR] = 1.04, P < 0.01) and persistent AF (HR = 1.5; P = 0.04) but not with CKD stage (HR = 0.98; P = 0.89). CONCLUSIONS: Restoring sinus rhythm with ablation leads to significant improvement of renal function in patients with chronic kidney disease. PMID- 25142838 TI - Immunologic assessment and KMT2D mutation detection in Kabuki syndrome. AB - Kabuki or Niikawa-Kuroki syndrome (KS) is a rare disorder with multiple malformations and recurrent infections, especially otitis media. This study aimed to investigate the genetic defects in Kabuki syndrome and determine if immune status is related to recurrent otitis media. Fourteen patients from 12 unrelated families were enrolled in the 9-year study period (2005-2013). All had Kabuki faces, cleft palate, developmental delay, mental retardation, and the short fifth finger. Recurrent otitis media (12/14) and hearing impairment (8/14) were also more common features. Immunologic analysis revealed lower memory CD19+ cells (11/13), lower memory CD4+ cells (8/13), undetectable anti-HBs antibodies (7/13), and antibody deficiency (7/13), including lower IgA (4), IgG (2), and IgG2 (1). Naive emigrant lymphocytes, lymphocyte proliferation function, complement activity, and superoxide production in polymorphonuclear cells were all normal. All the patients had KMT2D mutations and 10 novel mutations of R1252X, R1757X,Y1998C, P2550R fs2604X, Q4013X, G5379X, E5425K, R5432X, R5432W, and R5500W. Resembling the phenotype of common variable immunodeficiency, KS patients with antibody deficiency, decreased memory cells, and poor vaccine response increased susceptibility to recurrent otitis media. Large-scale prospective studies are warranted to determine if regular immunoglobulin supplementation decreases the frequency of otitis media and severity of hearing impairment. PMID- 25142839 TI - Goblet Cells and Mucus Types in the Digestive Intestine and Respiratory Intestine in Bronze Corydoras (Callichthyidae: Teleostei). AB - The structure and histochemical properties of the intestine in bronze corydoras (Corydoras aeneus), a stomach-containing teleost, are described, with emphasis on goblet cells and mucin types. The proximal intestine displayed a normal structure for teleosts, whereas the distal intestine was wide, translucent, thin-walled, richly vascularized and constantly filled with air, suggesting an important respiratory role. Goblet cells were common throughout the entire intestine and displayed a variable, but mainly faint metachromatic colour after toluidine blue. They were moderately coloured by alcian blue at both pH 2.5 and 0.2 and displayed no colour after periodic acid followed by Schiff's solution (PAS), but a distinct purple-brown colour after high iron diamine followed by alcian blue (pH 2.5). Together, these results suggest that the mucin in the intestine goblet cells consists mainly of sulphated proteoglycans. Further, the results from the present lectin and neuraminidase tests suggest that these mucins contain much N acetylglucoseamines and some N-acetylgalactosamines and sialic acid, but seem to lack glucose and mannose. They also contain some galactose-N-acetylgalactosamines sequences, normally hidden by sialic acid. The distinct brush border and mucus layer on the epithelial cells in the respiratory intestine may indicate some digestive roles, such as absorption of water, ions and simple carbohydrates. As sulphated proteoglycans are tough and attract much water, this mucus may play important roles in the protection against mechanical and chemical damages and in the defence against micro-organisms throughout the entire intestine, but in the respiratory intestine it may impede significantly the oxygen uptake. However, as this part of the intestine usually contains no digesta, but is completely filled with air, frequently renewed by dry air from the atmosphere, and the main function of the mucus may be to protect the respiratory epithelium against a destroying and dangerous desiccation. PMID- 25142840 TI - A novel microdeletion in LOR causing autosomal dominant loricrin keratoderma. PMID- 25142841 TI - Age-specific changes in intrinsic breast cancer subtypes: a focus on older women. AB - PURPOSE: Breast cancer (BC) is a disease of aging and the number of older BC patients in the U.S. is rising. Immunohistochemical data show that with increasing age, the incidence of hormone receptor-positive tumors increases, whereas the incidence of triple-negative tumors decreases. Few data exist on the frequency of molecular subtypes in older women. Here, we characterize the incidence and outcomes of BC patients by molecular subtypes and age. PATIENTS AND METHODS: Data from 3,947 patients were pooled from publicly available clinical and gene expression microarray data sets. The PAM50 algorithm was used to classify tumors into five BC intrinsic subtypes: luminal A, luminal B, HER2 enriched, basal-like, and normal-like. The association of age and subtype with recurrence-free survival (RFS), overall survival, and disease-specific survival (DSS) was assessed. RESULTS: The incidence of luminal (A, B, and A+B) tumors increased with age (p < .01, p < .0001, and p < .0001, respectively), whereas the percentage of basal-like tumors decreased (p < .0001). Among patients 70 years and older, luminal B, HER2-enriched, and basal-like tumors were found at a frequency of 32%, 11%, and 9%, respectively. In older women, luminal subtypes had better outcomes than basal-like and HER2-enriched subtypes. After controlling for subtype, treatment, tumor size, nodal status, and grade, increasing age had no impact on RFS or DSS. CONCLUSION: More favorable BC subtypes increase with age, but older patients still have a substantial percentage of high-risk tumor subtypes. After accounting for tumor subtypes, age at diagnosis is not an independent prognostic factor for outcome. PMID- 25142844 TI - [How to inhibit the incidence rate of myopia]. PMID- 25142845 TI - [Distribution of refraction and ocular biometric parameters in a population of junior middle school children in Anyang of Henan province]. AB - OBJECTIVE: To investigate the distribution of spherical equivalent and ocular biometric parameters in a population of grade 7 children in central China. METHODS: 2 363 grade 7 students of junior high schools were randomly sampled. The students have been examined at baseline and followed up annually. Detailed questionnaires and most of the ocular examinations were performed. Spherical equivalent (Seq) was calculated as sphere +1/2 cylinder from cycloplegic autorefraction. Myopia was defined as spherical equivalent <= -0.5D, hyperopia as spherical equivalent >= +0.5D and emmetropia between -0.5D and +0.5D. The Lensar LS900 was used to measure corneal curvatures, axial length and anterior chamber depth. Right eyes results were analyzed. RESULTS: Among 2 267 children who have the baseline examination, 1 839 children participated the follow up examination(response rate, 81.1%), with an mean age of 14.7 years (range, 12.9 17.6) and male ratio of 48.4%. The mean spherical equivalent refraction was ( 2.62 +/- 2.19)D. The prevalence rates of myopia, high myopia, emmetropia and hyperopia were 82.7%, 7.1%, 9.8% and 7.5%. The cumulative incidence rates of myopia and high myopia were 47.1% and 4.5% respectively. Axial length, anterior chamber depth, and corneal curvature were normally distributed. The mean axial length, anterior chamber depth, and corneal curvature were (24.8 +/- 1.1)mm, (3.18 +/- 0.25)mm, (42.8 +/- 1.4)D and (43.9 +/- 1.6)D respectively. Axial length was longer, anterior chamber depth was deeper, and corneal were flatter in the male(P = 0.000). Axial length and anterior chamber depth correlated negatively with refraction. CONCLUSIONS: A moderate myopic distribution of refraction was present in the grade 9 students in central China. The prevalence rates of myopia and high myopia were relatively high in this 14-year-old population compared to other countries. It is necessary to strengthen the prevention of juvenile myopia. PMID- 25142842 TI - How prognostic and predictive biomarkers are transforming our understanding and management of advanced gastric cancer. AB - BACKGROUND: Gastric cancer (GC) is the second leading cause of cancer death worldwide. GC is a heterogeneous disease in terms of histology, anatomy, and epidemiology. There is also wide variability in how GC is treated in both the resectable and unresectable settings. Identification of prognostic and predictive biomarkers is critical to help direct and tailor therapy for this deadly disease. METHODS: A literature search was done using Medline and MeSH terms for GC and predictive biomarkers and prognostic biomarkers. The search was limited to human subjects and the English language. There was no limit on dates. Published data and unpublished abstracts with clinical relevance were included. RESULTS: Many potential prognostic and predictive biomarkers have been assessed for GC, some of which are becoming practice changing. This review is focused on clinically relevant biomarkers, including EGFR, HER2, various markers of angiogenesis, proto oncogene MET, and the mammalian target of rapamycin. CONCLUSION: GC is a deadly and heterogeneous disease for which biomarkers are beginning to change our understanding of prognosis and management. The recognition of predictive biomarkers, such as HER2 and vascular endothelial growth factor, has been an exciting development in the management of GC, validating the use of targeted drugs trastuzumab and ramucirumab. MET is another potential predictive marker that may be targeted in GC with drugs such as rilotumumab, foretinib, and crizotinib. Further identification and validation of prognostic and predictive biomarkers has the potential transform how this deadly disease is managed. PMID- 25142843 TI - Phase I study of sunitinib in combination with gemcitabine and capecitabine for first-line treatment of metastatic or unresectable renal cell carcinoma. AB - BACKGROUND: The combination of gemcitabine plus capecitabine and sunitinib (GCS) shows activity in metastatic renal cell carcinoma (mRCC). We tested the multitargeted "chemo-switch" regimen as first-line treatment in patients with mRCC. METHODS: We assessed the maximum tolerated dose and antitumor activity of GCS in treatment-naive, advanced mRCC patients. Treatment consisted of intravenous gemcitabine on days 1 and 8, oral capecitabine twice daily on days 1 14, and oral sunitinib daily for six 21-day cycles, followed by sunitinib monotherapy at the investigator's discretion. Dose level 0 (DL0) was gemcitabine 1,000 mg/m(2) per day plus capecitabine 650 mg/m(2) per 12 hours plus sunitinib 37.5 mg/day; DL1 was gemcitabine 1,000 mg/m(2) per day plus capecitabine 850 mg/m(2) per 12 hours plus sunitinib 37.5 mg/day. RESULTS: Sixteen patients were enrolled. At DL1, two of four patients had dose-limiting toxicity (DLT; grade 3 diarrhea and grade 4 thrombocytopenia). The dose was reduced to DL0 when only 1 of 12 patients experienced DLT (grade 3 diarrhea, grade 3 mucositis, and grade 3 thrombocytopenia). Dose reductions were frequent (58% of patients), and only seven patients were able to receive the three drugs for more than three cycles. One patient achieved a complete response, three had partial responses, and the best response for four was stable disease. CONCLUSION: The safety profile of the combination does not seem manageable in this patient population. No further development of the combination is recommended. PMID- 25142846 TI - [Association of ZNF644, GRM6 and CTNND2 genes polymorphisms with high myopia]. AB - OBJECTIVE: To investigate the association of ZNF644, GRM6 and CTNND2 genes with high myopia in Jiangsu Chinese population. METHODS: Case-control association study was used in this research. The subjects consisted of 114 high myopia (all eyes AXL >= 26 mm) and 132 normal control subjects (AXL were 22.0-24.0 mm). Subjects were collected from Affiliated Hospital of Nantong University ophthalmic center. This project was approved by the Ethics Committee of Affiliated Hospital of Nantong University. Fourteen single nucleotide polymorphisms (SNP) of ZNF644, GRM6 and CTNND2 genes were genotyped by TaqMan MGB probes using the real-time PCR system. Chi-square was used to test the allelic and genotypic associations between cases and controls. RESULTS: ZNF644-rs358695 was associated with high myopia (P = 0.03). The frequency of the minor A allele of rs358695 was 41.2% in the high myopia and 50.8% in the controls, indicating a protective role. In genotype frequency analysis, ZNF644-rs358693 was significant difference between cases and controls in dominant model (P = 0.04). ZNF644-rs358695 was significant difference between cases and controls in recessive model (P = 0.02). In haplotype analysis, ACCG of ZNF644 showed statistical significance between cases and controls (P = 0.02). The other 9 SNP of GRM6 and CTNND2 were not associated with high myopia. CONCLUSION: ZNF644 gene mutation was associated with high myopia. ZNF644 gene may play a role in the development of high myopia. PMID- 25142847 TI - [Analysis on the relationship between adolescent myopia and serum sex hormone]. AB - OBJECTIVE: To investigate the quantitative changes of the serum sex hormone levels in juvenile myopia patients. METHODS: In January 2013, investigation of Wenzhou middle school 822 adolescents, including 432 male patients and 390 female patients were involved in the study Visual acuity >= 5 was set as the normal value. The subjects were divided into two groups, the myopia group and the non myopia group. Chemiluminescence immunoassay analyzer was used to detect the subjects' sex hormone concentration of estradiol (E2), testosterone (T), follicle stimulating hormone (FSH) and luteinizing hormone (LH). RESULTS: The follicle stimulating hormone and luteinizing hormone of the female patients were significantly higher than those of male counterparts (P < 0.01); among the two groups consisting female myopia and non-myopia patients, a significant difference in luteinizing hormone and follicle stimulating hormone was shown (P < 0.05); the distinct differences in the level of luteinizing hormone and testosterone level showed in the male myopia group and non-myopia group were of outstanding statistics significance (P < 0.01), showing the result that the level of sex hormone in myopia group was higher than that in the non-myopia group. CONCLUSION: A close relationship perhaps between the level of sex hormone with gender differences and juvenile myopia is confirmed. PMID- 25142848 TI - [Ecological executive function characteristics and effects of executive function on quality of life in young adult epileptics]. AB - OBJECTIVE: To explore the characteristics of ecological executive function in young adults with idiopathic or probably symptomatic epilepsy and examine the effects of executive function on quality of life. METHODS: Fifty-five epileptics (EP) and 39 matched healthy controls (HC) aged 18-44 years at our hospital were selected. The differences in ecological executive function and quality of life were compared between two groups with the Behavior Rating Inventory of Executive Function-adult version (BRIEF-A) and QOLIE-31. RESULTS: Comparing with controls, the epileptics yielded higher scores significantly on most subscales of BRIEF-A (P < 0.05), including total score [(55 +/- 9) vs (48 +/- 7)], inhibition [(54 +/- 7) vs (48 +/- 7)], emotion control [(56 +/- 8) vs (49 +/- 7)], self-monitor [(54 +/- 10) vs (47 +/- 7)], initiation [(51 +/- 10) vs (46 +/- 9)], working memory [(56 +/- 10) vs (50 +/- 9)], planning [(53 +/- 10) vs (47 +/- 7)], behavioral regulation index (BRI) and metacognition index (MI). Pearson's correlation test showed that the total score of QOLIE-31 had significantly negative correlations with the scores of BRIEF-A, such as global executive composite (GEC), behavioral regulation index (BRI), metacogniton index (MI), inhibition, emotional control, monitoring, initiation and working memory (r = -0.284- -0.457, P < 0.05). Moreover, seizure control and seizure type were also related with the total score of QOLIE-31(r = -0.302, r = 0.268, P < 0.05). Multiple stepwise regression analysis showed that emotional control in BRIEF-A was related with seizure worry and cognitive function in QOLIE-31(t = -2.137, t = -2.427, P < 0.05) . Behavioral regulation index (BRI) was closely related with emotional well-being in QOLIE 31(t = -2.148, P < 0.05). Also, working memory was related with cognitive function, overall quality of life and total score in QOLIE-31(t = -3.138, -3.564, -2.948, P < 0.05). And inhibition was related with energy, social function and total score in QOLIE-31(t = -3.007, -3.580, -2.191, P < 0.05). CONCLUSION: Young adults with idiopathic or probably symptomatic epilepsy may have significant executive function impairment. The aspects of emotional control, BRI, working memory and inhibition in ecological executive function are significantly related with quality of life in epilepsy. PMID- 25142849 TI - [Correlation between the changes of surface electromyographic signals of elbow flexor and extensor and motor function in stroke patients]. AB - OBJECTIVE: To explore the correlation between the changes of surface electromyography (sEMG) signals of biceps and triceps and torques for elbow flexion and extension during maximum isometric voluntary contraction (MIVC) and motor function in convalescent stroke patients so as to provide rationale for rehabilitation. METHODS: Fifteen stroke patients and 15 age and gender-matched normal controls were recruited. The sEMG signals of biceps and triceps were recorded during MIVC of elbow flexion and extension. Co-contraction ratio (CR) and torques of both groups were compared and analyzed. The motor function of upper extremity was assessed by Fugl-Meyer assessment upper extremity (FMA-UE). RESULTS: There were significant differences in EMG ((132 +/- 65) mV*s,(124 +/- 50) mV*s) and torques ((13 +/- 8) N*m, (10 +/- 6) N*m) at affected side with those at unaffected side and controls during MIVC of elbow flexion and extension (P < 0.05).Significant differences existed in CR ((30 +/- 13)%) at affected side with unaffected side ((18 +/- 8)%) and controls ((16 +/- 6)%) during MIVC of elbow extension (P < 0.05). The score of FMA-UE at affected side was significantly positively correlated with iEMG on biceps during MIVC of elbow flexion (r = 0.579, P = 0.024) and on triceps during MIVC of elbow extension (r = 0.618, P = 0.014). The score of FMA-UE at affected side was significantly positively correlated with torques during MIVC of elbow flexion and extension (rflexion = 0.518, P = 0.048; rextension = 0.679, P = 0.005). The score of FMA-UE at affected side was significantly negatively correlated with CR during MIVC of elbow flexion and extension (rflexion = -0.579, P = 0.024; rextension = -0.693, P = 0.004). CONCLUSION: The strength of flexor and extensor of bilateral elbow decreases in convalescent stroke patients. The spasticity of elbow flexor still exists. Besides increasing the strength of bilateral upper extremities, particularly affected side, rehabilitation should also focus upon reducing spasticity of flexor to enhance elbow joint stability and improve motor function. PMID- 25142850 TI - [Diagnostic value of (18)F-fluorodeoxyglucose positron emission tomography/ computed tomography for N-and M-staging of malignant melanoma]. AB - OBJECTIVE: To evaluate the effectiveness and advantages of positron emission tomography/computed tomography (PET/CT) for N and M staging of malignant melanoma. METHODS: A total of 114 patients (69 males, 45 females) with AJCC stage II-IV malignant melanoma were recruited. The diagnostic accuracy for N- and M staging was determined for CT alone, PET alone and PET/CT. RESULTS: PET/CT imaging provided significantly more accurate interpretations regarding overall N- and M-staging than PET or CT alone (97.4% vs 94.7% and 88.6%). Overall N- and M stage was correctly determined by PET/CT (98.2%) versus PET (93.9%) and CT (83.3%) and the differences were significant (P < 0.01). CONCLUSION: The diagnostic performance of FDG-PET/CT is excellent for N- and M-staging of melanoma patients, especially for detecting or excluding distant metastases. PMID- 25142851 TI - [Computed tomography-guided percutaneous microwave ablation for diaphragm abutting liver tumors: assessments of safety and short-term therapeutic efficacies]. AB - OBJECTIVE: To assess the safety and short-term therapeutic efficacies of computed tomography (CT)-guided percutaneous microwave ablation (PMA) for diaphragm abutting liver tumors. METHODS: A total of 69 patients with 75 diaphragm-abutting liver tumors (tumor from diaphragmc <= 5 mm) underwent CT-guided PMA. According to the site of diaphragm-abutting lesions, they were divided into neighboring muscle group (group A) and neighboring aponeurosis group (group B); According to the size of lesions, they were divided into <2.5 cm group (group I) and >= 2.5 cm group (group II). The complications of intra and post-ablation within 2 weeks were recorded. They underwent contrast enhanced CT (CECT) or contrast enhanced MRI (CEMRI) at Month 1, 3 and 6 post-ablation. Then CEMRI or CECT was re-checked every 3-6 months. All patients were followed up for 12-30 months. Comparative analyses were performed for short-term therapeutic efficacies. RESULTS: At Month 1 post-PMA, complete response (CR) rate was 86.7% (65/75) and incomplete response (ICR) rate 13.3% (10/75). After additional ablation, 5 lesions transformed into CR.No statistical difference in CR rate existed between groups A and B (95.0% vs 77.1%). The CR rate of group I was obviously higher than that of group II (95.0% vs 77.1%). The 1-year survival rate was 97.1%. The occurring rate of minor complications was 42.0% (29/69) and that of serious complications 2.9% (2/69).No statistical difference of occurring rates of minor complications existed between groups A and B(38.1%vs 45.5%). But the occurring rates of diaphragmatic burns, pulmonary exudation and pneumothorax had obvious statistical differences between two groups. The occurring rate of minor complications in group I was obviously lower than that of group II (30.0% vs 54.3%) and serious complications occurred in group II. Minor complications were reversible and recovered after non-special or symptomatic treatment. Two cases of serious complications improved after standard clinical treatment. CONCLUSION: CT-guided PMA for diaphragm-abutting liver tumors is both safe and effective.However puncture route and power/time should be optimized according to tumor size and location. PMID- 25142852 TI - [Comparative study of endorectal ultrasonography and magnetic resonance imaging in preoperative staging of rectal cancer]. AB - OBJECTIVE: To evaluate the diagnostic value of endorectal ultrasonography (ERUS) and magnetic resonance imaging (MRI) in preoperative staging of rectal carcinoma. METHODS: A total of 44 patients with biopsy proven rectal tumor underwent preoperative ERUS and MRI examinations. All patients were evaluated to determine the diagnostic accuracy of depth of transmural tumor invasion and lymph node metastases.Imaging results were compared with histopathological findings. RESULTS: The accuracy of T staging (uT1, uT2, uT3, uT4) for ERUS was 95.5%, 90.9%, 93.2% and 97.7% and the overall accuracy 88.6% (39/44) . The sensitivity was 83.3%, 72.7%, 72.2%, 77.8% and the specificity 97.3%, 92.9%, 96.2% and 97.6%. The accuracy of T staging (T1, T2, T3, T4) for MRI was 93.2%, 90.9%, 93.2%, 100.0% and the overall accuracy 86.4% (38/44) . The sensitivity was 71.4%, 93.8%, 94.4% and 100.0% and the specificity 97.3%, 89.3%, 92.3% and 100.0%. Detection of lymph node metastases:the accuracy of ERUS was 75.0% (33/44), MRI 93.2% (41/44). The sensitivity and specificity was found to be 68.4% (13/19) and 80.0% (20/25) on ERUS, 94.7% (18/19) and 92.0% (23/25) on MRI respectively. CONCLUSION: ERUS and MRI may be used for accurate preoperative staging of rectal cancer.ERUS has higher accuracy and sensitivity for T1 stage while MRI is preferred for lymph node metastasis. PMID- 25142853 TI - [Surgical correction of congenital vertical talus by one-stage comprehensive soft tissue release and peritalar reduction incorporating tibialis anterior transfer]. AB - OBJECTIVE: To evaluate the surgical efficacies of one-stage comprehensive soft tissue release and peritalar reduction incorporating tibialis anterior transfer (CSTR-PTR-TAT) in patients with congenital vertical talus (CVT) before the age of 4 years. METHODS: Thirty-five feet of 21 children with true congenital vertical talus were underwent one-stage CSTR-PTR-TAT. The male-to-female ratio was 2.5: 1. Twenty-three percent (5 patients with 8 feet) belonged to isolated CVT and the remainder CVT associated with other congenital or neuromuscular abnormalities. The mean operative age was 30.1 (12-48) months. All patients were available for clinical and radiological follow-ups for a mean period of 3.5 (1.5-7) years.Kodros scoring system was utilized for assessment of final outcomes. RESULTS: The outcomes of 3 feet (9%) were excellent, 27 (77%) good and 5 (14%) fair. All patients wore normal shoes and were satisfied by their functional results and appearance. The patients with fair results were associated with arthrogryposis. No talar avascular necrosis was encountered.None required further operation.Radiologically there was a statistically significant postoperative improvement of measured angles compared to preoperative values (P < 0.05). All radiological parameters were within normal ranges. There was no difference of post operative angles compared to those at the final follow-up (P > 0.05). CONCLUSION: As a complex deformity usually associated with other congenital or neuromuscular abnormalities, CVT may be satisfactorily managed with one-stage correction by CSTR-PTR-TAT before the age of 4 years. PMID- 25142854 TI - [Mid-term outcomes of unilateral pedicle screw fixation with lumbar interbody fusion for lumber degenerative diseases]. AB - OBJECTIVE: To evaluate the mid-term clinical outcomes of unilateral pedicle screw fixation with lumbar interbody fusion for lumber degenerative diseases. METHODS: From October 2008 to December 2010, unilateral pedicle screw fixation with lumbar interbody fusion was performed for a consecutive cohort of 42 patients. There were 18 males and 24 females with an average age of 52 (38-69) years. The operation level at L3-4 (n = 2), L4-5 (n = 19), L5-S1 (n = 21) and multilevel (n = 0). Their clinical outcomes were assessed by Oswestry (ODI) scores and Japanese Orthopedics Association (JOA) questionnaires before and after operation. Operative duration, intraoperative blood loss, incision status and complications were recorded. Radiological examination was performed to assess the height of intervertebral space, the postoperative intervertebrai fusion conditions and the degeneration of adjacent segments. RESULTS: The mean operative duration was 90 minutes and mean blood loss 150 ml. All incisions healed primarily. The mean follow-up period was 40 (36-58) months. The ODI scores decreased significantly from 59.1 +/- 9.6 preoperatively to 8.5 +/- 2.7 postoperatively (P < 0.05). The JOA scores improved markedly from 8.3 +/- 2.7 preoperatively to 23.3 +/- 2.1 postoperatively (P < 0.05). And the proportion of optimal outcomes was 88.1%. The ventral and dorsal heights of intervertebal disc were significantly higher than those before operation. The fusion rate was 95.2% and the incidence of adjacent segment degeneration 9.5%. There was no occurrence of such complications as secondary scoliosis, screw loosening, internal fixation failure and cage slippage. CONCLUSION: Unilateral pedicle screw fixation with lumbar interbody fusion is efficacious for lumber degenerative diseases with little surgical trauma. PMID- 25142855 TI - [Expression and significance of cyclophilin A in synovial fibroblasts from patients with rheumatoid arthritis]. AB - OBJECTIVE: To observe the expression of cyclophilin A (CyPA) and the effects of lipopolysaccharide (LPS) on CyPA expression in synovial fibroblasts (SF) from patients with rheumatoid arthritis (RA) and evaluate the potential significance of CyPA in the regulation of the onset and development of inflammation process in RA patients. METHODS: SF were separated and cultured from synovial tissues of 12 patients with RA, 9 with osteoarthritis (OA) and 5 with knee trauma. The protein and mRNA expression levels of CyPA in SF were detected by Western blot (WB) and real-time quantitative polymerase chain reaction (RT-qPCR) respectively. Correlation analysis was conducted between the protein expression of CyPA in SFs and clinical parameters. Then the effects of LPS on CyPA in SF from 3 groups were detected. RESULTS: The expression levels of CyPA protein and mRNA in RA group were 0.86 +/- 0.47 and 0.54 +/- 0.22 respectively, significantly higher than those in OA group (0.40 +/- 0.31 and 0.03 +/- 0.02, P < 0.05) and trauma group (0.34 +/- 0.21 and 0.03 +/- 0.01, P < 0.05). The protein expression level of CyPA in SF of RA group had positive correlations with erythroeyte sedimentation rate (ESR), rheumatoid factor (RF) and swelling joint counts (SJC) (P < 0.05). After LPS treatment, CyPA protein and mRNA levels were 2.65 +/- 1.16 and 1.82 +/- 0.39 in RA SF and they were significantly higher than those in RA SF without LPS treatment (P < 0.05). The CyPA expression of SF from OA and trauma groups slightly decreased after LPS treatment.However the differences were not statistically significant (P > 0.05). CONCLUSION: The expression of CyPA is up regulated in SF and it is positively correlated with ESR, RF and SJC in RA patients. It indicates that CyPA may be involved in the regulation of the onset and development of inflammation process of RA. And LPS may promote the expression of CyPA in SF of RA patients. PMID- 25142856 TI - [Therapeutic effect of endoscopic third ventriculostomy for pediatric hydrocephalus]. AB - OBJECTIVE: To validate the proposed endoscopic third ventriculostomy success score (ETVSS) for predicting successful ETV outcomes for pediatric hydrocephalus on the basis of individual characteristics. METHODS: For 121 cases at our department from June 2007 to June 2010 at both 6 and 24 months, Actual successful rates were compared with Chi-square test and 95% confidence interval for low, moderate and high chance of success strata based on the ETVSS. Long-term successful probability was calculated with Kaplan-Meier methods. RESULTS: The 6 month ETV successful rate was higher than the mean predicted probabilities of success for both moderate and low success strata, but slightly lower for the high chance of success strata. The ETVSS accurately predicted the outcomes at 24 months; the low, medium and high chance of success strata had actual success rates of 74% (37/50), 62% (28/45) and 41% (11/26) and mean predicted successful probabilities of 81.3%, 61.4% and 34.4% respectively. CONCLUSION: ETVSS may accurately predict the overall long-term successful rates in high, moderate and low-risk groups. Thus it will aid clinical decision-making through predicting the therapeutic effect of ETV. PMID- 25142857 TI - [Correlation between pelvic indices, pelvic spatial orientation and lumbar vertebrate instability]. AB - OBJECTIVE: To explore the correlation between the stability of lumbar vertebrate and pelvic indices of pelvic incidence (PI), lumber lordosis (LL), pelvic tilt (PT) and sacrum slope (SS). METHODS: The preoperative imaging data were analyzed retrospectively for 78 patients with lumbar disc protrusion. The values of PI, PT, SS and LL were measured and compared between lumbar vertebrate stability and lumbar vertebrate instability groups. RESULTS: No inter-group statistical difference existed in PI, LL, PT or SS. The average PI of lumbar vertebrate instability group was higher than that of lumbar vertebrate stability group.In patients with L4/5 segmental lesion, SS of lumbar vertebrate instability group was higher than that of lumbar vertebrate stability group (38.7 +/- 4.7) degrees vs (34.0 +/- 6.6) degrees , P = 0.023. And PT in patients with L5/S1 segmental lesion was higher than those with L4/5 segmental lesion (17.5 +/- 7.0 vs 14.9 +/- 5.3, P = 0.027). CONCLUSION: No statistical inter-group difference exists in PI. However, higher SS and PT may be risk indicators of instability for L4/5 and L5/S1 segments respectively. PMID- 25142858 TI - [Study on the heterogeneity of edema in severe preeclampsia]. AB - OBJECTIVE: The aim of this study was to analysis the clinical edema forms and explore the heterogeneity of edema in severe preeclampsia (PE) . METHOD: From February 2002 to February 2009, Peking University Third Hospital admitted with severe preeclampsia 228 cases who were enrolled in this study. The form is divided into no edema (A-type), pure interstitial edema (B-type), a simple cavity gap edema (C-type) and mixed interstitial edema that coexist with lacunar edema (D-type). Analysis and comparison of various types of edema in patients with different clinical manifestations of prenatal care models, laboratory parameters, the incidence of gestational age, complications and obstetric and perinatal outcomes, and analyze the relationship between different types of edema and albumins and the peak value of proteinuria. RESULTS: Edema was seen in 86% (197/228) of all of cases. Compared the cases who have regular prenatal care with those who have irregular care, differences were statistically significant in edema type composition ratio (P < 0.01) and the incidence of serious complications (P < 0.01), and serum albumin levels (P < 0.01), but not in the peak value of proteinuria (P > 0.05); Compared early-onset PE and late-onset PE patients, differences were statistically significant in edema type composition ratio (P < 0.01) and peak value of proteinuria (P < 0.01), but not in serum albumin levels and the incidence of serious complications (P > 0.05). Comparison between the various types of edema, differences were statistically significant in serum albumin levels and peak value of proteinuria and incidence of serious complications and the gestational week at PE onset and the incidence of treatment preterm labor (P < 0.05).Occurrence of placental abruption, heart failure and HELLP syndrome had statistical significance in different types of edema(P < 0.05). The varying degrees of interstitial edema were correlated with serum albumin levels (r = -0.19, P < 0.05) and serious complication occurrence (r = 0.232, P < 0.05), but no correlation displayed with the peak value of urinary protein (P > 0.05). CONCLUSIONS: The manifestations of edema were diverse in severe preeclampsia. The forms of edema were related to the PE onset of gestational age and serious complication involving in different organs.Strengthen prenatal care and early detection of edema may improve adverse obstetric outcomes. PMID- 25142859 TI - [Preliminary experiences of "Waffle cone" technique for the treatment of intracranial aneurysm]. AB - OBJECTIVE: To explore the preliminary experiences of "Waffle cone" technique for the treatment of intracranial aneurysm. METHODS: Retrospective data analyses were performed for patients with intracranial aneurysms embolized by the "Waffle cone" technique from stent-assisted coiling at our hospital from December 2010 to November 2012. RESULTS: Six patients used the "Waffle cone" technique from 138 stent-assisted coiling. All had complex wide-neck bifurcation cerebral aneurysms. And the angles between parental artery and distal vessels were acute. Six rupture aneurysms were at the terminus of basilar artery (BA) (n = 2), right anterior communicating artery (AcomA) (n = 3) and trifurcation middle cerebral artery (MCA) (n = 1). All stents were of Solitaire with specification 4*15 mm (ev3, USA) .Four patients had Raymond classification Class I while another 2 Class II. No perioperative complication occurred. The average follow-up period was 6 months. CONCLUSION: This technique is safe, time-saving, simple and effective for complex, wide-necked bifurcation aneurysms with acute angles between parental artery and distal vessels.Long-term follow-ups are needed to further evaluate its efficacy. PMID- 25142860 TI - [Analysis of prognostic factors for patients with traumatic acute subdural hematomas treated by surgery]. AB - OBJECTIVE: To analyze the factors correlated with the surgical prognosis of patients with traumatic acute subdural hematoma (ASDH). METHODS: A total of 117 surgical patients for traumatic ASDH between January 2007 and August 2012 were retrospectively reviewed. The clinical factors correlated with prognosis were statistically analyzed.Glasgow outcome score (GOS) was used for prognostic evaluations and favorable prognosis was defined as 4-5 points. RESULTS: The percentage of patients with favorable prognosis was 43.59% and the mortality 39.32%. The factors correlated with favorable prognosis included age <40 years, pre-operative GCS >8, no pre-operative herniation, duration between injury and surgical depression <= 4 h, without injury of drainage vein, mild brain edema and good brain palpation; the factors correlated with mortality included age >60 years, pre-operative GCS <= 8, pre-operative herniation, duration between injury and surgical depression >4 h, injury of drainage vein, serious brain edema and weak brain palpation Logistic regression confirmed preoperative GCS >8, no preoperative herniation, injury of drainage vein and postoperative good brain palpation were independent factors associated with favorable prognosis. CONCLUSION: Patients with age <40 years, preoperative GCS>8, no preoperative herniation, injury of drainage vein and postoperative good brain palpation tend to have favorable prognoses. PMID- 25142861 TI - [Effects of mild hypothermia plus ifenprodil on apoptosis inducing factor translocation after global cerebral ischemia-reperfusion in rats]. AB - OBJECTIVE: To explore the effects of mild hypothermia combined with ifenprodil on the survival of neuronal and translocation of apoptosis inducing factor (AIF) following global cerebral ischemia-reperfusion to understand the mechanism of combination in cerebral resuscitation. METHODS: Eighty male SD rats were randomly divided into 5 groups of sham (I), model (II), ifenprodil (III), mild hypothermia (IV) and ifenprodil plus mild hypothermia (V) (n = 16 each). Group I completed all procedures except for ventricular fibrillation (VF) and cardio pulmonary resuscitation (CPR). For groups II and V, the model of global cerebral ischemia reperfusion was established and VF induced with transoesophageal cardiac pacing; groups III and V received by an intraperitoneal injection of ifenprodil immediately after reperfusion and other groups had an equal volume of distilled water. Rectal temperature was cooled down to (32 +/- 1) degrees C in groups IV and V by rubbing body surface with ethanol in 10 min after reperfusion and maintained 4 hours continuously while other groups at (37 +/- 1) degrees C. In hippocampal CA1 region at 24 hours after reperfusion, the pathomorphological changes and quantity of pyramidal cells were detected with hematoxylin and eosin staining, nuclear translocation of AIF was shown with immunofluorescence technique and the nuclear expression level of AIF was measured with Western blot. RESULTS: Compared with group I (75.0 +/- 3.2), the number of pyramidal cells decreased in other groups (P < 0.05); compared with group II (36.0 +/- 1.2), the number increased in group III (46.8 +/- 1.3), IV (49.0 +/- 2.7) and V (61.3 +/- 2.60) (P < 0.05). In particular, cell count increased significantly in group V (P < 0.05). Compared to group I, the translocation of AIF form mitochondria to nucleus was detected in other groups; compared with group I (0.022 +/- 0.003), the expression level of AIF in the nucleus was higher in other groups (P < 0.05). Compared with group II (1.020 +/- 0.029) , the expression levels of AIF in groups III (0.870 +/- 0.016), IV (0.820 +/- 0.050) and V (0.550 +/- 0.050) were lower (P < 0.05). And it decreased significantly in group V (P < 0.05). CONCLUSION: Mild hypothermia plus ifenprodil may alleviate neuronal damage after global cerebral ischemia/reperfusion injury through mitigating its pro-apoptotic role after AIF translocation. PMID- 25142862 TI - PSAT1 regulates cyclin D1 degradation and sustains proliferation of non-small cell lung cancer cells. AB - Multiple nodes in the one-carbon metabolism pathway play important regulatory roles in cancer cell growth and tumorigenesis. The specific biological functions of metabolic enzymes in regulating the signaling pathways that are associated with tumor cell growth and survival, however, remain unclear. Our current study found that phosphoserine aminotransferase 1 (PSAT1), an enzyme catalyzing serine biosynthesis, was significantly up-regulated in non-small cell lung cancer (NSCLC) and was involved in the regulation of E2F activity. Loss- and gain-of function experiments demonstrated that PSAT1 promoted cell cycle progression, cell proliferation and tumorigenesis. Mechanistic study suggested that elevated PSAT1 led to inhibition of cyclin D1 degradation and subsequently an alteration in Rb-E2F pathway activity, which in turn enhanced G1 progression and proliferation of NSCLC cells. Moreover, phosphorylation of cyclin D1 at threonine 286 by GSK-3beta was required for PSAT1-induced blockage of cyclin D1 degradation. We also found that the activity of p70S6K mediated the effects of PSAT1 on GSK-3beta phosphorylation and cyclin D1 degradation. We further identified that PSAT1 was over-expressed in NSCLC and predicted poor clinical outcome of patients with the disease. Correlation analysis showed that PSAT1 expression positively correlated with the levels of phosphorylated GSK-3beta, cyclin D1 and phosphorylated Rb in NSCLC primary tumors. These findings uncover a mechanism for constitutive activation of E2F via which unrestrained cell cycle progression occurs in NSCLC and may represent a prognostic biomarker and therapeutic target. PMID- 25142863 TI - Transanal haemorrhoidal dearterialization for the treatment of grade III and IV haemorrhoids: a 3-year experience. AB - BACKGROUND: Transanal haemorrhoidal dearterialization (THD) is increasingly perceived as an effective and better tolerated alternative to excisional haemorrhoidectomy. The aim of this study was to evaluate outcomes and the patient experience of THD in an Australian population with grade III or IV haemorrhoids. METHODS: A retrospective review of prospectively maintained database on patients who had undergone THD over a 3-year period was performed. Data were collected on demographics, operative data, complications, recurrences and readmissions, postoperative pain and further interventions. Patient perceptions and satisfaction with the procedure were assessed with a telephone survey. RESULTS: A total of 85 patients with a mean age of 55 (+/-14) years with grade III (85%) or grade IV (15%) haemorrhoids underwent THD. Indications for surgery were predominantly bleeding (87%) and prolapse (41%). Median outpatients follow-up was 42 days and median telephone follow-up was 802 days. Median operating time was 25 min (+/-12). Twenty-four per cent of patients suffered complications, including postoperative bleeding (7%), constipation (7%), local sepsis (6%), anal fissure (5%) and temporary incontinence (2%). Severe postoperative pain occurred in 16% of the patients. The symptom recurrence rate was 19% and reintervention rate was 14%. About 98.8% of patients reported good or excellent overall satisfaction with the procedure. CONCLUSION: THD is a relatively new technique for the treatment of haemorrhoids, which is increasingly being used as an alternative to excisional haemorrhoidectomy. This study shows that patients' satisfaction with THD is high despite a moderate complication and recurrence rate and significant incidence of postoperative pain. PMID- 25142866 TI - Investigating the ring expansion reaction of pentaphenylborole and an azide. AB - The reaction between trimethylsilyl azide and pentaphenylborole was recently shown to produce the corresponding 1,2-azaborine. Investigating this transformation theoretically suggests that the reaction proceeds via coordination of the azide to the borole, rearrangement to a bicyclic species, and conversion to a kinetically favoured eight-membered BN3C4 heterocycle or expulsion of N2 to furnish the thermodynamically favoured 1,2-azaborine. The eight-membered species was structurally characterized as a borole adduct and represents an unusual analogue of cyclooctatetraene. PMID- 25142864 TI - Reduction of myeloid-derived suppressor cells and lymphoma growth by a natural triterpenoid. AB - Lymphoma is a potentially life threatening disease. The goal of this study was to investigate the therapeutic potential of a natural triterpenoid, Ganoderic acid A (GA-A) in controlling lymphoma growth both in vitro and in vivo. Here, we show that GA-A treatment induces caspase-dependent apoptotic cell death characterized by a dose-dependent increase in active caspases 9 and 3, up-regulation of pro apoptotic BIM and BAX proteins, and a subsequent loss of mitochondrial membrane potential with release of cytochrome c. In addition to GA-A's anti-growth activity, we show that lower doses of GA-A enhance HLA class II-mediated antigen (Ag) presentation and CD4+ T cell recognition of lymphoma cells in vitro. The therapeutic relevance of GA-A treatment was also tested in vivo using the EL4 syngeneic mouse model of metastatic lymphoma. GA-A-treatment significantly prolonged survival of EL4 challenged mice and decreased tumor metastasis to the liver, an outcome accompanied by a marked down-regulation of STAT3 phosphorylation, reduction myeloid-derived suppressor cells (MDSCs), and enhancement of cytotoxic CD8+ T cells in the host. Thus, GA-A not only selectively induces apoptosis in lymphoma cells, but also enhances cell-mediated immune responses by attenuating MDSCs, and elevating Ag presentation and T cell recognition. The demonstrated therapeutic benefit indicates that GA-A is a candidate for future drug design for the treatment of lymphoma. PMID- 25142865 TI - The reliability of a newborn foot length measurement tool used by community volunteers to identify low birth weight or premature babies born at home in southern Tanzania. AB - BACKGROUND: Low birthweight babies need extra care, and families need to know whether their newborn is low birthweight in settings where many births are at home and weighing scales are largely absent. In the context of a trial to improve newborn health in southern Tanzania, a counselling card was developed that incorporated a newborn foot length measurement tool to screen newborns for low birth weight and prematurity. This was used by community volunteers at home visits and shows a scale picture of a newborn foot with markers for a 'short foot' (<8 cm). The tool built on previous hospital based research that found newborn foot length <8 cm to have sensitivity and specificity to identify low birthweight (<2500 g) of 87% and 60% respectively. METHODS: Reliability of the tool used by community volunteers to identify newborns with short feet was tested. Between July-December 2010 a researcher accompanied volunteers to the homes of babies younger than seven days and conducted paired measures of newborn foot length using the counselling card tool and using a plastic ruler. Intra method reliability of foot length measures was assessed using kappa scores, and differences between measurers were analysed using Bland and Altman plots. RESULTS: 142 paired measures were conducted. The kappa statistic for the foot length tool to classify newborns as having small feet indicated that it was moderately reliable when applied by volunteers, with a kappa score of 0.53 (95% confidence interval 0.40 - 0.66) . Examination of differences revealed that community volunteers systematically underestimated the length of newborn feet compared to the researcher (mean difference -0.26 cm (95% confidence interval 0.31-0.22), thus overestimating the number of newborns needing extra care. CONCLUSIONS: The newborn foot length tool used by community volunteers to identify small babies born at home was moderately reliable in southern Tanzania where a large number of births occur at home and scales are not available. Newborn foot length is not the best anthropometric proxy for birthweight but was simple to implement at home in the first days of life when the risk of newborn death is highest. PMID- 25142867 TI - Repetitive transcranial magnetic stimulation in neuropathic pain secondary to malignancy: a randomized clinical trial. AB - BACKGROUND: Significant analgesic effects of repetitive transcranial magnetic stimulation (rTMS) have been found in several studies of patients with chronic pain of various origins, but never for malignancy. The objective of this study was to assess the efficacy of 10 sessions of rTMS over the primary motor cortex (M1) in patients suffering from malignant neuropathic pain. METHODS: Thirty-four patients were randomly allocated into one of two groups to receive real (20 Hz, 10 s, 10 trains with 80% intensity) or sham rTMS daily for 10 consecutive days. Patients were evaluated using a verbal descriptor scale (VDS), a visual analogue scale (VAS), Leeds assessment of neuropathic symptoms and signs (LANSS) and Hamilton rating scale for depression (HAM-D) at baseline, after the first, fifth and 10th treatment sessions, and then 15 days and 1 month after treatment. RESULTS: There were no significant differences between real and sham groups in the duration of illness or pain rating scores at the baseline. A significant 'Time * Group' interaction was recorded indicating that real and sham rTMS had different effects on the VDS, VAS, LANSS and HAM-D scales. Post-hoc testing showed that the group of patients treated with real rTMS had greater improvement in all scales that persisted up to 15 days, but were not present 1 month later. Significant positive correlations between the percentage of pain reduction and HAM-D after the 10th session and 15 days later were recorded. CONCLUSION: The results demonstrate that 10 rTMS sessions over the M1 can induce short-term pain relief in malignant neuropathic pain. PMID- 25142868 TI - Unbinding and unfolding of adhesion protein complexes through stretching: interplay between shear and tensile mechanical clamps. AB - Using coarse-grained molecular dynamics simulations, we analyze mechanically induced dissociation and unfolding of the protein complex CD48-2B4. This heterodimer is an indispensable component of the immunological system: 2B4 is a receptor on natural killer cells whereas CD48 is expressed on surfaces of various immune cells. So far, its mechanostability has not been assessed either experimentally or theoretically. We find that the dissociation processes strongly depend on the direction of pulling and may take place in several pathways. Interestingly, the CD48-2B4 interface can be divided into three distinct patches that act as units when resisting the pulling forces. At experimentally accessible pulling speeds, the characteristic mechanostability forces are in the range between 100 and 200 pN, depending on the pulling direction. These characteristic forces need not be associated with tensile forces involved in the act of separation of the complex because prior shear-involving unraveling within individual proteins may give rise to a higher force peak. PMID- 25142869 TI - The role of visual perception measures used in sports vision programmes in predicting actual game performance in Division I collegiate hockey players. AB - Abstract In the growing field of sports vision little is still known about unique attributes of visual processing in ice hockey and what role visual processing plays in the overall athlete's performance. In the present study we evaluated whether visual, perceptual and cognitive/motor variables collected using the Nike SPARQ Sensory Training Station have significant relevance to the real game statistics of 38 Division I collegiate male and female hockey players. The results demonstrated that 69% of variance in the goals made by forwards in 2011 2013 could be predicted by their faster reaction time to a visual stimulus, better visual memory, better visual discrimination and a faster ability to shift focus between near and far objects. Approximately 33% of variance in game points was significantly related to better discrimination among competing visual stimuli. In addition, reaction time to a visual stimulus as well as stereoptic quickness significantly accounted for 24% of variance in the mean duration of the player's penalty time. This is one of the first studies to show that some of the visual skills that state-of-the-art generalised sports vision programmes are purported to target may indeed be important for hockey players' actual performance on the ice. PMID- 25142871 TI - Thyroid volume and Doppler evaluation of inferior thyroid artery in ultrasound: Comparison between current and previous users of oral contraceptives. AB - BACKGROUND: This study aimed to compare thyroid volume and Doppler sonographic evaluation of the inferior thyroid artery using ultrasound in current and previous users of oral contraceptives (OCs). METHODS: We evaluated 119 women who either currently use (n = 66) or have previously used OCs (n = 53) using color Doppler ultrasound for thyroid volume and resistance index, peak-systolic, and end-diastolic velocities of the inferior thyroid artery. Previous OC users were divided into two groups: previous OC use for <1 year and previous OC use for >=1 year. RESULTS: A comparison of the thyroid volume revealed an increased volume in women with previous OC use for >=1 year and in current users compared with those with previous OC use for <1 year (previous OC use for >=1 year: 7.49 mL versus previous OC use for <1 year: 6.13 mL; p < 0.01). The relationship between OC use and an enlarged thyroid remained after adjusting for thyroid-stimulating hormone levels (p = 0.03). There were no differences in the inferior thyroid artery blood flow measurements. CONCLUSIONS: In healthy women, current use and previous OC use for >=1 year were associated with increased thyroid volume that was unrelated to increased blood flow in the gland. PMID- 25142870 TI - Physician-pharmacist collaborative management of asthma in primary care. AB - OBJECTIVE: To determine if asthma control improves in patients who receive physician-pharmacist collaborative management (PPCM) during visits to primary care medical offices. DESIGN: Prospective pre-post study of patients who received the intervention in primary care offices for 9 months. The primary outcome was the sum of asthma-related emergency department (ED) visits and hospitalizations at 9 months before, 9 months during, and 9 months after the intervention. Events were analyzed using linear mixed-effects regression. Secondary analysis was conducted for patients with uncontrolled asthma (Asthma Control Test [ACT] less than 20). Additional secondary outcomes included the ACT, the Asthma Quality of Life Questionnaire by Marks (AQLQ-M) scores, and medication changes. INTERVENTION: Pharmacists provided patients with an asthma self-management plan and education and made pharmacotherapy recommendations to physicians when appropriate. RESULTS: Of 126 patients, the number of emergency department (ED) visits and/or hospitalizations decreased 30% during the intervention (p=0.052) and then returned to preenrollment levels after the intervention was discontinued (p=0.83). Secondary analysis of patients with uncontrolled asthma at baseline (ACT less than 20), showed 37 ED visits and hospitalizations before the intervention, 21 during the intervention, and 33 after the intervention was discontinued (p=0.019). ACT and AQLQ-M scores improved during the intervention (ACT mean absolute increase of 2.11, AQLQ-M mean absolute decrease of 4.86, p<0.0001) and sustained a stable effect after discontinuation of the intervention. Inhaled corticosteroid use increased during the intervention (p=0.024). CONCLUSIONS: The PPCM care model reduced asthma-related ED visits and hospitalizations and improved asthma control and quality of life. However, the primary outcome was not statistically significant for all patients. There was a significant reduction in ED visits and hospitalizations during the intervention for patients with uncontrolled asthma at baseline. Our findings support the need for further studies to investigate asthma outcomes achievable with the PPCM model. PMID- 25142872 TI - Modulation of metabolizing enzymes by bisphenol a in human and animal models. AB - Xenobiotics, such as contaminants and drugs, can be converted to potentially toxic reactive metabolites by phase 1 oxidizing enzymes. These metabolites are further detoxified by phase 2 conjugating enzymes and eliminated from cells by phase 3 transporters. Moreover, many of these xenobiotics are also able to induce or inhibit these enzymes, potentially modulating their own toxicity or that of other chemicals. The present review is focused on bisphenol A, a synthetic monomer used for many industrial applications and exhibiting xenoestrogen properties. The impact of this contaminant on all major classes of metabolizing enzymes (i.e., cytochromes P450, glutathione-S-transferases, sulfotransferases, UDP-glucuronyltransferases, and transporters) was reviewed, with a highlight on the modulation of cytochromes P450 involved in steroid metabolism. Interestingly, most of the studies reported in this review show that BPA is able to induce or inhibit metabolizing enzymes at high doses but also at doses compatible with human exposure. PMID- 25142873 TI - Effects of UV-B radiation on total phenolic, flavonoid and hypericin contents in Hypericum retusum Aucher grown under in vitro conditions. AB - This study was conducted to increase total phenolics, flavonoids and hypericin accumulation in in vitro cultures of Hypericum retusum Aucher to determine the appropriate time of UV radiations. Proliferation of plantlets on Murashige-Skoog medium containing 0.5 mg L(- 1)N-6-benzylaminopurine was achieved under in vitro conditions. Then, the plantlets were exposed to UV-B radiation for different periods (15, 30, 45 and 60 min). The highest total phenolics, flavonoids and hypericin accumulation (43.17 +/- 0.8; 35.09 +/- 0.8; 2.7 +/- 0.05 mg g(- 1), respectively) was achieved at 45 minutes of exposure to UV-B radiation when compared with the contents of naturally growing plants (23.33 +/- 0.9, 18.62 +/- 0.3 and 1.6 +/- 0.01 mg g(- 1), respectively) and control groups (control group was not subjected to UV-B radiation). PMID- 25142874 TI - Molecular mapping of genes Yr64 and Yr65 for stripe rust resistance in hexaploid derivatives of durum wheat accessions PI 331260 and PI 480016. AB - KEY MESSAGE: This manuscript reports two new genes ( Yr64 and Yr65 ) for effective resistance to stripe rust and usefulness of their flanking SSR markers for marker-assisted selection. Stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most important diseases of wheat worldwide and resistance is the best control strategy. Durum wheat accessions PI 331260 and PI 480016 were resistant to all tested Pst races. To transfer the resistance genes to common wheat and map them to wheat chromosomes, both accessions were crossed with the stripe rust-susceptible spring wheat 'Avocet S'. Resistant F3 plants with 42 chromosomes were selected cytologically and by rust phenotype. A single dominant gene for resistance was identified in segregating F4 lines from each cross. F6 populations for each cross were developed from single F5 plants and used for genetic mapping. Different genes from PI 331260 and PI 480016 were mapped to different loci in chromosome 1BS using simple sequence repeat markers. The gene from PI 331260 was flanked by Xgwm413 and Xgdm33 in bin 1BS9-0.84-1.06 at genetic distances of 3.5 and 2.0 cM; and the gene from PI 480016 was flanked by Xgwm18 and Xgwm11 in chromosome bin C-1BS10-0.50 at 1.2 and 2.1 cM, respectively. Chromosomal locations and race and allelism tests indicated that the two genes are different from previously reported stripe rust resistance genes, and therefore are named as Yr64 from PI 331260 and Yr65 from PI 480016. These genes and their flanking markers, and selected common wheat lines with the genes should be valuable for diversifying resistance genes used in breeding wheat cultivars with stripe rust resistance. PMID- 25142875 TI - CLP1 as a novel player in linking tRNA splicing to neurodegenerative disorders. AB - Defects in RNA metabolic pathways are well-established causes for neurodegenerative disorders. Several mutations in genes involved in pre-messenger RNA (pre-mRNA) and tRNA metabolism, RNA stability and protein translation have been linked to motor neuron diseases. Our study on a mouse carrying a catalytically inactive version of the RNA kinase CLP1, a component of the tRNA splicing endonuclease complex, revealed a neurological disorder characterized by progressive loss of lower spinal motor neurons. Surprisingly, mutant mice accumulate a novel class of tRNA-derived fragments. In addition, patients with homozygous missense mutations in CLP1 (R140H) were recently identified who suffer from severe motor-sensory defects, cortical dysgenesis and microcephaly, and exhibit alterations in transfer RNA (tRNA) splicing. Here, we review functions of CLP1 in different RNA pathways and provide hypotheses on the role of the tRNA splicing machinery in the generation of tRNA fragments and the molecular links to neurodegenerative disorders. We further immerse the biology of tRNA splicing into topics of (t)RNA metabolism and oxidative stress, putting forward the idea that defects in tRNA processing leading to tRNA fragment accumulation might trigger the development of neurodegenerative diseases. PMID- 25142876 TI - Cholesterol and lipoprotein metabolism: Early Career Committee contribution. PMID- 25142878 TI - New role for histone deacetylase 9 in atherosclerosis and inflammation. PMID- 25142877 TI - Coenzyme Q10 increases cholesterol efflux and inhibits atherosclerosis through microRNAs. PMID- 25142879 TI - Reconstituted high-density lipoprotein therapies: a cause for optimism. PMID- 25142880 TI - The platelet: sensing shear and the endocrine regulation of cardiovascular sclerosis. PMID- 25142881 TI - Effect of disturbed blood flow on endothelial cell gene expression: a role for changes in RNA processing. PMID- 25142882 TI - From hairballs to an understanding of transendothelial migration of monocytes in atherosclerosis. PMID- 25142884 TI - Computational study on the kinetics and mechanism of the carbaryl + OH reaction. AB - Carbaryl is released into the atmosphere as a spray drift immediately following the application. In order to evaluate its fate in the atmosphere, a computational study on the kinetics of the OH radical reaction with carbaryl is presented. Different reaction paths are studied at the M05-2X/6-311++G(d,p) level. A complex mechanism involving the formation of a stable reactant complex is proposed and the temperature dependence of the rate coefficients is studied in the 280-650 K temperature range. The principal degradation path is the hydroxyl radical addition to naphthalene, but hydrogen abstractions from the methyl group are identified as a secondary significant path. The rate coefficients, computed using the conventional transition state theory, reproduce quite well the scarce experimental data available. PMID- 25142885 TI - Leptomeningeal metastases from a primary central nervous system melanoma: a case report and literature review. AB - Primary central nervous system (CNS) melanoma is a type of rare and aggressive tumor that can easily spread to the leptomeninges, and in fact, leptomeningeal metastasis is one of the most serious complications in patients with this carcinoma. Prognosis is extremely poor if a CNS melanoma has metastasized, and there are no effective treatments. Here, we present a case of a 37-year-old woman who presented with horizontal diplopia and progressive headache. Magnetic resonance imaging findings were consistent with the diagnosis of melanoma. The results of cytological examination of cerebrospinal fluid (CSF) showed malignant cells characteristic of melanoma. No extracranial lesions were observed. All of the available evidence confirmed a diagnosis of leptomeningeal metastases from a primary CNS melanoma. The patient received aggressive treatment, which consisted of concurrent radiotherapy and weekly intra-CSF methotrexate (MTX) followed by adjuvant monthly intra-CSF MTX. Her survival time was 13 months after diagnosis. This case report suggests that the modality of concurrent radiotherapy and weekly intra-CSF MTX followed by adjuvant monthly intra-CSF MTX may be used as the mainstay of treatment for such patients. PMID- 25142886 TI - We need both randomized trials and real-world data: the example of everolimus as second-line therapy for mRCC. PMID- 25142887 TI - Nut consumption decreases risk of some diseases. PMID- 25142888 TI - Reply to M Zhao and W Liu. PMID- 25142889 TI - Vitamin D supplementation in African Americans: dose-response. PMID- 25142890 TI - Reply to PM Brannon et al. PMID- 25142891 TI - Testing Satter's Division of Responsibility in Feeding in the context of restrictive snack-management practices. PMID- 25142892 TI - Reply to EM Satter. PMID- 25142895 TI - Watch what you type: the role of visual feedback from the screen and hands in skilled typewriting. AB - Skilled typing is controlled by two hierarchically structured processing loops (Logan & Crump, 2011): The outer loop, which produces words, commands the inner loop, which produces keystrokes. Here, we assessed the interplay between the two loops by investigating how visual feedback from the screen (responses either were or were not echoed on the screen) and the hands (the hands either were or were not covered with a box) influences the control of skilled typing. Our results indicated, first, that the reaction time of the first keystroke was longer when responses were not echoed than when they were. Also, the interkeystroke interval (IKSI) was longer when the hands were covered than when they were visible, and the IKSI for responses that were not echoed was longer when explicit error monitoring was required (Exp. 2) than when it was not required (Exp. 1). Finally, explicit error monitoring was more accurate when response echoes were present than when they were absent, and implicit error monitoring (i.e., posterror slowing) was not influenced by visual feedback from the screen or the hands. These findings suggest that the outer loop adjusts the inner-loop timing parameters to compensate for reductions in visual feedback. We suggest that these adjustments are preemptive control strategies designed to execute keystrokes more cautiously when visual feedback from the hands is absent, to generate more cautious motor programs when visual feedback from the screen is absent, and to enable enough time for the outer loop to monitor keystrokes when visual feedback from the screen is absent and explicit error reports are required. PMID- 25142896 TI - Diagnostic pitfalls of hyperprolactinemia: the importance of sequential pituitary imaging. AB - BACKGROUND: The purpose of this study is to confirm whether the serum prolactin cut-off value is definitive to distinguish prolactinoma and non-functioning pituitary adenoma with hyperprolactinemia. We retrospectively reviewed patients with non-functioning pituitary adenoma, including gonadotroph cell adenoma, null cell adenoma and prolactinoma who were surgically treated at Kohnan hospital between June 2005 and March 2012. The patients without endocrinological/neurological symptom and with the tumor larger than 40 mm in diameter were excluded. According to previously reported cut-off value of serum prolactin, mild hyperprolactinemia, which is considered non-definitive (border zone) concentration between prolactinoma and non-functioning pituitary adenoma, were defined as 90 - 200 ng/ml. Ninety-five prolactinoma patients and 212 patients with non-functioning pituitary adenoma were analyzed. The serum prolactin concentration, tumor size, and clinical characteristics were statistically compared. RESULTS: Receiver operating characteristic (ROC) curve analysis was performed, indicating that cut-off value of serum prolactin concentration to distinguish between non-functioning pituitary adenoma and prolactinoma was 38.6 ng/ml. Although it was statistically good accuracy (the area under the curve; 0.96, sensitivity; 0.99 and specificity; 0.81), the result did not fit the clinical situation as many false-positive cases (40 of 212, 18.9%) were included. Among them, mild hyperprolactinemia were shown in 9 (4.2%) and 53 (55.8%) non-functioning pituitary adenoma and prolactinoma, respectively. Four of 9 border zone patients with non-functioning pituitary adenoma were initially treated with dopamine agonists. Sequential head magnetic resonance imaging revealed no tumor shrinkage in all of them despite serum prolactin concentration was decreased. Surgery was chosen for them 24.6 months in average after the introduction of medication. CONCLUSIONS: Non-negligible number of patients with non-functioning pituitary adenoma presented unexpectedly high concentration of prolactin, fraught with a potential risk of misdiagnosis. While this equivocal population is not the majority, the prolactin cut-off value is not safely applicable. Especially for the patients with border zone prolactin concentration, meticulous follow up with sequential pituitary imaging is important. PMID- 25142897 TI - Timing and number of minor infections as risk factors for childhood arterial ischemic stroke. AB - OBJECTIVE: In a population-based case-control study, we examined whether the timing and number of minor infections increased risk of childhood arterial ischemic stroke (AIS). METHODS: Among 102 children with AIS and 306 age-matched controls identified from a cohort of 2.5 million children in a large integrated health care plan (1993-2007), we abstracted data on all medical visits for minor infection within the 2 years prior to AIS or index date for pairwise age-matched controls. We excluded cases of AIS with severe infection (e.g., sepsis, meningitis). Using conditional logistic regression, we examined the effect of timing and total number of minor infections on stroke risk. RESULTS: After adjusting for known pediatric stroke risk factors, the strongest association between infection and AIS was observed for infectious visits <=3 days prior to stroke (odds ratio [OR] 12.1, 95% confidence interval [CI] 2.5, 57, p = 0.002). Respiratory infections represented 80% of case infections in that time period. Cases had more infectious visits, but not significantly so, for all time periods >=4 days prior to the stroke. A greater cumulative number of infectious visits over 2 years did not increase risk of AIS. CONCLUSIONS: Minor infections appear to have a strong but short-lived effect on pediatric stroke risk, while cumulative burden of infection had no effect. Proposed mechanisms for the link between minor infection and stroke in adults include an inflammatory-mediated prothrombotic state and chronic endothelial injury. The transient effect of infection in children may suggest a greater role for a prothrombotic mechanism. PMID- 25142898 TI - A common cold is no stroke of luck: risk for cerebral ischemia in children. PMID- 25142899 TI - Severe paraspinal muscle involvement in facioscapulohumeral muscular dystrophy. AB - OBJECTIVE: In this study, involvement of paraspinal muscles in 50 patients with facioscapulohumeral dystrophy (FSHD) was evaluated using MRI. METHODS: The Dixon MRI technique was used in this observational study to quantify muscle fat content of paraspinal and leg muscles. Muscle strength in the neck, back, and legs was assessed with a handheld dynamometer. All subjects completed the Low Back Pain Rating Scale questionnaire. MRI findings were compared with 31 age-matched controls and correlated to muscle strength, back pain, and MRI findings in lower extremities. RESULTS: The fat fraction in muscles was significantly higher in patients with FSHD than in controls: paraspinal fat fraction was 38% in patients vs 20% in controls, thigh fat fraction was 36% vs 11%, and calf fat fraction was 37% vs 11%. Increased paraspinal fat fraction correlated with D4Z4 repeat size, FSHD severity score, fat fraction of the thigh, and muscle strength in the back. The prevalence of back pain was 3 times higher in patients with FSHD vs controls, but back pain did not correlate with the paraspinal fat fraction. CONCLUSIONS: This study shows a prominent involvement of paraspinal muscles in patients with FSHD, which should be considered in the management of this condition. PMID- 25142900 TI - NT-proBNP, blood pressure, and cognitive decline in the oldest old: The Leiden 85 plus Study. AB - OBJECTIVE: To study the relation between N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, used as a marker of heart failure in clinical practice, blood pressure (BP), and cognitive decline in the oldest old. METHODS: In 560 participants of the Leiden 85-plus Study, we measured NT-proBNP levels and BP at age 85 years, at baseline, and global cognitive function (Mini-Mental State Examination [MMSE]) annually during the follow-up of 5 years. RESULTS: Subjects in the highest tertile of NT-proBNP levels scored 1.7 points lower on the MMSE at age 85 years than subjects in the lowest tertile (p = 0.004), and had a 0.24 point-steeper decline in MMSE score per year (p = 0.021). The longitudinal association disappeared after full adjustment for possible confounders (0.14 point-steeper decline, p = 0.187). Subjects in the category "highest tertile of NT-proBNP and the lowest tertile of systolic BP" had a 3.7-point-lower MMSE score at baseline (p < 0.001) and a 0.49-point-steeper decline in MMSE score per year (p < 0.001) compared with subjects in the other categories. CONCLUSIONS: In the oldest old, high NT-proBNP levels are associated with lower MMSE scores. The combination of high NT-proBNP levels and low systolic BP is associated with worst global cognitive function and the steepest cognitive decline. Possibly, a failing pump function of the heart results in lower BP and lower brain perfusion with resultant brain dysfunction. PMID- 25142901 TI - Rasmussen encephalitis and comorbid autoimmune diseases: A window into disease mechanism? AB - OBJECTIVE: To describe a potential association between comorbid autoimmune disease and Rasmussen encephalitis (RE) and discuss potential insights into underlying RE pathogenesis. METHODS: We report a case series of 4 patients with RE in whom a comorbid autoimmune disease was subsequently diagnosed and review the literature on possible common susceptibility factors. RESULTS: In 4 patients who presented with typical clinical features of RE, a comorbid autoimmune disease was subsequently diagnosed: Hashimoto thyroiditis, ulcerative colitis, Crohn disease, and systemic lupus erythematosus. We discuss the possible common predisposing factors. CONCLUSIONS: The association of RE, a rare entity, with a comorbid autoimmune disease raises the possibility of shared mechanisms of susceptibility, including common immunogenetic and/or environmental risk factors. PMID- 25142903 TI - Is root DNA a reliable proxy to assess arbuscular mycorrhizal community structure? AB - Arbuscular mycorrhizal (AM) fungi are widespread plant symbionts that extensively colonize both soil and roots. Given their influence on ecosystem processes, such as plant growth, soil carbon storage, and nutrient cycling, there is great interest in understanding the drivers of their community structure. AM fungal communities are increasingly characterized by selectively amplifying their DNA from plant roots, thus assuming that AM fungal community structure within roots provides a reliable portrait of the total (i.e., soil + roots) community. Through numerical simulations, we test this assumption using published data. We show that community structure and diversity is well preserved when analyzing only a subset of the community biomass (i.e., roots or soil), provided that the community shows a typical skewed abundance distribution, with few very dominant species and a high prevalence of rare species. Given that this community structure has been shown to be common in natural AM fungal communities, the present work would suggest that characterizing AM fungal communities using only roots or soil can provide a reliable portrait of the overall community. However, we show through additional analyses that the proportion of sample biomass used for molecular methods must be over a minimal threshold to properly characterize the community. Using published molecular data sets, we validate those results, which suggest that typical molecular protocols using low amounts of biomass may strongly influence AM fungal community characterization. Finally, we also discuss other assumptions implied by the molecular analysis of AM fungal communities, and point out urgent knowledge gaps. PMID- 25142902 TI - Acute coronary syndromes in octogenarians referred for invasive evaluation: treatment profile and outcomes. AB - BACKGROUND: With increasing life expectancy in the western world, the aging population will compose a significant portion of the demographic. Notably, cardiovascular disease is particularly prevalent in the elderly population. The aim of the present study is to investigate the outcomes of octogenarians referred for urgent coronary angiography in the setting of acute coronary syndromes (ACS). METHODS: Between June 2007 and June 2012, consecutive patients with ACS were referred for evaluation and percutaneous intervention. Subsequently, the in hospital death and major adverse cardiovascular events (MACE) at 30 days were analyzed. Multivariate analysis was performed to identify the predictors for death and MACE. RESULTS: In patients >=80 years (n = 296) ST-segment elevation myocardial infarction (STEMI) occurred in 46.6%, non-ST-segment elevation myocardial infarction (NSTEMI) in 45.9%, and 7.4% had unstable angina. On the other hand, in patients <80 years (n = 2,316) STEMI was observed in 53.4%, NSTEMI in 37.8% and unstable angina in 9.0%. The primary end-point of total mortality was significantly higher in octogenarians (7.4 vs. 4.5%, p = 0.026). Similarly, the secondary end-point comprising overall MACE rate was significantly higher among the elderly (12.5 vs. 7.3%, p = 0.002). Within the group of octogenarians, no relation between age and outcomes was noted (for death: OR 0.99, 95% CI 0.84 1.16, p = 0.915; and for MACE: OR 1.10, 95% CI 0.88-1.36, p = 0.412); however, in patients <80 years, age was related to outcomes (for death: OR 1.05, 95% CI, 1.02 1.08, p = 0.003; and for MACE: OR 1.03, 95% CI, 1.01-1.05, p = 0.011). In a multivariate analysis, systolic blood pressure (OR 0.97 95% CI 0.94-0.99, p = 0.0058), maximal value of creatine kinase (OR 1.00, 95% CI 1.00-1.00, p = 0.033), and maximal value of NT-proBNP (OR 1.00, 95% CI 1.00-1.00, p = 0.0225) were independent predictors for death, while systolic blood pressure (OR 0.98, 95% CI 0.96-0.99, p = 0.0384) and maximal value of C-reactive protein (OR 1.01, 95% CI 1.00-1.01, p = 0.0265) were associated with overall MACE. CONCLUSIONS: Here we confirm that in-hospital death and MACE rate remain significantly elevated in octogenarians in spite of implementation of modern therapies. However, our real world registry strongly suggests that early revascularization appears safe and effective in elderly patients. Furthermore, we have identified that systolic blood pressure, creatine kinase, NT-proBNP, and C-reactive protein are strong predictors for outcomes in octogenarians. PMID- 25142904 TI - Safe use of rocuronium for a post-polio syndrome patient. PMID- 25142905 TI - beta-Blockade therapy in the perioperative period: is there convincing evidence? PMID- 25142906 TI - Precarious connections: making therapeutic production happen for malaria and tuberculosis. AB - The One Health Movement has been a primary advocate for collaboration across disciplinary and organizational sectors in the study of infectious diseases. There is potentially much to be gained by incorporating the interrelations of animal and human ecosystems, as well as the expertise of veterinary, medical, and public health practitioners. Too often, however, the idea rather than the realities of collaboration become valorized within One Health approaches. Paying little to no attention to the motivations, ontologies, and politics of collaborative arrangements, however, is a critical mistake, one that diminishes considerably One Health framework explanatory powers. Using Anna Tsing's framework of friction, in this paper I take the examples of malaria and tuberculosis pharmaceuticals collaborations, often called Product Development Partnerships, to argue for the need to attend to the conditions under which collaborations across divergent disciplines, geographies, organizations, and institutions might work productively and when they do not. PMID- 25142907 TI - Can arteriovenous malformation prevent the diagnosis of brain death? AB - We present a case of a 14-year-old boy with spontaneous intracranial hemorrhage that was referred to us to confirm the diagnosis of brain death with cerebral angiography. In the left carotid angiogram, there was no arterial flow above the craniovertebral junction. But in the right carotid angiogram, there was arterial flow up to the level of posterior communicating artery. Right posterior cerebral artery was filled with contrast medium via patent posterior communicating artery and later, an opacifying arteriovenous malformation (AVM) was detected which was also seen in the vertebral angiogram. Although the angiographic findings of the patient did not confirm the angiographic criteria for the diagnosis of brain death, it could not be also excluded because the only cerebral flow was the filling of the AVM and no other cerebral perfusion was detected. PMID- 25142908 TI - Skeletal imaging following reconstruction of the posterior cruciate ligament: in vivo comparison of fluoroscopy, radiography, and computed tomography. AB - OBJECTIVE: Intra- and postoperative validation of anatomic footprint replication in posterior cruciate ligament (PCL) reconstruction can be conducted using fluoroscopy, radiography, or computed tomography (CT) scans. However, effectiveness and exposure to radiation of these imaging modalities are unknown. The objective of this study was to evaluate the comparative effectiveness of fluoroscopy, radiography, and CT in detecting femoral and tibial tunnel positions following an all-inside reconstruction of the PCL ligament in vivo. The study design was a retrospective case series. MATERIALS AND METHODS: Intraoperative fluoroscopic images, postoperative radiographs, and CT scans were obtained in 50 consecutive patients following single-bundle PCL reconstruction. The centers of the tibial and femoral tunnel apertures were identified and correlated to measurement grid systems. The results of fluoroscopic, radiographic, and CT measurements were compared to each other and accumulated radiation dosages were calculated. RESULTS: Comparing the imaging groups, no statistically significant difference could be detected for the reference of the femoral tunnel to the intercondylar depth and height, for the reference of the tibial tunnel to the mediolateral diameter of the tibial plateau and for the superoinferior distance of the tibial tunnel entry to the tibial plateau and to the former physis line. Effective doses resulting from fluoroscopic, radiographic, and CT exposure averaged 2.9 mSv, standard deviation (+/-SD) 4.1 mSv, to 1.3 +/- 0.8 mSv and to 3.6 +/- 1.0 mSv, respectively. CONCLUSIONS: Fluoroscopy, radiography, and CT yield approximately equal effectiveness in detecting parameters used for quality validation intra- and postoperatively. An accumulating exposure to radiation must be considered. PMID- 25142910 TI - Chronic myelomonocytic leukemia prognostic classification and management: evidence base and current practice. AB - Chronic myelomonocytic leukemia is a clonal malignancy of the ageing hematopoietic stem cell characterized by a biased differentiation leading to persistent monocytosis and inconstant hypersensitivity of myeloid progenitors to granulo-monocyte colony-stimulating factor (GM-CSF). Cytogenetic abnormalities identified in 30-40 % of patients and gene mutations detected in every patient can be used to stratify patients into risk groups that guide the therapeutic choices. TET2, SRSF2, ASXL1, and genes of the Ras pathway are the most frequently mutated genes, with ASXL1 mutations negatively affecting the disease outcome. Allogeneic stem cell transplantation is the first option to consider, especially in younger patients with poor prognostic factors. There is no firm clinical guideline in transplant-ineligible patients, but hypomethylating agents might be an interesting option. A consensus prognostic scoring system and specific response criteria are now required to facilitate the evaluation of new therapeutic strategies in clinical trials specifically dedicated to this disease. PMID- 25142913 TI - Electrocapillary coupling during electrosorption. AB - The electrocapillary coupling coefficient, sigma, measures the response of the electrode potential, E, to tangential elastic strain at the surface of an electrode. Using dynamic electro-chemo-mechanical analysis, we study sigma(E) simultaneously with cyclic voltammetry. The study covers extended potential intervals on Au, Pt, and Pd, including the electrosorption of oxygen species and of hydrogen. The magnitude and sign of sigma vary during the scans, and quite generally the graphs of sigma(E) emphasize details which are less obvious or missing in the cyclic voltammograms (CVs). Capacitive processes on the clean electrode surfaces exhibit sigma < 0, whereas capacitive processes on oxygen covered surfaces are characterized by sigma < 0 on Au but sigma > 0 on Pt and Pd. The findings of sigma < 0 during the initial stages of oxygen species adsorption and sigma > 0 for hydrogen electrosorption agree with the trend that tensile strain makes surfaces more binding for adsorbates. However, the large hysteresis of oxygen electrosorption on all electrodes raises the question: is the exchange current associated with that process sufficient for its measurement by potential response during small cyclic strain? PMID- 25142912 TI - Release of erythropoietin and neuron-specific enolase after breath holding in competing free divers. AB - Free diving is associated with extreme hypoxia. This study evaluated the combined effect of maximal static breath holding and underwater swimming on plasma biomarkers of tissue hypoxemia: erythropoietin, neuron-specific enolase and S100B, C-reactive protein, pro-atrial natriuretic peptide, and troponin T. Venous blood samples were obtained from 17 competing free divers before and 3 h after sessions of static apnea and underwater swimming. The heart was evaluated by echocardiography. Static apnea for 293 +/- 78 s (mean +/- SD) and subsequent 88 +/- 21 m underwater swimming increased plasma erythropoietin from 10.6 +/- 3.4 to 12.4 +/- 4.1 mIU/L (P = 0.013) and neuron-specific enolase from 14.5 +/- 5.3 to 24.6 +/- 6.4 ng/mL (P = 0.017); C-reactive protein decreased from 0.84 +/- 1.0 to 0.71 +/- 0.67 mmol/L (P = 0.013). In contrast, plasma concentrations of S100B (P = 0.394), pro-atrial natriuretic peptide (P = 0.549), and troponin T (P = 0.125) remained unchanged and, as assessed by echocardiography, the heart was not affected. In competitive free divers, bouts of static and dynamic apnea increase plasma erythropoietin and neuron-specific enolase, suggesting that renal and neural tissue, rather than the heart, is affected by the hypoxia developed during apnea and underwater swimming. PMID- 25142911 TI - Simultaneous monitoring of cerebral metal accumulation in an experimental model of Wilson's disease by laser ablation inductively coupled plasma mass spectrometry. AB - BACKGROUND: Neuropsychiatric affection involving extrapyramidal symptoms is a frequent component of Wilson's disease (WD). WD is caused by a genetic defect of the copper (Cu) efflux pump ATPase7B. Mouse strains with natural or engineered transgenic defects of the Atp7b gene have served as model of WD. These show a gradual accumulation and concentration of Cu in liver, kidneys, and brain. However, still little is known about the regional distribution of Cu inside the brain, its influence on other metals and subsequent pathophysiological mechanisms. We have applied laser ablation inductively coupled plasma mass spectrometry and performed comparative metal bio-imaging in brain sections of wild type and Atp7b null mice in the age range of 11-24 months. Messenger RNA and protein expression of a panel of inflammatory markers were assessed using RT-PCR and Western blots of brain homogenates. RESULTS: We could confirm Cu accumulation in brain parenchyma by a factor of two in WD (5.5 MUg g(-1) in the cortex) vs. controls (2.7 MUg g(-1)) that was already fully established at 11 months. In the periventricular regions (PVR) known as structures of prominent Cu content, Cu was reduced in turn by a factor of 3. This corroborates the view of the PVR as efflux compartments with active transport of Cu into the cerebrospinal fluid. Furthermore, the gradient of Cu increasing downstream the PVR was relieved. Otherwise the architecture of Cu distribution was essentially maintained. Zinc (Zn) was increased by up to 40% especially in regions of high Cu but not in typical Zn accumulator regions, a side effect due to the fact that Zn is to some degree a substrate of Cu-ATPases. The concentrations of iron (Fe) and manganese (Mn) were constant throughout all regions assessed. Inflammatory markers TNF alpha, TIMP-1 and the capillary proliferation marker alpha-SMA were increased by a factor of 2-3 in WD. CONCLUSIONS: This study confirmed stable cerebral Cu accumulation in parenchyma and discovered reduced Cu in cerebrospinal fluid in Atp7b null mice underlining the diagnostic value of micro-local analytical techniques. PMID- 25142914 TI - The "joint-elevation" calcaneus fracture: a rare variant of the intra-articular calcaneus fracture-dislocation. AB - Calcaneus fractures are the most commonly fractured tarsal bone with approximately 75% being intra-articular in nature. Bohler's angle has been found to be reliable and prognostic, and it has been used as a proxy for joint depression and articular involvement. It often guides the need for advanced imaging and/or operative intervention. We describe a rare variant of intra articular calcaneus fracture-dislocation that results in elevation of a portion of the posterior facet above the posterior talus and a seemingly normal or increased Bohler's angle, which we call the "joint-elevation" calcaneus fracture. Orthopaedic surgeons should be aware of this previously undescribed variant in order to avoid inappropriate treatment or misdiagnosis. LEVEL OF EVIDENCE: Therapeutic Level IV: Case Series. PMID- 25142915 TI - The use of arthroscopy in acute foot and ankle trauma: a review. AB - The use of arthroscopy in the management of acute traumatic conditions of the foot and ankle has increased in recent years, primarily because of an appreciation of fracture morphology and the utility of reducing the surgical footprint. This article presents an overview of the use of this modality in foot and ankle trauma and presents an anatomical survey of the various fractures where arthroscopic assistance can be of benefit. In addition, a discussion of the seminal articles on this subject is included. LEVEL OF EVIDENCE: Therapeutic Level IV: Review. PMID- 25142916 TI - Bullous pemphigoid after bilateral forefoot surgery. AB - The case of a 76-year-old woman who developed blisters on both forefeet within 2 weeks of bilateral forefoot surgery is reported; the diagnosis of bullous pemphigoid was made by histological and immunofluorescence studies. The pathogenesis and management of this autoimmune condition, which occurs mainly in patients older than 70 years and may occasionally be associated with surgical wounds, are reviewed. It is important for foot and ankle specialists to be aware of and consider the diagnosis when a bullous contact dermatitis-like eruption persists at a surgical site. LEVEL OF EVIDENCE: Therapeutic Level IV: Case report. PMID- 25142917 TI - Contribution of the medial malleolus to tibiotalar joint contact characteristics. AB - BACKGROUND: Isolated medial malleolus fractures are typically treated operatively to minimize the potential for articular incongruity, instability, nonunion, and posttraumatic arthritis. The literature, however, has not clearly demonstrated inferior outcomes with conservative treatment of these injuries. This study measured the effects of medial malleolus fracture and its resultant instability on tibiotalar joint contact characteristics. We hypothesized that restoration of anatomical alignment and stability through fixation would significantly improve contact characteristics. METHODS: A Tekscan pressure sensor was inserted and centered over the talar dome in 8 cadaveric foot and ankle specimens. Each specimen was loaded at 700 N in multiple coronal and sagittal plane orientations. After testing fractured samples, the medial malleolus was anatomically fixed before repeat testing. Contact area and pressure were analyzed using a 2-way repeated-measure ANOVA. RESULTS: In treated fractures, contact areas were higher, and mean contact pressures were lower for all positions. These differences were statistically significant in the majority of orientations and approached statistical significance in pure plantarflexion and pure inversion. Decreases in contact area varied from 15.1% to 42.1%, with the most dramatic reductions in positions of hindfoot eversion. CONCLUSIONS: These data emphasize the importance of the medial malleolus in maintaining normal tibiotalar contact area and pressure. The average decrease in contact area after simulated medial malleolar fractures was 27.8% (>40% in positions of hindfoot eversion). Such differences become clinically relevant in cases of medial malleolar nonunion or malunion. Therefore, we recommend anatomical reduction and fixation of medial malleolus fractures with any displacement. LEVEL OF EVIDENCE: Therapeutic Level V-Cadaveric Study. PMID- 25142918 TI - Treatment of Catastrophic Infection After Surgery for Insertional Achilles Enthesopathy: A Case Report and Review of the Literature. AB - Wound complications after surgical treatment of insertional Achilles enthesopathy are well documented. Skin and tendon necroses pose a significant dilemma with the potential for catastrophic outcomes. Numerous treatment algorithms have been described to treat the resultant skin and tendon defects after catastrophic infection; however, to date, there is no consensus as to the optimal treatment modality. We report our experience in the management of deep infection of 2 patients who had previously undergone surgical treatment for insertional Achilles enthesopathy. A comprehensive review of the literature was undertaken with a focus on described treatment options. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case report. PMID- 25142919 TI - Simultaneous first metatarsophalangeal joint arthrodesis and sesamoidectomy with a single dorsomedial incision. AB - First metatarsophalangeal (MTP) arthrodesis is a well-accepted procedure for the treatment of end-stage hallux rigidus. Despite the excellent and predictable clinical results, the procedure does not address the metatarso-sesamoid joint complex. There has been one case report of arthritis of the metatarsal sesamoid joint as uncommon cause of post-arthrodesis hallux pain. Additionally, we have noted this complication in our practice as well despite the paucity of reported cases in the published literature. Resection of either the tibial or fibular sesamoid is an acceptable treatment for recalcitrant sesamoid pain; however, resection of both the tibial and fibular sesamoids as would be required for arthritic changes is not encouraged to prevent the risk of a cock-up toe deformity. Arthrodesis of the first MTP joint eliminates the possibility of this complication. Resection of the sesamoids following a first MTP fusion requires a separate incision with additional morbidity and risk to the medial plantar digital nerve. This second surgical intervention is not without morbidity and carries additional cast to the patient, which can be avoided if the pathology is appropriately identified preoperatively. We describe the surgical indications and novel technique for a first MTP arthrodesis and total sesamoid resection through a standard dorsomedial incision. The approach adds minimal surgical time and morbidity and eliminates the source of plantar first MTP pain that is present in a cohort of patients with hallux rigidus. LEVELS OF EVIDENCE: Level IV, Case Series. PMID- 25142920 TI - "Swan neck deformity" of the second toe corrected by flexor digitorum longus to flexor digitorum brevis tenodesis. AB - "Swan neck deformity" of the second toe is a rare deformity. It is a hyperextension of the proximal interphalangeal joint. The patient may complain of painful callosity underneath the proximal interphalangeal joint. Surgical correction should be considered if conservative treatment fails to relieve the pressure point. The optimal surgical option for this deformity has not yet been defined. We report a case of swan neck deformity of the second toe that was successfully corrected by flexor digitorum longus to brevis tenodesis. LEVELS OF EVIDENCE: Therapeutic Level IV: Case Report. PMID- 25142921 TI - Targeted therapy in lung cancer: survival, quality of life improved for some patients. PMID- 25142924 TI - Introduction: the limits of consent and conscience in medicine. PMID- 25142923 TI - Monocyte-derived dendritic cells from HLA-B27+ axial spondyloarthritis (SpA) patients display altered functional capacity and deregulated gene expression. AB - INTRODUCTION: This study aimed to compare the functional capacity and gene expression profile of monocyte-derived dendritic cells (MD-DCs) in HLA-B27+ axial spondyloarthritis (SpA) patients and healthy controls. METHODS: MD-DCs were differentiated with interleukin 4 (IL-4) and granulocyte-macrophage colony stimulating factor (GM-CSF) for seven days, starting from purified CD14+ monocytes and stimulated with lipopolysaccharide (LPS) for six and twenty four hours. Their capacity to stimulate allogeneic CD4+ T cells from unrelated healthy donor was tested. Transcriptomic study was performed with Affymetrix HuGene 1.0 ST microarrays. Gene expression levels were compared between patients and controls using a multivariate design under a linear model (LIMMA). Real-time quantitative PCR (qRT-PCR) was performed for validation of the most striking gene expression differences. RESULTS: The stimulatory capacity of allogeneic CD4+ T cells by MD-DCs from SpA patients was decreased. Transcriptomic analysis revealed 81 genes differentially expressed in MD-DCs between SpA patients and controls (P <0.01 and fold-change <0.66 or >1.5). Four selected genes were validated by q RT PCR: ADAMTS15, CITED2, F13A1 and SELL. Expression levels of ADAMTS15 and CITED2, encoding a metallopeptidase and a transcription factor, respectively, were inversely correlated with each other (R = 0.75, P = 0.0003). Furthermore, in silico analysis identified several genes of the Wnt signaling pathway having expression co-regulated with CITED2. CONCLUSION: This study revealed altered function and gene expression pattern in MD-DCs from HLA-B27+ axial SpA. Co expression study showed an inverse correlation between ADAMTS15 and CITED2. Moreover, the Wnt signaling pathway appeared as deregulated in SpA MD-DCs, a finding which may be connected to Th17-driven inflammatory responses. PMID- 25142925 TI - Comparison of thermodilution, lithium dilution, and pulse contour analysis for the measurement of cardiac output in 3 different hemodynamic states in dogs. AB - OBJECTIVE: To (1) evaluate lithium dilution (LiDCO) and transpulmonary thermodilution (PiCCOTD ) in relation to traditional thermodilution (PAC-TD) for determining cardiac output (CO) in 3 different hemodynamic states in dogs and to (2) compare the continuous CO values obtained using power analysis (PulseCO) with continuous PiCCO (PiCCOc). DESIGN: Prospective randomized study. SETTING: University research laboratory. ANIMALS: Fourteen healthy Beagles. INTERVENTIONS: CO was measured using PAC-TD, LiDCO, and PiCCOTD in 3 different hemodynamic states induced in random order and defined on the basis of the mean arterial pressure (MAP). Normodynamic state was defined as the baseline MAP and 1 MAC sevoflurane. The hypodynamic state was induced with a deep level of sevoflurane anesthesia. The hyperdynamic state was induced with noradrenaline. After these measurements were obtained in each hemodynamic state, CO was monitored continuously for 30 min using PulseCO and PiCCOc. Agreement was assessed using Bland-Altman analysis and intraclass correlation coefficients, and a trend score was determined for the continuous CO measurements. MEASUREMENTS AND MAIN RESULTS: There was good agreement among the 3 modalities of CO measurement in each hemodynamic state. The mean CIPAC-TD /CIPICCOTD bias was -0.04 +/- 1.19 L/min/m(2) (limits of agreement, -2.37/1.93 L/min/m(2) ), and the mean CIPAC-TD /CILiDCO bias was -0.11 +/- 1.55 L/min/m(2) (limits of agreement, -3.04/2.93 L/min/m(2) ). The mean CIPulseCO -CIPiCCOc bias was -0.04 +/- 1.91 L/min/m(2) (limits of agreement, -1.95/1.87 L/min/m(2) ), which suggested good agreement. The CIPulseCO -CIPiCCOc trend score, calculated from 252 paired comparisons, was 93.3% positive after zone exclusion (?CI < 15%). CONCLUSIONS: Both LiDCO and PiCCOTD agreed well with PAC-TD for the measurement of CO under different hemodynamic conditions. Moreover, PiCCOc appears to be an accurate method for monitoring continuous CO in dogs as its performance for measurement was similar to that of PulseCO. PMID- 25142927 TI - Eighty years of an influenza pandemic? PMID- 25142926 TI - Fate of xylem-transported 11C- and 13C-labeled CO2 in leaves of poplar. AB - In recent studies, assimilation of xylem-transported CO2 has gained considerable attention as a means of recycling respired CO2 in trees. However, we still lack a clear and detailed picture on the magnitude of xylem-transported CO2 assimilation, in particular within leaf tissues. To this end, detached poplar leaves (Populus * canadensis Moench 'Robusta') were allowed to take up a dissolved (13)CO2 label serving as a proxy of xylem-transported CO2 entering the leaf from the branch. The uptake rate of the (13)C was manipulated by altering the vapor pressure deficit (VPD) (0.84, 1.29 and 1.83 kPa). Highest tissue enrichments were observed under the highest VPD. Among tissues, highest enrichment was observed in the petiole and the veins, regardless of the VPD treatment. Analysis of non-labeled leaves showed that some (13)C diffused from the labeled leaves and was fixed in the mesophyll of the non-labeled leaves. However, (13)C leaf tissue enrichment analysis with elemental analysis coupled to isotope ratio mass spectrometry was limited in spatial resolution at the leaf tissue level. Therefore, (11)C-based CO2 labeling combined with positron autoradiography was used and showed a more detailed spatial distribution within a single tissue, in particular in secondary veins. Therefore, in addition to (13)C, (11) C-based autoradiography can be used to study the fate of xylem-transported CO2 at leaf level, allowing the acquisition of data at a yet unprecedented resolution. PMID- 25142928 TI - A conceptual framework for the developmental origins of health and disease. AB - In the last decades, the developmental origins of health and disease (DOHaD) have emerged as a vigorous field combining experimental, clinical, epidemiological and public health research. Its goal is to understand how events in early life shape later morbidity risk, especially of non-communicable chronic diseases. As these diseases become the major cause of morbidity and mortality worldwide, research arising from DOHaD is likely to gain significance to public health and economic development. But action may be hindered by the lack of a firm mechanistic explanation and of a conceptual basis, especially regarding the evolutionary significance of the DOHaD phenomenon. In this article, we provide a succinct historical review of the research into the relationship between development and later disease, consider the evolutionary and developmental significance and discuss the underlying mechanisms of the DOHaD phenomenon. DOHaD should be viewed as a part of a broader biological mechanism of plasticity by which organisms, in response to cues such as nutrition or hormones, adapt their phenotype to environment. These responses may be divided into those for immediate benefit and those aimed at prediction of a future environment: disease occurs in the mismatch between predicted and realized future. The likely mechanisms that enable plasticity involve epigenetic processes, affecting the expression of genes associated with regulatory pathways. There is now evidence that epigenetic marks may be inherited and so contribute to non-genomic heritable disease risk. We end by discussing the global significance of the DOHaD phenomenon and its potential applications for public health purposes. PMID- 25142929 TI - The economic cost of a poor start to life. AB - A primary challenge for nutrition policy in low-income settings is to position nutrition as an investment rather than simply as a form of social spending that governments grant poor people to the degree that governments prioritize equity. Various economic models have produced estimates of the economic costs of malnutrition as a combination of the impact of malnutrition on mortality, on health care costs for the survivors, including those that manifest in adult years, and on the lost productivity attributable to malnutrition. However, these estimates often center on the costs of early mortality and are sensitive to assumptions on how to place a dollar cost on mortality. This study argues that even when focusing only on the productivity impact of malnutrition - clearly a lower bound of the full costs - the economic consequences of malnutrition are substantial. Stating this somewhat differently, the economic returns to preventing malnutrition are on a par with those investments generally considered at the heart of economic development strategies. Moreover, the body of evidence that has been accumulated to indicate these productivity gains is both substantial and robust. PMID- 25142930 TI - The effect of late gestation foetal hypoglycaemia on cardiovascular and endocrine function in sheep. AB - An appropriate foetal cardiovascular (CV) response to reduced substrate supply (e.g. oxygen or other nutrients) is vital for growth and development, and may impact on CV control. The prevailing nutritional environment and associated CV changes may influence subsequent CV responses to challenges during late gestation, for example, umbilical cord occlusion (UCO). We investigated the effect of low-circulating glucose on foetal CV control mechanisms and response to UCO. Under general anaesthesia, late gestation foetal sheep (n = 7, 119 days gestational age (dGA), term ~147 days) were implanted with vascular catheters, a bladder catheter, electrocardiogram electrodes and an umbilical cord occluder. Mean arterial pressure (MAP), heart rate (HR) and kidney function were monitored during maternal saline (MSAL, 125dGA) and insulin (MINS, 126dGA) infusion, and foetal CV responses were assessed during incremental doses of angiotensin II, a 90-s total UCO, and administration of phenylephrine to assess baroreflex function. During MINS infusion, the decrease in maternal and foetal blood glucose was associated with a small but significant decrease in foetal HR and reduced foetal baroreflex sensitivity (P < 0.05). The increase in foetal MAP during a 90 s UCO was greater during hypoglycaemia (P < 0.05). The MAP response to angiotensin II was not affected by hypoglycaemia. Decreased foetal HR and baroreflex sensitivity and increased CV responsiveness to UCO during hypoglycaemia indicates altered CV homoestatic mechanisms. The combination of altered nutrition and a CV challenge, such as UCO, during late gestation may have a cumulative effect on foetal CV function. PMID- 25142931 TI - Relationships between early postnatal growth and metabolic function of 16-month old female offspring born to ewes exposed to different environments during pregnancy. AB - It was hypothesized that exposure of the fetus to adverse conditions in utero due to either maternal constraint or nutrition may result in developmental adaptations altering metabolism and postnatal growth of the offspring. Heavy (H) and light (L) Romney dams (G0) were allocated to ad libitum (A) or maintenance (M) nutritional regimens, from day 21-day 140 of pregnancy. Female twin-born offspring (G1) born to the dams in the four treatment groups will be referred to as HA-ewes, LA-ewes, HM-ewes and LM-ewes. At 16 months of age, offspring were catheterized and given intravenous insulin tolerance test (ITT), glucose tolerance test (GTT) and epinephrine tolerance test challenges to assess their glucose and fat metabolism in relation to their birth weight and postnatal growth. In HA-ewes, the regression coefficients of growth rates prior to puberty on insulin and glucose curves in response to GTT (InsAUCGTT) and ITT (GluAUCITT), respectively, were different from 0 (P < 0.05) and were different from the regression coefficients of HM-ewes. This may indicate that HA-ewes may have showed puberty-related insulin resistance at 16 months of age with increasing growth rates prior to puberty compared to HM- or LM-ewes. In HM-ewes, the regression coefficients of growth rates after puberty on InsAUCGTT and GluAUCITT were different from 0 (P < 0.05) and were different from those of HA-ewes. These results may indicate that offspring born to heavy dams fed maintenance during pregnancy and with greater postnatal growth rates after puberty could develop glucose intolerance and insulin resistance in later life. PMID- 25142932 TI - Cardiac and vascular disease prior to hatching in chick embryos incubated at high altitude. AB - The partial contributions of reductions in fetal nutrition and oxygenation to slow fetal growth and a developmental origin of cardiovascular disease remain unclear. By combining high altitude with the chick embryo model, we have previously isolated the direct effects of high-altitude hypoxia on growth. This study isolated the direct effects of high-altitude hypoxia on cardiovascular development. Fertilized eggs from sea-level or high-altitude hens were incubated at sea level or high altitude. Fertilized eggs from sea-level hens were also incubated at high altitude with oxygen supplementation. High altitude promoted embryonic growth restriction, cardiomegaly and aortic wall thickening, effects which could be prevented by incubating eggs from high-altitude hens at sea level or by incubating eggs from sea-level hens at high altitude with oxygen supplementation. Embryos from high-altitude hens showed reduced effects of altitude incubation on growth restriction but not on cardiovascular remodeling. The data show that: (1) high-altitude hypoxia promotes embryonic cardiac and vascular disease already evident prior to hatching and that this is associated with growth restriction; (2) the effects can be prevented by increased oxygenation; and (3) the effects are different in embryos from sea-level or high altitude hens. PMID- 25142933 TI - GDNF and MAPK-ERK pathway signaling is reduced during nephrogenesis following maternal under-nutrition. AB - Maternal under-nutrition (MUN) during gestation results in growth-restricted newborns with reduced glomerular number and subsequent hypertension. We investigated dysregulation of glial derived neurotrophic factor (GDNF) and MAPK ERK (mitogen-activated protein kinase-extracellular signal-regulated protein kinase) signal pathway gene expression following MUN. MUN rats were 50% food restricted from embryonic day 10 till postnatal day 1. Kidneys were harvested at embryonic day (E)20, and postnatal days (P)1 and 21. Kidney protein expression was determined by Western blot. At E20, protein expression of growth factor receptor alpha 1 (GFRalpha1) and phosphorylated ERK1/2 and mitogen-activated protein kinase kinase (MEK)1/2 were reduced significantly, and immunohistochemistry confirmed reduction of phosphorylated ERK (pERK) with maintenance of pERK localization. Total MEK and ERK were unchanged. At P1, only GFRalpha1 and pERK1/2 were reduced significantly while at P21, expression of all growth factors except total MEK was unchanged. Total MEK was increased. Glomerular number was decreased by 19% in P21 kidneys and blood pressure was increased in 12-week-old rats. In conclusion, GDNF and MAPK-ERK signaling are dysregulated during active nephrogenesis in fetal and early newborn offspring kidneys in the MUN model. This may be a key mechanism in reduced offspring nephrogenesis and programmed hypertension. PMID- 25142934 TI - Proteinuria in aging rats due to low-protein diet during mid-gestation. AB - Nephrogenesis in the rat starts mid-gestation and continues into lactation. Maternal low protein (LP) intake leads to renal injury in rats and associates with mild renal injury in humans. We hypothesized that LP during early nephrogenesis or throughout gestation would induce more renal injury in rat offspring than when LP was only present before nephrogenesis. Pregnant rats were fed LP diet (9% casein) at early gestation (LPE, day 0-7), mid (LPM, day 8-14), late (LPL, day 15-22) or throughout gestation (LPA, day 0-22) and compared to controls on 18% casein diet. Offspring were studied at 18 months. Renal injury was assessed by 24 h proteinuria, plasma urea, antioxidant enzyme activities, and apoptosis (Bax/Bcl2). Proteinuria was higher in LPM males and LPE and LPM females. In LPM males glutathione peroxidase activity was lower, while in LPE males catalase activity was higher. Antioxidants were not much affected in females. Bax expression was higher in LPM males and females, while Bcl2 expression was higher in LPA females. Thus even before nephrogenesis (day 0-7), LP impacted on renal integrity in adult life, while LP during a later phase (day 15-22) or throughout gestation had less effect. In summary, for aging rat kidney LP poses the greatest threat when restricted to early nephrogenesis. PMID- 25142935 TI - Protective effects of humanin on okadaic Acid-induced neurotoxicities in cultured cortical neurons. AB - Neurofibrillary tangles are pathological hallmarks of Alzheimer's disease (AD), which are mostly composed of hyperphosphorylated tau and directly correlate with dementia in AD patients. Okadaic acid (OA), a toxin extracted from marine life, can specifically inhibit protein phosphatases (PPs), including PP1 and Protein phosphatase 2A (PP2A), resulting in tau hyperphosphorylation. Humanin (HN), a peptide of 24 amino acids, was initially reported to protect neurons from AD related cell toxicities. The present study was designed to test if HN could attenuate OA-induced neurotoxicities, including neural insults, apoptosis, autophagy, and tau hyperphosphorylation. We found that administration of OA for 24 h induced neuronal insults, including lactate dehydrogenase released, decreased of cell viability and numbers of living cells, neuronal apoptosis, cells autophagy and tau protein hyperphosphorylation. Pretreatment of cells with HN produced significant protective effects against OA-induced neural insults, apoptosis, autophagy and tau hyperphosphorylation. We also found that OA treatment inhibited PP2A activity and HN pretreatment significantly attenuated the inhibitory effects of OA. This study demonstrated for the first time that HN protected cortical neurons against OA-induced neurotoxicities, including neuronal insults, apoptosis, autophagy, and tau hyperphosphorylation. The mechanisms underlying the protections of HN may involve restoration of PP2A activity. PMID- 25142936 TI - The non-classical N-glycan processing pathway of bovine brain ecto-nucleotide phosphodiesterase/pyrophosphatase 6 (eNPP6) is brain specific and not due to mannose-6-phosphorylation. AB - Ecto-nucleotide phosphodiesterase/pyrophosphatase 6 (eNPP6) is a glycosylphosphatidylinositol (GPI)-anchored alkaline lysophospholipase C which is predominantly expressed in brain myelin and kidney. Due to shedding of the GPI anchor eNPP6 occurs also as a soluble isoform (s-eNPP6). eNPP 6 consists of two identical monomers of 55 kDa joined by a disulfide bridge, and possesses four N glycans in each monomer. In brain s-eNPP6 the N-glycans are mainly hybrid and high mannose type structures, reminiscent of processed mannose-6-phosphorylated glycans. Here we completed characterization of the site-specific glycan structures of bovine brain s-eNPP6, and determined the endo H-sensitivity glycan profiles of s-eNPP6 from bovine liver and kidney. Whereas in brain s-eNPP6 all of the N-glycans were endo H-sensitive, in liver and kidney only one of the glycosylation sites was occupied by an endo H-sensitive glycan, likely N406, which is located within the cleft formed by the dimer interface. Thus, the non classical glycan processing pathway of brain eNPP 6 is not due to mannose-6 phosphorylation, suggesting that there is an alternative Golgi glycan-processing pathway of eNPP6 in brain. The resulting brain-specific expression of accessible hybrid and oligomannosidic glycans may be physiologically important within the cell-cell communication system of the brain. PMID- 25142937 TI - Challenges in diagnosing hepatic encephalopathy. AB - The term "hepatic encephalopathy" (HE) covers the neuropsychiatric syndrome associated with acute, chronic and acute-on-chronic liver disease (CLD). This paper deals with clinical features and diagnosis of HE in patients with liver cirrhosis and portal hypertension or porto-systemic shunts. The possible impact of concomitant disorders and the cirrhosis underlying liver disease upon brain function is described emphasizing the need of a detailed diagnostic work up of every individual case before diagnosing HE. Currently used methods for diagnosing minimal or covert hepatic encephalopathy are compared with regard to their sensitivity and specificity for diagnosing HE against the background of a multitude of concomitant disorders and diseases that could contribute to brain dysfunction. PMID- 25142938 TI - Ni2P nanoparticle films supported on a Ti plate as an efficient hydrogen evolution cathode. AB - In this communication, we report a two-step strategy for low-temperature construction of Ni2P nanoparticle films supported on a Ti plate (Ni2P/Ti). When used as an integrated hydrogen evolution cathode, the Ni2P/Ti electrode exhibits remarkable catalytic activity, superior stability and nearly 100% Faradaic efficiency in acidic solutions, and it needs overpotentials of 138 and 188 mV to afford current densities of 20 and 100 mA cm(-2), respectively. PMID- 25142939 TI - Engager T cells: a new class of antigen-specific T cells that redirect bystander T cells. AB - Adoptive immunotherapy with antigen-specific T cells has shown promise for the treatment of malignancies. However, infused T cells are unable to redirect resident T cells, limiting potential benefit. While the infusion of bispecific T cell engagers can redirect resident T cells to tumors, these molecules have a short half-life, and do not self amplify. To overcome these limitations, we generated T cells expressing a secretable T-cell engager specific for CD3 and EphA2, an antigen expressed on a broad range of human tumors (EphA2-ENG T cells). EphA2-ENG T cells were activated and recognized tumor cells in an antigen dependent manner, redirected bystander T cells to tumor cells, and had potent antitumor activity in glioma and lung cancer severe combined immunodeficiency (SCID) xenograft models associated with a significant survival benefit. This new class of tumor-specific T cells, with the unique ability to redirect bystander T cells, may be a promising alternative to current immunotherapies for cancer. PMID- 25142940 TI - Distribution of axon diameters in cortical white matter: an electron-microscopic study on three human brains and a macaque. AB - The aim of this study was to obtain information on the axonal diameters of cortico-cortical fibres in the human brain, connecting distant regions of the same hemisphere via the white matter. Samples for electron microscopy were taken from the region of the superior longitudinal fascicle and from the transitional white matter between temporal and frontal lobe where the uncinate and inferior occipitofrontal fascicle merge. We measured the inner diameter of cross sections of myelinated axons. For comparison with data from the literature on the human corpus callosum, we also took samples from that region. For comparison with well fixed material, we also included samples from corresponding regions of a monkey brain (Macaca mulatta). Fibre diameters in human brains ranged from 0.16 to 9 MUm. Distributions of diameters were similar in the three systems of cortico cortical fibres investigated, both in humans and the monkey, with most of the average values below 1 MUm diameter and a small population of much thicker fibres. Within individual human brains, the averages were larger in the superior longitudinal fascicle than in the transitional zone between temporal and frontal lobe. An asymmetry between left and right could be found in one of the human brains, as well as in the monkey brain. A correlation was also found between the thickness of the myelin sheath and the inner axon diameter for axons whose calibre was greater than about 0.6 MUm. The results are compared to white matter data in other mammals and are discussed with respect to conduction velocity, brain size, cognition, as well as diffusion weighted imaging studies. PMID- 25142941 TI - Five new anthraquinones from the seed of Cassia obtusifolia. AB - A phytochemical investigation on the seeds of Cassia obtusifolia led to the isolation of five new anthraquinones, including one aglycon and four glycosides. The structures were elucidated by analysis of extensive spectroscopic data and the results of acid hydrolysis. All these isolates were evaluated for their inhibitory effects against alpha-glucosidase, and 1 showed potent activity with IC50 value of 185 +/- 15 uM. PMID- 25142942 TI - Therapeutic effect of human clonal bone marrow-derived mesenchymal stem cells in severe acute pancreatitis. AB - Severe acute pancreatitis (SAP), a common necroinflammatory disease initiated by the premature activation of digestive enzymes within the pancreatic acinar cells, is associated with significant morbidity and mortality. In this study, we investigated whether human bone marrow-derived clonal mesenchymal stem cells (hcMSCs), isolated from human bone marrow aspirate according to our newly established isolation protocol, have potential therapeutic effects in SAP. SAP was induced by three intraperitoneal (i.p.) injections of cerulein (100 MUg/kg) and sequential LPS (10 mg/kg) in Sprague-Dawley (SD) rats. hcMSCs (1 * 10(6)/head) were infused on 24 h after LPS injection via the tail vein. The rats were sacrificed 3 days after infusion of hcMSCs. We observed that infused hcMSCs reduced the levels of serum amylase and lipase. Infused hcMSCs ameliorated acinar cell necrosis, pancreatic edema, and inflammatory infiltration. Also, infused hcMSCs decreased the level of malondialdehyde, and increased the levels of glutathione peroxidase and superoxide dismutase. The number of TUNEL positive acinar cells was reduced after hcMSCs infusion. In addition, hcMSCs reduced the expression levels of pro-inflammation mediators and cytokines, and increased the expression of SOX9 in SAP. Taken together, hcMSCs could effectively relieve injury of pancreatitis as a promising therapeutics for SAP. PMID- 25142943 TI - Role of multidetector CT in the recognition of hyperdense middle cerebral artery sign (HMCAS) in patients with acute cerebral ischaemia: correlation with DWI-MRI sequences and clinical data. AB - PURPOSE: The aim of this study was to verify the sensitivity and specificity of the hyperdense middle cerebral artery sign (HMCAS) obtained by multidetector computed tomography (CT) in predicting acute stroke, using diffusion-weighted (DW) magnetic resonance imaging (MRI) as a reference. The location of the HMCAS, the extension of the ischaemic lesion and its prognostic value were also assessed. MATERIALS AND METHODS: The CT examinations of 654 patients with symptoms related to acute cerebral stroke were retrospectively reviewed. DW-MRI confirmed recent stroke in 175 patients. Two expert neuroradiologists analysed the CT examinations of these patients in four phases. Sensitivity, specificity and interobserver reliability was evaluated. Patients were divided into three groups according to the HMCAS site (M1-M2-M3) and the Alberta Stroke Program Early CT Score (ASPECTS) on DW-MRI was calculated. The ASPECTS average score was correlated with the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) at 3 months. RESULTS: In 41 patients, the presence of HMCAS was confirmed (71 % sensitivity; 100 % specificity; Interobserver reliability k, 84 %). An inverse correlation was found by comparing the ASPECTS and NIHSS scores (Rsq = -0.206). After logistic regression analysis, HMCAS was found to be independently associated with a poor outcome (mRS >2) at 3 months after adjusting for age, NIHSS on admission, risk factors and aetiology of stroke. CONCLUSIONS: Our study demonstrated that HMCAS obtained with multidetector CT can be detected in more than 70 % of patients with large acute ischaemic lesion and it is an unfavourable prognostic sign. PMID- 25142944 TI - The role of CEUS in the assessment of haemodynamically stable patients with blunt abdominal trauma. AB - Computed tomography (CT) still represents the preferred imaging method in the assessment of patients presenting with multiple trauma. Nevertheless, in patients with low-energy abdominal trauma, the use of CT is debated because of the possible unnecessary radiation exposure. Accordingly, conventional ultrasound (US) imaging has been increasingly employed as the initial imaging modality in the workup of minor traumatic emergency conditions. Focused assessment with sonography for trauma is widely used to detect free intra-abdominal fluid, but its role is controversial, because the absence of free fluid does not exclude the presence of injuries to abdominal organ. Injection of an ultrasound contrast agent (UCA) may give the radiologist relevant additional information to that obtained with conventional US. Thus, in trauma patients, following early assessment with conventional US imaging, a contrast-enhanced US (CEUS) can provide a more reliable evaluation of solid organ injuries and related vascular complications, including active bleeding, pseudoaneurysms, and artero-venous fistulas. CEUS cannot replace abdominal CT, but it represents a noninvasive and repeatable imaging tool capable of providing a reliable assessment of trauma severity and expedite the patient's treatment. PMID- 25142945 TI - Podoplanin: a novel regulator of tumor invasion and metastasis. AB - Podoplanin, a small mucin-type sialoglycoprotein, was recently shown to be involved in tumor progression. Podoplanin is overexpressed in cancer cells of various human malignancies, and recently, it is also detected in intratumoral stromal cells. We now appreciate that podoplanin plays a dual role in cancer: it can not only suppress tumor growth but also promote tumor progression. Researchers have identified several potential pathways invoked by podoplanin, which participate in the epithelial-to-mesenchymal transition, collective-cell migration, platelet activation and aggregation, and lymphangiogenesis, and thus regulate the tumor invasion and metastasis. Here, we discuss the current experimental and human clinical data on podoplanin to validate the multiple context-dependent functions in different microenvironments and to delineate the diverse regulatory mechanisms. PMID- 25142946 TI - CCL21/CCR7 axis activating chemotaxis accompanied with epithelial-mesenchymal transition in human breast carcinoma. AB - Secondary lymphoid tissue chemokine (SLC/CCL21) and its receptor CCR7 have been implicated in lymph node metastasis, whereas the mechanism of which remains unclear. Epithelial-mesenchymal transition (EMT) plays an important role in invasion and migration of cancer cells. We presumed that CCL21/CCR7 axis activates EMT process to induce cancer cell invasion and metastasis. Firstly, the expressions of CCR7 and EMT markers were examined by immunohistochemical staining in the primary breast carcinoma tissues from 60 patients who underwent radical mastectomy. Then, we investigated whether CCL21/CCR7 induces EMT process during mediating cancer cell invasion or migration in vitro. By immunohistolochemistry, high expressions of CCR7, Slug and N-cadherin were seen in 60, 65, and 76.67 % of tumors, respectively, and significantly associated with lymph node metastases as well as clinical pathological stage. Furthermore, the CCR7 expression was significantly correlated to Slug and N-cadherin. In vitro, stimulating breast cancer cell lines 1428, MCF-7 and MDA-MB-231 with CCL21, the invasion and migration of tumor cells were promoted, and simultaneously, EMT phenotype of tumor cells was enhanced, including down-regulation of E-cadherin, up-regulation of Slug, Vimentin and N-cadherin at both protein and mRNA levels. Inversely, knockdown of CCR7 by shRNA suppressed tumor cell invasion, migration and EMT phenotype induced by CCL21. These results indicated that CCL21/CCR7 axis could activate EMT process during chemotaxis of breast carcinoma cells. PMID- 25142947 TI - Prognostic significance of serum beta-2 microglobulin level in Hodgkin lymphoma treated with ABVD-based therapy. AB - The levels of serum beta-2 microglobulin (beta2MG) are determined mainly from lymphoid tissue. To examine its prognostic value in Hodgkin lymphoma (HL), we conducted a retrospective analysis. We analyzed 67 patients with HL diagnosed and treated at seven institutes of the Yokohama City University Hematology Group between 1998 and 2011. The patients included 40 males and 27 females with a median age of 41 years (range 16-81 years). The HL subtypes were nodular sclerosis classical HL in 37 patients, mixed cellular classical HL in 23, lymphocyte-rich classical HL in 6, and nodular lymphocyte-predominant HL in 1. The 4-year overall survival (OS) rate of all 67 patients was 89 %. Patients with beta2MG levels >= 2.5 mg/L (n = 18) showed inferior progression-free survival (PFS; 4-year PFS rate, 42 %) and inferior OS (4-year OS rate, 60 %) compared to patients who had beta2MG levels <2.5 mg/L (n = 49; 4-year PFS rate, 87 %; 4-year OS rate, 98 %; P < 0.001). In multivariate analysis, only a serum beta2MG level >= 2.5 mg/L was a significant adverse prognostic factor in regard to PFS (P = 0.04; relative risk 3.57). However, it was not significant prognostic factor for OS (P = 0.16) in the multivariate analysis. The serum beta2MG level at diagnosis is a useful prognostic marker in patients with HL. PMID- 25142948 TI - Molecular signature of organic nitrogen in septic-impacted groundwater. AB - Dissolved inorganic and organic nitrogen levels are elevated in aquatic systems due to anthropogenic activities. Dissolved organic nitrogen (DON) arises from various sources, and its impact could be more clearly constrained if specific sources were identified and if the molecular-level composition of DON were better understood. In this work, the pharmaceutical carbamazepine was used to identify septic-impacted groundwater in a coastal watershed. Using ultrahigh resolution mass spectrometry data, the nitrogen-containing features of the dissolved organic matter in septic-impacted and non-impacted samples were compared. The septic impacted groundwater samples have a larger abundance of nitrogen-containing formulas. Impacted samples have additional DON features in the regions ascribed as 'protein-like' and 'lipid-like' in van Krevelen space and have more intense nitrogen-containing features in a specific region of a carbon versus mass plot. These features are potential indicators of dissolved organic nitrogen arising from septic effluents, and this work suggests that ultrahigh resolution mass spectrometry is a valuable tool to identify and characterize sources of DON. PMID- 25142949 TI - Proton-pump inhibitor use is associated with lower urinary magnesium excretion. AB - AIMS: Although multiple recent studies have confirmed an association between chronic proton-pump inhibitor (PPI) use and hypomagnesaemia, the physiologic explanation for this association remains uncertain. To address this, we investigated the association of PPI use with urinary magnesium excretion. METHODS: We measured 24-hour urine magnesium excretion in collections performed for nephrolithiasis evaluation in 278 consecutive ambulatory patients and determined PPI use from contemporaneous medical records. RESULTS: There were 50 (18%) PPI users at the time of urine collection. The mean daily urinary magnesium was 84.6 +/- 42.8 mg in PPI users, compared with 101.2 +/- 41.1 mg in non-PPI users (P = 0.01). In adjusted analyses, PPI use was associated with 10.54 +/- 5.30 mg/day lower daily urinary magnesium excretion (P = 0.05). Diuretic use did not significantly modify the effect of PPI on urinary magnesium. As a control, PPI use was not associated with other urinary indicators of nutritional intake. CONCLUSIONS: Our findings suggest that PPI use is associated with lower 24-hour urine magnesium excretion. Whether this reflects decreased intestinal uptake due to PPI exposure, or residual confounding due to decreased magnesium intake, requires further study. PMID- 25142950 TI - Parents of children with haemophilia at an early age: assessment of perceived stress and family functioning. AB - Haemophilia is a chronic disease that requires a multidisciplinary approach for proper management and control of its clinical manifestations. The perception and management of parents of children with haemophilia can be affected by stressful situations as a result of treatment or disease progression. The aim of this study was to evaluate the perception of stress and family functioning in parents of children with haemophilia 1-7 years. This is an observational clinical study involving 49 parents of children with haemophilia 1-7 years who attended the VIII Workshop for Parents of Children with haemophilia, organized by the Spanish Federation of Hemophilia in La Charca, Murcia (Spain). After obtaining parental consent, the questionnaires was applied to them, FACES III (family functioning) and Pediatric Inventory for Parents (perceived stress), and a record of data on the clinical characteristics and treatment. Significant differences in the perception of stressors by gender of parents were found. A family history of haemophilia, the use of port-a-cath, inhibitor development and gender of the parents were the descriptive variables most correlated with dependents variables. These variables, together with the type of haemophilia affect significantly in the parental stress and family functioning. Parents have difficulty adjusting to disease management, perceiving many stressors. Gender and family history, can hinder the proper compliance with treatments, reducing its effectiveness. PMID- 25142951 TI - HesF, an exoprotein required for filament adhesion and aggregation in Anabaena sp. PCC 7120. AB - Here, we report on the identification and characterization of a protein (Alr0267) named HesF, found in the extracellular milieu of Anabaena sp. PCC 7120 grown diazotrophically. hesF was found to be highly upregulated upon transition from non-nitrogen-fixing to nitrogen-fixing conditions, and the highest transcript levels were detected towards the end of the heterocyst differentiation process. The hesF promoter drives transcription of the gene in heterocysts only, and both NtcA and HetR are essential for the gene's in vivo activation. An examination of HesF's translocation showed that the secretion system is neither heterocyst specific nor dependent on nitrogen-fixing conditions. Furthermore, HesF was found to be a type I secretion system substrate, since an HgdD mutant failed to secrete HesF. Several analyses revealed that a HesF minus mutant strain lacks the heterocyst-specific polysaccharide fibrous layer, accumulates high amounts of polysaccharides in the medium and that HesF is essential for the typical aggregation phenotype in diazotrophic conditions. Thus, we propose that HesF is a carbohydrate-binding exoprotein that plays a role in maintaining the heterocyst cell wall structure. A combination of and possibly interaction between HesF and heterocyst-specific polysaccharides seems to be responsible for filament adhesion and culture aggregation in heterocyst-forming cyanobacteria. PMID- 25142952 TI - Maladaptive social information processing in childhood predicts young men's atypical amygdala reactivity to threat. AB - BACKGROUND: Maladaptive social information processing, such as hostile attributional bias and aggressive response generation, is associated with childhood maladjustment. Although social information processing problems are correlated with heightened physiological responses to social threat, few studies have examined their associations with neural threat circuitry, specifically amygdala activation to social threat. METHODS: A cohort of 310 boys participated in an ongoing longitudinal study and completed questionnaires and laboratory tasks assessing their social and cognitive characteristics the boys were between 10 and 12 years of age. At age 20, 178 of these young men underwent functional magnetic resonance imaging and a social threat task. At age 22, adult criminal arrest records and self-reports of impulsiveness were obtained. RESULTS: Path models indicated that maladaptive social information-processing at ages 10 and 11 predicted increased left amygdala reactivity to fear faces, an ambiguous threat, at age 20 while accounting for childhood antisocial behavior, empathy, IQ, and socioeconomic status. Exploratory analyses indicated that aggressive response generation - the tendency to respond to threat with reactive aggression - predicted left amygdala reactivity to fear faces and was concurrently associated with empathy, antisocial behavior, and hostile attributional bias, whereas hostile attributional bias correlated with IQ. Although unrelated to social information-processing problems, bilateral amygdala reactivity to anger faces at age 20 was unexpectedly predicted by low IQ at age 11. Amygdala activation did not mediate associations between social information processing and number of criminal arrests, but both impulsiveness at age 22 and arrests were correlated with right amygdala reactivity to anger facial expressions at age 20. CONCLUSIONS: Childhood social information processing and IQ predicted young men's amygdala response to threat a decade later, which suggests that childhood social cognitive characteristics are associated with the development of neural threat processing and adult adjustment. PMID- 25142953 TI - Community periodontal treatment needs in South Korea. AB - OBJECTIVES: This study aimed to assess the relationship between socio-economic factors and community periodontal treatment needs in Korea. METHODS: Data were obtained from the year 2009 Korean National Health and Nutrition Examination Survey. Our analysis included 7510 survey participants over the age of 19 years. To assess the relationship between socio-economic factors and the need for periodontal scaling, we performed multivariate logistic regression analyses for data with a complex sampling structure. PASW statistics 19.0 (SPSS Inc., Chicago, IL, USA) was used to perform the statistical analyses, and the results were expressed as odds ratios (OR) with corresponding 95% confidence intervals (CIs). RESULTS: A very high percentage of Korean adults required periodontal scaling (71.5%). After adjusting for sex, age, and socio-economic factors, the need for periodontal scaling was associated with low levels of education (OR: 1.41, 95% CI: 1.03-1.93), low incomes (OR: 1.27, 95% CI: 1.01-1.60), employment as a service and sales worker (OR: 1.39, 95% CI: 1.10-1.77), and employment as a manual worker (OR: 1.31, 95% CI: 1.02-1.69). CONCLUSIONS: In South Korea, the need for periodontal scaling was associated with socio-economic factors, such as low levels of education, low incomes, employment as a service and sales worker and employment as a manual worker. Consequently, clinical and community dental hygienists should consider adults with these risk factors as belonging to high priority subgroups to whom they should respond first. PMID- 25142954 TI - Cell-penetrating peptides as delivery enhancers for vaccine. AB - The poor permeability of cellular membrane is one of the principal hurdles of most drug administrations including vaccine system, consequently impairing drug efficiency. In order to address this natural barrier, cell-penetrating peptides (CPPs) have been developed to facilitate molecular cargos to enter cells. CPPs, generally short peptides with 5-30 amino acids, can be classified in to cationic, amphipathic and hydrophobic types according to physical-chemical properties. In this review, different processes of antigen uptake, subsequent processing and presentation of CPP-based vaccine are comprehensively summarized despite precise mechanisms are not still established. Some experimental factors such as cell types, concentration of CPPs and antigenic cargos have been reported to affect antigen uptake orientation. Moreover, this review discusses different antigenic cargos where CPPs can transport for vaccine delivery as well as the application of CPPs in vaccine system via different administration routes like transdermal, subcutaneous and mucosal immunization. PMID- 25142956 TI - [A case report: a patient with paralysis of the lower half of the body being diagnosed with prostate cancer and primary spinal malignant lymphoma]. AB - The patient was an 81-year-old man who visited our hospital for paralysis of the lower half of the body. He was suspected as having a spinal tumor by computed tomography and magetic resonance imaging, and also as having prostate cancer based on a high prostate specific antingen level. A prostate needle biopsy, thoracic spinal fusion and posterior decompression were performed. The patient was diagnosed as having prostate cancer and primary spinal malignant lymphoma. Hormone therapy and chemotherapy were started for the prostate cancer and primary spinal malignant lymphoma, respectively. However, the patient died of a complication from chemotherapy. PMID- 25142955 TI - [Clinical investigation of male infertile patients with chromosomal anomalies]. AB - We investigated 470 male patients who came to the Reproduction Medical Center of Yokohama City University Medical Center complaining of infertility between April 2,000 and August 2013. We analyzed the chromosomes of 90 patients whose sperm concentration was below 1.0 * 107/ml. Nineteen of the 90 (21.1%) patients showed sex chromosomal anomalies including 12 Klinefelter syndrome (47, XXY or 46, XY/47, XXY), Robertsonian translocation, 2 autosome-autosome translocation, Y autosome translocation, 46, X with marker chromosome (46, Xmar+), XX male and Y chromosome macrodeletion (46, XYq-). While patients with chromosomal abnormalities except XX male or some of 46, XYq- may succeed in reproduction using testicular sperm extraction-intracytoplasmic sperm injection, we need to inform the patients about the risks of chromosomal abnormalities in the resulting fetus. PMID- 25142957 TI - [A case of successful living related renal transplantation in a patient with end stage renal disease resulting from sarcoidosis]. AB - We report a case in a 44-year-old man with known past history of sarcoidosis associated with uveitis that was first diagnosed when he was 20 years old. He developed renal dysfunction 6 years after the diagnosis of sarcoidosis. At that time, a renal biopsy revealed non-necrotizing granulomatous interstitial nephritis, typical findings of renal involvement of sarcoidosis. Despite corticosteroid therapy administered soon after the biopsy, the renal dysfunction gradually progressed to end-stage renal disease. The patient underwent kidney transplantation from a living donor and the renal graft has been functioning well with no evidence of recurrence 10 months postoperatively, and with a serum creatinine level between 1.2 and 1.5 mg/dl. PMID- 25142958 TI - [Three cases of proliferative cystitis causing hydronephrosis]. AB - We report three cases of proliferative cystitis causing hydronephrosis. Three patients presented with a complaint of miction pain, gross hematuria or pollikisuria. Cystoscopic findings revealed papillary sessile tumor from neck to orifice. Transurethral resection of the bladder tumor (TURBT) was performed because the tumor was not responsive to medical treatment. The pathological diagnosis was intestinal type or typical type of cystitis glandularis and no malignant cells were observed. After the operation, although hydronephrosis improved in two cases, the left hydronephrosis did not improve in one case and ureteralileostomy was performed. Five year after the last operation, there is no evidence of recurrence of the tumor. Tumor formation arising from proliferative cystitis is relatively rare. Pathogenesis and management of this rare condition are discussed. PMID- 25142959 TI - [A pediatric wilms' tumor presenting with a right renal injury]. AB - We report a case of a pediatric Wilms' tumor presenting after a right renal injury. A 6-year-old girl presented to a nearby hospital with right back pain after a fall. An abdominal computed tomography (CT) scan revealed a right renal injury with active hemorrhaging. She was then referred to our hospital. There another CT scan and a magnetic resonance imaging (MRI) scan revealed the disappearance of the active hemorrhaging but also the presence of a large renal tumor. We performed a right nephrectomy. The renal tumor was diagnosed as a nephroblastoma. Considering dissemination by trauma, chemotherapy and radiation therapy were performed. PMID- 25142960 TI - [Renal arteriovenous fistula with a vein aneurysm: a case report]. AB - A 54-year-old woman presented with abdominal distension. Her medical history was unremarkable. Contrast-enhanced computed tomography (CT) revealed a left renal arteriovenous fistula and a large vein aneurysm, and she was diagnosed with aneurismal-type renal arteriovenous fistula. She was successfully treated with transcatheter arterial embolization using steel coils. Although she had pulmonary embolism as a serious post-operative complication, she recovered with anticoagulant therapy using heparin and warfarin. A contrast-enhanced CT scan performed 6 months after transcatheter arterial embolization did not show recanalization. PMID- 25142961 TI - Perioperative management of and recommendations for antithrombotic medications in dermatological surgery. AB - With the ever-increasing number of patients on anticoagulant or antiplatelet medications presenting for a dermatological surgical procedure, dermatological surgeons are facing the challenge of managing these drugs in order to balance the bleeding complications against the risk of thromboembolic events. The difficulty arises from the scarce available recommendations, the data in the literature that is in part contradictory and the rate of emergence of newer agents that have not been thoroughly studied and widely used. Although the common approach in the past was to stop any antithrombotic medications, including warfarin and aspirin, several days prior to cutaneous surgery, recent data suggest that this practice should be changed as the relatively low risk of bleeding does not justify the life-threatening nature of a likely thrombosis. For patients on warfarin, surgery should be avoided if the international normalized ratio is > 3.5; aspirin should not be stopped prior to dermatological surgery and in most other circumstances patients taking long-term antithrombotic medication should not stop this prior to dermatological surgery. In more complicated cases liaison with the prescriber is indispensable even when the therapy should be discontinued for a short period of time. This review studies the available data and presents the dermatological surgeon with up-to-date information about all studies concerning the old and new antithrombotic agents in the setting of dermatological surgery procedures. Our aim is to propose our recommendations based on the most recent evidence and our experience and provide a comprehensive approach to the dermatological surgeon without excluding the need for individual assessment of each case. PMID- 25142962 TI - Candida albicans adherence to denture base material: chemical disinfection and the effect of acquired salivary pellicle formation. AB - PURPOSE: The aim of this study was to evaluate the effect of 1% sodium hypochlorite (H1%) and 4% chlorhexidine gluconate (CG4%) on the adhesion of Candida albicans to denture base acrylic resins, as well as to verify the effect of the acquired salivary pellicle (ASP) formation on this process. MATERIALS AND METHODS: A total of 300 acrylic specimens were immersed in distilled water (control) (n = 100), H1% (n = 100), or CG4% (n = 100) for 30 days. Twenty specimens were used in each experimental period (0, 1, 7, 15, 30 days). At the end of disinfection testing periods, 10 specimens of each group were exposed to human whole saliva to simulate ASP formation, and then all specimens were incubated with C. albicans ATTC 90028. Microorganism adhesion was analyzed by fluorescence microscopy, after staining with Acridine orange. RESULTS: In the 30(th) disinfection cycle in relation to baseline, the H1% or CG4%, without ASP formation, reduced the C. albicans adhesion by approximately 80%; however, with ASP, this reduction after disinfection with H1% was higher (88%). The presence of ASP resulted in higher reduction of adhered fungal cells in comparison to resin without ASP, at the 1(st) H1% or CG4% disinfection cycle, as well as at 30(th) H1% disinfection cycles. CONCLUSIONS: Our results suggest that the presence of saliva might influence the adhesion of C. albicans and improve the effectiveness of methods to reduce fungal adhesion. PMID- 25142963 TI - Simultaneous dissection and comparison of IL-2 and IL-15 signaling pathways by global quantitative phosphoproteomics. AB - Common gamma-chain family of cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, where IL stands for interleukin) are key regulators of the immune homeostasis that exhibit pleiotropic biological activities and even sometimes redundant roles as a result of the utilization of the same receptor subunit. However, they also exert distinct functions that make each of them to be indispensable. For instance, all family members can act as T-cell growth factors; however, we found that IL-15 but not IL-7 can replace IL-2 to promote and sustain the proliferation of Kit225T cells. In addition to the gamma-chain, IL-2 and IL-15 share the beta chain, which creates the paradox of how they can trigger diverse phenotypes despite signaling through the same receptors. To investigate this paradigm, we combined SILAC with enrichment of tyrosine-phosphorylated proteins and peptides followed by mass spectrometric analysis to quantitatively assess the signaling networks triggered downstream IL-2/IL-2R and IL-15/IL-15R. This study confirmed that the transduction pathways initiated by both cytokines are highly similar and revealed that the main signaling branches, JAK/STAT, RAS/MAPK and PI3K/AKT, were nearly equivalently activated in response to both ILs. Despite that, our study revealed that receptor internalization rates differ in IL-2- and IL-15-treated cells indicating a discrete modulation of cytokine signaling. All MS data have been deposited in the ProteomeXchange with identifier PXD001129 (http://proteomecentral.proteomexchange.org/dataset/PXD001129). PMID- 25142964 TI - Serological versus molecular typing of surface-associated immune evading polysaccharide antigens-based phenotypes of Staphylococcus aureus. AB - The aim of this study was to compare the performance of serological versus molecular typing methods to detect capsular polysaccharide (CP) and surface associated polysaccharide antigen 336 phenotypes of Staphylococcus aureus isolates. Molecular typing of CP types 1, 5 and 8 was carried out using PCR, whereas serological typing of CP1, 2, 5, 8 and antigen 336 was carried out by slide agglutination using specific antisera. By genotyping, 14/31 strains were CP8 positive, 12/31 strains were CP5 and the remaining 6/31 isolates were non typable (NT). One isolate was positive for both CP5 and CP8 by PCR, but was confirmed as CP8 type serologically. Detection of CP2 and type 336 by PCR was not possible because specific primers were either not available or non-specific. Using serotyping, 14/31 strains were CP8 positive, 11/31 CP5 positive and 2/31 positive for antigen 336. The remaining four S. aureus isolates were serologically NT. However, three of four NT and two 336-positive S. aureus isolates were encapsulated as determined by light microscopy after capsular staining. This discovery was surprising and warrants further investigations on the identification and characterization of additional capsular phenotypes prevalent among S. aureus clinical isolates. It was concluded that serological typing was a better method than molecular typing for use in epidemiological investigations based upon the distribution of surface-associated polysaccharide antigens-based phenotypes. PMID- 25142965 TI - An outbreak of blaOXA-51-like- and blaOXA-66-positive Acinetobacter baumannii ST208 in the emergency intensive care unit. AB - A series of clinical isolates of drug-resistant (DR) Acinetobacter baumannii with diverse drug susceptibility was detected from eight patients in the emergency intensive care unit of Tokai University Hospital. The initial isolate was obtained in March 2010 (A. baumannii Tokai strain 1); subsequently, seven isolates were obtained from patients (A. baumannii Tokai strains 2-8) and one isolate was obtained from an air-fluidized bed used by five of the patients during the 3 months from August to November 2011. The isolates were classified into three types of antimicrobial drug resistance patterns (RRR, SRR and SSR) according to their susceptibility (S) or resistance (R) to imipenem, amikacin and ciprofloxacin, respectively. Genotyping of these isolates by multilocus sequence typing revealed one sequence type, ST208, whilst that by a DiversiLab analysis revealed two subtypes. All the isolates were positive for blaOXA-51-like and blaOXA-66, as assessed by PCR and DNA sequencing. A. baumannii Tokai strains 1-8 and 10 (RRR, SRR and SSR) had quinolone resistance-associated mutations in gyrA/parC, as revealed by DNA sequencing. The ISAba1 upstream of blaOXA-51-like and aminoglycoside resistance-associated gene, armA, were detected in A. baumannii Tokai strains 1-7 and 10 (RRR and SRR) as assessed by PCR. Among the genes encoding resistance-nodulation-division family pumps (adeB, adeG and adeJ) and outer-membrane porins (oprD and carO), overexpression of adeB and adeJ and suppression of oprD and carO were seen in isolates of A. baumannii Tokai strain 2 (RRR), as assessed by real-time PCR. Thus, the molecular characterization of a series of isolates of DR A. baumannii revealed the outbreak of ST208 and diverse antimicrobial drug susceptibilities, which almost correlated with differential gene alterations responsible for each type of drug resistance. PMID- 25142966 TI - Experimental study of the impact of antimicrobial treatments on Campylobacter, Enterococcus and PCR-capillary electrophoresis single-strand conformation polymorphism profiles of the gut microbiota of chickens. AB - An experiment was conducted to compare the impact of antimicrobial treatments on the susceptibility of Campylobacter, Enterococcus faecium and Enterococcus faecalis, and on the diversity of broiler microbiota. Specific-pathogen-free chickens were first orally inoculated with strains of Campylobacter and Enterococcus faecium. Birds were then orally treated with recommended doses of oxytetracycline, sulfadimethoxine/trimethoprim, amoxicillin or enrofloxacin. Faecal samples were collected before, during and after antimicrobial treatment. The susceptibility of Campylobacter, Enterococcus faecium and Enterococcus faecalis strains isolated on supplemented or non-supplemented media was studied and PCR-capillary electrophoresis single-strand conformation polymorphism (CE SSCP) profiles of the gut microbiota were analysed. Enrofloxacin-resistant Campylobacter were selected in the enrofloxacin-treated group and showed the Thr86Ile mutation in the gyrA gene. Acquisition of the tetO gene in Campylobacter coli isolates was significantly more frequent in birds given oxytetracycline. No impact of amoxicillin treatment on the susceptibility of Campylobacter could be detected. Ampicillin- and sulfadimethoxine/trimethoprim-resistant Enterococcus faecium were selected in amoxicillin-treated broilers, but no selection of the inoculated vancomycin-resistant Enterococcus faecium could be detected, although it was also resistant to tetracycline and sulfadimethoxine/trimethoprim. PCR-CE SSCP revealed significant variations in a few peaks in treated birds as compared with non-treated chickens. In conclusion, antimicrobial treatments perturbed chicken gut microbiota, and certain antimicrobial treatments selected or co selected resistant strains of Campylobacter and Enterococcus. PMID- 25142967 TI - Morphology, Morphometry and Spatial Distribution of Secondary Osteons in Equine Femur. AB - A high number of differences exist in bone histological features depending on the species, breed, age and bone. Moreover, osteon distribution may vary in the different sides of a bone as a consequence of different biomechanical strains. The aim of this work was to study the distribution and morphology of osteons in different sides of the equine femoral diaphysis with the attempt to correlate them to the main strains operating on them. The following parameters of secondary osteons and Haversian canals were measured in the transverse sections of diaphyses: perimeter, area, minimum and maximum diameter, eccentricity and osteon population density. A typical Haversian tissue was observed with elliptic secondary osteons consisting in about 10 well-defined lamellae surrounding a circular Haversian canal. Quantitative analysis displays a different population density of secondary osteons depending on the side. The caudal and medial sides, where compression strains are higher, have more secondary osteons in comparison with the cranial and lateral sides, where tension strains are prevalent. These data suggest that secondary osteon population density may depend on the predominant strains. Even the elliptical shape of secondary osteons may be related to biomechanical strains, as their major axes are oriented cranio caudally parallel to prevalent strains. PMID- 25142969 TI - Novel treatment strategies for schizophrenia from improved understanding of genetic risk. AB - Recent years have seen significant advances in our understanding of the genetic basis of schizophrenia. In particular, genome-wide approaches have suggested the involvement of many common genetic variants of small effect, together with a few rare variants exerting relatively large effects. While unequivocal identification of the relevant genes has, for the most part, remained elusive, the genes revealed as potential candidates can in many cases be clustered into functionally related groups which are potentially open to therapeutic intervention. In this review, we summarise this information, focusing on the accumulating evidence that genetic dysfunction at glutamatergic synapses and post-synaptic signalling complexes contributes to the aetiology of the disease. In particular, there is converging support for involvement of post-synaptic JNK pathways in disease aetiology. An expansion of our neurobiological knowledge of the basis of schizophrenia is urgently needed, yet some promising novel pharmacological targets can already be discerned. PMID- 25142968 TI - Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin. AB - BACKGROUND: The residual risk that remains after statin treatment supports the addition of other LDL-C-lowering agents and has stimulated the search for secondary treatment targets. Epidemiological studies propose HDL-C as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL. The CETP inhibitor anacetrapib decreases (V)LDL-C by ~15-40% and increases HDL-C by ~40-140% in clinical trials. We evaluated the effects of a broad dose range of anacetrapib on atherosclerosis and HDL function, and examined possible additive/synergistic effects of anacetrapib on top of atorvastatin in APOE*3Leiden.CETP mice. METHODS AND RESULTS: Mice were fed a diet without or with ascending dosages of anacetrapib (0.03; 0.3; 3; 30 mg/kg/day), atorvastatin (2.4 mg/kg/day) alone or in combination with anacetrapib (0.3 mg/kg/day) for 21 weeks. Anacetrapib dose dependently reduced CETP activity (-59 to -100%, P < 0.001), thereby decreasing non-HDL-C (-24 to -45%, P < 0.001) and increasing HDL-C (+30 to +86%, P < 0.001). Anacetrapib dose-dependently reduced the atherosclerotic lesion area (-41 to 92%, P < 0.01) and severity, increased plaque stability index and added to the effects of atorvastatin by further decreasing lesion size (-95%, P < 0.001) and severity. Analysis of covariance showed that both anacetrapib (P < 0.05) and non HDL-C (P < 0.001), but not HDL-C (P = 0.76), independently determined lesion size. CONCLUSION: Anacetrapib dose-dependently reduces atherosclerosis, and adds to the anti-atherogenic effects of atorvastatin, which is mainly ascribed to a reduction in non-HDL-C. In addition, anacetrapib improves lesion stability. PMID- 25142970 TI - Characteristics and associations of high-mitotic-rate melanoma. AB - IMPORTANCE: Mitotic rate is now recognized as having independent prognostic significance in melanoma survival. However, its clinicopathologic associations have not been the focus of any previous study. OBJECTIVE: To identify a set of patient and tumor characteristics associated with high-mitotic-rate melanoma with the aim of facilitating the earlier detection of aggressive primary invasive melanoma. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of patients from a multidisciplinary melanoma clinic based in a public hospital. A total of 2397 cases from January 2006 to December 2011 were reviewed by the Victorian Melanoma Service, and 1441 patients with 1500 primary invasive melanomas were included in the study. MAIN OUTCOMES AND MEASURES: Mitotic rate was measured as number of mitoses per mm2 and analyzed as ordered categories (0, <1, 1 and <2, 2, 3-4, 5-9, and >=10) according to patient demographics, phenotypic markers, historical data, tumor presentation, and histopathologic features. RESULTS: Melanomas with higher mitotic rates were more likely to occur in men (odds ratio [OR], 1.5; 95% CI, 1.3-1.8), patients 70 years or older (OR, 2.1; 95% CI, 1.7 2.8), and those with a history of solar keratosis (OR, 1.3; 95% CI, 1.1-1.6). These melanomas occurred more frequently on the head and neck (OR, 1.4; 95% CI, 1.0-1.9) and presented more often as amelanotic (OR, 1.9; 95% CI, 1.4-2.5) and rapidly growing (>=2 mm/mo) lesions (OR, 12.5; 95% CI, 8.4-18.5). An association was seen with the nodular melanoma subtype (vs superficial spreading [reference]) (OR, 2.5; 95% CI, 1.8-3.4), greater tumor thickness (vs <=1 mm [reference]) (>1-4 mm: OR, 4.5; 95% CI, 3.2-6.1; >4 mm: OR, 12.6; 95% CI, 7.5-21.1), and ulceration (OR, 2.0; 95% CI, 1.5-2.7). These histopathologic features, along with amelanosis and rate of growth, remained as significant associations with high mitotic rate in the overall multivariate analysis. CONCLUSIONS AND RELEVANCE: High-mitotic rate primary cutaneous melanoma is associated with aggressive histologic features and atypical clinical presentation. It has a predilection for the head and neck region and is more likely to be seen in elderly men with a history of cumulative solar damage who present clinically with rapidly developing disease. PMID- 25142971 TI - Self-reported health and subsequent mortality: an analysis of 767 deaths from a large Thai cohort study. AB - BACKGROUND: Few studies have examined the link between self-reported health (SRH) and subsequent mortality in developing countries, and very few considered mortality effects of changes in SRH. We examined the relationship between SRH and subsequent all cause or cause-specific mortality in Thailand. We also noted if mortality varied after people changed their SRH. METHODS: We used longitudinal data including SRH from a nationwide Thai Cohort Study (baseline 2005-follow-up 2009) and linked to official death records (2005-2012). Cox regression examined the association between SRH in 2005 and subsequent all-cause mortality or cause specific mortality, with results given as confounder-adjusted hazard ratios (HR). We further assessed association between changes in SRH during 2005-2009 and mortality from 2009 to 2012. RESULTS: Poor SRH at baseline independently relates strongly with subsequent cardiovascular disease (CVD) mortality (HR = 2.8, CI: 1.3-5.9) and "other" causes of death (HR = 1.9, CI: 1.1-3.3) but moderately with cancer mortality (HR = 1.4, CI: 0.7-3.0). SRH did not exhibit a relationship with injury mortality (HR = 1.0, CI: 0.5-2.1). Worsening SRH from 2005 to 2009 associated with increased mortality in 2009-2012 for females but not for males. CONCLUSIONS: In Thailand, SRH is a good predictor of population mortality due to internal causes (e.g. CVD). SRH is holistic, simple to measure and low cost; when repeated it measures dynamic health status. In many developing countries chronic diseases are emerging and morbidity information is limited. SRH could help monitor such transitions in burdens and trends of population health. PMID- 25142972 TI - Amplified lipid rafts of malignant cells constitute a target for inhibition of aberrantly active NFAT and melanoma tumor growth by the aminobisphosphonate zoledronic acid. AB - Nuclear factors of activated T cells (NFAT) are critical modulators of cancer cell growth and survival. However, the mechanisms of their oncogenic dysregulation and strategies for targeting in tumors remain elusive. Here, we report coupling of anti- apoptotic NFAT (NFAT2) activation to cholesterol enriched lipid raft microdomains of malignant melanoma cells and interruption of this pathway by the aminobisphosphonate zoledronic acid (Zol). The pathway was indicated by capability of Zol to promote apoptosis and to retard in vivo outgrowth of tumorigenic melanoma cell variants through inhibition of permanently active NFAT2. NFAT2 inhibition resulted from disintegration of cholesterol enriched rafts due to reduction of cellular cholesterol by Zol. Mechanistically, raft disruption abolished raft-localized robust store-operated Ca(2+) (SOC) entry, blocking constitutive activation of protein kinase B/Akt (PKB) and thereby reactivating the NFAT repressor glycogen synthase kinase 3beta (GSK3beta). Pro apoptotic inactivation of NFAT2 also followed reactivation of GSK3beta by direct inhibition of PKB or SOC, whereas GSK3beta blockade prevented Zol-induced NFAT2 inhibition and cell death. The rescuing effect of GSK3beta blockade was reproduced by recovery of entire SOC/PKB/GSK3beta cascade after reconstitution of rafts by cholesterol replenishment of Zol-treated tumorigenic cells. Remarkably, these malignant cells displayed higher cholesterol and lipid raft content than non-tumorigenic cells, which expressed weak SOC, PKB and NFAT2 activities and resisted raft-ablating action of Zol. Together, the results underscore the functional relevance of amplified melanoma rafts for tumor-promoting NFAT2 signaling and reveal these distinctive microdomains as a target for in vitro and in vivo demise of tumorigenic cells through NFAT2 inhibition by the clinical agent Zol. PMID- 25142973 TI - CHRNA9 polymorphisms and smoking exposure synergize to increase the risk of breast cancer in Taiwan. AB - Previous studies indicated that smoking exposure is associated with an increased risk of breast cancer, and alpha9-nicotine acetylcholine receptors (alpha9 nAChRs) are involved in breast tumorigenesis. However, no studies have explored the joint effect of alpha9-nAChRs (CHRNA9) genes and cigarette smoking exposure on breast cancer risk. A case-control study was conducted on 737 breast cancer patients and 719 age-matched healthy controls. Three single-nucleotide polymorphisms (SNPs) of CHRNA9 located in the promoter region were genotyped and compared between cases and controls to identify those SNPs associated with breast cancer susceptibility. A dual-luciferase reporter assay was used to analyze the promoter activities of these SNPs of the CHRNA9 gene. After a Bonferroni correction, the G allele of the CHRNA9 rs7329797 SNP was significantly associated with an increased risk of developing breast cancer compared with A/A genotype carriers (odds ratio, 1.8; 95% confidence interval, 1.2-2.6). A multiplicative interaction between passive smoking exposure and the CHRNA9 rs73229797 SNP on the risk of breast malignancy was observed. A functional assay further showed that rs73229797 was associated with increased promoter activity of the CHRNA9 gene. Our findings support a significant interaction effect existing between the CHRNA9 gene and smoking exposure on the risk of breast cancer development. PMID- 25142974 TI - FOXA2 suppresses the metastasis of hepatocellular carcinoma partially through matrix metalloproteinase-9 inhibition. AB - The forkhead box transcription factor A2 (FOXA2) is a member of the hepatocyte nuclear factor family and plays an important role in liver development and metabolic homeostasis, but its role in the metastasis of hepatocellular carcinoma (HCC) has not been evaluated. In this study, we found that the expression of FOXA2 was decreased in 68.1% (49/72) of human HCC tissues compared with their paired non-cancerous adjacent tissues. Clinicopathological analysis revealed that reduced FOXA2 expression was correlated with aggressive characteristics (venous invasion, poor differentiation, high tumor node metastasis grade). FOXA2 level was even lower in portal vein tumor thrombus compared with primary tumor tissues and correlated with epithelial-mesenchymal transition in HCC cells. Overexpression of FOXA2 inhibited migration and invasion of Focus cells, whereas knockdown of FOXA2 in HepG2 showed the opposite effect. Moreover, upregulation of FOXA2 suppressed HCC metastasis to bone, brain and lung in two distinct mouse models. Finally, we proved that FOXA2 repressed the transcription of matrix metalloproteinase (MMP)-9 and exerted its antimetastasis effect partially through downregulation of MMP-9. In conclusion, our findings indicate that FOXA2 plays a critical role in HCC metastasis and may serve as a novel therapeutic target for HCC. PMID- 25142976 TI - Isomerisation of 1,4-dichlorobenzene using highly acidic alkali chloroaluminate melts. AB - The isomerisation reaction of 1,4-dichlorobenzene leading to the thermodynamically favoured and technically desired 1,3-dichlorobenzene has been studied comparing highly acidic chloroaluminate melts with organic imidazolium and alkali metal ions. Interestingly, the inorganic melts show much higher reactivity and full recyclability if small AlCl3 losses are compensated and the reaction is carried out under slight HCl pressure. PMID- 25142975 TI - Genetic evidence suggests that Spata22 is required for the maintenance of Rad51 foci in mammalian meiosis. AB - Meiotic nodules are the sites of double-stranded DNA break repair. Rpa is a single-stranded DNA-binding protein, and Rad51 is a protein that assists in the repair of DNA double strand breaks. The localisation of Rad51 to meiotic nodules before the localisation of Rpa in mice introduces the issue of whether Rpa is involved in presynaptic filament formation during mammalian meiosis. Here, we show that a protein with unknown function, Spata22, colocalises with Rpa in meiotic nodules in rat spermatocytes. In spermatocytes of Spata22-deficient mutant rats, meiosis was arrested at the zygotene-like stage, and a normal number of Rpa foci was observed during leptotene- and zygotene-like stages. The number of Rad51 foci was initially normal but declined from the leptotene-like stage. These results suggest that both formation and maintenance of Rpa foci are independent of Spata22, and the maintenance, but not the formation, of Rad51 foci requires Spata22. We propose a possible model of presynaptic filament formation in mammalian meiosis, which involves Rpa and Spata22. PMID- 25142977 TI - The first water-soluble hexarhenium cluster complexes with a heterocyclic ligand environment: synthesis, luminescence, and biological properties. AB - The hexarhenium cluster complexes with benzotriazolate apical ligands [{Re6(MU3 Q)8}(BTA)6](4-) (Q = S, Se; BTA = benzotriazolate ion) were obtained by the reaction of [{Re6(MU3-Q)8}(OH)6](4-) with molten 1H-BTA (1H-benzotriazole). The clusters were crystallized as potassium salts and characterized by X-ray single crystal diffraction, elemental analyses, and UV-vis and luminescence spectroscopy. In addition, their cellular uptake and toxicity were evaluated. It was found that both clusters exhibited luminescence with high lifetimes and quantum yield values; they were taken up by the cells illuminating them under UV irradiation and, at the same time, did not exhibit acute cytotoxic effects. PMID- 25142978 TI - Establishing a robotic colorectal surgery programme. AB - BACKGROUND: This paper aimed to describe the training available and the process taken to establish a robotic colorectal surgery programme in a large Australian academic private hospital. Through this we hope to guide other surgeons and hospitals planning to introduce this technology in circumstances where such guidelines do not exist. METHODS: The available training and credentialing pathways are described, including the da Vinci Surgery Training Pathway provided by Intuitive Surgical and hospital-based supports. A proposed 9-point training and credentialing pathway is presented, along with the activities undertaken by each surgeon. RESULTS: From December 2011 to December 2013, 48 robotic colorectal procedures were performed at the Cabrini Hospital. Operations performed were as follows: 23 anterior resections, seven abdominoperineal resections, 11 rectopexies, three proctectomies and ileal pouch-anal anastomosis and four right hemicolectomies. There have been no conversions, and no major complications. There were no robot-specific complications. CONCLUSION: We believe that this thorough and methodical approach to introducing robotics to colorectal surgery has been safe and effective, and should be applicable to other surgeons and hospitals wishing to introduce robotic technology to colorectal surgery. PMID- 25142979 TI - A novel two-dimensional preparative chromatography method designed for the separation of traditional animal Tibetan medicine Osteon Myospalacem Baileyi. AB - Animal medicine is an important part in traditional Tibetan medicine. However, information about the chemical composition of animal medicine is very limited, and there is a lack of comprehensive chromatographic purification methods. In the present work, animal medicine Osteon Myospalacem Baileyi was taken as an example and a novel two-dimensional preparative chromatographic method was established for the preparation of single compounds with high purity from the extract of Osteon Myospalacem Baileyi. The first-dimension preparation was carried on a DAISO Silica prep column, and ten fractions were obtained from the 112.3 g crude sample within 12 injections. A diol prep column used in nonaqueous mobile phase was selected for the second-dimension preparation. The purity of the compounds isolated from the crude extract was >98%, which indicated that the method built in this work was efficient to manufacture single compounds of high purity from the extract of Osteon Myospalacem Baileyi. Additionally, this method showed great potential in the purification of weakly polar chemicals and it could act as a good example in the purification of other traditional animal medicines. PMID- 25142980 TI - [Governing violence in health sector: international consensus and strategies]. PMID- 25142981 TI - [Total mesopancreas excision in pancreatic cancer-clinical practice and controversy]. PMID- 25142982 TI - [Why violence against doctors cases happened so frequently? An inquiry]. PMID- 25142983 TI - [The doctor can do first for the better patient-doctor relationship]. PMID- 25142984 TI - [A.J. M. Milne's theory of rights and the precaution of killing medical staff cases]. PMID- 25142985 TI - [True stories in an emergency ICU]. PMID- 25142986 TI - [The research to improve the people's mediation mechanism of medical dispute of Beijing]. PMID- 25142987 TI - [Effects of metformin therapy on serum CA125 levels and its related factors in type 2 diabetics]. AB - OBJECTIVE: To explore the effects of metformin therapy on serum carbohydrate antigen 125 (CA125) levels and its related factors in type 2 diabetics with normal liver and kidney function. METHODS: Serum CA125 level was measured and compared for a total of 1 136 type 2 diabetics. They were assigned into groups according to gender, age and body mass in dex (BMI) and subgroups according to metformin dosing. Associations between CA125 and other variables were assessed with Spearman or Pearson's correlation and multiple stepwise regression analysis. RESULTS: The CA125 level of metformin group was significantly lower than that of non-metformin group (10.51(8.18, 13.80) vs 11.93(9.05, 15.52) U/ml, P < 0.01) . The CA125 levels of males aged 30-39 and 50-59 as well as females aged over 50 remarkably decreased after metformin dosing (all P < 0.05). The difference of CA125 level between metformin and non-metformin groups in patients with normal BMI and obese females reached statistical significance (all P < 0.05). The correlation analysis showed that serum CA125 level was positively associated with gender, HbA1c, glycated serum albumin, triglyceride, total cholesterol (P < 0.05), but negatively with metformin and creatinine (P < 0.01). Multiple stepwise regression analysis further revealed that GA, metformin dosing, gender and total glycerides were independent influencing factors of CA125 concentrations (all P < 0.05). CONCLUSION: Metformin dosing is an independent associated factor of serum CA125 levels reduction in type 2 diabetics, especially females. PMID- 25142988 TI - [Serum HER2 ECD level and its clinical significance in advanced breast cancer patients with different molecular subtypes]. AB - OBJECTIVE: To evaluate the serum HER2 ECD level and its significance in advanced breast cancer patients with different molecular subtypes. METHODS: A total of 322 advanced breast cancer patients were enrolled. The serum HER2 ECD concentrations were quantitatively detected by enzyme-linked immunosorbent assay(ELISA). Its relationship with clinicopathological characteristics and clinical significance were analyzed. RESULTS: It was found that 55.9% (19/34)Luminal A, 42.7% (44/103) Luminal B-HER2(-), 70.6% (60/85) Luminal B-HER2(+), 73.8% (45/61)HER2-enriched and 23.1% (9/39) triple-negative patients had serum concentrations of HER2 ECD at least 15 ng/ml respectively. The prevalence of elevated ECD level in patients of different molecular subtypes differed significantly (P < 0.001). Tissue HER2 status, number of metastatic sites, visceral metastasis, CA15-3 and carcinoembryonic antigen(CEA) levels exhibited statistically significant correlations with the prevalence of elevated serum HER2 ECD level. The serum concentrations of HER2 ECD decreased after effective targeted therapy in tissue HER2-positive patients. CONCLUSION: The prevalence of elevated serum levels of HER2 ECD differed significantly in advanced breast cancer patients with different molecular subtypes. The serum HER2 ECD level may reflect both histological HER2 status and tumor load. And the dynamic changes of ECD concentrations are somewhat correlated with the efficacies of targeted treatment. PMID- 25142989 TI - [Significance of 2-hour blood glucose after standardized steamed bread meal in diabetic screening]. AB - OBJECTIVE: To explore the significance of 2-hour blood glucose after standardized steamed bread meal (SB-2 hBG) in diabetic screening. METHODS: A retrospective study was conducted for diabetic screening data of annual check-up at PLA General Hospital from May 1996 to June 2002. And 100 g standardized steamed bread meal test was performed for non-diabetic subjects. Those subjects with SB-2 h BG >= 7.2 mmol/L underwent a 75 g oral glucose tolerance test (OGTT) within 2 weeks to determine whether the diagnosis of diabetes mellitus (DM) could be established (WHO, 1985, 1999, Diagnostic Criteria for Diabetes). By extracting the data for 7 consecutive years, we analyzed the significance and the cut-off point of SB-2 hBG in the diagnosis of DM and investigated the changes of blood glucose curves in different glucose tolerance status after different glucose loading tests. RESULTS: A total of 3 343 subjects with complete information were recruited. There were 3 101 males and 242 females with an age range of 40-94 years. According to the results of OGTT, 429 (12.8%) subjects were diagnosed as DM, 1 405 (42.1%) were diagnosed as impaired glucose regulation (IGR) and 1 509(45.1%) had normal glucose tolerance (NGT).With a deterioration of glucose tolerance status, the difference between SB-2 hBG and OGTT-2 hBG increased gradually in 3 group (P < 0.01), namely the NGT group 1.7 (0.8-2.8) mmol/L, IGR group -0.4 (-1.2 0.6) mmol/L, DM group -2.7(-3.8-1.1) mmol/L. The cut-off points of FBG for the diagnosis of IGR and DM were 5.3 (sensitivity of 46.2%, specificity of 68.5%) and 5.6 (sensitivity of 57.4%, specificity of 76.4%) mmol/L respectively. The cut-off points of SB-2 h BG were 8.2 mmol/L for the diagnosis of IGR (sensitivity of 63.8%, specificity of 59.9%) and 9.2 mmol/L for the diagnosis of DM (sensitivity of 66.4%, specificity of 76.4%).If the cut-off point of SB-2 h BG was set at 7.2 mmol/L, the diagnostic specificity became quite low.However, at 11.1 mmol/L, the sensitivity was 31.5% and the specificity 95.7% for the diagnosis of DM. The coincidences of cut-off points of FBG and SB-2 hBG for the diagnosis of IGR and DM were equal (P > 0.05).When the cut-off point of SB-2 h BG was set at 7.8 mmol/L, the sensitivity was 77.4% and the specificity 41.8% for the diagnosis of IGR. And it was much better than FBG at 5.6 mmol/L (P < 0.01). CONCLUSIONS: With a deterioration of glucose tolerance, the difference between SB-2 hBG and OGTT-2 hBG increases gradually. Compared to the diagnostic criteria of OGTT, the optimal cut-off points for the diagnosis of IGR and DM were 5.3 vs 5.6 mmol/L for FBG and 8.2 vs 9.2 mmol/L for SB-2 hBG respectively.For diabetic screening in middle-aged and elders, the cut-off points of FBG at 5.3 mmol/L and SB-2 hBG at 7.8 mmol/L are indicators for further OGTT. PMID- 25142990 TI - [Immune mechanism and clinical significance of infection immunity activation for medullary hematopoietic injury of immune-related hematocytopenia syndrome]. AB - OBJECTIVE: To observe the pathologic effects of marrow hematopoietic cell with immunologic injury induced by infection immunity activation in patients with immune related hematocytopenia syndrome (IRHS) and elucidate its immunologic mechanism and clinical significance. METHODS: A total of 276 IRHS patients with acute and chronic infections were recruited from 2008 to 2013. ELISA was used to detect the levels of interleukin-6 (IL-6), IL-12, IL-17 and interferon gamma (IFN gamma) in peripheral blood sera of IRHS patients before and after therapy. Flow cytometry was performed to detect the proportion of lymphocyte subgroups in peripheral blood. Immunochemical staining was used to analyze the expressive states of peroxydase (POX), HLA-DR in bone marrow and non-specific esterase. The expressive states of CD4, CD8, CD56, IFN-gamma, porforin, granzyme, FcgammaRII, anti-human IgG, mannose receptor (MR), IL-12 and IL-17A in bone marrow cells and hematopoietic microenvironment were analyzed with immunofluorescence (IF). According to the above immunological indices, antibiotics were prescribed along with medaron and ciclosporin A (CsA). RESULTS: Among 276 patients, the levels of IL-6, IL-12, IL-17 and IFN-gamma were higher than those in control group (all P < 0.05) . After treatment, the cytokine levels above decreased to normal gradually. The levels of CD3(+) CD4(+) T and NK cells increased respectively in those with concurrent viral or mycoplasma infection(54.23% +/- 3.07% and 50.11% +/- 3.09% vs 35.25% +/- 5.16%, 22.71% +/- 2.26% and 19.49% +/- 2.07% vs 14.91% +/- 4.87%) . The proportions of CD3(+) CD4(+) T and CD19(+) B cells increased in sera of patients with bacterial infection (40.22% +/- 4.31% vs 35.25% +/- 5.16%, 29.01% +/- 4.32% vs 11.56% +/- 2.54%) . But the proportion of CD3(+) CD8(+) T cells increased in patients with viral infection of type B hepatitis(32.51% +/- 3.44% vs 25.08% +/- 4.43%) (all P < 0.05). In patient marrow samples, dendritic cell, T lymphocyte, eosinophilic granulocyte and macrophage were activated to express many above mentioned immunological molecules. Both the destructive pattern of hemocyte and the degree of pathological lesion induced by these immunocytes were related with the cause of infection immunity activation and morbid state of patients. After individualized treatment, 264 patients showed elevated hemogram at 4-8 weeks while the relapse of 12 patients persisted until an initiation of cytotoxic drug and a gradual restoration of hemogram. CONCLUSIONS: Infection is one of the most important factors of IRHS. Excessive activation of infection immunity may induce the disorder of immune system. Then immunocytes destroy or damage those hemocytes with pathological changes through different immunological pathways. The pathogenetic condition and outcome is related with infected pathogen and intrasubject immune state. Control of pathogenic microorganism infection and glucocorticoid treatment may suppress the excessive activation of immunocytes so as to become important preventive and curing measures of IRHS. PMID- 25142991 TI - [Influencing factors of pathologic complete response after neoadjuvant chemotherapy in locally advanced breast cancer patients: results of a single center 10-year retrospective study]. AB - OBJECTIVE: To analyze the influencing factors of pathologic complete response (PCR) to neoadjuvant chemotherapy in locally advanced breast cancer patients. METHODS: A retrospective study was conducted to analyze the clinical data of 620 locally advanced breast cancer patients at Henan Cancer Hospital between April 2003 to February 2013. After neoadjuvant chemotherapy, 94 patients achieved PCR. The correlation between clinicopathological factors and PCR was analyzed. RESULTS: No significant correlations existed between PCR with patient age, menstrual status or pretherapeutic lymph node status. Increased chemotherapeutic cycles could improve the rate of PCR (14.1% or 19.5 %), but it had no statistical difference. The rate of PCR achieved by regimens of anthracycline plus taxane was higher (20.1%)than that by anthracycline-based regimens (12.7%). And the rate of PCR had significant difference between two regimens. In terms of biological indicators, PCR rate after neoadjuvant chemotherapy was associated with estrogen/progesterone receptor, but it had no correlation with Ki-67 index or the status of epidermal growth factor receptor. Logistic multifactorial analysis showed that tumor size <= 5 cm were significantly correlated with PCR. Trastuzumab could obviously increase the PCR rate (15.7% or 41.7 %) and there was statistical difference (P = 0.031). CONCLUSION: The regimens of anthracycline plus taxane can achieve a higher PCR rate. Patient age, menstrual status and pretherapeutic lymph node have no significant correlation with PCR. PCR rate is associated with the expression of ER/PR negative in breast cancer. Trastuzumab increase the PCR rate in the HER-2 positive patients. Tumor size <= 5 cm is a significant influencing factor of PCR rate. PMID- 25142992 TI - [Mutation analysis and prenatal diagnosis in families of X-linked agammaglobulinemia caused by BTK gene mutation]. AB - OBJECTIVE: To evaluate the genetic diagnostic feasibility of Bruton's tyrosine kinase (BTK) gene in three families with X-linked agammagobulinemia (XLA) birth history, mutation analysis and prenatal genetic diagnosis of BTK gene for two families with XLA. METHODS: Polymerase chain reaction (PCR) was applied to amplify the regions of exon and exon-intron boundaries of BTK gene in 3 unrelated patients of XLA and their mothers from January 2011 to June 2012. The PCR products were further analyzed by direct sequencing. Prenatal genetic diagnosis was performed by chorionic villus sampling after genotyping of mothers of probands. RESULTS: Three novel mutations of BTK gene were identified in 3 pedigrees of XLA. A missense mutation c.1117C > A (p.L373I) were detected in pedigree 1. The mutation was possible damage by predicting in sillico. A nonsense mutation c.126T > G (p.Y42X) was found in pedigree 2. A single base deletion mutation c.1679delC (p. P560fsX10) was found in pedigree 3. The three mutations, p.L373I, p.Y42X and p. P560fsX10 were novel. The three novel mutations were absent in the 100 normal controls. The male fetus in pedigree 3 was free of mutations identical to the proband and the female fetus in pedigree 2 was a carrier. The two families continued the pregnancies and the infants showed no symptom of XLA after one year old. CONCLUSIONS: Three novel mutations were identified. The mutations of p.Y42X and p. P560fsX10 in BTK gene may be the major causes of pedigrees 2 and 3 with XLA. The mutation p.L373I of BTK gene is possibly the cause of pedigree 1 with XLA, but functional verification is needed. For pedigree of XLA, direct sequencing of BTK gene is available for providing genetic counseling, prenatal diagnosis. PMID- 25142993 TI - [Relationship between cyclooxygenase-2 in nasopharyngeal carcinoma and cervical lymph node metastasis]. AB - OBJECTIVE: To explore the expression of cyclooxygenase-2 (COX-2) in lowly differentiated nasopharyngeal carcinoma and examine its relationship with cervical lymph node metastasis. METHODS: On the basis of COX expression, a total of 104 patients with lowly differentiated squamous cell carcinoma NPC were divided into 2 groups of COX-2 high-expression and COX-2 low-expression. The influence on prognosis was assessed by retrospective analysis. RESULTS: The overall positive rate for COX-2 staining was 78.8% (82/104) . The rate of patients with lymph node metastasis was significantly higher than that in those without (84.5% vs 55.0%, chi(2) = 6.765, P = 0.009). Further comparison showed that patients with age <45 years and neck lymph node metastasis had higher rate of COX-2 high expression than those with age >45 years and no cervical lymph node metastasis (58.7% vs 37.7%, chi(2) = 4.439, P = 0.035; 52.4% vs 25.0%, chi(2) = 4.861, P = 0.027). At the end of follow-up, the recurrence rate with inter-group statistical differences (chi(2) = 4.786, P = 0.029) was 32.7% (16/49) and 14.6% (8/55) respectively. Meanwhile, as compared with COX-2 high-expression group, the transferring rate in COX-2 low-expression group significantly decreased (17.7% vs 28.6%, chi(2) = 4.037, P = 0.045). Multiple logistic regression analysis showed that COX-2 high expression was a risk factor of nasopharyngeal carcinoma recurrence [OR = 2.039, 95%CI (1.042-5.875)]. CONCLUSION: COX-2 expression is up regulated in lowly differentiated nasopharyngeal carcinoma tissues. And it may be risk factor influencing the prognosis of NPC. PMID- 25142994 TI - [Diagnosis and treatment of adrenal medullary hyperplasia]. AB - OBJECTIVE: To explore the clinical characters of adrenal medullary hyperplasia (AMH). METHODS: The clinical data of 7 cases of AMH admitted from 1996 to 2013 were analyzed with a review of literature. RESULTS: There were 3 males and 4 females with a median age of 36 (23-69) years. All had hypertension at first diagnosis and 2 were paroxysmal. Computed tomography (CT) scan revealed unilateral adrenal nodule in all cases, including left (n = 5) and right (n = 2) side. The diameter of nodules was 0.9 cm to 3.0 cm.Hypokalemia was found in 2 cases. And 24-hour output of urine catecholamine was higher than normal level in 2 cases. An abnormal rise of 24-hour output of urine free cortisol was found in 1 case with a lower level of adrenocorticotropic hormone (ACTH) simultaneously while a lower level of plasma renin activity in vertical position was found in another case. Three patients received (131)I-meta-iodobenzylguanidine scan and one had positive result. Pre-operative diagnosis included pheochromocytoma (n = 2), adrenocortical adenoma (n = 3) (2 aldosterone-producing adenomas, 1 Cushing adenoma) and undetermined adrenal tumor (n = 2). All underwent surgery, including unilateral adrenalectomy (n = 4) and resection of adrenal disease (n = 3). All cases had a pathologic diagnosis of AMH. One had concurrent Cushing adenoma while another with cortical hyperplasia.One case achieved normotension postoperatively while others showed varying decreases of blood pressure, but remained hypertensive. CONCLUSION: With a common feature of hypertension, AMH is difficult to diagnose preoperatively. CT scan has a certain diagnostic significance and a definite diagnosis depends on pathological examination; because of inaccurate preoperative and intraoperative diagnosis, the extent of surgery may be incomplete and results in unsatisfied outcomes. PMID- 25142995 TI - [Expressions of Dab2 and ERK1 in esophageal carcinoma tissues and their clinical significance]. AB - OBJECTIVE: To explore the expressions of protein and mRNA of disabled-2 (Dab2) and extracellular signal-regulated kinase1 (ERK1) in esophageal squamous cell carcinoma tissue (ESCC) and their clinical significance. METHODS: The expressions of protein and mRNA of Dab2 and ERK1 were detected in ESCC (n = 59), atypical hyperplasia (n = 27) and normal esophageal mucosa (n = 36) tissues by immunohistochemistry, in situ hybridization and reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The expressions of protein and mRNA of Dab2 were lesser in ESCC than those in atypical hyperplasia and normal esophageal mucosa tissues (23.7% vs 94.4%, 44.4% and 18.6% vs 97.2%, 33.3%). And the expressions of protein and mRNA ERK1 were higher in ESCC than those in atypical hyperplasia and normal esophageal mucosa tissues (81.4% vs 44.4%, 63.0% and 78.0% vs 30.6%, 51.9%) (all P < 0.05). Additionally, the expressions of protein and mRNA of Dab2 and ERK1 were closely related with lymph node metastasis in ESCC tissue and the expressions of protein and mRNA of ERK1 closely related with the depth of tumor invasion in ESCC tissue (all P < 0.05). Furthermore, the results of correlation analysis revealed that expressions of protein and mRNA of Dab2 and ERK1 in ESCC had a negative correlation (all P < 0.05). CONCLUSION: The expressions of protein and mRNA of Dab2 and ERK1 play important roles in the infiltration, metastasis and carcinogenesis of ESCC and their effects may be antagonistic to each other. PMID- 25142996 TI - [Clinical efficacies of bilevel positive airway pressure ventilator treatment in uremic patients with acute heart failure]. AB - OBJECTIVE: To explore the clinical efficacies of bilevel positive airway pressure (BiPAP) ventilation in uremic patients with acute heart failure. METHODS: Fifty uremic patients with acute heart failure on dialysis were recruited from February 2008 to October 2012 at our center. All of them received angiectasis, heart strengthening and continuous renal replacement therapy (CRRT), but their clinical symptoms had no relief 30 min later. Non-invasive ventilation was administered immediately. And the parametric changes of systolic pressure (SBP), diastolic pressure (DBP), heart rate (HR), breathing rate (R), partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2) were observed at 30 min after conventional therapy and 1, 2 h later after non-invasive ventilation. And the levels of blood brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF) and clinical manifestations were observed at 2 h after non-invasive ventilation. RESULTS: Their clinical symptoms improved after BiPAP ventilation. And SBP, DBP, P, R and BNP showed a declining tendency, but PaO2 and LVEF showed a rising trend. Compared to conventional therapy, SBP ((160 +/- 17), (147 +/- 18) vs (172 +/- 20) mmHg) (1 mmHg = 0.133 kPa), DBP ((90 +/- 9), (85 +/- 10) vs (98 +/- 10) mmHg), HR ((95 +/- 8), (88 +/- 9) vs (102 +/- 12) times/min), R ((20 +/- 3), (17 +/- 4) vs (26 +/- 3) times/min) declined while PaO2 ((87 +/- 9), (94 +/- 12) vs (81 +/- 9) mmHg) increased significantly, 1, 2 h later after noninvasive ventilator treatment (all P < 0.05); the blood level of BNP decreased ((1084 +/- 398) vs (2686 +/- 576) ug/L), LVEF elevated (52% +/- 7% vs 39% +/- 9%) significantly, 2 h later after noninvasive ventilator treatment (both P < 0.01). CONCLUSION: As a safe and effective intervention, early use of BiPAP ventilator assisted breathing in uremic patients with acute heart failure effectively ameliorates their clinical manifestations and improve heart function. PMID- 25142997 TI - [Effects of AS1411 on the apoptosis of taxol-resistant lung adenocarcinoma A549 cell]. AB - OBJECTIVE: To explore the effects of AS1411 on the apoptosis of taxol-resistant lung adenocarinoma A549 cell (A549/T cell). METHODS: A549/T cells were treated with AS1411 at a concentration gradient of 0-20.0 umol/L. The assays of methyl tolyl sulfide (MTS) and colony formation were used to detect the cellular vitality (absorbance value (A490 nm)) and proliferation. The apoptotic effects were detected by flow cytometer and the relevant apoptotic signaling proteins detected by Western blot. RESULTS: A549/T cells exhibited some characteristics of epithelial mesenchymal transition (EMT) and a negative expression of epidermal growth factor receptor (EGFR). After a treatment of 5.0 umol/L AS1411, compared to the control sequence, cell vitality was inhibited (A490 nm: 0.185 +/- 0.009 vs 0.272 +/- 0.006, P < 0.001) and the number of clone formation decreased (74 +/- 13 vs 120 +/- 12, P = 0.010). With rising AS1411 concentration, A549/T cells vitality decreased in a dose-dependent manner. After a 48-hour treatment of 20.0 umol/L AS1411, the ratio of apoptosis ((19.9 +/- 2.6)%) had significant difference (P = 0.002) with the control sequence group ((8.8 +/- 1.3)%). Compared to the control sequence group, the expressions of protein kinase B (AKT), extracellular regulated protein kinases 1/2 (ERK1/2) and B-cell lymphoma 2 (Bcl 2) protein declined (0.353 +/- 0.003, 0.432 +/- 0.015, 0.294 +/- 0.015 vs 0.688 +/- 0.003, 0.911 +/- 0.019, 0.422 +/- 0.018, all P < 0.001). CONCLUSION: AS1411 may induce the apoptosis of A549/T cells through inhibiting the AKT-ERK pathways. PMID- 25142998 TI - [Effects of tripterygium wilfordii polyglucoside on expression of Activin A and influence of transdifferentiation in renal tubulointerstitium of rats with diabetic nephropathy]. AB - OBJECTIVE: To explore the effects of tripterygium wilfordii polyglucoside (TWP) on expression of Activin A (Act-A) and influence of transdifferentiation in renal tubulointerstitium of rats with diabetes nephropathy (DN). METHODS: A total of 40 male Wistar rats were randomly divided into normal control, DN model, irbesartan treatment and TWP treatment groups (n = 10 each). The animal model of DN was established by an injection of streptozotocin. After modeling, irbesartan treatment and TWP treatment groups received an intragastric injection of corresponding drugs. The body weights were recorded and the 24 h Pro quantitative levels detected at Weeks 4, 8, 12 and 16 respectively. After sacrificing at Week 16, serum creatinine (Scr) was detected. The renal tissues were excised and examined after HE and PAS staining. The expressions of Act-A, alpha-smooth muscle actin (alpha-SMA), collagen type IV (Co-IV) and E-cad in renal tubulointerstitium were detected by immunohistochemistry. And the expressions of Act-A, alpha-SMA, Co-IV and mRNA of E-cad in renal tissue were detected by real-time quantitative fluorescent polymerase chain reaction (PCR). RESULTS: Compared with DN model group, 24 hPro ((67.1 +/- 9.6), (61.8 +/- 8.0) vs (158.3 +/- 13.3) mg), quantitative Scr ((31.7 +/- 4.1), (32.6 +/- 6.2) vs (55.3 +/- 8.9) umol/L) and renal hypertrophic index ((9.14 +/- 0.65), (7.50 +/- 0.34) vs (11.28 +/- 0.70) mg/g) of irbesartan treatment and TWP treatment groups decreased obviously at Week 16 (all P < 0.05). However, no statistical significance existed between irbesartan treatment and TWP treatment groups. The body weights of irbesartan treatment and TWP treatment groups increased versus DN model group. Pathological sections showed that lesion degree of renal tubulointerstitium became alleviated in each group. Yet no statistical significance existed between irbesartan treatment and TWP treatment groups. Both immunohistochemistry and real-time quantitative fluorescent PCR showed that the expressions of Act-A, alpha-SMA and Co-IV significantly decreased in renal tubulointerstitium (P < 0.01) while the expression E-cad significantly increased (P < 0.01) in inirbesartan treatment and TWP treatment groups versus DN model group. And no statistical significance existed between irbesartan treatment and TWP treatment groups. CONCLUSION: TWP may down-regulate the expression of Act-A and inhibit the transdifferentiation of renal tubulointerstitial so as to delay renal fibrosis. PMID- 25142999 TI - Influence of Panax ginseng on the steady state pharmacokinetic profile of lopinavir-ritonavir in healthy volunteers. AB - STUDY OBJECTIVE: Panax ginseng has been shown in preclinical studies to modulate cytochrome P450 enzymes involved in the metabolism of HIV protease inhibitors. Therefore, the purpose of this study was to determine the influence of P. ginseng on the pharmacokinetics of the HIV protease inhibitor combination lopinavir ritonavir (LPV-r) in healthy volunteers. DESIGN: Single-sequence, open-label, single-center pharmacokinetic investigation. SETTING: Government health care facility. SUBJECTS: Twelve healthy human volunteers. MEASUREMENTS AND MAIN RESULTS: Twelve healthy volunteers received LPV-r (400-100 mg) twice/day for 29.5 days. On day 15 of LPV-r administration, serial blood samples were collected over 12 hours for determination of lopinavir and ritonavir concentrations. On study day 16, subjects began taking P. ginseng 500 mg twice/day, which they continued for 2 weeks in combination with LPV-r. On day 30 of LPV-r administration, serial blood samples were again collected over 12 hours for determination of lopinavir and ritonavir concentrations. Lopinavir and ritonavir pharmacokinetic parameter values were determined using noncompartmental methods, and preadministration and postadministration ginseng values were compared using a Student t test, where p<0.05 was accepted as statistically significant. CONCLUSION: Neither lopinavir nor ritonavir steady-state pharmacokinetics were altered by 2 weeks of P. ginseng administration to healthy human volunteers. Thus, a clinically significant interaction between P. ginseng and LPV-r is unlikely to occur in HIV-infected patients who choose to take these agents concurrently. It is also unlikely that P. ginseng will interact with other ritonavir-boosted protease inhibitor combinations, although confirmatory data are necessary. PMID- 25143001 TI - Effects of herbicide-treated host plants on the development of Mamestra brassicae L. caterpillars. AB - Herbicides are widely used pesticides that affect plants by changing their chemistry. In doing so, herbicides might also influence the quality of plants as food for herbivores. To study the effects of herbicides on host plant quality, 3 plant species (Plantago lanceolata L., P. major L., and Ranunculus acris L.) were treated with sublethal rates of either a sulfonylurea (Atlantis WG, Bayer CropScience) or a glyphosate (Roundup LB Plus, Monsanto) herbicide, and the development of caterpillars of the cabbage moth Mamestra brassicae L. that fed on these plants was observed. Of the 6 tested plant-herbicide combinations, 1 combination (R. acris + sulfonylurea herbicide) resulted in significantly lower caterpillar weight, increased time to pupation, and increased overall development time compared with larvae that were fed unsprayed plants. These results might be caused by a lower nutritional value of these host plants or increased concentrations of secondary metabolites that are involved in plant defense. The results of the present and other studies suggest potential risks to herbivores that feed on host plants treated with sublethal rates of herbicides. However, as the effects of herbicides on host plant quality appear to be species-specific and as there are numerous plant-herbicide-herbivore relationships in agricultural landscapes, a general reduction in herbicide contamination of nontarget habitats (e.g., field margins) might mitigate the negative effects of herbicides on host plant quality. PMID- 25143000 TI - MicroRNA-155 deficiency enhances the recruitment and functions of myeloid-derived suppressor cells in tumor microenvironment and promotes solid tumor growth. AB - Immune cells in tumor microenvironment play a prominent role in tumor progression and metastasis. MicroRNA-155 (miR-155) represents an important player in innate and adaptive immunity by regulating differentiation, maturation and activation of macrophages, dendritic cells, B cells and T cells. However, the role of miR-155 expression in immune cells in solid tumor development is less elucidated. Our current study showed that both B16-F10 melanoma and Lewis lung carcinoma tumors grew much faster in bic/miR-155 knockout (miR-155(-/-) ) mice along with an increase of myeloid-derived suppressor cells (MDSCs) accumulation in tumors, compared to that in wild-type mice. Bone marrow transplantation study showed that bone marrow miR-155 deficiency could replicate the above tumor-promoting phenotype. In vitro study demonstrated that tumor-infiltrating miR-155(-/-) MDSCs showed greater migration ability and expressed higher level of multiple chemokines. Furthermore, we found that the level of HIF-1alpha, a direct target of miR-155, was increased in miR-155 deficient MDSCs, and that the increased HIF 1alpha upregulated CXCL1, CXCL3 and CXCL8 expression in MDSCs, contributing to the enhanced recruitment of miR-155(-/-) MDSCs to the tumors. Moreover, miR-155( /-) MDSCs showed enhanced immunosuppressive and pro-angiogenic capacities. Taken together, our study, for the first time, demonstrated that miR-155 deficiency promoted solid tumor growth through increasing the recruitment of MDSCs to tumor microenvironment and enhancing the tumor-promoting functions of the recruited MDSCs. Thus, upregulating miR-155 expression in MDSCs may be developed as a therapeutic approach to halt tumor development. PMID- 25143002 TI - Effects of N-acetyl-L-cysteine-capped CdTe quantum dots on bovine serum albumin and bovine hemoglobin: isothermal titration calorimetry and spectroscopic investigations. AB - The interactions of N-acetyl-L-cysteine-capped CdTe quantum dots (QDs) with bovine serum albumin (BSA) and bovine hemoglobin (BHb) were investigated by isothermal titration calorimetry (ITC), fluorescence, synchronous fluorescence, fluorescence lifetime, ultraviolet-visible absorption, and circular dichroism techniques. Fluorescence data of BSA-QDs and BHb-QDs revealed that the quenching was static in every system. While CdTe QDs changed the microenvironment of tryptophan in BHb, the microenvironment of BSA kept unchanged. Adding CdTe QDs affected the skeleton and secondary structure of the protein (BSA and BHb). The ITC results indicated that the interaction between the protein (BSA and BHb) and QDs-612 was spontaneous and the predominant force was hydrophobic interaction. In addition, the binding constants were determined to be 1.19 * 10(5) L mol(-1) (BSA QDs) and 2.19 * 10(5) L mol(-1) (BHb-QDs) at 298 K. From these results, we conclude that CdTe QDs have a larger impact on the structure of BHb than BSA. PMID- 25143003 TI - Learning From Leaders: Life-span Trends in Olympians and Supercentenarians. AB - Life-span trends progression has worldwide practical implications as it may affect the sustainability of modern societies. We aimed to describe the secular life-span trends of populations with a propensity to live longer-Olympians and supercentenarians-under two hypotheses: an ongoing life-span extension versus a biologic "probabilistic barrier" limiting further progression. In a study of life span densities (total number of life durations per birth date), we analyzed 19,012 Olympians and 1,205 supercentenarians deceased between 1900 and 2013. Among most Olympians, we observed a trend toward increased life duration. This trend, however, decelerates at advanced ages leveling off with the upper values with a perennial gap between Olympians and supercentenarians during the whole observation period. Similar tendencies are observed among supercentenarians, and over the last years, a plateau attests to a stable longevity pattern among the longest-lived humans. The common trends between Olympians and supercentenarians indicate similar mortality pressures over both populations that increase with age, scenario better explained by a biologic "barrier" forecast. PMID- 25143004 TI - Recovery of Indicators of Mitochondrial Biogenesis, Oxidative Stress, and Aging With (-)-Epicatechin in Senile Mice. AB - There is evidence implicating oxidative stress (OS) as the cause of the deleterious effects of aging. In this study, we evaluated the capacity of the flavanol (-)-epicatechin (Epi) to reduce aging-induced OS and restore mitochondrial biogenesis, as well as, structural and functional endpoints in aged mice. Senile (S; 26-month-old) C57BL/6 male mice were randomly assigned to receive either water (vehicle) or 1mg/kg of Epi via oral gavage (twice daily) for 15 days. Young (Y; 6-month-old) mice were used as controls. In S brain, kidney, heart, and skeletal muscle (compared with Y animals) an increase in OS was observed as evidenced by increased protein-free carbonyls and decreased reduced glutathione levels as well as sirtuin 3, superoxide dismutase 2, catalase, thioredoxin and glutathione peroxidase protein levels. Well-recognized factors (eg, sirtuin 1) that regulate mitochondrial biogenesis and mitochondrial structure- and/or function-related endpoints (eg, mitofilin and citrate synthase) protein levels were also reduced in S organs. In contrast, the aging biomarker senescence-associated beta-galactosidase was increased in S compared with Y animals, and Epi administration reduced levels towards those observed in Y animals. Altogether, these data suggest that Epi is capable of shifting the biology of S mice towards that of Y animals. PMID- 25143005 TI - Comparative in silico analysis of EST-SSRs in angiosperm and gymnosperm tree genera. AB - BACKGROUND: Simple Sequence Repeats (SSRs) derived from Expressed Sequence Tags (ESTs) belong to the expressed fraction of the genome and are important for gene regulation, recombination, DNA replication, cell cycle and mismatch repair. Here, we present a comparative analysis of the SSR motif distribution in the 5'UTR, ORF and 3'UTR fractions of ESTs across selected genera of woody trees representing gymnosperms (17 species from seven genera) and angiosperms (40 species from eight genera). RESULTS: Our analysis supports a modest contribution of EST-SSR length to genome size in gymnosperms, while EST-SSR density was not associated with genome size in neither angiosperms nor gymnosperms. Multiple factors seem to have contributed to the lower abundance of EST-SSRs in gymnosperms that has resulted in a non-linear relationship with genome size diversity. The AG/CT motif was found to be the most abundant in SSRs of both angiosperms and gymnosperms, with a relative increase in AT/AT in the latter. Our data also reveals a higher abundance of hexamers across the gymnosperm genera. CONCLUSIONS: Our analysis provides the foundation for future comparative studies at the species level to unravel the evolutionary processes that control the SSR genesis and divergence between angiosperm and gymnosperm tree species. PMID- 25143006 TI - Finale furioso: referee-biased injury times and their effects on home advantage in football. AB - The role of referees has become a central issue in the investigation of home advantage. The main aim of this study was a thorough examination of the referee bias concerning injury time in football, which is currently seen as an important example for the assertion that referees contribute to home advantage. First, we use archival data from the German Bundesliga (seasons 2000/2001-2010/2011) to confirm the existence of an asymmetry in the allocation of injury time. We show this asymmetry to be a bias by ruling out hitherto remaining alternative explanations (effect = 18 s, P < 0.001, R2(adj) = 0.05). Second, we identify a further referee bias, stating that referees systematically accord more injury time when one team leads in the game compared to a draw (effect = 21 s, P = 0.004, R2(adj) = 0.06). Third, the quantitative benefit of home or away teams in goals and points due to these biases is assessed. Overall, referee decisions on injury time indeed reveal biases, but they do not contribute to the home advantage, that is, there is no significant effect on goals scored by the teams. The qualitative findings (a new bias on injury time) as well as the quantitative findings (no overall effect) shed new light on the role of referees for home advantage. PMID- 25143007 TI - The introduction of mid-urethral slings: an evaluation of literature. AB - INTRODUCTION AND HYPOTHESIS: The objective of this study was to evaluate the degree and reliability of evidence used by manufacturers before the introduction of mid-urethral slings (MUS) onto the commercial market. Furthermore, minimum standards for marketed slings are recommended by evaluating recent suggestions for the introduction of gynecological meshes. METHODS: A systematic literature search was conducted using PubMed and commercial internet search engines in order to identify slings introduced by the industry over the last decade. Moreover, manufacturers were contacted by email, mail, and phone to provide data from before the introduction of the slings onto the commercial market. Once contact had been initiated, a 6-month deadline was set for data collection. RESULTS: Forty-one slings introduced between 1996 and 2012 were identified. Ten slings were described in a total of 20 studies with sample sizes varying from 10 to 368. The 41 MUS were produced by a total of 19 different companies. Seven companies never responded to recurrent emails, phone calls or other means of attempted contact. Thirty-one slings (76%) remained without any comparative pre-launch data. CONCLUSIONS: Mid-urethral slings were often introduced without any scientifically proven basis or pre-launch research. The US Food and Drug Administration and the European authorities should undertake immediate action by imposing strict rules before the launch of new MUS comparable with those recently suggested for meshes used in vaginal prolapse surgery. PMID- 25143009 TI - Adverse effects of small-volume red blood cell transfusions in the neonatal population. AB - BACKGROUND: Adverse transfusion reactions in the neonatal population are poorly understood and defined. The incidence and pattern of adverse effects due to red blood cell (RBC) transfusion are not well known, and there has been no systematic review of published adverse events. RBC transfusions continue to be linked to the development of morbidities unique to neonates, including chronic lung disease, retinopathy of prematurity, intraventricular haemorrhage and necrotising enterocolitis. Uncertainties about the exact nature of risks alongside benefits of RBC transfusion may contribute to evidence of widespread variation in neonatal RBC transfusion practice.Our review aims to describe clinical adverse effects attributed to small-volume (10-20 mL/kg) RBC transfusions and, where possible, their incidence rates in the neonatal population through the systematic identification of all relevant studies. METHODS: A comprehensive search of the following bibliographic databases will be performed: MEDLINE (PubMed/OVID which includes the Cochrane Library) and EMBASE (OVID). The intervention of interest is small-volume (10-20 mL/kg) RBC transfusions in the neonatal population.We will undertake a narrative synthesis of the evidence. If clinical similarity and data quantity and quality permit, we will also carry out meta-analyses on the listed outcomes. DISCUSSION: This systematic review will identify and synthesise the reported adverse effects and associations of RBC transfusions in the neonatal population. We believe that this systematic review is timely and will make a valuable contribution to highlight an existing research gap. TRIAL REGISTRATION: PROSPERO, CRD42013005107http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD4201300 107. PMID- 25143008 TI - Manufacture of gene-modified human T-cells with a memory stem/central memory phenotype. AB - Advances in genetic engineering have made it possible to generate human T-cell products that carry desired functionalities, such as the ability to recognize cancer cells. The currently used strategies for the generation of gene-modified T cell products lead to highly differentiated cells within the infusion product, and on the basis of data obtained in preclinical models, this is likely to impact the efficacy of these products. We set out to develop a good manufacturing practice (GMP) protocol that yields T-cell receptor (TCR) gene-modified T-cells with more favorable properties for clinical application. Here, we show the robust clinical-scale production of human peripheral blood T-cells with an early memory phenotype that express a MART-1-specific TCR. By combining selection and stimulation using anti-CD3/CD28 beads for retroviral transduction, followed by expansion in the presence of IL-7 and IL-15, production of a well-defined clinical-scale TCR gene-modified T-cell product could be achieved. A major fraction of the T-cells generated in this fashion were shown to coexpress CD62L and CD45RA, and express CD27 and CD28, indicating a central memory or memory stemlike phenotype. Furthermore, these cells produced IFNgamma, TNFalpha, and IL 2 and displayed cytolytic activity against target cells expressing the relevant antigen. The T-cell products manufactured by this robust and validated GMP production process are now undergoing testing in a phase I/IIa clinical trial in HLA-A*02:01 MART-1-positive advanced stage melanoma patients. To our knowledge, this is the first clinical trial protocol in which the combination of IL-7 and IL 15 has been applied for the generation of gene-modified T-cell products. PMID- 25143010 TI - Rubredoxin refolding on nanostructured hydrophobic surfaces: evidence for a new type of biomimetic chaperones. AB - Rubredoxins (Rds) are small proteins containing a tetrahedral Fe(SCys)4 site. Folded forms of metal free Rds (apoRds) show greatly impaired ability to incorporate iron compared with chaotropically unfolded apoRds. In this study, formation of the Rd holoprotein (holoRd) on addition of iron to a structured, but iron-uptake incompetent apoRd was investigated in the presence of polystyrene nanoparticles (NP). In our rationale, hydrophobic contacts between apoRd and the NP surface would expose protein regions (including ligand cysteines) buried in the structured apoRd, allowing iron incorporation and folding to the native holoRd. Burial of the hydrophobic regions in the folded holoRd would allow its detachment from the NP surface. We found that both rate and yield of holoRd formation increased significantly in the presence of NP and were influenced by the NP concentration and size. Rates and yields had an optimum at "catalytic" NP concentrations (0.2 g/L NP) when using relatively small NP (46 nm diameter). At these optimal conditions, only a fraction of the apoRd was bound to the NP, consistent with the occurrence of turnover events on the NP surface. Lower rates and yields at higher NP concentrations or when using larger NP (200 nm) suggest that steric effects and molecular crowding on the NP surface favor specific "iron uptake-competent" conformations of apoRd on the NP surface. This bio-mimetic chaperone system may be applicable to other proteins requiring an unfolding step before cofactor-triggered refolding, particularly when over-expressed under limited cofactor accessibility. PMID- 25143011 TI - Association of nucleated red blood cells with mortality in critically ill dogs. AB - The occurrence of nucleated red blood cells (NRBC) in the peripheral blood of critically ill human patients is associated with increased mortality. In dogs, the presence of NRBCs in peripheral blood has been used as a sensitive and specific marker of complications and outcome associated with heatstroke. However, no study has investigated their prevalence in critically ill dogs. Thus, the aim of this study was to determine the prevalence of NRBCs in the peripheral blood, and to evaluate their occurrence as a prognostic factor in critically ill dogs. One hundred and one dogs were prospectively included; the presence of NRBCs was studied on a daily basis from the time of admission until day 3 in the intensive care unit (or less if discharged or death occurred earlier). Dogs fulfilled at least two systemic inflammatory response syndrome (SIRS) criteria and suffered from various diseases. Survival was defined as being alive 28 days postdischarge from hospital. In 42 dogs, NRBCs were detected at least once; 59 patients were NRBC negative. Mortality was significantly higher in NRBC-positive than NRBC negative patients (54.8 v 30.5 per cent) (P=0.014). However, this association was not present when anaemic dogs were excluded from the analysis. Detection of NRBCs in the peripheral blood may be an indicator for regenerative anaemia and may have potential for use as a prognostic tool or in addition to established scoring systems in critically ill dogs. PMID- 25143012 TI - High dose lansoprazole combined with metronomic chemotherapy: a phase I/II study in companion animals with spontaneously occurring tumors. AB - BACKGROUND: The treatment of human cancer has been seriously hampered for decades by resistance to chemotherapeutic drugs. A very efficient mechanism of tumor resistance to drugs is the proton pumps-mediated acidification of tumor microenvironment. Metronomic chemotherapy has shown efficacy in adjuvant fashion as well as in the treatment of pets with advanced disease. Moreover, we have shown in veterinary clinical settings that pre-treatment with proton-pumps inhibitors (PPI) increases tumor responsiveness to chemotherapeutics. In this study pet with spontaneously occurring cancer have been recruited to be treated by a combination of metronomic chemotherapy and high dose PPIs and their responses have been matched to those of a historical control of ten patients treated with metronomic chemotherapy alone. METHODS: Single arm, non randomized phase II open study, with historical control group, evaluating safety and efficacy of the combination of metronomic chemotherapy and alkalization. Twenty four companion animals (22 dogs and 2 cats) were treated adding to their metronomic chemotherapy protocol the pump inhibitor lansoprazole at high dose, and a water alkalizer. Their responses have been evaluated by clinical and instrumental evaluation and matched to those of the control group. RESULTS: The protocol was overall well tolerated, with only two dogs experiencing side effects due to gastric hypochlorhydria consisting with vomiting and or diarrhea. In terms of overall response, in the alkalized cohort, 18 out of 24 had partial or complete responses (75%), two patients had a stable disease and the remaining patients experienced no response or progressive disease. On the other hand, only one patient in the control group experienced a complete response (10%) and three other experienced short lived responses. Median time to terminal event was 34 weeks for the experimental group versus 2 weeks in the controls (p= 0.042). CONCLUSIONS: Patient alkalization has shown to be well tolerated and to increase tumor response to metronomic chemotherapy as well the quality of life in pets with advanced cancer. Further studies are warranted to assess the efficacy of this strategy in patients with advanced cancers in companion animals as well as in humans. PMID- 25143013 TI - Theoretical study of the hydration of atmospheric nucleation precursors with acetic acid. AB - While atmosphere is known to contain a significant fraction of organic substance and the effect of acetic acid to stabilize hydrated sulfuric acids is found to be close that of ammonia, the details about the hydration of (CH3COOH)(H2SO4)2 are poorly understood, especially for the larger clusters with more water molecules. We have investigated structural characteristics and thermodynamics of the hydrates using density functional theory (DFT) at PW91PW91/6-311++G(3df,3pd) level. The phenomena of the structural evolution may exist during the early stage of the clusters formation, and we tentatively proposed a calculation path for the Gibbs free energies of the clusters formation via the structural evolution. The results in this study supply a picture of the first deprotonation of sulfuric acids for a system consisting of two sulfuric acid molecules, an acetic acid molecule, and up to three waters at 0 and 298.15 K, respectively. We also replace one of the sulfuric acids with a bisulfate anion in (CH3COOH)(H2SO4)2 to explore the difference of acid dissociation between two series of clusters and interaction of performance in clusters growth between ion-mediated nucleation and organics-enhanced nucleation. PMID- 25143014 TI - Cerebral blood flow measurements in infants using look-locker arterial spin labeling. AB - PURPOSE: To measure cerebral blood flow (CBF) using Look-Locker arterial spin labeling (ASL) in children under 1 year of age and to investigate the advantages of using subject-specific estimates of ASL model parameters in this population. MATERIALS AND METHODS: Of 12 scanned infants, we successfully acquired CBF maps in 7 (postmenstrual age: 32 to 78 weeks) using a Look-Locker ASL scheme and both adult literature-derived and subject-specific model parameters. ASL global CBF measurements were compared with independent global CBF measurements obtained in the same scanning session using phase-contrast angiography. RESULTS: Measured global CBF values ranged from 24 to 56 mL/100g/min in the scanned infants, increasing significantly with postmenstrual age (rhoSpearman = 0.89, P-value = 0.01). Using subject-specific model parameters yielded CBF estimates in significantly better agreement with phase-contrast angiography values (P-value: 0.80) than when standard adult parameters were used (P-value: 0.04). CONCLUSION: Look-Locker ASL can be used to measure CBF in infants and its accuracy is improved with the use of infant-specific auxiliary parameters, particularly blood and tissue T1 , which were much more variable in the imaged infants in than adults. PMID- 25143015 TI - Fungal cell-wall lytic enzymes, antifungal metabolite(s) production, and characterization from Streptomyces exfoliatus MT9 for controlling fruit-rotting fungi. AB - An antifungal actinomycete strain MT9 was isolated from Loktak Lake, Manipur, India and its cultural characteristics, fatty acid methyl ester, 16S rRNA gene analysis suggests that strain MT9 is identical to Streptomyces exfoliatus. Strain MT9 displayed strong and broad-spectrum antagonism towards several fruit-rotting fungi by mycelial growth suppression. Crude fungal cell-wall lytic enzymes, i.e., chitinase, beta-1,3-glucanase, and protease produced by S. exfoliatus MT9 were optimally active at pH 8.0 and 50 degrees C, pH 5.0 and 60 degrees C, pH 9.0 and 70 degrees C, respectively. All three mycolytic enzymes had good stability over a wide pH range of 5.0-10.0, with protease being more thermostable than both chitinase and beta-1,3-glucanase. Interestingly zymogram analysis revealed that S. exfoliatus MT9 secretes six distinct chitinase isoenzymes with approximate molecular weights of 9.42, 13.93, 27.87, 36.43, 54.95, 103.27 kDa, six active protease isoenzymes with apparent molecular weights of 12.45, 30.20, 37.45, 46.32, 52.46, 131.46 kDa, and an active band of 119.39 kDa as beta-1,3-glucanase enzyme. Extracellular fluid and its organic solvent extracts also exhibited inhibitory activity to various fruit-rotting fungi. The MIC value of n-butanol extract was 2-25 ug/ml against tested fruit-rotting fungi. Antifungal secondary metabolite(s) was found to be polyene in nature. To the best of our knowledge, this is the first report on extracellular production of fungal cell-wall lytic enzymes and antifungal metabolites by bioactive S. exfoliatus MT9 under submerged fermentation. PMID- 25143016 TI - Comparison of the histopathology and prognosis of bilateral versus unilateral multifocal multicentric breast cancers. AB - BACKGROUND: Multiple breast cancers may present with different clinical and biological characteristics. The data indicate that multifocal (MF), multicentric (MC), and bilateral synchronous (BS) breast cancers (BC) are more aggressive and have an equivalent or moderately poorer survival rate compared with unilateral cases. However, a comparison of these multiple breast cancers has not been covered in the literature. The aim of this study was to describe the histopathological characteristics of patients suffering from MF, MC, and BS breast carcinoma and to compare their prognoses. METHODS: Retrospective data for MF, MC, and BS breast carcinoma patients treated in five different breast cancer units in Turkey between 2003 and 2012 were collected. MF and MC cancers were defined as more than one lesion in the same quadrant or in separate quadrants, respectively. RESULTS: There were 507 patients (271 MF, 147 MC, and 89 BS) treated in this time period. BS breast carcinoma patients were younger than the other groups (44.83 +/- 9.6, 47.27 +/- 11.6, and 51.11 +/- 11.8 years for BS, MF, and MC breast carcinoma patients, respectively). MFBC and MCBC patients in this study were younger than the ages reported in Western literature, but this result was similar to the ages reported in Eastern literature. The five-year survival rates and recurrence rates were not statistically different among groups (P = 0.996 and P = 0.263, respectively). According to univariate analyses, tumor size, histological grade, and lymph node status were statistically significant factors that affected survival. However, only lymph node involvement was significant for survival according to multivariate analyses. CONCLUSIONS: The clinical significance of MF, MC, and BS breast cancers is still unclear and their influence on prognosis is controversial. Disease-free and overall survival rates of BS breast cancers might be similar to MF and MC breast cancers. PMID- 25143017 TI - Why do women not deliver in health facilities: a qualitative study of the community perspectives in south central Ethiopia? AB - BACKGROUND: In Ethiopia most childbirth occurs at home and is not assisted by skilled birth attendants. On the other hand having a birth attendant with midwifery skills during child birth is one of the most important interventions in reducing maternal morbidity and mortality. The objective of this study was to make an in-depth assessment of reasons why mothers do not use health facilities for child delivery. METHODS: Focus Group Discussions were used to gather information on use of health facilities for delivery in Butajira districts of South Central Ethiopia. The study was conducted from January to February 2012. Information was collected from four groups of women who had delivered in the past two years and four groups of men whose wives/partners have delivered in the same period. Data was coded and categorized using open code, qualitative data management software and analyzed based on thematic analysis. RESULTS: A total of eight FGD sessions, four with women and four with men groups were conducted involving 81 residents of the Butajira district. FGD participants answered that a large majority of women in the district gave birth at home. Two major themes, client related factors and facility/staff factors, emerged. Factors that emerged within major themes of client factors were decision making on place of delivery, reliance on Traditional Birth Attendants (TBAs), misconception about services provided at health facility, inability of family members to be present at time of labor and delivery, lack of privacy, traditional and/or spiritual factors, economic factors and accessibility to health care facilities. Within major themes of facility/staff factors subthemes that emerged were poor reception, refusal of admission, lack of privacy, information gap, poor competence and shortage of staff and materials at health facilities. CONCLUSION: Women in the study areas do not deliver in health facilities because of reasons that can be attributed to health care system and client related factors. These need to be addressed by considering the specific factors related to the health system and community perspectives. PMID- 25143018 TI - Muslim and Hindu Women's public and private behaviors: gender, family, and communalized politics in India. AB - Prior research on fundamentalist religious movements has focused attention on the complicated relationship among gender, family, and religion. Using data from a nationally representative survey of 30,000 Hindu and Muslim women, this study compares the daily public and private behaviors of women in India to examine how gender and family norms are shaped in the context of communalized identity politics. Building on the theoretical framework of "doing gender," we argue that because communal identities are expressed through externally visible behaviors, greater religious differences are expected in external markers of gendered behaviors and family norms. Results indicate that Muslim women are more likely to engage in veiling and less likely to venture outside the home for recreation and employment. However, religious differences are absent when attention is directed at private behaviors, such as household decision-making power, gender segregation within households, and discrimination against daughters. Results underscore the multidimensionality of gender. PMID- 25143019 TI - Happiness: before and after the kids. AB - Understanding how having children influences parents' subjective well-being ("happiness") has great potential to explain fertility behavior. We study parental happiness trajectories before and after the birth of a child, using large British and German longitudinal data sets. We account for unobserved parental characteristics using fixed-effects models and study how sociodemographic factors modify the parental happiness trajectories. Consistent with existing work, we find that happiness increases in the years around the birth of a first child and then decreases to before-child levels. Moreover, happiness increases before birth, suggesting that the trajectories may capture not only the effect of the birth but also the broader process of childbearing, which may include partnership formation and quality. Sociodemographic factors strongly modify this pattern. Those who have children at older ages or who have more education have a particularly positive happiness response to a first birth; and although having the first two children increases happiness, having a third child does not. The results, which are similar in Britain and Germany, suggest that having up to two children increases happiness, and mostly for those who have postponed childbearing. This pattern is consistent with the fertility behavior that emerged during the second demographic transition and provides new insights into low and late fertility. PMID- 25143020 TI - Effective dose assessment in the maxillofacial region using thermoluminescent (TLD) and metal oxide semiconductor field-effect transistor (MOSFET) dosemeters: a comparative study. AB - OBJECTIVES: The objective of this study was to compare the performance of metal oxide semiconductor field-effect transistor (MOSFET) technology dosemeters with thermoluminescent dosemeters (TLDs) (TLD 100; Thermo Fisher Scientific, Waltham, MA) in the maxillofacial area. METHODS: Organ and effective dose measurements were performed using 40 TLD and 20 MOSFET dosemeters that were alternately placed in 20 different locations in 1 anthropomorphic RANDO((r)) head phantom (the Phantom Laboratory, Salem, NY). The phantom was exposed to four different CBCT default maxillofacial protocols using small (4 * 5 cm) to full face (20 * 17 cm) fields of view (FOVs). RESULTS: The TLD effective doses ranged between 7.0 and 158.0 uSv and the MOSFET doses between 6.1 and 175.0 uSv. The MOSFET and TLD effective doses acquired using four different (FOV) protocols were as follows: face maxillofacial (FOV 20 * 17 cm) (MOSFET, 83.4 uSv; TLD, 87.6 uSv; -5%); teeth, upper jaw (FOV, 8.5 * 5.0 cm) (MOSFET, 6.1 uSv; TLD, 7.0 uSv; -14%); tooth, mandible and left molar (FOV, 4 * 5 cm) (MOSFET, 10.3 uSv; TLD, 12.3 uSv; 16%) and teeth, both jaws (FOV, 10 * 10 cm) (MOSFET, 175 uSv; TLD, 158 uSv; +11%). The largest variation in organ and effective dose was recorded in the small FOV protocols. CONCLUSIONS: Taking into account the uncertainties of both measurement methods and the results of the statistical analysis, the effective doses acquired using MOSFET dosemeters were found to be in good agreement with those obtained using TLD dosemeters. The MOSFET dosemeters constitute a feasible alternative for TLDs for the effective dose assessment of CBCT devices in the maxillofacial region. PMID- 25143021 TI - Anterior multiple cervical corpectomy and fusion. PMID- 25143022 TI - Clinical and immunologic predictors of death after an acute opportunistic infection: results from ACTG A5164. AB - BACKGROUND: In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era. OBJECTIVE: To determine clinical and immunological predictors of death after an OI. METHODS: We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both. RESULTS: The median CD4+ T-cell count in study participants at baseline was 29 cells/uL. Sixty-four percent of subjects had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death. CONCLUSIONS: In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI. PMID- 25143023 TI - Efficacy and safety of darunavir/ritonavir plus etravirine dual regimen in antiretroviral therapy-experienced patients: a multicenter clinical experience. AB - OBJECTIVES: To assess the outcome of a dual regimen combining darunavir/ritonavir plus etravirine in a cohort of antiretroviral therapy (ART)-experienced patients. METHODS: A retrospective analysis was performed on all ART-experienced patients starting a darunavir/ritonavir plus etravirine regimen at the 3 clinics. Patients were stratified according to HIV RNA detectability (>= 40 copies/mL) at baseline. Two efficacy endpoints were evaluated by Kaplan-Meier and Cox multivariable models: virological failure (confirmed HIV RNA >= 40 copies/mL after 6 months) and therapeutic failure (including virological failure and treatment discontinuation for any reason). RESULTS: Sixty-eight patients were included in the study. They had a median of 10.8 years on ART and 5 previous ART regimens; 61.3% showed primary protease inhibitor (PI) mutations and 70% showed previous non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure. HIV RNA was detectable in 34 (50%) patients. The median observation period was 21 (interquartile range [IQR], 11.9-25.1) months. After 24 months, 75.1% of the patients were still on the study regimen and 88.8% remained free from virological failure. Although a higher therapeutic failure rate was reported in patients with detectable viremia at baseline, only the immunological status revealed an independent predictive role. No differences in virological failure were observed according to HIV RNA detectability at baseline; a higher number of previous ART regimens was the only predictor. Discontinuation due to adverse events occurred in 5.9%. CONCLUSIONS: Darunavir/ritonavir plus etravirine regimen proved virological efficacy and safety in heavily pretreated patients with a high rate of virological success, even in patients who switched during virological failure. PMID- 25143024 TI - Liver enzyme elevation during darunavir-based antiretroviral treatment in HIV-1 infected patients with or without hepatitis C coinfection: data from the ICONA foundation cohort. AB - OBJECTIVES: To investigate differences in liver enzyme elevation (LEE) between HIV-infected patients with and without HCV coinfection who start a darunavir/ritonavir-containing regimen. METHODS: HIV-infected patients enrolled in the Italian Cohort of Naive to Antiretrovirals (ICONA) Foundation Study were included if they started darunavir/ritonavir for the first time. Patients were classified as not HCV coinfected, HCV active coinfected (HCV RNA positive), and HCV nonactive coinfected (HCV-Ab positive/HCV RNA negative). Time to LEE endpoint was defined using the ACTG toxicity scale, based on changes relative to baseline. Kaplan-Meier was used to estimate 1-year and 2-year probability of LEE. The incidence rate ratios (IRRs) of LEEs were estimated until the last follow-up (intention-to-treat analysis [ITT]) and up to darunavir/ritonavir discontinuation (on-treatment analysis [OT]). RESULTS: Overall, 703 patients were included. Ninety-one were HCV-Ab positive; of those, 68 (9.7%) had active HCV coinfection. In 879 person-years of follow-up, 101 LEEs occurred (ITT). No severe hepatotoxicity event was registered in active HCV coinfected patients. HCV active coinfection was predictive of LEE in the overall population (OT: adjusted incidence rate ratio (IRR), 2.25; 95% CI, 0.70-7.24; P = .17; ITT: adjusted IRR, 3.62; 95% CI, 1.67-7.83; P < .001) and in naive patients (OT: adjusted IRR, 6.29; 95% CI, 2.54-15.55; P = .00; ITT: adjusted IRR, 3.87; 95% CI, 0.99-15.16; P = .05). CONCLUSIONS: No grade 3-4 LEEs occurred in HCV active coinfected patients. HCV active coinfected patients experienced low grade LEEs more frequently than HCV-Ab negative patients. Darunavir/ritonavir seems to be safe whatever the HCV status, when liver enzymes are carefully monitored. PMID- 25143025 TI - Citalopram for the prevention of depression and its consequences in HIV-hepatitis C coinfected individuals initiating pegylated interferon/ribavirin therapy: a multicenter randomized double-blind placebo-controlled trial. AB - BACKGROUND: Depression related to interferon-alpha (IFN-alpha) is common, may reduce adherence, and can be treatment limiting. HIV-HCV coinfected persons experience lower sustained virologic response rates and commonly have psychiatric comorbidities, thus they may benefit from prevention of depression. OBJECTIVE: The aim of the study was to determine whether prophylactic citalopram can increase HCV treatment adherence and reduce the incidence of moderate depression in HIV-HCV coinfected patients initiating PEG-IFN-alpha/ribavirin therapy. METHODS: This was an investigator-initiated Canadian multicenter randomized, double-blind placebo-controlled trial. HIV-HCV coinfected patients were randomized in a 1:1 ratio to receive citalopram or placebo 3 weeks prior to starting PEG-IFN-alpha2b/ribavirin, stratified by study center and HCV genotype. The protocol design permitted the comparison of prophylaxis with the treatment of emergent depression. The primary outcomes were adherence (assessed through questionnaire and returned medication) and time to moderate depression measured by Beck Depression Inventory-II (BDI- II) score greater than 15, confirmed 2 weeks apart. RESULTS: Seventy-six patients (36 citalopram/40 placebo) were randomized. Overall adherence was high, ranging from 95% (week 12) to 91% (week 48). There was no difference between arms with respect to mean or median adherence at any study time point. Cumulative incidence of moderate depression did not differ significantly by group (log rank P = .32). The hazard ratio for moderate depression was 0.81 (95% CI, 0.26 to 2.54) for citalopram compared with placebo when adjusted for baseline BDI-II score. CONCLUSIONS: A strategy of prophylactic citalopram compared to treatment of emergent depression was not associated with higher adherence or a reduction in treatment-limiting depression nor did it significantly reduce depressive symptoms among HIV-HCV coinfected persons during treatment for HCV. PMID- 25143026 TI - Relationship between health-related quality of life measures and high HIV viral load in HIV-infected triple-class-experienced patients. AB - BACKGROUND: Health-related quality of life (HRQoL) has been recognized as a central measure of the overall health status in HIV patients. With the availability of different highly effective drug combinations, maximizing quality adjusted survival has become a major target of HIV treatment. Although the association of HIV RNA and CD4 cell count with clinical HIV progression has been well established, the relation between these markers and HRQoL measures is still unclear. METHOD: This cross-sectional study investigated the relationship linking HIV RNA and CD4 to HRQoL measures in 181 triple-class-experienced patients with advanced HIV disease. The instrument used was the ISSQoL, a self-administered and HIV-specific HRQoL questionnaire. RESULTS: Data showed no correlation between HRQoL measures and CD4 counts. Higher HIV RNA levels were, however, associated with poor HRQoL scores in 3 out of 9 scales of social functioning, depression and anxiety, and satisfaction with quality of life. In multivariable analyses, only the satisfaction with quality of life mean score remained significantly lower for the HIV RNA ?100,000 copies/mL group compared to the HIV RNA 50 to 10,000 copies/mL group. CONCLUSIONS: Although other determinants of HRQoL in people with HIV should also be considered, this finding suggests a negative impact of high viral load on perceived HRQoL that adds to other described determinants of lower quality of life in people with HIV, such as lower social support and self reported symptoms. PMID- 25143027 TI - Morbidity and mortality following elective splenectomy for benign and malignant hematologic conditions: analysis of the American College of Surgeons National Surgical Quality Improvement Program data. AB - IMPORTANCE: Splenectomy is a commonly performed operation; however, data from large series regarding operative outcomes to help guide decision making and informed consent are lacking. OBJECTIVE: To evaluate clinical and pathologic variables associated with morbidity and mortality following elective splenectomy for benign and malignant hematologic conditions in the United States. DESIGN, SETTING, AND PARTICIPANTS: A review of the American College of Surgeons National Surgical Quality Improvement Program data for elective splenectomy between January 1, 2005, and December 31, 2011, was performed, and 1715 eligible individuals were identified. INTERVENTION: Elective splenectomy for hematologic conditions. MAIN OUTCOMES AND MEASURES: Complications and operative mortality were evaluated for the entire cohort and compared between patients with benign vs malignant diseases. Multivariable logistic regression was used to evaluate factors predictive of operative complications and death. RESULTS: Splenectomy was performed in 1344 patients (78.4%) for benign disease and in 371 patients (21.6%) for malignant disease. Two hundred ninety-one patients (17.0%) had a complication, and operative mortality occurred in 27 patients (mortality rate, 1.6%). Patients treated for malignant disease had a higher rate of overall complications (27.2%) compared with patients treated for benign disease (14.1%) (P < .001). Several variables were independent predictors of complications, including malignant disease (vs benign) (Odds Ratio [OR], 1.86; 95% CI, 1.23 2.80; P = .003), independent performance status (vs dependent) (OR, 0.33; 95% CI, 0.07-1.52; P = .02), and increasing albumin level (OR, 0.75; 95% CI, 0.66-0.86; P < .001). Increasing age (OR, 1.03; 95% CI, 1.00-1.06; P = .05) was an independent predictor of mortality while increasing albumin level (OR, 0.63; 95% CI, 0.46 0.86; P = .003) predicted lower risk of operative death. From these data, a patient older than 60 years with a low preoperative albumin level has a predicted probability for operative death as high as 10.0%. CONCLUSIONS AND RELEVANCE: Preoperative performance and nutritional status are significant risk factors for complications and mortality following elective splenectomy. Although operative mortality continues to decrease over time, specific preoperative variables may help with patient selection before elective splenectomy for certain patients. PMID- 25143028 TI - Pericytes: a double-edged sword in cancer therapy. AB - Pericytes, which envelope the vascular endothelium throughout the body, are often targeted to promote vascular normalization and restore normal function of blood vessels in cancer treatment. The goals of pericyte-targeted therapy tend to promote proper vascular normalization of the tumor. Tumor vascular normalization prevents metastasis, increases tumor oxygenation (making radiation more effective in killing tumor cells), optimizes Starling forces to increase delivery of cancer cell-directed therapies (e.g., chemotherapy or targeted agents), increases the efficacy of focal therapies (e.g., surgery or radiation), and increases recognition by the host immune system. We review how approaches in pericyte targeted therapy aim to reach a balance between pro-angiogenic and anti angiogenic function (i.e., by targeting platelet-derived growth factor beta receptors, vascular endothelial growth factor receptors and Tie-2) for tumor vascular normalization. PMID- 25143029 TI - Towards a synthesis of frameworks in nutritional ecology: interacting effects of protein, carbohydrate and phosphorus on field cricket fitness. AB - Phosphorus has been identified as an important determinant of nutrition-related biological variation. The macronutrients protein (P) and carbohydrates (C), both alone and interactively, are known to affect animal performance. No study, however, has investigated the importance of phosphorus relative to dietary protein or carbohydrates, or the interactive effects of phosphorus with these macronutrients, on fitness-related traits in animals. We used a nutritional geometry framework to address this question in adult field crickets (Gryllus veletis). Our results showed that lifespan, weight gain, acoustic mate signalling and egg production were maximized on diets with different P : C ratios, that phosphorus did not positively affect any of these fitness traits, and that males and females had different optimal macronutrient intake ratios for reproductive performance. When given a choice, crickets selected diets that maximized both lifespan and reproductive performance by preferentially eating diets with low P : C ratios, and females selected diets with a higher P : C ratio than males. Conversely, phosphorus intake was not regulated. Overall, our findings highlight the importance of disentangling the influences of different nutrients, and of quantifying both their individual and interactive effects, on animal fitness traits, so as to gain a more integrative understanding of their nutritional ecology. PMID- 25143030 TI - Time flies: Time of day and social environment affect cuticular hydrocarbon sexual displays in Drosophila serrata. AB - Recent work on Drosophila cuticular hydrocarbons (CHCs) challenges a historical assumption that CHCs in flies are largely invariant. Here, we examine the effect of time of day and social environment on a suite of sexually selected CHCs in Drosophila serrata. We demonstrate that males become more attractive to females during the time of day that flies are most active and when most matings occur, but females become less attractive to males during the same time of day. These opposing temporal changes may reflect differences in selection among the sexes. To evaluate the effect of social environment on male CHC attractiveness, we manipulated male opportunity for mating: male flies were housed either alone, with five females, with five males or with five males and five females. We found that males had the most attractive CHCs when with females, and less attractive CHCs when with competitor males. Social environment mediated how male CHC attractiveness cycled: males housed with females and/or other males showed temporal changes in CHC attractiveness, whereas males housed alone did not. In total, our results demonstrate temporal patterning of male CHCs that is dependent on social environment, and suggest that such changes may be beneficial to males. PMID- 25143031 TI - Nasal aerodynamics protects brain and lung from inhaled dust in subterranean diggers, Ellobius talpinus. AB - Inhalation of air-dispersed sub-micrometre and nano-sized particles presents a risk factor for animal and human health. Here, we show that nasal aerodynamics plays a pivotal role in the protection of the subterranean mole vole Ellobius talpinus from an increased exposure to nano-aerosols. Quantitative simulation of particle flow has shown that their deposition on the total surface of the nasal cavity is higher in the mole vole than in a terrestrial rodent Mus musculus (mouse), but lower on the olfactory epithelium. In agreement with simulation results, we found a reduced accumulation of manganese in olfactory bulbs of mole voles in comparison with mice after the inhalation of nano-sized MnCl2 aerosols. We ruled out the possibility that this reduction is owing to a lower transportation from epithelium to brain in the mole vole as intranasal instillations of MnCl2 solution and hydrated nanoparticles of manganese oxide MnO . (H2O)x revealed similar uptake rates for both species. Together, we conclude that nasal geometry contributes to the protection of brain and lung from accumulation of air-dispersed particles in mole voles. PMID- 25143032 TI - Stress-induced mutagenesis and complex adaptation. AB - Because mutations are mostly deleterious, mutation rates should be reduced by natural selection. However, mutations also provide the raw material for adaptation. Therefore, evolutionary theory suggests that the mutation rate must balance between adaptability-the ability to adapt-and adaptedness-the ability to remain adapted. We model an asexual population crossing a fitness valley and analyse the rate of complex adaptation with and without stress-induced mutagenesis (SIM)-the increase of mutation rates in response to stress or maladaptation. We show that SIM increases the rate of complex adaptation without reducing the population mean fitness, thus breaking the evolutionary trade-off between adaptability and adaptedness. Our theoretical results support the hypothesis that SIM promotes adaptation and provide quantitative predictions of the rate of complex adaptation with different mutational strategies. PMID- 25143033 TI - The roles of demography and genetics in the early stages of colonization. AB - Colonization success increases with the size of the founding group. Both demographic and genetic factors underlie this relationship, yet because genetic diversity normally increases with numbers of individuals, their relative importance remains unclear. Furthermore, their influence may depend on the environment and may change as colonization progresses from establishment through population growth and then dispersal. We tested the roles of genetics, demography and environment in the founding of Tribolium castaneum populations. Using three genetic backgrounds (inbred to outbred), we released individuals of four founding sizes (2-32) into two environments (natal and novel), and measured establishment success, initial population growth and dispersal. Establishment increased with founding size, whereas population growth was shaped by founding size, genetic background and environment. Population growth was depressed by inbreeding at small founding sizes, but growth rates were similar across genetic backgrounds at large founding size, an interaction indicating that the magnitude of the genetic effects depends upon founding population size. Dispersal rates increased with genetic diversity. These results suggest that numbers of individuals may drive initial establishment, but that subsequent population growth and spread, even in the first generation of colonization, can be driven by genetic processes, including both reduced growth owing to inbreeding depression, and increased dispersal with increased genetic diversity. PMID- 25143034 TI - Starvation reveals the cause of infection-induced castration and gigantism. AB - Parasites often induce life-history changes in their hosts. In many cases, these infection-induced life-history changes are driven by changes in the pattern of energy allocation and utilization within the host. Because these processes will affect both host and parasite fitness, it can be challenging to determine who benefits from them. Determining the causes and consequences of infection-induced life-history changes requires the ability to experimentally manipulate life history and a framework for connecting life history to host and parasite fitness. Here, we combine a novel starvation manipulation with energy budget models to provide new insights into castration and gigantism in the Daphnia magna-Pasteuria ramosa host-parasite system. Our results show that starvation primarily affects investment in reproduction, and increasing starvation stress reduces gigantism and parasite fitness without affecting castration. These results are consistent with an energetic structure where the parasite uses growth energy as a resource. This finding gives us new understanding of the role of castration and gigantism in this system, and how life-history variation will affect infection outcome and epidemiological dynamics. The approach of combining targeted life-history manipulations with energy budget models can be adapted to understand life-history changes in other disease systems. PMID- 25143036 TI - Foster carers influence brood pathogen resistance in ants. AB - Social organisms face a high risk of epidemics, and respond to this threat by combining efficient individual and collective defences against pathogens. An intriguing and little studied feature of social animals is that individual pathogen resistance may depend not only on genetic or maternal factors, but also on the social environment during development. Here, we used a cross-fostering experiment to investigate whether the pathogen resistance of individual ant workers was shaped by their own colony of origin or by the colony of origin of their carers. The origin of care-giving workers significantly influenced the ability of newly eclosed cross-fostered Formica selysi workers to resist the fungal entomopathogen Beauveria bassiana. In particular, carers that were more resistant to the fungal entomopathogen reared more resistant workers. This effect occurred in the absence of post-infection social interactions, such as trophallaxis and allogrooming. The colony of origin of eggs significantly influenced the survival of the resulting individuals in both control and pathogen treatments. There was no significant effect of the social organization (i.e. whether colonies contain a single or multiple queens) of the colony of origin of either carers or eggs. Our experiment reveals that social interactions during development play a central role in moulding the resistance of emerging workers. PMID- 25143035 TI - Thermal adaptation and clinal mitochondrial DNA variation of European anchovy. AB - Natural populations of widely distributed organisms often exhibit genetic clinal variation over their geographical ranges. The European anchovy, Engraulis encrasicolus, illustrates this by displaying a two-clade mitochondrial structure clinally arranged along the eastern Atlantic. One clade has low frequencies at higher latitudes, whereas the other has an anti-tropical distribution, with frequencies decreasing towards the tropics. The distribution pattern of these clades has been explained as a consequence of secondary contact after an ancient geographical isolation. However, it is not unlikely that selection acts on mitochondria whose genes are involved in relevant oxidative phosphorylation processes. In this study, we performed selection tests on a fragment of 1044 bp of the mitochondrial cytochrome b gene using 455 individuals from 18 locations. We also tested correlations of six environmental features: temperature, salinity, apparent oxygen utilization and nutrient concentrations of phosphate, nitrate and silicate, on a compilation of mitochondrial clade frequencies from 66 sampling sites comprising 2776 specimens from previously published studies. Positive selection in a single codon was detected predominantly (99%) in the anti-tropical clade and temperature was the most relevant environmental predictor, contributing with 59% of the variance in the geographical distribution of clade frequencies. These findings strongly suggest that temperature is shaping the contemporary distribution of mitochondrial DNA clade frequencies in the European anchovy. PMID- 25143037 TI - Animal vocal sequences: not the Markov chains we thought they were. AB - Many animals produce vocal sequences that appear complex. Most researchers assume that these sequences are well characterized as Markov chains (i.e. that the probability of a particular vocal element can be calculated from the history of only a finite number of preceding elements). However, this assumption has never been explicitly tested. Furthermore, it is unclear how language could evolve in a single step from a Markovian origin, as is frequently assumed, as no intermediate forms have been found between animal communication and human language. Here, we assess whether animal taxa produce vocal sequences that are better described by Markov chains, or by non-Markovian dynamics such as the 'renewal process' (RP), characterized by a strong tendency to repeat elements. We examined vocal sequences of seven taxa: Bengalese finches Lonchura striata domestica, Carolina chickadees Poecile carolinensis, free-tailed bats Tadarida brasiliensis, rock hyraxes Procavia capensis, pilot whales Globicephala macrorhynchus, killer whales Orcinus orca and orangutans Pongo spp. The vocal systems of most of these species are more consistent with a non-Markovian RP than with the Markovian models traditionally assumed. Our data suggest that non-Markovian vocal sequences may be more common than Markov sequences, which must be taken into account when evaluating alternative hypotheses for the evolution of signalling complexity, and perhaps human language origins. PMID- 25143038 TI - A global model of the response of tropical and sub-tropical forest biodiversity to anthropogenic pressures. AB - Habitat loss and degradation, driven largely by agricultural expansion and intensification, present the greatest immediate threat to biodiversity. Tropical forests harbour among the highest levels of terrestrial species diversity and are likely to experience rapid land-use change in the coming decades. Synthetic analyses of observed responses of species are useful for quantifying how land use affects biodiversity and for predicting outcomes under land-use scenarios. Previous applications of this approach have typically focused on individual taxonomic groups, analysing the average response of the whole community to changes in land use. Here, we incorporate quantitative remotely sensed data about habitats in, to our knowledge, the first worldwide synthetic analysis of how individual species in four major taxonomic groups--invertebrates, 'herptiles' (reptiles and amphibians), mammals and birds--respond to multiple human pressures in tropical and sub-tropical forests. We show significant independent impacts of land use, human vegetation offtake, forest cover and human population density on both occurrence and abundance of species, highlighting the value of analysing multiple explanatory variables simultaneously. Responses differ among the four groups considered, and--within birds and mammals--between habitat specialists and habitat generalists and between narrow-ranged and wide-ranged species. PMID- 25143039 TI - Inferring species roles in metacommunity structure from species co-occurrence networks. AB - A long-standing question in community ecology is what determines the identity of species that coexist across local communities or metacommunity assembly. To shed light upon this question, we used a network approach to analyse the drivers of species co-occurrence patterns. In particular, we focus on the potential roles of body size and trophic status as determinants of metacommunity cohesion because of their link to resource use and dispersal ability. Small-sized individuals at low trophic levels, and with limited dispersal potential, are expected to form highly linked subgroups, whereas large-size individuals at higher trophic positions, and with good dispersal potential, will foster the spatial coupling of subgroups and the cohesion of the whole metacommunity. By using modularity analysis, we identified six modules of species with similar responses to ecological conditions and high co-occurrence across local communities. Most species either co-occur with species from a single module or are connectors of the whole network. Among the latter are carnivorous species of intermediate body size, which by virtue of their high incidence provide connectivity to otherwise isolated communities playing the role of spatial couplers. Our study also demonstrates that the incorporation of network tools to the analysis of metacommunity ecology can help unveil the mechanisms underlying patterns and processes in metacommunity assembly. PMID- 25143040 TI - Exclusion of agricultural lands in spatial conservation prioritization strategies: consequences for biodiversity and ecosystem service representation. AB - Agroecosystems have traditionally been considered incompatible with biological conservation goals, and often been excluded from spatial conservation prioritization strategies. The consequences for the representativeness of identified priority areas have been little explored. Here, we evaluate these for biodiversity and carbon storage representation when agricultural land areas are excluded from a spatial prioritization strategy for South America. Comparing different prioritization approaches, we also assess how the spatial overlap of priority areas changes. The exclusion of agricultural lands was detrimental to biodiversity representation, indicating that priority areas for agricultural production overlap with areas of relatively high occurrence of species. By contrast, exclusion of agricultural lands benefits representation of carbon storage within priority areas, as lands of high value for agriculture and carbon storage overlap little. When agricultural lands were included and equally weighted with biodiversity and carbon storage, a balanced representation resulted. Our findings suggest that with appropriate management, South American agroecosystems can significantly contribute to biodiversity conservation. PMID- 25143041 TI - The youngest South American rhynchocephalian, a survivor of the K/Pg extinction. AB - Rhynchocephalian lepidosaurs, though once widespread worldwide, are represented today only by the tuatara (Sphenodon) of New Zealand. After their apparent early Cretaceous extinction in Laurasia, they survived in southern continents. In South America, they are represented by different lineages of Late Cretaceous eupropalinal forms until their disappearance by the Cretaceous/Palaeogene (K/Pg) boundary. We describe here the only unambiguous Palaeogene rhynchocephalian from South America; this new taxon is a younger species of the otherwise Late Cretaceous genus Kawasphenodon. Phylogenetic analysis confirms the allocation of the genus to the clade Opisthodontia. The new form from the Palaeogene of Central Patagonia is much smaller than Kawasphenodon expectatus from the Late Cretaceous of Northern Patagonia. The new species shows that at least one group of rhynchocephalians not related to the extant Sphenodon survived in South America beyond the K/Pg extinction event. Furthermore, it adds to other trans-K/Pg ectotherm tetrapod taxa, suggesting that the end-Cretaceous extinction affected Patagonia more benignly than the Laurasian landmasses. PMID- 25143042 TI - Cooperation and conflict: field experiments in Northern Ireland. AB - The idea that cohesive groups, in which individuals help each other, have a competitive advantage over groups composed of selfish individuals has been widely suggested as an explanation for the evolution of cooperation in humans. Recent theoretical models propose the coevolution of parochial altruism and intergroup conflict, when in-group altruism and out-group hostility contribute to the group's success in these conflicts. However, the few empirical attempts to test this hypothesis do not use natural groups and conflate measures of in-group and unbiased cooperative behaviour. We conducted field experiments based on naturalistic measures of cooperation (school/charity donations and lost letters' returns) with two religious groups with an on-going history of conflict-Catholics and Protestants in Northern Ireland. Conflict was associated with reduced donations to out-group schools and the return of out-group letters, but we found no evidence that it influences in-group cooperation. Rather, socio-economic status was the major determinant of cooperative behaviour. Our study presents a challenge to dominant perspectives on the origins of human cooperation, and has implications for initiatives aiming to promote conflict resolution and social cohesion. PMID- 25143043 TI - Improving risk estimates of metastasis from uveal melanoma through mutation profiling. PMID- 25143044 TI - Mitochondrial heat shock protein 70: new target for optic neuritis therapy. PMID- 25143045 TI - Characterization of the Antarctic sea urchin (Sterechinus neumayeri) transcriptome and mitogenome: a molecular resource for phylogenetics, ecophysiology and global change biology. AB - This is the first de novo transcriptome and complete mitochondrial genome of an Antarctic sea urchin species sequenced to date. Sterechinus neumayeri is an Antarctic sea urchin and a model species for ecology, development, physiology and global change biology. To identify transcripts important to ocean acidification (OA) and thermal stress, this transcriptome was created pooling, and 13 larval samples representing developmental stages on day 11 (late gastrula), 19 (early pluteus) and 30 (mid pluteus) maintained at three CO2 levels (421, 652, and 1071 MUatm) as well as four additional heat-shocked samples. The normalized cDNA pool was sequenced using emulsion PCR (pyrosequencing) resulting in 1.34M reads with an average read length of 492 base pairs. 40,994 isotigs were identified, averaging 1188 bp with a median coverage of 11*. Additional primer design and gap sequencing were required to complete the mitochondrial genome. The mitogenome of S. neumayeri is a circular DNA molecule with a length of 15 684 bp that contains all 37 genes normally found in metazoans. We detail the main features of the transcriptome and the mitogenome architecture and investigate the phylogenetic relationships of S. neumayeri within Echinoidea. In addition, we provide comparative analyses of S. neumayeri with its closest relative, Strongylocentrotus purpuratus, including a list of potential OA gene targets. The resources described here will support a variety of quantitative (genomic, proteomic, multistress and comparative) studies to interrogate physiological responses to OA and other stressors in this important Antarctic calcifier. PMID- 25143046 TI - Practice guidelines in the context of primary care, learning and usability in the physicians' decision-making process--a qualitative study. AB - BACKGROUND: Decision-making is central for general practitioners (GP). Practice guidelines are important tools in this process but implementation of them in the complex context of primary care is a challenge. The purpose of this study was to explore how GPs approach, learn from and use practice guidelines in their day-to day decision-making process in primary care. METHOD: A qualitative approach using focus-group interviews was chosen in order to provide in-depth information. The participants were 22 GPs with a median of seven years of experience in primary care, representing seven primary healthcare centres in Stockholm, Sweden in 2011. The interviews focused on how the GPs use guidelines in their decision-making, factors that influence their decision how to approach these guidelines, and how they could encourage the learning process in routine practice.Data were analysed by qualitative content analysis. Meaning units were condensed and grouped in categories. After interpreting the content in the categories, themes were created. RESULTS: Three themes were conceptualized. The first theme emphasized to use guidelines by interactive contextualized dialogues. The categories underpinning this theme: 1. Feedback by peer-learning 2. Feedback by collaboration, mutual learning, and equality between specialties, identified important ways to achieve this learning dialogue. Confidence was central in the second theme, learning that establishes confidence to provide high quality care. Three aspects of confidence were identified in the categories of this theme: 1. Confidence by confirmation, 2. Confidence by reliability and 3. Confidence by evaluation of own results. In the third theme, learning by use of relevant evidence in the decision-making process, we identified two categories: 1. Design and lay-out visualizing the evidence 2. Accessibility adapted to the clinical decision-making process as prerequisites for using the practice guidelines. CONCLUSIONS: Decision-making in primary care is a dual process that involves use of intuitive and analytic thinking in a balanced way in order to provide high quality care. Key aspects of effective learning in this clinical decision-making process were: contextualized dialogue, which was based on the GPs' own experiences, feedback on own results and easy access to short guidelines perceived as trustworthy. PMID- 25143047 TI - Who's behind that mask and cape? The Asian leopard cat's Agouti (ASIP) allele likely affects coat colour phenotype in the Bengal cat breed. AB - Coat colours and patterns are highly variable in cats and are determined mainly by several genes with Mendelian inheritance. A 2-bp deletion in agouti signalling protein (ASIP) is associated with melanism in domestic cats. Bengal cats are hybrids between domestic cats and Asian leopard cats (Prionailurus bengalensis), and the charcoal coat colouration/pattern in Bengals presents as a possible incomplete melanism. The complete coding region of ASIP was directly sequenced in Asian leopard, domestic and Bengal cats. Twenty-seven variants were identified between domestic and leopard cats and were investigated in Bengals and Savannahs, a hybrid with servals (Leptailurus serval). The leopard cat ASIP haplotype was distinguished from domestic cat by four synonymous and four non-synonymous exonic SNPs, as well as 19 intronic variants, including a 42-bp deletion in intron 4. Fifty-six of 64 reported charcoal cats were compound heterozygotes at ASIP, with leopard cat agouti (A(P) (be) ) and domestic cat non-agouti (a) haplotypes. Twenty-four Bengals had an additional unique haplotype (A2) for exon 2 that was not identified in leopard cats, servals or jungle cats (Felis chaus). The compound heterozygote state suggests the leopard cat allele, in combination with the recessive non-agouti allele, influences Bengal markings, producing a darker, yet not completely melanistic coat. This is the first validation of a leopard cat allele segregating in the Bengal breed and likely affecting their overall pelage phenotype. Genetic testing services need to be aware of the possible segregation of wild felid alleles in all assays performed on hybrid cats. PMID- 25143048 TI - Eliminating radiotherapy to the contralateral retropharyngeal and high level II lymph nodes in head and neck squamous cell carcinoma is safe and improves quality of life. AB - BACKGROUND: Radiation treatment volumes in head and neck squamous cell carcinoma (HNSCC) are controversial. The authors report the outcomes, patterns of failure, and quality of life (QOL) of patients who received treatment for HNSCC using intensity-modulated radiation therapy (IMRT) that eliminated the treatment of contralateral retropharyngeal lymph nodes (RPLNs) in the clinically uninvolved neck. METHODS: A prospective institutional database was used to identify patients who had primary oral cavity, oropharyngeal, hypopharyngeal, laryngeal, and unknown primary HNSCC for which they received IMRT. There were 3 temporal groups (generations 1-3). Generation 1 received comprehensive neck IMRT with parotid sparing, generation 2 eliminated the contralateral high level II (HLII) lymph nodes, and generation 3 further eliminated the contralateral RPLNs in the clinically uninvolved neck. Patterns of failure and survival analyses were completed, and QOL data measured using the MD Anderson Dysphagia Inventory were compared in a subset of patients from generations 1 and 3. RESULTS: In total, 748 patients were identified. Of the 488 patients who received treatment in generation 2 or 3, 406 had a clinically uninvolved contralateral neck. There were no failures in the spared RPLNs (95% confidence interval, 0%-1.3%) or in the high contralateral neck (95% confidence interval, 0%-0.7%). QOL data were compared between 44 patients in generation 1 and 51 patients in generation 3. QOL improved both globally and in all domains assessed for generation 3, in which reduced radiotherapy volumes were used (P < .007). CONCLUSIONS: For patients with locally advanced HNSCC, eliminating coverage to the contralateral HLII lymph nodes and contralateral RPLNs in the clinically uninvolved side of the neck is associated with minimal risk of failure in these regions and significantly improved patient reported QOL. PMID- 25143049 TI - Incidence and Survival of Pediatric Soft Tissue Sarcomas: Comparison between Adults and Children. AB - PURPOSE: Pediatric-type sarcomas such as rhabdomyosarcoma (RMS), Ewing sarcoma (EWS), primitive neuroectodermal tumor (PNET), and desmoplastic small round-cell tumor (DSRCT) are rare in adults, with limited studies on their prognosis and optimal treatment strategies. We aimed to examine the outcome of children and adult patients with RMS, EWS, PNET, and DSRCT and relevant prognostic factors. MATERIALS AND METHODS: We retrospectively reviewed 220 pediatric-type sarcoma patients at a single institution between 1985 and 2011. Comparisons were made in order to examine differences in demographics, disease characteristics, and survival. Survival analyses were performed using the Kaplan-Meier method with log rank tests and Cox proportional hazards models. RESULTS: A total of 220 consecutive patients were identified at our institute. Median age was 15.6 years (range, 0 to 81 years) and there were 108 children (49%) and 112 adult patients (51%). According to histological classification, 106 patients (48.2%) had RMS, 60 (27.3%) had EWS, 50 (22.7%) had PNET, and 4 (1.8%) had DSRCT. With a median follow-up period of 6.6 years, the estimated median overall survival (OS) of all patients was 75 months (95% confidence interval [CI], 27.2 to 122.8 months) and median event-free survival (EFS) for all patients was 11 months (95% CI, 8.8 to 13.2 months). No significant difference in OS and EFS was observed between adults and children. In multivariate analysis, distant metastasis (hazard ratio [HR], 1.617; 95% CI, 1.022 to 2.557; p=0.040) and no debulking surgery (HR, 1.443; 95% CI, 1.104 to 1.812; p=0.012) showed independent association with worse OS. CONCLUSION: Metastatic disease and no surgical treatment are poor prognostic factors for OS among pediatric-type sarcomas for both adults and children. PMID- 25143050 TI - A Phase I/II Trial to Evaluate the Technical Feasibility of Partial Breast Irradiation with Three-Dimensional Conformal Radiation Therapy in Korean Women with Stage I Breast Carcinoma: An Initial Report of the Korean Radiation Therapy Oncology Group (KROG) Study 0804. AB - PURPOSE: This prospective study was designed to verify the technical feasibility of partial breast irradiation in breast cancer patients with small breasts, which are commonly encountered in Korean women. MATERIALS AND METHODS: A total of 40 Gy, administered in 10 fractions on consecutive days (one fraction per day), was prescribed to the isocenters of the fields using three-dimensional conformal radiotherapy (3-DCRT). For all patients, treatment planning and dose parameters strictly adhered to the constraints set forth in the Radiation Therapy Oncology Group (RTOG) 0319 protocol. This study was designed such that if fewer than five of the first 42 evaluable patients received unacceptable scores, the treatment would be considered reproducible. RESULTS: Ten treatment plans (23.8%) were determined to have major variations. There was no major variation in planning target volume (PTV) coverage. The ipsilateral and contralateral breast dose limitations were not met in four (9.5%) and four cases (9.5%), respectively. Major variations in ipsilateral and contralateral lung dose limitations were observed in two cases (4.8%). Major variations in the heart and thyroid dose limitations were observed in one (2.4%) and one case (2.4%), respectively. In multivariate analysis, a ratio of PTV to ipsilateral breast volume (PTV/IB) > 0.16 was the only significant factor that statistically affected major variations. CONCLUSION: We concluded that partial breast irradiation using 3-DCRT could not be reproduced in Korean breast cancer patients, particularly small volumed breast surrogated as PTV/IB > 0.16. The dominant cause was the major variation in surrounding normal breast tissues. PMID- 25143051 TI - Changes in the mean corpuscular volume after capecitabine treatment are associated with clinical response and survival in patients with advanced gastric cancer. AB - PURPOSE: Capecitabine is known to increase mean corpuscular volume (MCV). To define the incidence of capecitabine-induced macrocytosis and its association with chemotherapy outcomes, we investigated data of 89 patients with advanced gastric cancer (AGC) who were enrolled in a randomized chemotherapy trial involving capecitabine. MATERIALS AND METHODS: Chemotherapy-naive AGC patients were treated with capecitabine (1,000 mg/m(2)/day on days 1-14) plus cisplatin (75 mg/m(2) on day 1), with or without epirubicin (50 mg/m(2) on day 1). Complete blood counts including MCV were measured at baseline and on day 1 of each 3-week chemotherapy course. Macrocytosis was defined as a MCV increase > 10 fL from baseline. Multivariate Cox proportional hazards models were used for analysis of the impact of clinical and MCV values on chemotherapy outcomes. RESULTS: At baseline, the mean MCV was 88.2 fL (normal range, 80 to 100 fL). During chemotherapy, MCV increased in a dose-dependent manner with a mean increase of 11.3 fL. MCV elevation after capecitabine treatment in 74 patients (90%) and 44 patients (42%) developed macrocytosis. RESULTS: of multivariate analysis showed that development of macrocytosis was independent of baseline hemoglobin level, liver metastasis, performance status, or liver function. The number of chemotherapy cycles showed strong association with development of macrocytosis and hematologic adverse events. In addition, a significant association was observed between macrocytosis and clinical response or survival. CONCLUSION: Macrocytosis developed with more frequent and prolonged use of capecitabine. It is possible that association with treatment outcomes warrants further investigation. PMID- 25143053 TI - Hybrid SPECT/CT imaging in neurology. AB - In recent years, the SPECT/CT hybrid modality has led to a rapid development of imaging techniques in nuclear medicine, opening new perspectives for imaging staff and patients as well. However, while, the clinical role of positron emission tomography-computed tomography (PET-CT) is well consolidated, the diffusion and the consequent value of single-photon emission tomography-computed tomography (SPECT-CT) has yet to be weighed, Hence, there is a need for a careful analysis, comparing the "potential" benefits of the hybrid modality with the "established" ones of the standalone machine. The aim of this article is to analyze the impact of this hybrid tool on the diagnosis of diseases of the central nervous system, comparing strengths and weaknesses of both modalities through the use of SWOT analysis. PMID- 25143052 TI - Identification of hypoxanthine and phosphoenolpyruvic Acid as serum markers of chemoradiotherapy response in locally advanced rectal cancer. AB - PURPOSE: Patients show variable responses to chemoradiotherapy (CRT), which is generally administered before surgery for locally advanced rectal cancer (LARC). The aim of this study was to identify molecular markers predictive of CRT responses by analysis of low-mass ions (LMIs) in serum of LARC patients. MATERIALS AND METHODS: LMIs (< 1,000 m/z) in serum obtained before CRT from 73 LARC (cT3-4) patients were profiled using matrix-assisted laser desorption/ionization mass spectrometry. LMIs with higher weighting factors in discriminating CRT responses were selected using principal components analysis and discriminant analysis. Selected LMIs were identified using the Human Metabolome Database. The concentrations of identified LMIs were determined by colorimetric enzyme assay, and compared according to post-CRT pathological stage (ypStage) or Dworak's tumor regression grade (TRG). RESULTS: The nine highest ranking LMIs were selected. Among them, two LMIs with 137.08 and 169.04 m/z were identified as hypoxanthine (HX) and phosphoenolpyruvic acid (PEP), respectively. Higher HX concentration was observed in patients with ypStage 0-1 compared to ypStage 2-4 (p=0.034) or ypStage 3-4 (p=0.030); a similar difference was observed between TRG 4-3 and TRG 1 (p=0.035). HX > 16.0 MUM showed significant association with ypStage 0-1 or TRG 4-3 than ypStage 3-4 (p=0.009) or TRG 1 (p=0.024), respectively. In contrast, a significantly lower concentration of PEP was observed in TRG 4-3 compared with TRG 2-1 (p=0.012). CONCLUSION: Findings of this study demonstrated that serum concentrations of HX and PEP, identified using LMI profiling, may be useful for predicting the CRT response of LARC patients before treatment. PMID- 25143054 TI - Accelerated labeling methods and syntheses of radiotracers utilizing microfluidic technology. AB - Positron emission tomography [PET] is a powerful nuclear clinical imaging technique used for the detection and treatment of central nervous system (CNS) disorders, cardiovascular diseases, and certain cancers. Due to the often short half-lives of the radiolabeled compounds employed, the availability of relevant tracers is severely limited. Through the use of microfluidic techniques many of the limitations of conventional synthesis of radiotracers are alleviated, paving the way for diverse families of compounds to be developed with defined targets for imaging. This review will survey syntheses of various radiotracers using new microfluidic techniques being developed. PMID- 25143056 TI - Tissue cell assisted fabrication of tubular catalytic platinum microengines. AB - We report a facile platform for mass production of robust self-propelled tubular microengines. Tissue cells extracted from fruits of banana and apple, Musa acuminata and Malus domestica, are used as the support on which a thin platinum film is deposited by means of physical vapor deposition. Upon sonication of the cells/Pt-coated substrate in water, microscrolls of highly uniform sizes are spontaneously formed. Tubular microengines fabricated with the fruit cell assisted method exhibit a fast motion of ~100 bodylengths per s (~1 mm s(-1)). An extremely simple and affordable platform for mass production of the micromotors is crucial for the envisioned swarms of thousands and millions of autonomous micromotors performing biomedical and environmental remediation tasks. PMID- 25143055 TI - Low virulent infectious salmon anaemia virus (ISAV) replicates and initiates the immune response earlier than a highly virulent virus in Atlantic salmon gills. AB - Observations from the field and experimental evidence suggest that different strains of infectious salmon anaemia virus (ISAV) can induce disease of varying severity in Atlantic salmon. Variation in host mortality and dissemination of ISAV isolates with high and low virulence was investigated using immersion challenge; from which mortality, pathological, immunohistochemical and preliminary molecular results have been previously published. Here, real-time RT PCR analysis and statistical modelling have been used to further investigate variation in virus load and the response of four select immune genes. Expression of type I and II interferon (IFN), Mx and gammaIFN induced protein (gammaIP) to high and low pathogenic virus infection were examined in gill, heart and anterior kidney. In addition, a novel RNA species-specific assay targeting individual RNA types was used to investigate the separate viral processes of transcription and replication. Unexpectedly, the low virulent ISAV (LVI) replicated and transcribed more rapidly in the gills compared to the highly virulent virus (HVI). Subsequently LVI was able to disseminate to the internal organs more quickly and induced a more rapid systemic immune response in the host that may have offered some protection. Contrary to this, HVI initially progressed more slowly in the gills resulting in a slower generalised infection. However HVI ultimately reached a higher viral load and induced a greater mortality. PMID- 25143057 TI - High-temperature inhibition of biosynthesis and transportation of anthocyanins results in the poor red coloration in red-fleshed Actinidia chinensis. AB - In plants, the role of anthocyanins trafficking in response to high temperature has been rarely studied, and therefore poorly understood. Red-fleshed kiwifruit has stimulated the world kiwifruit industry owing to its appealing color. However, fruit in warmer climates have been found to have poor flesh coloration, and the factors responsible for this response remain elusive. Partial correlation and regression analysis confirmed that accumulative temperatures above 25 degrees C (T25) was one of the dominant factors inhibiting anthocyanin accumulation in red-fleshed Actinidia chinensis, 'Hongyang'. Expression of structural genes, AcMRP and AcMYB1 in inner pericarp sampled from the two high altitudes (low temperature area), was notably higher than the low altitude (high temperature area) during fruit coloration. AcMYB1 and structural genes coordinate expression supported the MYB-bHLH (basic helix-loop-helix)-WD40 regulatory complex mediated downregulation of anthocyanin biosynthesis induced by high temperatures in kiwifruit. Moreover, cytological observations using the light and transmission electronic microscopy showed that there were a series of anthocyanic vacuolar inclusion (AVI)-like structures involved in their vacuolization process and dissolution of the pigmented bodies inside cells of fruit inner pericarp. Anthocyanin transport was inhibited by high temperature via retardation of vacuolization or reduction in AIV-like structure formation. Our findings strongly suggested that complex multimechanisms influenced the effects of high temperature on red-fleshed kiwifruit coloration. PMID- 25143058 TI - Multi-stress resistance in Lactococcus lactis is actually escape from purine induced stress sensitivity. AB - Multi-stress resistance is a widely documented and fascinating phenotype of lactococci where single mutations, preferentially in genes involved in nucleotide metabolism and phosphate uptake, result in elevated tolerance to multiple stresses simultaneously. In this report, we have analysed the metabolic basis behind this multi-stress-resistance phenotype in Lactococcus lactis subsp. cremoris MG1363 using acid stress as a model of multi-stress resistance. Surprisingly, we found that L. lactis MG1363 is fully resistant to pH 3.0 in the chemically defined SA medium, contrary to its sensitivity in the rich and complex M17 medium. When salvage of purines and subsequent conversion to GTP was permitted in various genetic backgrounds of L. lactis MG1363, the cells became sensitive to acid stress, indicating that an excess of guanine nucleotides induces stress sensitivity. The addition of phosphate to the acid-stress medium increased the stress sensitivity of L. lactis MG1363. It is also shown that high intracellular guanine nucleotide pools confer increased sensitivity to high temperatures, thus showing that it is indeed a multi-stress phenotype. Our analysis suggests that an increased level of guanine nucleotides is formed as a result of an improved conversion of guanosine in the salvage pathway. Based upon our findings, we suggest that L. lactis MG1363 is naturally multi-stress resistant in habitats devoid of any purine source. However, any exogenous purine that results in increased guanine nucleotide pools renders the bacterium sensitive to environmental stresses. PMID- 25143059 TI - Microstructure, microbial profile and quality characteristics of high-pressure treated chicken nuggets. AB - High-pressure processing (300 MPa for 5 min) as a non-thermal post-processing intervention was employed to improve the shelf life and qualities of cooked refrigerated chicken nuggets. Pomegranate peel extract (1%) was also used as a source of natural antioxidant and antimicrobial in chicken nuggets. Microstructure, microbial profile, instrumental colour, texture profile and lipid oxidation were evaluated. High-pressure treatment and pomegranate peel extract did not influence significantly the colour and textural properties of cooked chicken nuggets. Thiobarbituric acid reactive substance values significantly (p < 0.05) increased in pressure-treated nuggets. Microstructural studies revealed shrinkage in the structure and loosening of the dense network of meat emulsion due to high-pressure treatment. Pressure treatment resulted in a reduction of 2 3.0 log10 cfu/g in total plate count and Enterobacteriaceae count. Molecular characterization studies revealed that Enterobacter amnigenus and Enterobacter sp. in control and Bacillus licheniformis, Enterococcus gallinarum and Acinetobacter baumannii in high-pressure-treated chicken nuggets were the major spoilage bacteria. PMID- 25143060 TI - Evaluation of contrast Sonazoid-enhanced ultrasonography for the detection of hepatic metastases in breast cancer. AB - BACKGROUND: The present study was aimed to evaluate the usefulness of contrast Sonazoid-enhanced ultrasonography (US) for the detection of hepatic metastases in breast cancer patients and compare the clinical efficacy and sensitivity of this technique with conventional contrast unenhanced B-mode US in follow-up examinations of breast cancer patients with liver metastasis. METHODS: We assessed a total of 84 hepatic tumors from 24 patients diagnosed with or suspected of having metastatic cancer. These hepatic nodules were diagnosed through imaging, including dynamic magnetic resonance imaging (MRI), contrast enhanced computed tomography (CECT) scan, B-mode US or contrast Sonazoid-enhanced US (SEUS). Differences in the sensitivity between US and SEUS were compared using MR imaging, CECT, and follow-up imaging. RESULTS: A total of 79 nodules were diagnosed as metastatic tumors. The remaining nodules were diagnosed as benign tumors (hepatic hemangioma: n = 3; local fatty change: n = 2). SEUS precisely detected the presence or absence of hepatic tumors in the 24 patients examined, showing a sensitivity of 98.8 % (83 of 84 lesions) for total imaged solid liver lesions, with an accuracy of 98.7 % (78 of 79 lesions) for total metastatic breast cancer lesions. In contrast, conventional B-mode US imaging revealed hepatic tumor lesions at a sensitivity of 66.7 % (56 of 84 lesions) and an accuracy of 64.6 % (51 of 79 lesions), respectively. Furthermore, the false positive and false negative rates were, respectively, 6.33 and 29.1 % for B-mode US and 0 and 1.3 % for SEUS. Moreover, twenty-seven metastatic tumors and five benign lesions (3 hemangiomas and 2 focal fatty changes/sparings) were imaged using SEUS but not conventional B-mode US. Significant differences in diagnostic accuracy rates between contrast Sonazoid-enhanced US and conventional B-mode US were observed (Wilcoxon signed rank test: p = 0.0009). No severe adverse events occurred during SEUS after the administration of Sonazoid, except for a grade 1 skin reaction and nausea in one patient. CONCLUSION: These results suggested that Sonazoid could be safely administrated to breast cancer patients with liver metastatic disease. Thus, contrast Sonazoid-enhanced US is a feasible and more effective method than B-mode US for the detection of hepatic metastasis, particularly for small metastatic breast cancer lesions less than 14 mm in diameter, showing significant high sensitivity and accuracy. PMID- 25143061 TI - A telephone-based motivational interviewing intervention has positive effects on psoriasis severity and self-management: a randomized controlled trial. AB - BACKGROUND: Psoriasis is a common skin disease with extensive comorbidity risks, which may affect multiple aspects of life. Self-management is essential for skin treatment and lifestyle choices, but few disease-specific tailored self management and educational programmes appear to be available. OBJECTIVES: To evaluate the effects of a 3-month individual motivational interviewing intervention in patients with psoriasis (with a total follow-up of 6 months) after climate therapy/heliotherapy (CHT). METHODS: A randomized controlled trial with 169 patients with psoriasis was conducted in the context of CHT at Gran Canaria, Spain. The main outcome measures were Self-Administered Psoriasis Area and Severity Index (SAPASI) and Health Education Impact Questionnaire (heiQ), and the secondary outcomes were illness perception, psoriasis knowledge and lifestyle change assessments. Outcomes were measured at baseline, after 3 weeks of CHT, and 3 months and 6 months later. RESULTS: There were significant overall treatment effects in the study group in terms of the SAPASI score, three self-management domains of heiQ and the self-efficacy scores (P < 0?05). The lifestyle change parameters were significantly better in the study group. Illness perception differed between the groups at 3 months (P = 0?014), and psoriasis knowledge was significantly better in the study group at 6 months (P = 0?017). CONCLUSIONS: A 3 month motivational interviewing intervention following CHT had positive overall effects on disease severity, self-efficacy, psoriasis knowledge and health behaviour change. This approach has the potential to be an important complement to medical management, self-management and education in patients with psoriasis. PMID- 25143062 TI - Impact of the periconceptional environment on the programming of adult disease. AB - The periconceptional period of mammalian development has been identified as an early 'developmental window' during which environmental conditions may influence the pattern of future growth and physiology. Studies in humans and animal models have revealed that factors such as maternal nutritional status or in vitro culture and manipulation of developing gametes and preimplantation embryos can impact upon the long-term health and physiology of the offspring. However, the mechanisms involved in the programming of adult disease in response to altered periconceptional development require increased investigation. The role of epigenetic modifications to DNA and chromatin organisation has been identified as a likely mechanism through which environmental perturbations can affect gene expression patterns resulting in phenotypic change. This study will highlight the sensitivity of two critical stages in early mammalian development, gametogenesis and preimplantation development. We will detail how changes to the immediate environment can not only impact upon developmental processes taking place at that time, but can also affect long-term aspects of offspring health and physiology. We will also discuss the emerging role of epigenetics as a mechanistic link between the environment and the later phenotype of the developing organism. PMID- 25143063 TI - Genetic influences on the association between fetal growth and susceptibility to type 2 diabetes. AB - The fetal insulin hypothesis proposes that low birth weight and susceptibility to type 2 diabetes (T2D) could both be two phenotypes of the same genotype. Insulin is a key growth factor in utero, and T2D is characterized by insulin resistance and/or beta-cell dysfunction. Therefore, genetic variants impacting on insulin secretion and action are likely to alter both fetal growth and susceptibility to T2D. There are three lines of evidence in support of this hypothesis. (1) Studies of rare monogenic diabetes have shown mutations in a single gene, such as GCK or KCNJ11, can cause diabetes by reducing insulin secretion, and these mutations are also associated with reduced birth weight. (2) Epidemiological studies have indicated that children born to fathers with diabetes are born smaller. As the father cannot influence the intrauterine environment, this association is likely to reflect genes inherited by the fetus from the father. (3) The most compelling evidence comes from recent genome-wide association studies. Variants in the CDKAL1 and HHEX-IDE genes that predispose to diabetes, if present in the fetus, are associated with reduced birth weight. These data provide evidence for a genetic contribution to the association between low birth weight and susceptibility to T2D. This genetic background is important to take into consideration when investigating the impact of environmental determinants and developing strategies for intervention and prevention. PMID- 25143064 TI - Agreement between self-reported birth weight and birth certificate weights. AB - Birth weight is emerging as a potentially important risk factor for several chronic diseases with adult onset, including breast cancer. Because participant recall is frequently used to gather data on early life exposures, it is essential that the accuracy of recall be assessed and validated. Self-reported birth weights and birth certificate weights were compared in women aged 35-51 years from the Western New York Exposures and Breast Cancer (WEB) Study, a population based case-control study. A total of 180 participants had both birth certificate and interview data on birth weight. Participants reported birth weight to one of six categories (<5, 5-5.5, 5.6-7, 7.1-8.5, 8.6-10 and >10 lbs). The Spearman correlation for self-reported and birth certificate weights was 0.67. Sixty percent of participants reported weights with exact agreement with birth certificate; unweighted and weighted kappas (kappa) were 0.39 and 0.68, respectively. Spearman correlations were similar for cases (0.67) and controls (0.68). Controls exhibited a significantly higher unweighted kappa (0.51) than cases (0.27; P = 0.03), but weighted kappa were not statistically different [controls, 0.73; cases, 0.64 (P = 0.32)]. Demographic and anthropometric characteristics were not different between participants who underreported, overreported, or correctly reported their birth weight for either cases or controls. Overall, the level of agreement for report of birth weight and actual birth weight was fair to moderate. PMID- 25143065 TI - Size at birth is associated with blood pressure but not insulin resistance in 6-8 year old children in rural Nepal. AB - Earlier, we reported that antenatal micronutrient supplementation reduced the risk of metabolic syndrome and microalbuminuria among offspring at 6-8 years of age in rural Nepal. In the same birth cohort, we examined associations of size at birth (weight, length and ponderal index), and gestational age, with cardiometabolic risk factors in childhood across all antenatal micronutrient interventions. There was an inverse association between birth weight and systolic blood pressure (SBP, beta = -1.20 mm Hg/kg; 95% confidence interval (CI): -1.93, 0.46) and diastolic blood pressure (DBP, beta = -1.24 mm Hg/kg; 95% CI: -2.00, 0.49). Current child body mass index was positively associated with SBP but not with DBP. Birth weight was unassociated with insulin resistance, but each kilogram of increase was associated with a reduced risk of high triglycerides (odds ratio (OR) = 0.64/kg; 95% CI: 0.41, 0.97) and an increased risk of high waist circumference (OR = 3.16/kg; 95% CI: 2.47, 4.41). In this rural Nepalese population of children 6-8 years of age with a high prevalence of undernutrition, size at birth was inversely associated with blood pressure and triglycerides and positively associated with waist circumference. PMID- 25143066 TI - Birth weights smaller or larger than the placenta predict BMI and blood pressure at age 7 years. AB - We hypothesized that the altered placental proportions that influence birth weight affect childhood body proportions, and that these effects would be independent of birth weight. We also hypothesized that altered placental proportions might affect the fetal cardiovascular system, and may be reflected in variation in childhood blood pressure. By using linear regression with birth weight as the dependent variable, placental variables were entered as predictors. The predicted birth weights based on placental factors were then obtained. The ratio of the actual birth weight to that predicted by placental parameters (observed/expected ratio, OER) was used as the independent variable in analyses of age 7 year body mass index (BMI) and diastolic blood pressure (DBP) in the 15,902 singleton liveborns delivered between 34 and 43 weeks. The standardized residual birth weight was also used as a variable to examine the effects of birth weight that is not consistent with placental parameters. For each unit increase in the OER, BMI at 7 years increased 1 kg/m2 (P < 0.0001). The OER also had a significant effect on DBP (beta = 4.52, P < 0.001) at 7 years of age but only among African-American children. Results for the standardized residual birth weight variable were consistent with the OER. All results were adjusted for gestational age, sex, socioeconomic status, African-American race and maternal pre-pregnancy BMI. Being larger or smaller than predicted by one's placenta affects childhood body composition and blood pressure. The placental measurements provide insight into pathophysiological mechanisms of the developmental origins of adult disease. PMID- 25143067 TI - Maternal copper deficiency perpetuates altered vascular function in Sprague Dawley rat offspring. AB - Little is known about the consequences of maternal copper (Cu) deficiency on the vascular function of offspring or on perpetuation of vascular effects to a second generation. We examined vascular functional responses in mesenteric arteries from Cu-deficient Sprague-Dawley rat dams and from offspring directly exposed to maternal Cu deficiency during development and lactation and perpetuation of the effects in a second generation of offspring. Dams were fed a diet with marginal (1 mg Cu/kg) or adequate (6 mg Cu/kg) Cu for 3 weeks before conception and throughout pregnancy and lactation periods. Half of the first generation (F1) litters were cross-fostered. At reproductive maturity, F1 pairs were bred within groups resulting in second generation (F2) offspring. At 9 weeks of age, mesenteric artery (200 MUm) isometric tension was determined in response to vasoconstrictors and vasorelaxants using a small artery wire myograph. Cu deficiency did not alter the vascular function in dams. In F1 offspring, increased responsiveness to potassium chloride in male offspring was due to direct exposure to maternal Cu deficiency in the birth mother, while enhanced endothelium-dependent relaxation responses in female offspring resulted from postnatal exposure to maternal Cu deficiency. Increased endothelium independent and decreased endothelium-dependent relaxation responses were identified in F2 Cu deficient male offspring. These data indicate that exposure to maternal Cu deficiency during critical windows of development alter the vascular function across two generations of offspring. PMID- 25143068 TI - A multispecies probiotic reduces oral Candida colonization in denture wearers. AB - PURPOSE: The prevalence of Candida infections has been rising with an increasingly aging population and a larger population of immunocompromised individuals. The use of probiotics may be an alternative approach to antifungal agents in the prevention and treatment of oral candidiasis. This study aimed to evaluate the short-term effect of probiotics in reducing the infection level of oral Candida in candidiasis-asymptomatic elderly denture wearers. MATERIALS AND METHODS: In a double-blind randomized study, 59 denture wearers harboring Candida spp. in the oral cavity with no clinical symptoms were allocated into two groups: probiotic and placebo. All patients were instructed to clean the denture daily. The probiotic group poured a capsule containing lyophilized Lactobacillus rhamnosus HS111, Lactobacillus acidophillus HS101, and Bifidobacterium bifidum daily on the palatal surface of the maxillary denture, whereas the placebo group was submitted to the same regimen using placebo capsules. Candida spp. infection levels were evaluated in palate mucosa samples obtained before and after a 5-week experimental period. RESULTS: All patients harbored Candida in the palate mucosa at baseline. Fifty-five individuals completed the experimental period. The detection rate of Candida spp. was 92.0% in the placebo group after the experimental period, whereas it was reduced to 16.7% in the probiotic group. The reduction promoted by the probiotic regimen was independent of baseline characteristics such as Candida infection level and colonizing species, age of denture, and other variables. CONCLUSION: The probiotic product was effective in reducing the colonization of the oral cavity with Candida in candidiasis asymptomatic elderly denture wearers, suggesting that this multispecies probiotic could be used to prevent oral candidiasis. CLINICAL IMPLICATIONS: Colonization of oral surfaces by Candida is considered a risk factor for invasive fungal infections. The use of a product with L. rhamnosus, L. acidophilus, and B. bifidum may represent an alternative treatment for reduction of Candida infections in elderly denture wearers. PMID- 25143070 TI - Knee flexion contracture in haemophilia: treatment with circular external fixator. AB - Haemophilia, a bleeding disorder, causes recurrent intra-articular bleeding of the joints result-ing in chronic haemophilic arthropathy with fixed knee flexion deformity. Mid-long-term results (between 2002 and 2006) of deformity correction in haemophilic patients with Ilizarov type circular external fixators were retrospectively evaluated. There were six patients (five haemophilia A and one haemophilia B). The mean age was 14.7 years (range, 8-22 years) at the time of initial surgery. The mean knee flexion contracture was 45 degrees (range, 30-75 degrees). The mean arc of motion was 58.3 degrees (range, 40-100) before the surgery. The mean duration of follow-up was 8 years (range, 5.5-10 years). The mean duration of external fixation was 4.4 months (range, 2.5-10.5 months). Full extension of the knee joint was obtained in all patients in the early postoperative period. No bleeding, neurological or vascular complications were encountered. The mean amount of recurrence in knee flexion contracture was 10 degrees (range, 0-15 degrees). The amount of the correction was significant (P = 0.0012) and the mean arc of motion was 51.6 degrees (range, 25-90 degrees) that show a decrease of 6.7 degrees (P = 0.04) at the end of follow-up. The circular external fixator is an important, safe and less invasive alternative surgical treatment modality with low recurrence rate. Using the external hinges and distraction during the correction has a protective effect on the joint. It requires a team-work consisting of a haematologist, an orthopaedic surgeon and a physical therapist. PMID- 25143069 TI - How does it STAC up? Revisiting the scaffolding theory of aging and cognition. AB - "The Scaffolding Theory of Aging and Cognition (STAC)", proposed in 2009, is a conceptual model of cognitive aging that integrated evidence from structural and functional neuroimaging to explain how the combined effects of adverse and compensatory neural processes produce varying levels of cognitive function. The model made clear and testable predictions about how different brain variables, both structural and functional, were related to cognitive function, focusing on the core construct of compensatory scaffolding. The present paper provides a revised model that integrates new evidence about the aging brain that has emerged since STAC was published 5 years ago. Unlike the original STAC model, STAC-r incorporates life-course factors that serve to enhance or deplete neural resources, thereby influencing the developmental course of brain structure and function, as well as cognition, over time. Life-course factors also influence compensatory processes that are engaged to meet cognitive challenge, and to ameliorate the adverse effects of structural and functional decline. The revised model is discussed in relation to recent lifespan and longitudinal data as well as emerging evidence about the effects of training interventions. STAC-r goes beyond the previous model by combining a life-span approach with a life-course approach to understand and predict cognitive status and rate of cognitive change over time. PMID- 25143071 TI - 89Zr-huJ591 immuno-PET imaging in patients with advanced metastatic prostate cancer. AB - PURPOSE: Given the bone tropism of prostate cancer, conventional imaging modalities poorly identify or quantify metastatic disease. (89)Zr-huJ591 positron emission tomography (PET) imaging was performed in patients with metastatic prostate cancer to analyze and validate this as an imaging biomarker for metastatic disease. The purpose of this initial study was to assess safety, biodistribution, normal organ dosimetry, and optimal imaging time post-injection for lesion detection. METHODS: Ten patients with metastatic prostate cancer received 5 mCi of (89)Zr-huJ591. Four whole-body scans with multiple whole-body count rate measurements and serum activity concentration measurements were obtained in all patients. Biodistribution, clearance, and lesion uptake by (89)Zr huJ591 immuno-PET imaging was analyzed and dosimetry was estimated using MIRD techniques. Initial assessment of lesion targeting of (89)Zr-huJ591 was done. Optimal time for imaging post-injection was determined. RESULTS: The dose was well tolerated with mild chills and rigors seen in two patients. The clearance of (89)Zr-huJ591 from serum was bi-exponential with biological half-lives of 7 +/- 4.5 h (range 1.1-14 h) and 62 +/- 13 h (range 51-89 h) for initial rapid and later slow phase. Whole-body biological clearance was 219 +/- 48 h (range 153-317 h). The mean whole-body and liver residence time was 78.7 and 25.6 h, respectively. Dosimetric estimates to critical organs included liver 7.7 +/- 1.5 cGy/mCi, renal cortex 3.5 +/- 0.4 cGy/mCi, and bone marrow 1.2 +/- 0.2 cGy/mCi. Optimal time for patient imaging after injection was 7 +/- 1 days. Lesion targeting of bone or soft tissue was seen in all patients. Biopsies were performed in 8 patients for a total 12 lesions, all of which were histologically confirmed as metastatic prostate cancer. One biopsy-proven lesion was not positive on (89)Zr-huJ591, while the remaining 11 lesions were (89)Zr-huJ591 positive. Two biopsy-positive nodal lesions were noted only on (89)Zr-huJ591 study, while the conventional imaging modality was negative. CONCLUSION: (89)Zr huJ591 PET imaging of prostate-specific membrane antigen expression is safe and shows good localization of disease in prostate cancer patients. Liver is the critical organ for dosimetry, and 7 +/- 1 days is the optimal imaging time. A larger study is underway to determine lesion detection in an expanded cohort of patients with metastatic prostate cancer. PMID- 25143072 TI - Quantitation of myocardial blood flow and myocardial flow reserve with 99mTc sestamibi dynamic SPECT/CT to enhance detection of coronary artery disease. AB - PURPOSE: Conventional dual-head single photon emission computed tomography (SPECT)/CT systems capable of fast dynamic SPECT (DySPECT) imaging have a potential for flow quantitation. This study introduced a new method to quantify myocardial blood flow (MBF) and myocardial flow reserve (MFR) with DySPECT scan and evaluated the diagnostic performance of detecting coronary artery disease (CAD) compared with perfusion using invasive coronary angiography (CAG) as the reference standard. METHODS: This study included 21 patients with suspected or known CAD who had received DySPECT, ECG-gated SPECT (GSPECT), and CAG (13 with >= 50% stenosis in any vessel; non-CAD group: 8 with patent arteries or < 50% stenosis). DySPECT and GSPECT scans were performed on a widely used dual-head SPECT/CT scanner. The DySPECT imaging protocol utilized 12-min multiple back-and forth gantry rotations during injections of (99m)Tc-sestamibi (MIBI) tracer at rest or dipyridamole-stress stages. DySPECT images were reconstructed with full physical corrections and converted to the physical unit of becquerels per milliliter. Stress MBF (SMBF), rest MBF (RMBF), and MFR were quantified by a one tissue compartment flow model using time-activity curves derived from DySPECT images. Perfusion images were processed for GSPECT scan and interpreted to obtain summed stress score (SSS) and summed difference score (SDS). Receiver-operating characteristic (ROC) analyses were conducted to evaluate the diagnostic performance of flow and perfusion. RESULTS: Using the criteria of >= 50% stenosis as positive CAD, areas under the ROC curve (AUCs) of flow assessment were overall significantly greater than those of perfusion. For patient-based analysis, AUCs for MFR, SMBF, SSS, and SDS were 0.91 +/- 0.07, 0.86 +/- 0.09, 0.64 +/- 0.12, and 0.59 +/- 0.13. For vessel-based analysis, AUCs for MFR, SMBF, SSS, and SDS were 0.81 +/- 0.05, 0.76 +/- 0.06, 0.62 +/- 0.07, and 0.56 +/- 0.08, respectively. CONCLUSION: The preliminary data suggest that MBF quantitation with a conventional SPECT/CT system and the flow quantitation method is a clinically effective approach to enhance CAD detection. PMID- 25143074 TI - Introduction to EANM guideline for the preparation of an Investigational Medicinal Product Dossier (IMPD). PMID- 25143073 TI - Ethnic comparison of pharmacokinetics of (18)F-florbetaben, a PET tracer for beta amyloid imaging, in healthy Caucasian and Japanese subjects. AB - PURPOSE: (18)F-Florbetaben is a positron emission tomography (PET) tracer indicated for imaging cerebral beta-amyloid deposition in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease and other causes of cognitive decline. The present study examined ethnic comparability of the plasma pharmacokinetics, which is the input to the brain, between Caucasian and Japanese subjects. METHODS: Two identical phase I trials were performed in 18 German and 18 Japanese healthy volunteers to evaluate the plasma pharmacokinetics of a single dose of 300 MBq (18)F-florbetaben, either of low (<=5 MUg, LD) or high (50-55 MUg, HD) mass dose. Pharmacokinetic parameters were evaluated based on the total (18)F radioactivity measurements in plasma followed by metabolite analysis using radio-HPLC. RESULTS: The pharmacokinetics of (18)F-florbetaben was characterized by a rapid elimination from plasma. The dose-normalized areas under the curve of (18)F-florbetaben in plasma as an indicator of the input to the brain were comparable between Germans (LD: 0.38 min/l, HD: 0.55 min/l) and Japanese (LD: 0.35 min/l, HD: 0.45 min/l) suggesting ethnic similarity, and the mass dose effect was minimal. A polar metabolite fraction was the main radiolabelled degradation product in plasma and was also similar between the doses and the ethnic groups. CONCLUSION: Absence of a difference in the pharmacokinetics of (18)F-florbetaben in Germans and Japanese has warranted further global development of the PET imaging agent. PMID- 25143075 TI - A viral transcription factor exhibits antiviral RNA silencing suppression activity independent of its nuclear localization. AB - Viral suppressors of RNA silencing (VSRs) are critical for the success of virus infection and efficient accumulation of virus progeny. The chrysanthemum virus B p12 protein acts as a transcription factor to regulate cell size and proliferation favourable for virus infection. Here, we showed that the p12 protein suppressed RNA silencing and was able to complement a VSR-deficient unrelated virus. Moreover, p12 counter-silencing activity could be uncoupled from its function as a transcription factor in the nucleus. The altered p12 protein, which lacked a nuclear localization signal and was not imported into the nucleus, was able to suppress RNA silencing as efficiently as the native protein. The data revealed new aspects of p12 functioning and identified a novel role for this viral zinc-finger transcription factor. The results provided a general insight into one of the activities of the p12 protein, which appeared to possess more than one function. PMID- 25143076 TI - Invasive crayfish as vectors of mercury in freshwater food webs of the Pacific Northwest. AB - Invasive species are important drivers of environmental change in aquatic ecosystems and can alter habitat characteristics, community composition, and ecosystem energetics. Such changes have important implications for many ecosystem processes, including the bioaccumulation and biomagnification of contaminants through food webs. Mercury concentrations were measured in 2 nonnative and 1 native crayfish species from western Oregon (USA). Nonnative red swamp crayfish had mercury concentrations similar to those in native signal crayfish (0.29 +/- 0.05 ug/g dry wt and 0.36 +/- 0.06 ug/g dry wt, respectively), whereas the nonnative ringed crayfish had lower mercury concentrations (0.10 +/- 0.02 ug/g dry wt) than either of the other species. The mean energy content of muscle was similar between the native signal crayfish and nonnative ringed crayfish but was significantly higher in the nonnative red swamp crayfish. Across species, mercury concentrations were negatively correlated with energy density. Such energetic differences could exacerbate changes in mercury transfer through trophic pathways of food webs, especially via alterations to the growth dynamics of consumers. Thus, it is important to consider the role of energy content in determining effective mercury exposure even when mercury concentrations on a per-unit mass basis do not differ between species. Environ Toxicol Chem 2014;33:2639-2645. Published 2014 Wiley Periodicals, Inc. on behalf of SETAC. This article is a US Government work and as such, is in the public domain in the United States of America. PMID- 25143077 TI - Finding the root. PMID- 25143078 TI - What goes up. PMID- 25143079 TI - Scale up the supply of experimental Ebola drugs. PMID- 25143092 TI - US drone research hits regulatory turbulence. PMID- 25143093 TI - Double threat for Tibet. PMID- 25143094 TI - Bone technique redrafts prehistory. PMID- 25143096 TI - NIH to probe racial disparity in grant awards. PMID- 25143097 TI - Lakes under the ice: Antarctica's secret garden. PMID- 25143098 TI - Microbiology: Microbiome science needs a healthy dose of scepticism. PMID- 25143102 TI - Ageing: Develop models of frailty. PMID- 25143103 TI - Non-native species: UK bill could prompt biodiversity loss. PMID- 25143104 TI - Archiving: Don't let microbial samples perish. PMID- 25143105 TI - Madagascar: Risk review is under way for invasive toad. PMID- 25143106 TI - Ageing: Research needs social science. PMID- 25143107 TI - Biogeochemistry: Microbes eat rock under ice. PMID- 25143108 TI - Palaeoanthropology: The time of the last Neanderthals. PMID- 25143109 TI - Molecular physics: Complexity trapped by simplicity. PMID- 25143110 TI - Population history: Human melting pots in Southeast Asia. PMID- 25143111 TI - Magneto-optical trapping of a diatomic molecule. AB - Laser cooling and trapping are central to modern atomic physics. The most used technique in cold-atom physics is the magneto-optical trap (MOT), which combines laser cooling with a restoring force from radiation pressure. For a variety of atomic species, MOTs can capture and cool large numbers of particles to ultracold temperatures (less than ~1 millikelvin); this has enabled advances in areas that range from optical clocks to the study of ultracold collisions, while also serving as the ubiquitous starting point for further cooling into the regime of quantum degeneracy. Magneto-optical trapping of molecules could provide a similarly powerful starting point for the study and manipulation of ultracold molecular gases. The additional degrees of freedom associated with the vibration and rotation of molecules, particularly their permanent electric dipole moments, allow a broad array of applications not possible with ultracold atoms. Spurred by these ideas, a variety of methods has been developed to create ultracold molecules. Temperatures below 1 microkelvin have been demonstrated for diatomic molecules assembled from pre-cooled alkali atoms, but for the wider range of species amenable to direct cooling and trapping, only recently have temperatures below 100 millikelvin been achieved. The complex internal structure of molecules complicates magneto-optical trapping. However, ideas and methods necessary for creating a molecular MOT have been developed recently. Here we demonstrate three dimensional magneto-optical trapping of a diatomic molecule, strontium monofluoride (SrF), at a temperature of approximately 2.5 millikelvin, the lowest yet achieved by direct cooling of a molecule. This method is a straightforward extension of atomic techniques and is expected to be viable for a significant number of diatomic species. With further development, we anticipate that this technique may be employed in any number of existing and proposed molecular experiments, in applications ranging from precision measurement to quantum simulation and quantum information to ultracold chemistry. PMID- 25143112 TI - Dietary specializations and diversity in feeding ecology of the earliest stem mammals. AB - The origin and radiation of mammals are key events in the history of life, with fossils placing the origin at 220 million years ago, in the Late Triassic period. The earliest mammals, representing the first 50 million years of their evolution and including the most basal taxa, are widely considered to be generalized insectivores. This implies that the first phase of the mammalian radiation- associated with the appearance in the fossil record of important innovations such as heterodont dentition, diphyodonty and the dentary-squamosal jaw joint--was decoupled from ecomorphological diversification. Finds of exceptionally complete specimens of later Mesozoic mammals have revealed greater ecomorphological diversity than previously suspected, including adaptations for swimming, burrowing, digging and even gliding, but such well-preserved fossils of earlier mammals do not exist, and robust analysis of their ecomorphological diversity has previously been lacking. Here we present the results of an integrated analysis, using synchrotron X-ray tomography and analyses of biomechanics, finite element models and tooth microwear textures. We find significant differences in function and dietary ecology between two of the earliest mammaliaform taxa, Morganucodon and Kuehneotherium--taxa that are central to the debate on mammalian evolution. Morganucodon possessed comparatively more forceful and robust jaws and consumed 'harder' prey, comparable to extant small-bodied mammals that eat considerable amounts of coleopterans. Kuehneotherium ingested a diet comparable to extant mixed feeders and specialists on 'soft' prey such as lepidopterans. Our results reveal previously hidden trophic specialization at the base of the mammalian radiation; hence even the earliest mammaliaforms were beginning to diversify- morphologically, functionally and ecologically. In contrast to the prevailing view, this pattern suggests that lineage splitting during the earliest stages of mammalian evolution was associated with ecomorphological specialization and niche partitioning. PMID- 25143113 TI - The timing and spatiotemporal patterning of Neanderthal disappearance. AB - The timing of Neanderthal disappearance and the extent to which they overlapped with the earliest incoming anatomically modern humans (AMHs) in Eurasia are key questions in palaeoanthropology. Determining the spatiotemporal relationship between the two populations is crucial if we are to understand the processes, timing and reasons leading to the disappearance of Neanderthals and the likelihood of cultural and genetic exchange. Serious technical challenges, however, have hindered reliable dating of the period, as the radiocarbon method reaches its limit at ~50,000 years ago. Here we apply improved accelerator mass spectrometry (14)C techniques to construct robust chronologies from 40 key Mousterian and Neanderthal archaeological sites, ranging from Russia to Spain. Bayesian age modelling was used to generate probability distribution functions to determine the latest appearance date. We show that the Mousterian ended by 41,030 39,260 calibrated years bp (at 95.4% probability) across Europe. We also demonstrate that succeeding 'transitional' archaeological industries, one of which has been linked with Neanderthals (Chatelperronian), end at a similar time. Our data indicate that the disappearance of Neanderthals occurred at different times in different regions. Comparing the data with results obtained from the earliest dated AMH sites in Europe, associated with the Uluzzian technocomplex, allows us to quantify the temporal overlap between the two human groups. The results reveal a significant overlap of 2,600-5,400 years (at 95.4% probability). This has important implications for models seeking to explain the cultural, technological and biological elements involved in the replacement of Neanderthals by AMHs. A mosaic of populations in Europe during the Middle to Upper Palaeolithic transition suggests that there was ample time for the transmission of cultural and symbolic behaviours, as well as possible genetic exchanges, between the two groups. PMID- 25143114 TI - A microbial ecosystem beneath the West Antarctic ice sheet. AB - Liquid water has been known to occur beneath the Antarctic ice sheet for more than 40 years, but only recently have these subglacial aqueous environments been recognized as microbial ecosystems that may influence biogeochemical transformations on a global scale. Here we present the first geomicrobiological description of water and surficial sediments obtained from direct sampling of a subglacial Antarctic lake. Subglacial Lake Whillans (SLW) lies beneath approximately 800 m of ice on the lower portion of the Whillans Ice Stream (WIS) in West Antarctica and is part of an extensive and evolving subglacial drainage network. The water column of SLW contained metabolically active microorganisms and was derived primarily from glacial ice melt with solute sources from lithogenic weathering and a minor seawater component. Heterotrophic and autotrophic production data together with small subunit ribosomal RNA gene sequencing and biogeochemical data indicate that SLW is a chemosynthetically driven ecosystem inhabited by a diverse assemblage of bacteria and archaea. Our results confirm that aquatic environments beneath the Antarctic ice sheet support viable microbial ecosystems, corroborating previous reports suggesting that they contain globally relevant pools of carbon and microbes that can mobilize elements from the lithosphere and influence Southern Ocean geochemical and biological systems. PMID- 25143115 TI - X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors. AB - Cys-loop receptors are neurotransmitter-gated ion channels that are essential mediators of fast chemical neurotransmission and are associated with a large number of neurological diseases and disorders, as well as parasitic infections. Members of this ion channel superfamily mediate excitatory or inhibitory neurotransmission depending on their ligand and ion selectivity. Structural information for Cys-loop receptors comes from several sources including electron microscopic studies of the nicotinic acetylcholine receptor, high-resolution X ray structures of extracellular domains and X-ray structures of bacterial orthologues. In 2011 our group published structures of the Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in complex with the allosteric partial agonist ivermectin, which provided insights into the structure of a possibly open state of a eukaryotic Cys-loop receptor, the basis for anion selectivity and channel block, and the mechanism by which ivermectin and related molecules stabilize the open state and potentiate neurotransmitter binding. However, there remain unanswered questions about the mechanism of channel opening and closing, the location and nature of the shut ion channel gate, the transitions between the closed/resting, open/activated and closed/desensitized states, and the mechanism by which conformational changes are coupled between the extracellular, orthosteric agonist binding domain and the transmembrane, ion channel domain. Here we present two conformationally distinct structures of C. elegans GluCl in the absence of ivermectin. Structural comparisons reveal a quaternary activation mechanism arising from rigid-body movements between the extracellular and transmembrane domains and a mechanism for modulation of the receptor by phospholipids. PMID- 25143118 TI - Early ventricular remodeling and dysfunction in obese children and adolescents. AB - OPINION STATEMENT: Obesity is an independent predictor of heart failure in adults. Obese individuals have increased hemodynamic load and neuro-hormonal activation that contribute, but cannot entirely explain the reported changes in ventricular structure and function leading to heart failure. There are intrinsic alterations in the myocardium that are independent of load. Insulin resistance promotes alterations in myocardial substrate metabolism that may play a role in the pathogenesis of decreased myocardial efficiency and cardiac dysfunction in obese individuals. The prevalence of obesity in childhood and adolescence has increased significantly over the last decade. Obese children and adolescents have left ventricular remodeling that transpires into adulthood, and subclinical systolic and diastolic dysfunction despite normal conventional parameters of ventricular function. These findings suggest that obesity has an early impact in the cardiovascular health of obese adolescents. Life-style modifications causing weight loss can reverse the ventricular dysfunction observed in this young population and must be strongly encouraged. PMID- 25143119 TI - Coarctation of the aorta: management, indications for intervention, and advances in care. AB - OPINION STATEMENT: Coarctation of the aorta (CoAo) accounts for 9 % of congenital heart defects. Balloon angioplasty has been the conventional endovascular treatment of choice for both native and recurrent coarctation in adults. Recent advancement in stent technology with the development of the covered stents has enhanced the scope for percutaneous management of both native CoAo and post surgical CoAo. Stent implantation provides better hemodynamic results with larger acute diameter gain and better long-term hemodynamic benefit. Stenting also decreases the incidence of aneurysm formation. The development of biodegradable stents may revolutionize the percutaneous management of coarctation, as the degradation of the stent scaffold within 6 months of implantation will further decrease the incidence of restenosis. In the future stenting may suffice and obviate the need for open repair. Until then, surgical repair of CoAo is the preferred method in both infants and complicated lesions, leaving stenting to adults with focal and uncomplicated disease. PMID- 25143121 TI - Practitioner review: Effective ingredients of prevention programs for youth at risk of persistent juvenile delinquency--recommendations for clinical practice. AB - BACKGROUND: There is a lack of knowledge about specific effective ingredients of prevention programs for youth at risk for persistent delinquent behavior. The present study combines findings of previous studies by examining the effectiveness of programs in preventing persistent juvenile delinquency and by studying which particular program, sample, and study characteristics contribute to the effects. Information on effective ingredients offers specific indications of how programs may be improved in clinical practice. METHOD: A literature search in PsychINFO, ERIC, PubMed, Sociological Abstracts, Criminal Justice Abstracts, and Google Scholar was performed. Only (quasi)experimental studies and studies that focused on adolescents at risk for (persistent) delinquent behavior were included. Multilevel meta-analysis was conducted on 39 studies (N = 9,084). Participants' ages ranged from 6 to 20 years (M = 14 years, SD = 2.45). RESULTS: The overall effect size was significant and small in magnitude (d = 0.24, p < .001). Behavioral-oriented programs, focusing on parenting skills training, behavioral modeling, or behavioral contracting yielded the largest effects. Multimodal programs and programs carried out in the family context proved to be more beneficial than individual and group-based programs. Less intensive programs yielded larger effects. CONCLUSIONS: Prevention programs have positive effects on preventing persistent juvenile delinquency. In order to improve program effectiveness, interventions should be behavioral-oriented, delivered in a family or multimodal format, and the intensity of the program should be matched to the level of risk of the juvenile. PMID- 25143120 TI - Childhood obesity and autonomic dysfunction: risk for cardiac morbidity and mortality. AB - OPINION STATEMENT: The epidemic of childhood obesity is becoming a major predictor for risk of cardiovascular diseases (CVD) and mortality during adulthood. Alterations in the morphology of the heart due to obesity could be a predictor for the dysfunction of cardiac autonomic modulation (CAM). A number of epidemiologic studies have evaluated the effect of obesity and CAM in children, finding that obesity impaired the balance of CAM toward a sympathetic overflow and reduced parasympathetic modulation, a significant predictor of CVD morbidity and mortality in adults. Lifestyle modifications, for example long-term exercise programs, have been shown to improve CAM in the obese. This review discusses the recent evidence on childhood and adolescent obesity and its impact on CAM, as well as how early lifestyle changes could help improve CAM, which may in turn reduce the burden of CVD in adults. PMID- 25143122 TI - Production of a plant-derived immunogenic protein targeting ApoB100 and CETP: toward a plant-based atherosclerosis vaccine. AB - In an effort to initiate the development of a plant-based vaccination model against atherosclerosis, a cholera toxin B subunit (CTB)-based chimeric protein was designed to target both ApoB100 and CETP epitopes associated with immunotherapeutic effects in atherosclerosis. Epitopes were fused at the C terminus of CTB to yield a protein called CTB:p210:CETPe. A synthetic gene coding for CTB:p210:CETPe was successfully transferred to tobacco plants with no phenotypic alterations. Plant-derived CTB:p210:CETPe was expressed and assembled in the pentameric form. This protein retained the target antigenic determinants, as revealed by GM1-ELISA and Western blot analyses. Higher expresser lines reached recombinant protein accumulation levels up to 10 ug/g fresh weight in leaf tissues and these lines carry a single insertion of the transgene as determined by qPCR. Moreover, when subcutaneously administered, the biomass from these CTB:p210:CETPe-producing plants was able to elicit humoral responses in mice against both ApoB100 and CETP epitopes and human serum proteins. These findings evidenced for the first time that atherosclerosis-related epitopes can be expressed in plants retaining immunogenicity, which opens a new path in the molecular farming field for the development of vaccines against atherosclerosis. PMID- 25143123 TI - Expression of a novel chimeric-truncated tPA in Pichia pastoris with improved biochemical properties. AB - Thrombolytic therapy by plasminogen activators (PAs) has been a main goal in the treatment of acute myocardial infarction. Despite improved outcomes of currently available thrombolytic therapies, all these agents have different drawbacks that may result in less than optimal outcomes. In order to make tissue plasminogen activator (tPA) more potent, while being more resistant to plasminogen activator inhibitor-1 (PAI-1) and having a higher affinity to fibrin, a new chimeric truncated form of tPA (CT tPA) was designed and expressed in Pichia pastoris. This novel variant consists of a finger domain of Desmoteplase, an epidermal growth factor (EGF) domain, a kringle 1 (K1) domain, a kringle 2 (K2) domain, in which the lysine binding site (LBS) was deleted, and a protease domain, where the four amino acids lysine 296, arginine 298, arginine 299, and arginine 304 were substituted by aspartic acid. The chimera CT tPA showed 14-fold increase in its activity in the presence of fibrin compared to the absence of fibrin. Furthermore, CT tPA showed about 10-fold more potency than commercially available full-length tPA (Actylase((r))) and provided 1.2-fold greater affinity to fibrin. A residual activity of only 68 % was observed after incubation of Actylase((r)) with PAI-1, however, 91 % activity remained for CT tPA. These promising findings suggest that the novel CT tPA variant might be an acceptable PA with superior characteristics and properties. PMID- 25143124 TI - Expression of developing neural transcription factors in lung carcinoid tumors. AB - In lung tumors, the association between carcinoids and high-grade neuroendocrine tumors (HGNETs) is controversial. To understand the phenotypic similarities/differences between lung carcinoids and HGNETs, we comparatively investigated the expression of three kinds of developing neural transcription factors (DNTFs: BRN2, TTF1 and ASCL1) and multiple endocrine neoplasia type 1 (MEN1) as well as RB1 and P53 using 18 carcinoids and 16 HGNETs. The DNTFs were expressed in 10 of the 18 carcinoids and in all the HGNETs, while normal neuroendocrine cells, which are considered the major cell origin of lung carcinoids and small cell carcinomas, did not express DNTFs. Both the DNTF(-) and DNTF(+) carcinoids contained typical and atypical carcinoids. All the DNTF(-) carcinoids examined were formed in the bronchial wall. All the MEN1(-) carcinoids examined were classified into the DNTF(-) carcinoids, while all the HGNETs expressed MEN1. This finding suggests that DNTF(-) MEN1(-) carcinoids are unlikely to be precursors of HGNETs. Although the status of RB1 and P53 between carcinoids and HGNETs were apparently different, the DNTF(+) carcinoids of two male patients and one female patient revealed morphologies resembling HGNET cells and relatively high Ki67 indices. Further investigation of DNTF expression in carcinoids might provide important clues to understand the association between carcinoids and HGNETs. PMID- 25143125 TI - Nested and microcystic variants of urothelial carcinoma displaying immunohistochemical features of basal-like urothelial cells: an immunohistochemical and histopathogenetic study. AB - Nested/microcystic (NV/MV) urothelial carcinoma (UC) variants are associated with mild cytologic atypia and commonly present at high-stage disease. The histopathogenesis is investigated using urothelial basal cell markers. Archival 14 NV/MV and three inverted papilloma (IP) were immunostained for CD44, cytokeratin 5 (CK5), CK34bE12 and p63. Twenty consecutive cases of invasive high grade UC including 14 superficial and 6 muscle-invasive UC cases were used as control. Immunostaining was scored as high for staining of full or more than 50% thickness of the epithelial nest or epithelium and low for lesser immunoreactivity and negative reactivity. All 14 NV/MV, 3 IP and 6 control cases showed a high score of immunoreactivity for CK5, CD44, CK34bE12 and focally for p63. The remaining control cases showed a high score of immunoreactivity for CK34bE12, while negative or low for CK5, CD44 and p63. In conclusion, immunoreactivity CK5 and CD44 commonly immunostained NV/MV and some invasive high grade UC. Other basal cell markers (CK34bE12 and p63) appear to be non specific or non sensitive. NV and MV and some UC likely represent a subset of UC displaying immunohistochemical features of urothelial basal cells. They had tendency of endophytic growth and early invasion despite the innocuous cytologic appearance. PMID- 25143126 TI - Prognostic significance of immunophenotypes and a nodular pattern in primary mediastinal large B-cell lymphoma. AB - To investigate the clinicopathological and prognostic significance of a nodular pattern and immunophenotypes in primary mediastinal large B-cell lymphoma (PMBL), histopathological features, including a nodular pattern and immunophenotypes, were analyzed in 58 Japanese PMBL patients. The patients were 23 men and 35 women with a median age of 31 years. The 4-year progression free survival (PFS) rate was 78%, and the 4-year overall survival (OS) rate was 89%. Among the histopathological and immunohistochemical features, Bcl6(+) (P = 0.013), MUM1(+) (P = 0.091), and pale cytoplasm (P = 0.064) were favorable prognostic indicators of PFS, and Bcl6(+) (P = 0.051) and MUM1(+) (P = 0.07) were favorable prognostic indicators of OS. Patients with Bcl2 negativity (n = 11) had 4-year PFS and OS rates of 100%. Histologically, a nodular pattern, resembling nodular sclerosis classical Hodgkin lymphoma (CHL), was observed in 22 patients (38%). However, this was not a significant prognostic indicator. In conclusion, Bcl6(+) , MUM1(+) , Bcl2(-) , and pale cytoplasm are candidate favorable prognostic indicators for PMBL and should be further examined in larger studies. We suggest that PMBL with a nodular pattern may belong to the same histological spectrum as nodular sclerosis CHL. PMID- 25143127 TI - Therapeutic effects of exon skipping and losartan on skeletal muscle of mdx mice. AB - Various attempts have been made to find treatments for Duchenne muscular dystrophy (DMD) patients. Exon skipping is one of the promising technologies for DMD treatment by restoring dystropin protein, which is one of the muscle components. It is well known that losartan, an angiotensin II type1 receptor blocker, promotes muscle regeneration and differentiation by lowering the level of transforming growth factor-beta1 signaling. In this study, we illustrated the combined effects of exon skipping and losartan on skeletal muscle of mdx mice. We supplied mdx mice with losartan for 2 weeks before exon skipping treatment. The losartan with the exon skipping group showed less expression of myf5 than the losartan treated group. Also the losartan with exon skipping group recovered normal muscle architecture, in contrast to the losartan group which still showed many central nuclei. However, the exon skipping efficiency and the restoration of dystrophin protein were lower in the losartan with exon skipping group compared to the exon skipping group. We reveal that losartan promotes muscle regeneration and shortens the time taken to restore normal muscle structure when combined with exon skipping. However, combined treatment of exon skipping and losartan decreases the restoration of dystrophin protein meaning decrease of exon skipping efficiency. PMID- 25143128 TI - Esophageal adenocarcinoma arising in cervical inlet patch with synchronous Barrett's esophagus-related dysplasia. AB - Esophageal adenocarcinomas usually develop in Barrett's esophagus, typically through the metaplasia-dysplasia-carcinoma sequence, but adenocarcinomas can occur from heterotopic gastric mucosa in cervical esophagus (inlet patch). This report describes the first case of synchronous presentation of adenocarcinoma arising from cervical inlet patch and Barrett's esophagus-related dysplasia in a 76-year-old man. Surveillance CT detected a 3-cm polypoid mass in the cervical esophagus. Endoscopic biopsies confirmed a diagnosis of adenocarcinoma of the cervical esophagus. Barrett's esophagus was present also in the lower esophagus. Histologic examination of the surgically resected specimen revealed the polypoid mass as composed of tubular adenocarcinoma, and was associated with non neoplastic columnar mucosa representing pre-existing inlet patch. Another isolated cervical inlet patch with intestinal metaplasia was also recognized. In the lower esophagus, high-grade dysplasia was noted within the Barrett's esophagus. Immunohistochemically, the adenocarcinoma associated with inlet patch had intestinal immunophenotype (CDX2-, CD10- and MUC2-positive), whereas the Barrett's esophagus-related high-grade dysplasia showed mixed immunophenotype (MUC5AC- and MUC6-positive, with scattered MUC2-positive goblet cells). Previous studies and our findings suggest that intestinal metaplasia might predispose to the development of adenocarcinoma in the inlet patch. Therefore, endoscopists and pathologists should be aware of rare malignant transformation of inlet patches, especially those with intestinal metaplasia. PMID- 25143129 TI - Gastric carcinoma with an invasive micropapillary carcinoma component showing HER2 gene amplification and CD10 expression: a case report and review of the literature. AB - An 81-year-old man was referred to our hospital because gastric cancer was detected on screening esophagogastroduodenoscopy. Surgical resection of the tumor was performed. It was 25 * 20 mm in size and swollen lymph nodes were present nearby. Lymphadenectomy was also performed. Histopathologically, the tumor reached the proper muscle layer via venous invasion. There were three components that constituted the tumor, that is, 40% of mass was invasive micropapillary carcinoma (IMPC), 40% was papillary adenocarcinoma and 20% tubular adenocarcinoma. Vascular invasion was prominent. Immunohistochemistry revealed that the tumor showed an entirely intestinal mucin phenotype, being positive only for CD10 and negative for MUC2, MUC5AC, and MUC6. HER2 staining score ranged from 2+ to 3+, depending on the components described above. HER2 gene amplification was present in all the components according to dual-color in situ hybridization. The metastatic lymph nodes were similar to the primary site in morphology and immunohistochemistry, but HER2 amplification was higher in the lymph nodes. The IMPC component with HER2 amplification is rarely seen and its positivity for CD10 is an unexpected finding for gastric IMPC. Hence, this is a highly unusual case judging by the literature; further studies are needed to clarify the nature of gastric IMPC. PMID- 25143130 TI - Chondroblastoma-like osteosarcoma. PMID- 25143131 TI - Type A thymoma exhibiting neuroendocrine differentiation. PMID- 25143132 TI - Poly(N-isopropylacrylamide-co-tris-nitrilotriacetic acid acrylamide) for a combined study of molecular recognition and spatial constraints in protein binding and interactions. AB - Many biological processes require precise regulation and synergy of proteins, and consequently involve molecular recognition and spatial constraints between biomolecules. Here, a library of poly(N-isopropylacrylamide-co-tris nitrilotriacetic acid acrylamide) (PNTs) has been synthesized and complexed with Cu(2+) in order to serve as models for investigation of the combined effects of molecular recognition and spatial constraints in biomolecular interactions. The average distance between Cu(2+)-trisNTA binding sites in PNTs polymers was varied from 4.3 to 31.5 nm by adjusting their trisNTA contents. His tag (His6), His tagged enhanced yellow fluorescent protein (His6-eYFP), and His6-tagged collagenase G (His6-ColG), with sizes ranging from 1 to 11 nm, were used as models to assess whether the binding ability is influenced by a cooperative topology based on molecular recognition interactions with Cu(2+)-trisNTA binding sites, and spatial constraints created by decreasing average distance between trisNTAs. His-tagged molecules bound to all PNTs polymers due to their molecular recognition interaction involving histidines and Cu(2+)-trisNTA pockets, but with a binding ability that was highly modulated by the average distance between the trisNTA binding sites. Small molecular mass molecules (His6) exhibit a high binding ability to all PNTs polymers, whereas his-tagged proteins bind to PNTs efficiently only when the average distance between trisNTA binding sites is larger than the protein dimensions. PMID- 25143133 TI - Generic anthropometric and performance characteristics among elite adolescent boys in nine different sports. AB - The aim of the present study was to evaluate the Flemish Sports Compass (FSC), a non-sport-specific generic testing battery. It was hypothesised that a set of 22 tests would have sufficient discriminant power to allocate athletes to their own sport based on a unique combination of test scores. First, discriminant analyses were applied to the 22 tests of anthropometry, physical fitness and motor coordination in 141 boys under age 18 (16.1 +/- 0.8 years) and post age at peak height velocity (maturity offset = 2.674 +/- 0.926) from Flemish Top Sport Academies for badminton, basketball, gymnastics, handball, judo, soccer, table tennis, triathlon and volleyball. Second, nine sequential discriminant analyses were used to assess the ability of a set of relevant performance characteristics classifying participants and non-participants for the respective sports. Discriminant analyses resulted in a 96.4% correct classification of all participants for the nine different sports. When focusing on relevant performance characteristics, 80.1% to 97.2% of the total test sample was classified correctly within their respective disciplines. The discriminating characteristics were briefly the following: flexibility in gymnastics, explosive lower-limb strength in badminton and volleyball, speed and agility in badminton, judo, soccer and volleyball, upper-body strength in badminton, basketball and gymnastics, cardiorespiratory endurance in triathletes, dribbling skills in handball, basketball and soccer and overhead-throwing skills in badminton and volleyball. The generic talent characteristics of the FSC enable the distinction of adolescent boys according to their particular sport. Implications for talent programmes are discussed. PMID- 25143134 TI - Deciphering the uniqueness of Mucoromycotina cell walls by combining biochemical and phylogenomic approaches. AB - Most fungi from the Mucoromycotina lineage occur in ecosystems as saprobes, although some species are phytopathogens or may induce human mycosis. Mucoromycotina represent early diverging models that are most valuable for understanding fungal evolution. Here we reveal the uniqueness of the cell wall structure of the Mucoromycotina Rhizopus oryzae and Phycomyces blakesleeanus compared with the better characterized cell wall of the ascomycete Neurospora crassa. We have analysed the corresponding polysaccharide biosynthetic and modifying pathways, and highlight their evolutionary features and higher complexity in terms of gene copy numbers compared with species from other lineages. This work uncovers the presence in Mucoromycotina of abundant fucose based polysaccharides similar to algal fucoidans. These unexpected polymers are associated with unusually low amounts of glucans and a higher proportion of chitin compared with N. crassa. The specific structural features are supported by the identification of genes potentially involved in the corresponding metabolic pathways. Phylogenomic analyses of genes encoding carbohydrate synthases, polysaccharide modifying enzymes and enzymes involved in nucleotide-sugar formation provide evidence for duplication events during evolution of cell wall metabolism in fungi. Altogether, the data highlight the specificity of Mucoromycotina cell walls and pave the way for a finer understanding of their metabolism. PMID- 25143135 TI - Proteome analysis of early lineage specification in bovine embryos. AB - During mammalian embryo development, the zygote undergoes embryonic cleavage in the oviduct and reaches the uterus at the morula stage, when compaction and early lineage specification take place. To increase knowledge about the associated changes of the embryonic protein repertoire, we performed a comprehensive proteomic analysis of in vitro produced bovine morulae and blastocysts (six biological replicates), using an iTRAQ-based approach. A total of 560 proteins were identified of which 502 were quantified. The abundance of 140 proteins was significantly different between morulae and blastocysts, among them nucleophosmin (NPM1), eukaryotic translation initiation factor 5A-1 (EIF5A), receptor of activated protein kinase C 1 (GNB2L1/RACK1), and annexin A6 (ANXA6) with increased, and glutathione S-transferase mu 3 (GSTM3), peroxiredoxin 2 (PRDX2), and aldo-keto reductase family 1 member B1 (AKR1B1) with decreased abundance in blastocysts. Seventy-three percent of abundance altered proteins increased, reflecting an increase of translation activity in this period. This is further supported by an increase in the abundance of proteins involved in the translation machinery and the synthesis of ATP. Additionally, a complementary 2D saturation DIGE analysis led to the detection of protein isoforms, e.g. of GSTM3 and PRDX2, relevant for this period of mammalian development, and exemplarily verified the results of the iTRAQ approach. In summary, our systematic differential proteome analysis of bovine morulae and blastocysts revealed new molecular correlates of early lineage specification and differentiation events during bovine embryogenesis. PMID- 25143136 TI - Evaluation of the antitumor effects of c-Myc-Max heterodimerization inhibitor 100258-F4 in ovarian cancer cells. AB - Epithelial ovarian carcinoma is the most lethal gynecological cancer due to its silent onset and recurrence with resistance to chemotherapy. Overexpression of oncogene c-Myc is one of the most frequently encountered events present in ovarian carcinoma. Disrupting the function of c-Myc and its downstream target genes is a promising strategy for cancer therapy. Our objective was to evaluate the potential effects of small-molecule c-Myc inhibitor, 10058-F4, on ovarian carcinoma cells and the underlying mechanisms by which 10058-F4 exerts its actions. Using MTT assay, colony formation, flow cytometry and Annexin V FITC assays, we found that 10058-F4 significantly inhibited cell proliferation of both SKOV3 and Hey ovarian cancer cells in a dose dependent manner through induction of apoptosis and cell cycle G1 arrest. Treatment with 10058-F4 reduced cellular ATP production and ROS levels in SKOV3 and Hey cells. Consistently, primary cultures of ovarian cancer treated with 10058-F4 showed induction of caspase-3 activity and inhibition of cell proliferation in 15 of 18 cases. The response to 10058-F4 was independent the level of c-Myc protein over-expression in primary cultures of ovarian carcinoma. These novel findings suggest that the growth of ovarian cancer cells is dependent upon c-MYC activity and that targeting c-Myc Max heterodimerization could be a potential therapeutic strategy for ovarian cancer. PMID- 25143137 TI - Bioinformatics evaluation of NPHS2 deletion mutation associated with congenital nephrotic syndrome in a consanguineous Pakistani family. PMID- 25143139 TI - Inhibition of flavonoids on acetylcholine esterase: binding and structure activity relationship. AB - The inhibitory effects of flavonoids on acetylcholinesterase (AChE) have attracted great interest among researchers. However, few reports have focused on the structure-activity relationship for AChE inhibition of flavonoids. This work mainly concerns the structural aspects of inhibitory activities and binding affinities of flavonoids as AChE inhibitors. The results show that hydroxyl groups in the A ring of flavonoids are favorable for inhibiting AChE, and the hydroxylation increases the affinities for AChE. However, methoxylation may decrease or increase the activities depending on the class of flavonoids. The glycosylation decreases the AChE inhibitory activities of flavonoids and lowers the affinities for AChE by 1 to 5 times depending on the conjunction site and the type of sugar moiety. The hydrogenation of the C2-C3 double bond of apigenin decreases both the affinity for AChE and AChE inhibition. The molecular property affinity relationship reveals that the hydrogen bond force plays an important role in binding flavonoids to AChE. The AChE inhibitions generally increase with the increasing affinities of flavonoids within the class, especially for flavones and flavonols. PMID- 25143138 TI - NKCCs in the fibrocytes of the spiral ligament are silent on the unidirectional K+ transport that controls the electrochemical properties in the mammalian cochlea. AB - Unidirectional K(+) transport across the lateral cochlear wall contributes to the endocochlear potential (EP) of +80 mV in the endolymph, a property essential for hearing. The wall comprises two epithelial layers, the syncytium and the marginal cells. The basolateral surface of the former and the apical membranes of the latter face the perilymph and the endolymph, respectively. Intrastrial space (IS), an extracellular compartment between the two layers, exhibits low [K(+)] and a potential similar to the EP. This IS potential (ISP) dominates the EP and represents a K(+) diffusion potential elicited by a large K(+) gradient across the syncytial apical surface. The K(+) gradient depends on the unidirectional K(+) transport driven by Na(+),K(+)-ATPases on the basolateral surface of each layer and the concomitant Na(+),K(+),2Cl(-)-cotransporters (NKCCs) in the marginal cell layer. The NKCCs coexpressed with the Na(+),K(+)-ATPases in the syncytial layer also seem to participate in the K(+) transport. To test this hypothesis, we examined the electrochemical properties of the lateral wall with electrodes measuring [K(+)] and potential. Blocking NKCCs by perilymphatic perfusion of bumetanide suppressed the ISP. Unexpectedly and unlike the inhibition of the syncytial Na(+),K(+)-ATPases, the perfusion barely altered the electrochemical properties of the syncytium but markedly augmented [K(+)] of the IS. Consequently, the K(+) gradient decreased and the ISP declined. These observations resembled those when the marginal cells' Na(+),K(+)-ATPases or NKCCs were blocked with vascularly applied inhibitors. It is plausible that NKCCs in the marginal cells are affected by the perilymphatically perfused bumetanide, and these transporters, but not those in the syncytium, mediate the unidirectional K(+) transport. PMID- 25143141 TI - Quantum molecular processes induced by electrons, positrons, atoms, and ions: from eV to nano-eV. PMID- 25143140 TI - Naming game on networks: let everyone be both speaker and hearer. AB - To investigate how consensus is reached on a large self-organized peer-to-peer network, we extended the naming game model commonly used in language and communication to Naming Game in Groups (NGG). Differing from other existing naming game models, in NGG everyone in the population (network) can be both speaker and hearer simultaneously, which resembles in a closer manner to real life scenarios. Moreover, NGG allows the transmission (communication) of multiple words (opinions) for multiple intra-group consensuses. The communications among indirectly-connected nodes are also enabled in NGG. We simulated and analyzed the consensus process in some typical network topologies, including random-graph networks, small-world networks and scale-free networks, to better understand how global convergence (consensus) could be reached on one common word. The results are interpreted on group negotiation of a peer-to-peer network, which shows that global consensus in the population can be reached more rapidly when more opinions are permitted within each group or when the negotiating groups in the population are larger in size. The novel features and properties introduced by our model have demonstrated its applicability in better investigating general consensus problems on peer-to-peer networks. PMID- 25143142 TI - Learning new things often and all along the way: a personal account of 50 years in science. PMID- 25143146 TI - Application of solid-phase extraction for the concentration of chromophores, fluorophores, and photosensitizers from lens protein digests. AB - Solid-phase extraction was applied for the separation of protein digests obtained from aged human lenses, cataractous human lenses, calf lens proteins in vitro glycated with dehydroascorbic acid and native calf lens proteins. Four fractions were collected after stepwise elution with different solvents. The first fraction contained about 80% of the digested material possessing free amino groups. At the same time, the third and the fourth fractions were enriched in chromophores, fluorophores, and photosensitizing structures that originate mainly from advanced protein glycation. The comparison between the total digest and the fourth fraction based on their UV absorption at 330 nm, intensity of fluorescence (excitation/emission 350/450 nm), and production of singlet oxygen upon UVA irradiation argues that the solid-phase extraction was capable of concentrating the advanced glycation end-products about a hundredfold. Thus, this technique is a useful step for separation and concentration of fluorophores, chromophores, and photosensitizers from aged and glycated lens protein digests. PMID- 25143147 TI - Pre-operative visual evaluation for implantable collamer lenses in highly myopic eyes. AB - PURPOSE: The aim of this study was to evaluate a clinical procedure based on trial rigid gas-permeable (RGP) contact lenses fitting to assess the real pre operative visual acuity (VA) of highly myopic eyes undergoing surgery with an implantable collamer lens. METHODS: Highly myopic eyes with a spectacle visual acuity (SVA) of 0.2 logMAR (6/9.6 Snellen) or worse were enrolled. A trial RGP contact lens with high dioptric power was fitted before collamer lens implantation. The trial contact lens residual refractive error was corrected by spectacle over-refraction to estimate contact lens VA (CLVA). The three-month post-operative uncorrected vision and visual acuities were also measured. The safety and efficacy indices of collamer lens implantation were calculated based on pre-operative SVA and CLVA, respectively. RESULTS: The study enrolled 42 patients with 68 highly myopic eyes with a mean pre-operative spherical equivalent of -16.40 +/- 4.43 D. The mean pre-operative SVA was 0.38 +/- 0.19 logMAR. Pre-operative trial RGP contact lens fitting resulted in a significant improvement of VA (2.02 +/- 1.05 lines), which was statistically insignificantly different from the VA with the implantable collamer lens (2.07 +/- 0.8 lines). The safety index of collamer lens implantation was 1.70 +/- 0.38 in reference to the pre-operative SVA but significantly decreased to 1.02 +/- 0.17 in reference to CLVA. Similarly, the efficacy index of 1.17 +/- 0.48 on SVA decreased to 0.71 +/- 0.28 on CLVA. CONCLUSIONS: Trial RGP contact lens fitting was found to indicate the potential implantable collamer lens VA more accurately than spectacle refraction. Consideration should be given to the use a trial RGP contact lens as part of the pre-operative work-up prior to collamer lens implantation in order to provide an assessment of the patient's potential post operative VA. PMID- 25143148 TI - Evaluation of antioxidant activities of the edible and medicinal Acacia albida organs related to phenolic compounds. AB - This study compared phenolic contents and antioxidant activity in different organs of Acacia albida (leaves and bark) and focuses on identification of phenolic compounds of leaves by HPLC-DAD. The analysed organs exhibited differences in total polyphenol contents (100 and 59.5 mg GAE g(-1) DW). Phenolic contents of leaves were two times higher than those in bark. Ethanolic extracts exhibited good antioxidant activities with IC50 = 26 MUg mL(-1) for DPPH and EC50 = 50 MUg mL(-1) for FRAP. Identification by HPLC-DAD revealed the presence of nine phenolic compounds known for their high antioxidant activity. The results suggested that this species can be used as source of natural antioxidants. PMID- 25143149 TI - Nickel-catalyzed substitution reactions of propargyl halides with organotitanium reagents. AB - A simple and mild catalytic coupling reaction of propargyl halides with organotitanium reagents is reported. The reaction of propargyl bromide with organo-titanium reagents mediated by NiCl2 (2 mol%) and PCy3 (4 mol%) in CH2Cl2 afforded coupling product allenes in good to excellent yields (up to 95%) at room temperature. However, NiCl2(PPh3)2 was the best catalyst for substituted propargyl halides to yield allenes or alkynes preferentially. On the basis of the experimental results, a possible catalytic cycle has been proposed. PMID- 25143150 TI - Modified elliptical rotation flap for sacrococcygeal pilonidal sinus disease. AB - BACKGROUND: Although various surgical procedures have been described for pilonidal sinus disease, the best surgical technique is still controversial. The aim of this study was to evaluate the short-term results of modified elliptical rotation flap (MERF) for pilonidal sinus disease in terms of post-operative complications, recurrence and quality of life. METHOD: Data of 121 patients (10 women, 111 men) who were operated on for sacrococcygeal pilonidal sinus disease between 2011 and 2013 were analysed. Elliptical rotation flap procedure which was described by Nessar et al. was modified. Complications, quality of life and recurrence were evaluated. RESULTS: The mean operating time was 31 (range, 20-55) min. The mean time for complete healing was 2.26+/-0.72 weeks. The mean time for returning to daily activities was 9.0+/-2.2 days. There were no flap necrosis and recurrence. Post-operative infection developed in five (4.1%) patients, which was managed by removal of a few skin sutures, drainage and prolonged antibiotic use. Four patients (3.3%) developed a seroma, three of them having a partial wound dehiscence (2.5%). Neither haematoma formation nor complete dehiscence were observed. CONCLUSION: MERF seems to be an effective and reliable procedure having low morbidity rates and no recurrence. Further prospective randomized studies comparing the MERF with other flap techniques will provide better information about the technique. PMID- 25143151 TI - Advances in dendritic cell immunotherapies for HIV-1 infection. AB - Augmentation of adaptive immunity via HIV therapeutic vaccination may be a key component of curative strategies. Adoptive dendritic cell (DC) immunotherapies may prove useful in enhancing the success of these approaches by circumventing certain defects in DC function during HIV infection. Thus far, DC immunotherapies that utilize autologous, inactivated virus as an immunogen have provided the most promising results however, are beset with practical constraints. Consequently, alternative forms of immunogens are under investigation, with an emphasis on RNA based approaches. Here we review the data from DC immunotherapy trials for HIV infection and discuss challenges and future directions in the field. PMID- 25143152 TI - Cryptic genetic variation uncovers evolution of environmentally sensitive parameters in Caenorhabditis vulval development. AB - Understanding the robustness of developmental systems requires insights into the sensitivity of underlying molecular and cellular parameters to perturbations, and how such sensitivity evolves. We address these issues using vulval cell fate determination--a reproducible and robust patterning process regulated by a cross talk of EGF-Ras-MAPK and Delta-Notch pathways. Although the final vulval cell fate pattern is identical in all Caenorhabditis species, the patterning process underlies extensive cryptic genetic variation between and within species. Here, we tested whether this cryptic genetic variation translates into variation in developmental sensitivity to environmental perturbations. We disrupted vulval patterning using thermal perturbations to quantify and compare environmental sensitivity of different system parameters between distinct genotypes of C. elegans and C. briggsae. Thermal perturbations globally debuffered vulval development, triggering diverse pattering variants, whose frequency and spectra were strongly species- and genotype-dependent. This condition-dependent variation indicates that environmental sensitivity of different system properties, such as vulval competence or vulval induction, is subject to evolutionary change. High temperature induced a genotype-specific decrease of secondary fate induction and corresponding Notch pathway activity in the C. elegans N2 strain; in contrast, hypoinduction of the primary cell fate was never observed. Vulval precursor cells therefore differ in temperature sensitivity and such cell-specific sensitivity shows evolutionary variation. We further compared spectra of temperature-induced vulval variants to the ones induced by mutation accumulation in the same genotypes. In response to either perturbation, we observed similar genotype dependence of variant production, allowing identification of distinct system features most sensitive to both mutation and environment. Taken together, we show how sensitivity of system parameters regulating Caenorhabditis vulval development depends on subtle interactions between perturbations and genetic background. Our results imply that cryptic genetic variation may reflect evolutionary variation in developmental robustness, therefore potentially contributing to the maintenance of phenotypic precision when facing perturbations. PMID- 25143153 TI - Extraordinarily high pseudocapacitance of metal organic framework derived nanostructured cerium oxide. AB - MOF derived CeO2 showed a pseudocapacitance of 1204 F g(-1) at 0.2 A g(-1), far exceeding its theoretical capacitance (560 F g(-1)). The present study demonstrates that combination of a two-way strategy, controlled nano-architecture and redox active electrolyte additive, could potentially alleviate both low energy density and capacitance fading issues plaguing the current metal oxide pseudocapacitors. PMID- 25143154 TI - PARP1 expression in mantle cell lymphoma: the utility of PARP1 immunohistochemistry and its relationship with markers of DNA damage. AB - Mantle cell lymphoma (MCL) is an aggressive disease with poor overall survival, attributable in part to frequent defects of the DNA repair genes. In such malignancies, additional inhibition of the ubiquitous DNA damage repair protein, poly-ADP ribose polymerase-1 (PARP1) has shown enhanced cytotoxicity (so-called synthetic lethality). We studied PARP1 expression in a series of clinical cases of MCL, with the secondary aim to ascertain the relationship between PARP1 expression and DNA repair gene expression (namely ATM and p53) by immunohistochemical methods. We also examined the relationship between PARP1 expression and the well-established prognostic biomarker Ki-67, in addition to correlating PARP1 expression with the overall survival. From amongst our series of 79 unselected cases of MCL, we detected PARP1 expression in all but two cases with variable intensity. We also noted correlations between PARP1 expression and ATM and p53 expression. As described in previous studies, we identified a significant survival difference on the basis of Ki-67 and p53 expression. When digital H-score analysis of PARP1 expression was performed, there was a distinct survival advantage noted in patients with lower levels of expression. When our biomarker data were assessed by Cox regression, furthermore, the dominant effects of p53 and PARP1 expression were highlighted. Our data support the need for further research into the potential utility of PARP1 as a biomarker in MCL and for the potential direction of future PARP1 inhibitor-targeted therapy studies. PMID- 25143155 TI - Non-neuronal acetylcholine as an endogenous regulator of proliferation and differentiation of Lgr5-positive stem cells in mice. AB - Non-neuronal acetylcholine (ACh) is predicted to function as a local cell signaling molecule. However, the physiological significance of the synthesis of non-neuronal ACh in the intestine remains unclear. Here, experiments using crypt villus organoids that lack nerve and immune cells in culture led us to suggest that endogenous ACh is synthesized in the intestinal epithelium to evoke growth and differentiation of the organoids through activation of muscarinic ACh receptors (mAChRs). The extracts of the cultured organoids showed a noticeable capacity for ACh synthesis that was sensitive to a potent inhibitor of choline acetyltransferase. Imaging MS revealed endogenous ACh localized in the epithelial layer in mouse small intestinal epithelium in vivo, suggesting that there are non neuronal resources of ACh. Treatment of organoids with carbachol downregulated the growth of organoids and the expression of marker genes for epithelial cells. On the other hand, antagonists for mAChRs enhanced the growth and differentiation of organoids, indicating the involvement of mAChRs in regulating the proliferation and differentiation of Lgr5-positive stem cells. Collectively, our data provide evidence that endogenous ACh released from intestinal epithelium maintains homeostasis of intestinal epithelial cell growth and differentiation via mAChRs in mice. PMID- 25143156 TI - How an online intervention to prevent excessive gestational weight gain is used and by whom: a randomized controlled process evaluation. AB - BACKGROUND: Online interventions have emerged as a popular strategy to promote healthy behaviors. Currently, there is little agreement about how to capture online intervention engagement. It is also uncertain who engages with weight related online interventions and how engagement differs by demographic and weight characteristics. OBJECTIVE: The objectives of this study were to (1) characterize how pregnant women engaged with features of an online intervention to prevent excessive gestational weight gain, (2) identify demographic and weight status subgroups of women within the sample, and (3) examine differences in use of intervention features across the demographic and weight status subgroups. METHODS: A sample of racially and socioeconomically diverse pregnant women from a northeastern US city was assigned to the intervention group in a randomized controlled trial to prevent excessive gestational weight gain (n=1014). The intervention website included these features: weight-gain tracker, health-related articles, blogs, physical activity and diet goal-setting tools, and local resources. Engagement variables were created to capture the amount, consistency, and patterns of feature use across pregnancy using latent class analysis. Demographic/weight status subgroups were also created using latent class analysis. Differences in engagement across the demographic/weight status subgroups were examined using chi-square analysis. RESULTS: Six engagement patterns emerged: "super-users" (13.02%, 132/1014), "medium-users" (14.00%, 142/1014), "consistent weight-tracker users" (14.99%, 152/1014); "almost consistent weight-tracker users" (21.99%, 223/1014), "inconsistent weight-tracker users" (15.98%, 162/1014), and "non-users" (20.02%, 203/1014). Four demographic/weight status subgroups emerged: three minority and one white. There were different engagement patterns by demographic/weight status subgroups. Super users were more likely to be in the white subgroup, while non-users were more likely to be in the minority subgroups. However, around a third of women in minority subgroups were consistently or almost consistently engaging with the weight-tracker (black, young women, 32.2%, 67/208; black, heavier women, 37.9%, 50/132; Hispanic women, 27.4%, 32/117). CONCLUSIONS: While white and higher income women had higher engagement in general, depending on the measure, there was still considerable engagement by the minority and low-income women. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01331564; http://clinicaltrials.gov/ct2/show/NCT01331564 (Archived by WebCite at http://www.webcitation.org/6Rw4yKxI5). PMID- 25143158 TI - [Development of diagnosis and treatment of spinal cord tumors]. PMID- 25143157 TI - Crystal structure of juvenile hormone epoxide hydrolase from the silkworm Bombyx mori. PMID- 25143159 TI - [Clinical classification and selection of surgical approaches for cervical spinal dumbbell tumors]. AB - OBJECTIVE: To explore the clinical classification and selection of surgical approaches for cervical spinal dumbbell tumors. METHODS: The clinical data of 87 patients with cervical spinal dumbbell tumors undergoing surgical operations from January 2005 to December 2012 at our hospital were analyzed retrospectively. According to the size of inner and outer parts of tumors and the presence or absence of spinal bone damage, the cervical spinal dumbbell tumors were divided into 4 types of intraspinal predominant (I, n = 48), extraspinal predominant (II, n = 1), intrapinal and extraspinal without damage of spinal bone (III, n = 15) and intrapinal and extraspinal type with damage of spinal bone (IV, n = 7). Different surgical approaches were selected on the basis of tumor classification: posterior median-hemilamina approaches for type I tumors, lateral-muscle gap approaches for type II tumors, ateral-muscle gap-hemilamina or lateral-muscle gap posterior median-hemilamina approaches for type III tumors, posterior far lateral muscle gap-hemilamina or posterior median-muscle gap-hemilamina approaches plus posterior occipital cervical or cervical spinal bone graft fusion and internal fixation for type IV tumors. RESULTS: Among them, 83 cases underwent total resection and another 4 subtotal resection in one-stage operation. The postoperative follow-up period had a range of 9 months to 6 years (mean, 3.2 years). There was no recurrence of tumors for total resection and 1 case of tumor recurrence for subtotal resection. During the follow-up period, the clinical manifestations of 85 patients improved while another 2 deteriorated. And there was no occurrence of spinal deformity. CONCLUSION: Clinical classification of cervical spinal dumbbell tumor plays an important guiding role in the selection of surgical approaches. Adopting appropriate surgical approaches based on tumor type can not only improve the rate of total resection of tumor but also reduce the incidence of postoperative spinal deformity. PMID- 25143160 TI - [Clinical classification and surgical management of cervicothoracic intraspinal lipomas]. AB - OBJECTIVE: To explore the clinical classification and surgical management of cervicothoracic intraspinal lipomas. METHODS: A total of 22 patients with cervicothoracic intraspinal lipomas were analyzed retrospectively with regards to clinical manifestations, radiographic features, intraoperative findings, surgical techniques and follow-ups. RESULTS: Total (n = 4), subtotal (n = 7) and partial (n = 11) resection was performed. Long-term neurological outcomes were evaluated by modified McCormick classification scheme. Their symptoms improved (n = 15), unchanged (n = 3) and deteriorated (n = 4). And cervicothoracic intraspinal lipomas could be classified into extradural, transitional, chaotic and secondary intramedullary groups. CONCLUSION: Different groups of cervicothoracic intraspinal lipomas vary in the degree of resection and surgical efficacy. Total resection may be performed on most extradural lipomas. The surgical objective of transitional lipomas is decompression. Chaotic and secondary intramedullary lipomas should target effective resection to avoid neurological function injury. Intraoperative use of laser facilitates tumor resection. Intraoperative electrophysiological monitoring protects spinal cord. PMID- 25143161 TI - [Microsurgical treatment of multi-segment cervical intramedullary ependymomas]. AB - OBJECTIVE: To explore the microsurgical skills of multi-segment cervical ependymomas and evaluate preoperative and postoperative neurological functions. METHODS: A total of 61 patients with multi-segment cervical ependymoma from January 2008 to July 2013 at our hospital were analyzed to summarize their clinical features, imaging findings, diagnosis, tumor resection and changes of neurological functions. RESULTS: Total (n = 58) and subtotal (n = 3) resections were performed. And postoperative nerve functions unchanged (n = 43) and aggravated (n = 18). There was no mortality. CONCLUSION: Proper planning and refined microsurgical techniques are essential in the treatment of multi-segment cervical ependymomas. PMID- 25143162 TI - [Prognostic analyses of intramedullary high grade astrocytomas]. AB - OBJECTIVE: To explore the prognostic factors of intramedullary high grade astrocytomas. METHODS: Retrospective analyses were conducted for 21 surgical patients with high grade astrocytoma in spinal cord during 2008 to 2012 at our hospital. Their preoperative and postoperative profiles were recorded and evaluated by modified McCormick classification scheme. RESULTS: Their median age was 32.5 years. There were anaplastic astrocytoma (n = 14) and glioblastoma (n = 7). The prognoses of high grade astrocytomas were correlated with pathology grade and MIB-1 index. No statistic significance existed in age, gender, McCormick score, extent of resection, radiotherapy or chemotherapy. CONCLUSION: Intramedullary high grade astrocytoma has a low incidence, but its outcome is poor. Once definitely diagnosed, operation is recommended as early as possible. Frozen pathology should be performed to determine the extent of resection. After operation, chemotherapy and radiotherapy are also suggested. PMID- 25143163 TI - [Clinical features and microsurgical treatment of spinal intramedullary cavernoma]. AB - OBJECTIVE: To explore the clinical features and microsurgical treatment of spinal intramedullary cavernomas (SICs). METHODS: A total of 21 patients with pathologically confirmed SIC undergoing microsurgical resection of cavernomas at Beijing Tiantan Hospital and Taian Central Hospital from June 2005 to December 2012 were reviewed retrospectively. RESULTS: The postoperative neurological status improved (n = 13) and remained unchanged (n = 6) and aggravated (n = 2). CONCLUSION: The clinical features of SICs are related with their different pathological processes. Magnetic resonance imaging (MRI) is specific for the diagnosis of SICs. Appropriate strategies and refined microsurgical techniques are essential for improving the clinical efficacies of SICs. PMID- 25143164 TI - [Single-center experience on clinical application of "anatomic fixation" unibody bifurcated stent-graft in endovascular repair]. AB - OBJECTIVE: To evaluate the clinical outcomes of unibody bifurcated stent-graft in endovascular repair (EVAR). METHODS: Retrospective analyses were conducted for the clinical data and postoperative follow-up results of 125 patients (102 cases from Shanghai Changhai Hospital and another 23 from Shanghai Changzheng Hospital) undergoing EVAR with unibody bifurcated stent-graft from January 2008 to January 2013. RESULTS: The technical success rate was 100%. Perioperative complications including type I endoleak (n = 3, 2.4%) and type II endoleak (n = 4, 3.2%). The incidence of type I endoleak in challenging neck cases was higher than non challenging ones. And the difference was statistically significant (P = 0.001). Except for 1 dead case, the remainder was followed up for a mean of 26.4 +/- 1.5 (1-60) months. Neither aneurysm rupture nor stent-graft migration occurred. Late type I endoleak occurred (n = 2, 1.6%). There were left lower extremity arterial thrombosis (n = 1, 0.8%) and surgical reintervention (n = 1, 0.8%). Among 3 dead cases, 2 died from acute myocardial infarction and another 1 contrast-induced nephropathy. CONCLUSION: Unibody bifurcated stent-graft is both safe and efficacious in the treatment of abdominal aortic aneurysm without the risk of long-term migration. Moreover, it has excellent outcomes for hostile neck or narrow abdominal aortic bifurcation. PMID- 25143165 TI - [Effect of single-dose dexmedetomidine on recovery profiles after sevoflurane anesthesia with spontaneous respiration in pediatric patients undergoing cleft lip and palate repair]. AB - OBJECTIVE: To explore the effect of single-dose dexmedetomidine on recovery period after sevoflurane anesthesia with spontaneous respiration in pediatric patients undergoing cleft lip and palate repair. METHODS: A total of 60 American Society of Anesthesiologists (ASA) I-II pediatric patients undergoing cleft lip and palate repair from October to December 2013 were randomly divided into groups D and C (n = 30 each) . Dexmedetomidine 0.5 ug/kg (group D) or an equal volume of normal saline (group C) was ad ministered intravenously over a period of 10 min at 30 min before the end of surgery. Anesthesia was induced and maintained with sevoflurane under spontaneous ventilation. Heart rate, mean arterial pressure (MAP), hemoglobin oxygen saturation (SpO2), respiratory rate, tidal volume (VT) and pressure of end-tidal carbon dioxide (PETCO2) were recorded at the time before induction (T0), 30 min before the end of surgery (T1) , 20 min before the end of surgery (T2), 15 min before the end of surgery (T3), 10 min before the end of surgery (T4), the end of surgery (T5), extubation (T6), 5 min after transferal into post-anesthesia care unit (PACU) (T7) , 1 h after surgery (T8) , extubation time, length of PACU stay, fentanyl consumption and adverse events were all recorded. The incidence and severity of coughing and emergence agitation were assessed. RESULTS: Compared to T0, MAP and heart rate at T1 to T5 all decreased in two groups (P < 0.05). MAP and heart rate at T6 both increased in two groups and group C was higher than group D (P < 0.05). No inter-group differences existed in SpO2, respiratory rate, VT or PETCO2. The incidence of coughing and emergence agitation (30% and 13.3%), fentanyl consumption of group D (0.8 +/- 2.1 ug) were all significantly lower than that of group C [(66.7% vs 56.7%) and (4.9 +/- 6.50) ug, P < 0.05]. Length of PACU stay in group D was shorter than that in group C [(15 +/- 6) vs (23 +/- 19) min, P < 0.05]. No inter-group difference existed in extubation time or adverse events. CONCLUSION: A single intravenous dose of dexmedetomidine is effective in reducing emergence agitation and coughing, shortening length of PACU stay and improving the quality of recovery period after sevoflurane anesthesia in pediatric patients undergoing cleft lip and palate repair. PMID- 25143166 TI - [Differential diagnosis between renal cell carcinoma associated with XP11.2 translocation/TFE gene fusion and papillary renal cell carcinoma based on CT and MRI findings]. AB - OBJECTIVE: To comparative study of CT and MRI appearances in renal cell carcinoma associated with XP11.2 translocation/TFE gene fusion (XP11.2 RCC) and papillary renal cell carcinoma (PRCC). METHODS: 12 patients with XP11.2 RCC and 18 patients with PRCC were retrospectively studied, and the data was analyzed by AVONA and chi-square text. RESULTS: 12 patients with XP11.2 RCC and 18 patients with PRCC, cystic components (2 vs 11, P < 0.05), calcification (0 vs 6, P < 0.05), hemorrhage (9 vs 5, P < 0.05), homogeneous enhancement (10 vs 7, P < 0.05) and had lymph node (3 vs 0) or hepatic metastasis (1vs 0) (P < 0.05). On unenhanced CT, the density of XP11.2 RCC was greater than PRCC, normal renal cortex or medulla (P < 0.05). Their degree of enhancement were less than normal renal cortex on all enhanced phases (P < 0.05). The enhancement degree of XP11.2 RCC was higher than PRCC (on all phases) and renal medulla (on cortical and medullary phase) (P < 0.05), but less than normal renal medulla on the delayed phase (P < 0.05). The enhancement degree of PRCC was lower than renal medulla on all phases (P < 0.05). The XP11.2 RCC was isointense on T1-weighted imaging, hypointense on T2-weighted imaging. The PRCC was isointense or hypointense on T1-weighted imaging, isointense on T2-weighted imaging. CONCLUSION: The CT and MRI could show imagings features of XP11.2 RCC and PRCC, and these features were helpful in predicting a specific subtype of renal cell carcinoma. PMID- 25143167 TI - [MR manifestations and clinical significance of iliotibial band friction syndrome]. AB - OBJECTIVE: To describe the MRI features of Iliotibial band friction syndrome (ITBFS), in order to improve the understanding and diagnosis of ITBFS. METHODS: The MR findings of 16 patients (18 knees )of clinically diagnosis ITBFS were reviewed retrospectively. RESULTS: The MRI features of ITBFS:(1)Ill- defined abnormal signal intensity extended to the lateral femoral epicondyle.(2) Poorly defined abnormal signal intensity presented deep to the ITB adjacent to the lateral femoral epicondyle. (3) Fluid collections medial to the ITB adjacent to the lateral femoral epicondyle. (4) The part of ITB over the lateral femoral epicondyle was thicker. (5) Joint effusion. (6)Other abnormal signs. CONCLUSION: MRI is a relatively good method for detection of ITBFS. PMID- 25143168 TI - [Characteristics of cognitive impairment in depressive elders in Shanghai community]. AB - OBJECTIVE: To explore the characteristics of cognitive impairment in depressive elders in Shanghai. METHODS: A total of 1 068 participants randomly selected from 4 communities in Shanghai underwent neuropsychiatric and psychiatrists clinical assessment. Among them, 102 depressive ones with a score of geriatric depression scale (GDS) > 10 and 102 non-depressive ones with a score of GDS <= 10 were selected as depression and non-depression groups respectively. The SPSS statistic software V17.0 was used. RESULTS: Significant differences existed between the depressive and non-depressive patients in the total score of Montreal Cognitive Assessment (MoCA) (t = 2.353), trail making B task (t = 2.236), attention (t = 2.621), sustained attention (t = 2.381), calculation (t = 2.612) and fixed orientation (t = 2.259) (P < 0.05). The negative correlation had significant inter-group differences in the total score of MoCA (r = -0.142), attention (r = 0.161), sustained attention (r = -0.160), calculation (r = -0.150), fluency (r = 0.156), delayed recall (r = -0.175) and orientation to place (r = -0.172) (P < 0.05). Cognitive impairment in depression group had lower scores than non depression group in the total score MoCA (14.9 +/- 7.3 vs 17.5 +/- 6.7), attention (1.1 +/- 0.8 vs 1.4 +/- 0.8), calculation (1.9 +/- 1.2 vs 2.3 +/- 1.1) and fixed orientation (1.7 +/- 0.7 vs 1.8 +/- 0.5) (P < 0.05). CONCLUSION: In depressive elders, cognitive impairment occurs in multiple cognitive domains of attention, executive function and orientation to place. There is a negative correlation between GDS score and MoCA. The higher GDS score, the worse cognitive function. PMID- 25143169 TI - [Application of dezoxine plus dexmedetomidine in strabismus surgery]. AB - OBJECTIVE: To observe the effects of intra-operative combined dosing of dezoxine and dexmedetomidine on sedation, analgesia and the incidence of untoward events during and after surgery in teenagers undergoing horizontal concomitant strabismus surgery. METHODS: For this prospective and randomized trial, approval was obtained from the Ethical Committee and informed consent from their parents. A total of 60 patients aged 10-16 years undergoing strabismus surgery at Second Affiliated Hospital from September to December 2013 were collected. The treatment group received an intravenous dose of dezoxine 0.1 mg*kg(-1) at 15 minutes before surgery. And another intravenous injection of dexmedetomidine was administered at 0.4 ug*kg(-1)*h(-1) until the end of the first ocular muscle correcting. The control group received the same volume of normal saline. Observational parameters including visual analogue scale (VAS), Ramsay scores, self-rating anxiety scale (SAS), heart rate (HR), blood pressure and the incidence of untoward events such as nausea and vomiting or arrhythmia were recorded. RESULTS: The VAS pain scores in the treatment group at T2-T5 decreased significantly versus the control group (P < 0.05) . The Ramsay scores in the treatment group at T2-T3 increased and significantly differences existed with the control group (P < 0.05). SAS scores showed significant differences between pre-operative and post-operative periods in the treatment group (P < 0.05). The treatment group has shorter operative duration with 5 cases of dragging pain in the treatment group versus 25 in the control group (P < 0.05). During dragging reflex, HR was lower in the control group at T2 and T3. There were significant differences with the control group (P < 0.05). CONCLUSION: A combination of dezoxine and dexmedetomidine provide multiple benefits for patients undergoing strabismus surgery. Compared with simple local anesthesia, it effectively attenuates pain and anxiety and provides mild sedation and better cooperation during strabismus surgery. PMID- 25143170 TI - [Treatment of autotransplantation of NT-3 gene modified OECs and NSCs complex adhering to scaffold on spontaneous cerebral hemorrhage]. AB - OBJECTIVE: To explore the effects of autotransplantation of NT-3 gene modified olfactory ensheathing cell (OEC) and neural stem cell (NSC) complex adhering to collagen protein-heparin sulfate scaffold on motor function of rats with cerebral hemorrhage. METHODS: The cerebral hemorrhage model was established with caudate nucleus bleeding in Wistar rats. The animals were randomly divided into 4 groups: A (transplantation of NT-3 modified OEC-NSC complex adhering to scaffold), B (transplantation of NT-3 modified OEC-NSC complex), C (transplantation of scaffold) and D (blank control group). The motor function of hind limbs was assessed at Day 1, 3, 7, 14 and 30 post-transplantation respectively. The survival, distribution and differentiation of transplanted cells were tested by immunohistochemistry and fluorescent staining. RESULTS: The neurological functional score of group A (2.12 +/- 0.12, 1.50 +/- 0.11, 0.52 +/- 0.08) or B (2.10 +/- 0.16, 1.79 +/- 0.09, 0.91 +/- 0.10) was obviously inferior to group C/D at Days 7, 14 and 30. No significant difference existed between groups C and D (P > 0.05) . The scores of A were markedly lower than those of B at Days 14 and 30 (P < 0.05, P < 0.01) . The numbers of surviving NSCs and cells migrating to focal area after transplantation was much more in group A than those in other groups. CONCLUSION: Autotransplantation of NT-3 gene modified OEC-NSC complex adhering to collagen protein-heparin sulfate scaffold may markedly ameliorate the motor function of cerebral hemorrhagic in rats. And the transplanted NSCs have better capacities of survival, migration and differentiation. PMID- 25143171 TI - [Effects of physical training on pyramidal tract regeneration in hypertensive rats with focal cerebral infarction]. AB - OBJECTIVE: To explore the effects of exercise training on motor functional recovery and pyramidal tract regeneration in hypertensive rats with focal cerebral infarction. METHODS: Middle cerebral artery occlusion (MCAO) model was generated by electric coagulation on stroke-prone renovascular hypertensive Sprague-Dawley rats. The rats were randomly allocated to three groups of sham (n = 15), exercise training (n = 10) and control (n = 12). The exercise training group had running wheel exercise. The neurological function was evaluated with the modified neurological severity scores (mNSS) and forelimb grip strength test at Days 3, 7, 14, 21, 28, 35 and 42 post-ischemia. The pathological changes of neurons around infarct cortex were measured by Nissl staining. At Day 42 post ischemia, anterograde tract tracers of biotinylated dextran amine (BDA) and cascade blue-labeled dextran amine (CB) were injected into cortex. And axonal extension of ipsi- and contra-lesional pyramidal tract was observed at Day 14 post-injection. RESULTS: The mNSS score declined in the exercise training group (4.0 +/- 1.1, 2.7 +/- 0.7, 2.6 +/- 0.5) versus those in the control group (6.0 +/ 1.3, 5.6 +/- 1.0, 5.6 +/- 1.1) at Days 28, 21 and 35 post-ischemia (all P < 0.01). The grip strength of paralytic forelimb increased in the exercise training group ((379 +/- 41, 344 +/- 15, 430 +/- 48, 471 +/- 47, 454 +/- 17)g) versus those in the control group ((276 +/- 8, 170 +/- 5, 236 +/- 12, 283 +/- 14, 317 +/ 15)g) at Days 14, 21, 28, 35 and 42 post-infarction (all P < 0.05). Compared with the control group (0.571 +/- 0.060) , exercise training (0.734 +/- 0.035) reduced neuron loss (P < 0.05). Moreover, the percentage of the number of BDA positive, midline-crossing fibers over the number of labeled fibers in cerebral peduncle ipsilateral to injection site increased in the exercise training group (0.096 8 +/- 0.022 6) versus those in the control group (0.014 2 +/- 0.003 9) at the level of cervical enlargement (P < 0.016 7). The percentage of CB immunofluorescence in striatum ipsilateral to lesion-sided motor cortex over those in ischemic cortex was lower in the control group (0.521 +/- 0.020) and the exercise training group (0.499 +/- 0.034) than that in the sham group (0.824 +/- 0.017) (all P < 0.01). However, no significant difference existed between control and exercise training groups (P > 0.05). CONCLUSION: Exercise training promotes the recovery of motor function and contralesional pyramidal tract regeneration after cerebral infarction. PMID- 25143172 TI - [Experimental study of repairing severe ligament injury with transgenetic bone mesenchymal stem cells]. AB - OBJECTIVE: To evaluate the efficacies of transgenetic bone mesenchymal stem cells (BMSCs) carring basic fibroblast growth factor (bFGF) gene on repairing severe ligament injury. METHODS: The genes of bFGF and enhanced green fluorescent protein (eGFP) were transfected into BMSCs through adenovirus vector. According to different cell transplantations, the operated rabbits were divided into 3 groups of transgenetic BMSCs, BMSCs and no cells. And group 4 was normal ligament group. The distribution of transgenetic BMSCs in ligament injury area, the expression of bFGF and ligament specific extracellular matrix, i.e. type I collagen, type III collagen, fibronectin, alpha-smooth muscle actin and vimentin, histology and biomechanics of ligament healing were recorded at different timepoints. RESULTS: The transgenetic BMSCs could be observed in injury area within one month. The expression of bFGF in the transgenetic BMSCs group was significantly higher than that in the control groups at Days 3-14 (P < 0.001) and peaked at Day 7. In the transgenetic BMSCs group, the gene expression of ligament specific extracellular matrix was significantly higher than that in the control groups within one month (P < 0.001). And immunohistochemistry showed strong positive expression. After 3 months, in group 1, hematoxylin and eosin staining showed the arrangement and density of collagen fibers of healing area were better than that in the control groups. And biomechanical testing showed that tensile load were stronger than that in the control groups (P < 0.05). CONCLUSION: Transgenetic BMSCs carrying bFGF gene can obviously promote ligament injury healing and increase ligament healing strength. PMID- 25143173 TI - [Selective Laser Sintering-produced porous titanium alloy scaffold for bone tissue engineering]. AB - OBJECTIVE: To evaluate the biocompatibility of SLS-produced titanium alloy scaffold in vitro and investigate the therapeutic effects in repairing segmental bone defects. METHODS: Porous titanium alloy scaffolds were produced by SLS and their surfaces were either left untreated or acid etched. In vitro, mouse pre osteoblasts (MC3T3-E1 cells) were cultured on these 2 group scaffolds, and then cell proliferation and differentiation were examined after cell seeding. In vivo, bone defects were artificially made in 15 New Zealand rabbits and the porous titanium specimens were implanted into the radius of rabbits for 3 months. The regulating checks of X-ray were determined. The osteointegration of the implants was investigated by Micro-CT and histological examination at 12 weeks after surgery. RESULTS: A gradual increase in cell-specific ALP synthesis by cells cultured in both groups was observed with longer culture time (14 d). ALP activity did not differ significantly between two groups (0.834 +/- 0.092 vs 0.815 +/- 0.081, P > 0.05) . Both Micro-CT and the histological analysis indicated that the titanium alloy scaffolds had excellent ability to facilitate the osteointegration in vivo. The results were significantly different between the empty control and the 2 different surface modifications of SLS-implants (25.4% +/- 4.2% vs 23.6% +/- 8.4% vs 12.3% +/- 4.7%, P < 0.05). Between the groups with implants, the number of bone points was not significantly different, irrespective of the surface treatment (25.4% +/- 4.2% vs 23.6% +/- 8.4%, P > 0.05). CONCLUSION: Selective Laser Sintering-Produced porous titanium alloy scaffold possessed admirable biocompatibility in vitro. It also could be contributed to the healing of long tulular bone defect. The porous Ti6Al4V implant not only reduced the stress-shielding but also exerted appropriate osteoconductive properties. PMID- 25143174 TI - [Role of new K(+) channel blocker 4-AP-3-MeOH in acute spinal cord compression injury in rats]. AB - OBJECTIVE: To evaluate the effects of 4-aminopyridine-3-methyl hydroxide (4-AP-3 MeOH) in rat's acute spinal cord injury. METHODS: A total of 12 adult male SD rats (250-300 g) were randomly divided into treatment (n = 6) and control (n = 6) groups. After compressing segment T11 of spinal cord for 30 min, the injured segment received 1 ml 4-AP-3-MeOH (100 umol/ml) by topically application in treatment group while the control group received 1 ml saline.Somatosensory evoked potential (SSEP) was detected in both groups at pre-injury, 30 min post-injury and post-dosing. Then Luxol fast blue (LFB) staining of target spinal segment was performed. RESULTS: In treatment group, the values of SSEP at pre-injury, 30 min post-injury and post-dosing were 1.26 +/- 0.35, 0.03 +/- 0.05 and 0.45 +/- 0.19 uv respectively. Comparing SSEP of 30 min post-injury with post-dosing, the difference was statistically significant (P < 0.01).While in control group, the values of SSEP at pre-injury, 30 min post-injury and post-dosing were 1.05 +/- 0.39, 0.01 +/- 0.02 and 0.02 +/- 0.02 uv respectively. Comparing SSEP of 30 min post-injury with post-dosing, there was no statistical difference (P > 0.05). After 30 min injury, there were swelling and bleeding of spinal cord.LFB staining showed that both gray and white matter had swelling and bleeding and central canal was destroyed with varying degrees of demyelination. CONCLUSION: After 30 min of acute spinal cord injury, there are bleeding of gray and white matter with varying degrees of demyelination. Topical usage of K(+) blocker 4-AP-3-MeOH can effectively improve the conduction of SSEP after acute spinal cord injury in rats. PMID- 25143175 TI - [Targeted inhibition of WISP1 enhanced radiosensitivity in glioma cells]. AB - OBJECTIVE: To explore the effects of differencial expression of WISP1 upon the radiosenstivity and migration in glioma cell lines M059K and M059J, as well as WISP1 knockdown cell line M059K-WISP1-. METHODS: The expression of WISP1 in different cell lines was detected by Western blot assay. The lentivirus mediated RNA interference technology was employed to knockdown the endogenous expression of gene WISP1 in human glioma cells(M059K). A stable cell line was established by infecting M059K cells with the lentivirus particles, the transfection efficiency was examined by fluorescence microscopy. The radiosensitivity and migration ability of cells were assessed by Colony-forming and Scratch Wound Assays respectively. RESULTS: WISP1 was highly expressed in M059K cells compared with M059J cells. M059K cells were less radiosensitive than M059J cells , and had a better ability of migration. M059K cells were transfected into by the lentiviral vector pGLV3/H1/GFP+puro vector -WISP1. And M059K-WISP1- cell line with stable WISP1 downregulation was established successfully. Western blot demonstrated significantly downregulated WISP1 expression in M059K-WISP1- cells, which showed obviously improved radiosensitivity in Colony-forming assay and suppressed migration ability in Scratch Wound Assay. Colony-forming assay based on the muti target/single-hit model indicated that radiosensitivity of M059K-WISP1- was significantly decreased. CONCLUSION: Compared with WISP1 low expression cell line M059J , WISP1 high expression cell line M059K was less radiosensitive and had a better ability of migration.We have successfully established a glioma cell line M059K-WISP1- stably downregulating WISP1, which shows a better radiosensitivity and a lowered migration activity in vitro. This may provide a novel therapeutic target for the treatment of human glioma. PMID- 25143176 TI - Effect of minimally invasive surgery on the risk for surgical site infections: results from the National Surgical Quality Improvement Program (NSQIP) Database. AB - IMPORTANCE: Surgical site infection (SSI) represents the second most common cause of hospital-acquired infection and the most common type of infection in patients undergoing surgery. However, evidence is scarce regarding the effect of the surgical approach (open surgery vs minimally invasive surgery [MIS]) on the risk for SSIs. OBJECTIVE: To evaluate the role of the surgical approach on the risk for SSIs in a large contemporary cohort of patients undergoing surgery across different specialties. DESIGN, SETTING, AND PARTICIPANTS: The American College of Surgeons National Surgical Quality Improvement Program database is a national, prospective perioperative database specifically developed to assess quality of surgical care. We queried the database from January 1, 2005, through December 31, 2011, for patients undergoing appendectomy (n = 97,780), colectomy (n = 118,407), hysterectomy (n = 26,639), or radical prostatectomy (n = 11,183). EXPOSURES: Thirty-day SSIs. MAIN OUTCOMES AND MEASURES: We abstracted the data on 30-day SSIs and compared patients undergoing open procedures and MIS using propensity score matching. Logistic regression analyses of the matched cohorts tested the association between the surgical approach and risk for SSIs. RESULTS: The overall 30-day rates of SSIs were 5.4% for appendectomy, 12.1% for colectomy, 2.8% for hysterectomy, and 1.7% for prostatectomy. After propensity score matching, MIS was associated with lower rates of postoperative SSIs in patients undergoing MIS vs open procedures for appendectomy (3.8% vs 7.0%; P < .001), colectomy (9.3% vs 15.0%; P < .001), hysterectomy (1.8% vs 3.9%; P < .001), and radical prostatectomy (1.0% vs 2.4%; P < .001). In logistic regression analyses, MIS was associated with lower odds of SSIs in patients treated with appendectomy (odds ratio [OR], 0.52 [95% CI, 0.48-0.58]; P < .001), colectomy (OR, 0.58 [95% CI, 0.55-0.61]; P < .001), hysterectomy (OR, 0.44 [95% CI, 0.37-0.53]; P < .001), and radical prostatectomy (OR, 0.39 [95% CI, 0.25-0.61]; P < .001). CONCLUSIONS AND RELEVANCE: The proportion of patients developing SSIs within 30 days after surgery can be substantial and depends on the type of surgery. Minimally invasive surgery is significantly associated with reduced odds of SSIs. This advantage should be considered when assessing the overall benefits of minimally invasive techniques. PMID- 25143177 TI - Pentraxin-3 level at admission is a strong predictor of short-term mortality in a community-based hospital setting. AB - BACKGROUND: The pattern recognition molecule pentraxin-3 (PTX3) is a novel potential marker of prognosis, as elevated levels are associated with both disease severity and mortality in patients with a wide range of conditions. However, the usefulness of PTX3 as a prognostic biomarker in a general hospital setting is unknown. PATIENTS AND METHODS: The study cohort consisted of 1326 unselected, consecutive patients (age >40 years) admitted to a community hospital in Copenhagen, Denmark. Patients were followed until death or for a median of 11.5 years after admission. The main outcome measure was all-cause mortality. Serum samples collected from patients at admission and from 192 healthy control subjects were quantified for PTX3 level by enzyme-linked immunosorbent assay. RESULTS: PTX3 was elevated in patients (median 3.7 ng mL(-1) , range 0.5-209.8) compared with healthy nonhospitalized subjects (median 3.5 ng mL(-1) , range 0.0 8.3; P = 0.0003). Elevated PTX3 levels, defined as above the 95th percentile of the concentration in healthy subjects, were associated with increased overall mortality during the study (P < 0.0001). This increase in mortality was greatest in the short term, with an unadjusted hazard ratio (HR) of 6.4 [95% confidence interval (CI) 3.8-11.0] at 28 days after admission, compared to 1.7 (95% CI 1.4 2.0) at the end of follow-up. These results were still significant after adjustment for age, gender and glomerular filtration rate: adjusted HR of 5.0 (95% CI 2.9-8.8) and 1.4 (95% CI 1.2-1.8), respectively. CONCLUSION: These results suggest that PTX3 could be a widely applicable marker of short-term mortality in hospitalized patients and may be useful in the initial risk stratification. PMID- 25143178 TI - Adaptive framework for uncertainty analysis in electromagnetic field measurements. AB - Misinterpretation of uncertainty in the measurement of the electromagnetic field (EMF) strength may lead to an underestimation of exposure risk or an overestimation of required measurements. The Guide to the Expression of Uncertainty in Measurement (GUM) has internationally been adopted as a de facto standard for uncertainty assessment. However, analyses under such an approach commonly assume unrealistic static models or neglect relevant prior information, resulting in non-robust uncertainties. This study proposes a principled and systematic framework for uncertainty analysis that fuses information from current measurements and prior knowledge. Such a framework dynamically adapts to data by exploiting a likelihood function based on kernel mixtures and incorporates flexible choices of prior information by applying importance sampling. The validity of the proposed techniques is assessed from measurements performed with a broadband radiation meter and an isotropic field probe. The developed framework significantly outperforms GUM approach, achieving a reduction of 28% in measurement uncertainty. PMID- 25143179 TI - The impact of dermatology consultation on diagnostic accuracy and antibiotic use among patients with suspected cellulitis seen at outpatient internal medicine offices: a randomized clinical trial. AB - IMPORTANCE: Cellulitis is a common and costly problem, often diagnosed in the outpatient setting. Many cutaneous conditions may clinically mimic cellulitis, but little research has been done to assess the magnitude of the problem. OBJECTIVE: To determine if obtaining dermatology consultations in the outpatient primary care setting could assist in the diagnosis of pseudocellulitic conditions and reduce the rate of unnecessary antibiotic use. DESIGN, SETTING, AND PARTICIPANTS: Nonblinded randomized clinical trial of competent adults who were diagnosed as having cellulitis by their primary care physicians (PCPs), conducted at outpatient internal medical primary care offices affiliated with a large academic medical center. INTERVENTIONS: Outpatient dermatology consultation. MAIN OUTCOMES AND MEASURES: Primary outcomes were final diagnosis, antibiotic use, and need for hospitalization. RESULTS: A total of 29 patients (12 male and 17 female) were enrolled for participation in this trial. Nine patients were randomized to continue with PCP management (control group), and 20 patients were randomized to receive a dermatology consultation (treatment group). Of the 20 patients in the dermatology consultation group, 2 (10%) were diagnosed as having cellulitis. In the control group, all 9 patients were diagnosed as having cellulitis by PCPs, but dermatologist evaluation determined that 6 (67%) of these patients had a psuedocellulitis rather than true infection. All 9 patients (100%) in the control group were treated for cellulitis with antibiotics vs 2 patients (10%) in the treatment group (P < .001). One patient in the control group was hospitalized. All patients in the treatment group reported improvement of their cutaneous condition at the 1-week follow-up examination. CONCLUSIONS AND RELEVANCE: Dermatology consultation in the primary care setting improves the diagnostic accuracy of suspected cellulitis and decreases unnecessary antibiotic use in patients with pseudocellulitic conditions. Obtaining an outpatient dermatology consultation may be a cost-effective strategy that improves quality of care. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01795092. PMID- 25143180 TI - Treatment of malignant phaeochromocytoma with a combination of cyclophosphamide, vincristine and dacarbazine: own experience and overview of the contemporary literature. AB - OBJECTIVE: Malignant phaeochromocytomas are rare and highly aggressive tumours. This retrospective study evaluated the outcome of combined chemotherapy with cyclophosphamide, vincristine and dacarbazine (also known as CVD regimen). METHODS: Patients with histologically and radiologically confirmed malignant phaeochromocytoma who were treated with the CVD regimen for progressive disease were retrospectively identified from chart review. Treatment cycles were usually repeated at 21-day intervals, with cyclophosphamide (750 mg/m(2) ), vincristine (1.4 mg/m(2) ) and dacarbazine (600 mg/m(2) ) on day 1, and dacarbazine only (600 mg/m(2) ) on day 2. The main outcome measures were best response during treatment and progression-free survival. RESULTS: Eight patients (4 males; median age 55.5 (range 31-77) years) with progressive disease underwent a median of 6 (range 3 11) cycles. Best treatment responses were as follows: partial response, n = 2 (25%); stable disease, n = 3 (38%); and progressive disease, n = 3 (38%). The median progression-free survival was 5.4 (range 2.5-26.8) months. After the initial administration of 6 cycles, two patients received a second course of chemotherapy with another 6 cycles after new progressive disease had been detected. Subsequently, these patients were progression-free for another 6.0 and 6.4 months. Mild gastrointestinal symptoms and fatigue were the most common adverse events. CONCLUSION: Although objective tumour response rates were lower than previously reported in small series, the CVD regimen allowed disease stabilization for a substantial period of time and may therefore be considered as a treatment option in advanced stages. To improve disease outcome, however, new therapeutic approaches and larger multicentre studies are needed. PMID- 25143181 TI - The effect of social health insurance on prenatal care: the case of Ghana. AB - Many developing countries have introduced social health insurance programs to help address two of the United Nations' millennium development goals-reducing infant mortality and improving maternal health outcomes. By making modern health care more accessible and affordable, policymakers hope that more women will seek prenatal care and thereby improve health outcomes. This paper studies how Ghana's social health insurance program affects prenatal care use and out-of-pocket expenditures, using the two-part model to model prenatal care expenditures. We test whether Ghana's social health insurance improved prenatal care use, reduced out-of-pocket expenditures, and increased the number of prenatal care visits. District-level differences in the timing of implementation provide exogenous variation in access to health insurance, and therefore strong identification. Those with access to social health insurance have a higher probability of receiving care, a higher number of prenatal care visits, and lower out-of-pocket expenditures conditional on spending on care. PMID- 25143182 TI - Identification of Belgian mosquito species (Diptera: Culicidae) by DNA barcoding. AB - Since its introduction in 2003, DNA barcoding has proven to be a promising method for the identification of many taxa, including mosquitoes (Diptera: Culicidae). Many mosquito species are potential vectors of pathogens, and correct identification in all life stages is essential for effective mosquito monitoring and control. To use DNA barcoding for species identification, a reliable and comprehensive reference database of verified DNA sequences is required. Hence, DNA sequence diversity of mosquitoes in Belgium was assessed using a 658 bp fragment of the mitochondrial cytochrome oxidase I (COI) gene, and a reference data set was established. Most species appeared as well-supported clusters. Intraspecific Kimura 2-parameter (K2P) distances averaged 0.7%, and the maximum observed K2P distance was 6.2% for Aedes koreicus. A small overlap between intra- and interspecific K2P distances for congeneric sequences was observed. Overall, the identification success using best match and the best close match criteria were high, that is above 98%. No clear genetic division was found between the closely related species Aedes annulipes and Aedes cantans, which can be confused using morphological identification only. The members of the Anopheles maculipennis complex, that is Anopheles maculipennis s.s. and An. messeae, were weakly supported as monophyletic taxa. This study showed that DNA barcoding offers a reliable framework for mosquito species identification in Belgium except for some closely related species. PMID- 25143183 TI - Copackaging of multiple adeno-associated viral vectors in a single production step. AB - Limiting factors in large preclinical and clinical studies utilizing adeno associated virus (AAV) for gene therapy are focused on the restrictive packaging capacity, the overall yields, and the versatility of the production methods for single AAV vector production. Furthermore, applications where multiple vectors are needed to provide long expression cassettes, whether because of long cDNA sequences or the need of different regulatory elements, require that each vector be packaged and characterized separately, directly affecting labor and cost associated with such manufacturing strategies. To overcome these limitations, we propose a novel method of vector production that allows for the packaging of multiple expression cassettes in a single transfection step. Here we combined two expression cassettes in predetermined ratios before transfection and empirically demonstrate that the output vector recapitulates the predicted ratios. Titration by quantitative polymerase chain reaction of AAV vector genome copies using shared or unique genetic elements allowed for delineation of the individual vector contribution to the total preparation that showed the predicted differential packaging outcomes. By copackaging green fluorescent protein (GFP) and mCherry constructs, we demonstrate that both vector genome and infectious titers reiterated the ratios utilized to produce the constructs by transfection. Copackaged therapeutic constructs that only differ in transcriptional elements produced a heterogeneous vector population of both constructs in the predefined ratios. This study shows feasibility and reproducibility of a method that allows for two constructs, differing in either transgene or transcription elements, to be efficiently copackaged and characterized simultaneously, reducing cost of manufacturing and release testing. PMID- 25143184 TI - How I do it: the endoscopic endonasal optic nerve and orbital apex decompression. AB - BACKGROUND: With the refinement of the technique, endoscopic endonasal surgery increases its field of indications. The orbital compartment is among the locations easily reached through the nostril. This anteromedial approach has been described primarily for inflammatory or traumatic diseases, with few data for tumoral diseases. METHOD: Since 2010, this route has been used at our institution either for decompression or for biopsy of orbital tumoral diseases. FINDINGS/CONCLUSIONS: Even if further studies are warranted, this strategy proved to be beneficial for patients, with improvements in visual outcome. In this article, the authors summarize their technique and their experience with endonasal endoscopic orbital decompression. KEY POINTS: Nasal and sphenoidal anatomies determine the feasibility and risks for doing an efficient medial optic or orbit decompression. * Techniques and tools used are those developed for pituitary surgery. * A middle turbinectomy and posterior ethmoidectomy are mandatory to expose the medial wall of the orbit. * The Onodi cell is a key marker for the optic canal and must be opened up with caution. * The lamina papyracea is opened first with a spatula and the optic canal opened up by a gentle drilling under continuous irrigation from distal to proximal. * Drilling might always be used under continuous irrigation to avoid overheating of the optic nerve. An ultrasonic device can be used as well. * The nasal corridor is narrow and instruments may hide the infrared neuronavigation probe. To overcome this issue, a magnetic device could be useful. * Doppler control could be useful to locate the ICA. * The optic canal must be opened up from the tuberculum of the sella to the orbital apex and from the planum (anterior cranial fossa) to the lateral OCR or ICA canal * At the end of the procedure, the optic nerve becomes frequently pulsatile, which is a good marker of decompression. PMID- 25143185 TI - Predictors of shunt dependency after aneurysmal subarachnoid hemorrhage: results of a single-center clinical trial. AB - BACKGROUND: Hydrocephalus (HC) after aneurysmal subarachnoid hemorrhage (aSAH) is a common sequel. Proper selection of patients in need of permanent cerebrospinal fluid (CSF) diversion is, however, not straightforward. The aim of this study was to identify predictors of CSF shunt dependency following aSAH. METHODS: We re analyzed data acquired from aSAH patients previously enrolled in a prospective, controlled single-center clinical trial in which shunt dependency was not one of the end points. In the present study patients were allocated into two groups: those receiving a shunt (here denoted as shunt dependent) and those not receiving a shunt, based on a clinical decision process. Predictors of shunt dependency were identified by applying uni- and multivariable analysis. We tested a set of predefined possible risk factors based on the results of the clinical trial, including the impact of CSF drainage volume exceeding 1,500 ml during the 1st week after ictus. RESULTS: Ninety patients were included in the study. Significant predictors of shunt dependency were poor clinical grade at admission [odds ratio (OR) 4.7, 95% confidence interval (CI) 1.2-18.4], large amounts of subarachnoid blood (OR 3.8, 95% CI 1.0-14.0), large ventricular size on preoperative cerebral computer tomographic (CT) scans (OR 1.0, 95% CI 1.0-1.1), and CSF volume drainage exceeding 1,500 ml during the 1st week after the ictus (OR 16.3, 95% CI 4.0-67.1). Age >=70 years, larger amounts of intraventricular blood, vertebrobasilar aneurysm, and endovascular treatment tended to increase the likelihood of receiving a shunt. Outcome was not significantly different between shunted and non-shunted patients. CONCLUSIONS: In this cohort of patients with clinical grade aSAH at admission, larger amounts of subarachnoid blood and large ventricular size on preoperative cerebral CT, and CSF drainage in excess of 1,500 ml during the 1st week after the ictus were significant predictors of shunt dependency. Shunt dependency did not hamper outcome. PMID- 25143187 TI - Compositional redistribution and dynamic heterogeneity in mixed lipid membrane induced by polyelectrolyte adsorption: effects of chain rigidity. AB - Monte Carlo simulation is employed to investigate the interaction between a polyelectrolyte and a fluid mixed membrane containing neutral (phosphatidyl choline, PC), monovalent anionic (phosphatidylserine, PS), and multivalent anionic (phosphatidylinositol, PIP2) lipids. The effects of the intrinsic polyelectrolyte rigidity and solution ionic strength on the lateral rearrangement and dynamics of different anionic lipid species are systematically studied. Our results show that, the increase of polyelectrolyte chain rigidity reduces the loss of polyelectrolyte conformational entropy and the energy gains in electrostatic interaction, but raises the demixing entropy loss of the segregated anionic lipids. Therefore, the polyelectrolyte/membrane adsorption strength exhibits a non-monotonic dependence on the polyelectrolyte rigid parameter k ang, and there exists a certain optimal k ang for which the adsorption strength is maximal. Because the less loss of chain conformational entropy dominates the increase of the demixing entropy loss of the segregated anionic lipids and the decreases of the electrostatic energy gains, the semiflexible polyelectrolyte adsorbs onto the membrane more firmly than the flexible one. Whereas, for the adsorption of rigid polyelectrolyte, larger anionic lipid demixing entropy loss and less energy gain in the electrostatic interaction dominate over the decrease of the polyelectrolyte conformation entropy loss, leading to the desorption of the chain from the membrane. By decreasing the ionic concentration of the salt solution, the certain optimal k ang shifts to larger values. The cooperative effects of the adsorbing polyelectrolyte beads determine the concentration gradients and hierarchical mobility of the bound anionic lipids, as well as the polyelectrolyte dynamics. PMID- 25143188 TI - Lixisenatide treatment for older patients with type 2 diabetes mellitus uncontrolled on oral antidiabetics: meta-analysis of five randomized controlled trials. AB - AIM: Evaluate the efficacy and safety of lixisenatide, a once-daily prandial glucagon-like peptide-1 receptor agonist, in older patients with type 2 diabetes mellitus (T2DM) insufficiently controlled on oral antidiabetics (OADs). METHODS: A meta-analysis was conducted on data from older patients (>=65 years) from five of the GetGoal trials, in which patients with T2DM were treated with lixisenatide 20 ug once daily or placebo, as an add-on to OADs. The primary endpoint in all trials was change from baseline at week 24 in glycated hemoglobin (HbA1c). Other endpoints included changes in post-prandial plasma glucose (PPG), fasting plasma glucose (FPG) and weight. Composite and safety endpoints were also analyzed. RESULTS: A total of 501 patients aged >=65 years were included in this meta analysis: 304 received lixisenatide plus OADs and 197 received placebo as add-on to OADs. Lixisenatide as an add-on to OADs significantly reduced HbA1c, PPG, FPG and weight, with placebo-corrected treatment effects at week 24 of -0.54% (p<0.0001), -126 mg/dL (p<0.0001), -13 mg/dL (p=0.0005) and -0.90 kg (p=0.0021), respectively. Patients receiving lixisenatide plus OADs were significantly more likely to achieve composite (HbA1c levels<7%, HbA1c levels<7% and no symptomatic hypoglycemia, and HbA1c levels<7%, no weight gain and no symptomatic hypoglycemia) and safety endpoints than those receiving placebo plus OADs. Symptomatic hypoglycemia was experienced by 8.55% and 3.55% of patients in the lixisenatide plus OADs and placebo plus OADs groups, respectively (p=0.0276), although no serious hypoglycemic episodes were reported. CONCLUSIONS: Lixisenatide plus OADs improved glycemic control in older patients inadequately controlled on OADs compared with placebo plus OADs. Lixisenatide is well tailored to the pathophysiology of T2DM in older patients. PMID- 25143186 TI - Mobilization characteristics and strategies to improve hematopoietic progenitor cell mobilization and collection in patients with chronic granulomatous disease and severe combined immunodeficiency. AB - BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF)-mobilized autologous hematopoietic progenitor cells (HPCs) may be collected by apheresis of patients with chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID) for use in gene therapy trials. CD34+ cell mobilization has not been well characterized in such patients. STUDY DESIGN AND METHODS: We retrospectively evaluated CD34+ cell mobilization and collection in 73 consecutive CGD and SCID patients and in 99 age-, weight-, and G-CSF dose-matched healthy allogeneic controls. RESULTS: In subjects aged not more than 20 years, Day 5 preapheresis circulating CD34+ counts were significantly lower in CGD and SCID patients than in controls; mean peak CD34+ cell counts were 58 * 10(6) , 64 * 10(6) , and 87 * 10(6) /L, respectively (p = 0.01). The SCIDs had lower CD34+ collection efficiency than CGDs and controls; mean efficiencies were 40, 63, and 57%, respectively (p = 0.003). In subjects aged more than 20 years, the CGDs had significantly lower CD34+ cell mobilization than controls; mean peak CD34+ cell counts were 41 * 10(6) and 113 * 10(6) /L, respectively (p < 0.0001). In a multivariate analysis, lower erythrocyte sedimentation rate (ESR) at mobilization was significantly correlated with better CD34+ cell mobilization (p = 0.007). In SCIDs, CD34 collection efficiency was positively correlated with higher red blood cell (RBC) indices (mean RBC volume, R(2) = 0.77; mean corpuscular hemoglobin [Hb], R(2) = 0.94; mean corpuscular Hb concentration, R(2) = 0.7; p < 0.007) but not Hb. CONCLUSIONS: CGD and SCID populations are characterized by significantly less robust CD34+ HPC mobilization than healthy controls. The presence of active inflammation or infection as suggested by an elevated ESR may negatively impact mobilization. Among SCIDs, markedly reduced CD34 collection efficiencies were related to iron deficiency, wherein decreased RBC size and density may impair apheresis cell separation mechanics. PMID- 25143189 TI - Pazopanib in metastatic osteosarcoma: significant clinical response in three consecutive patients. PMID- 25143190 TI - Horizontal transfer of short and degraded DNA has evolutionary implications for microbes and eukaryotic sexual reproduction. AB - Horizontal gene transfer in the form of long DNA fragments has changed our view of bacterial evolution. Recently, we discovered that such processes may also occur with the massive amounts of short and damaged DNA in the environment, and even with truly ancient DNA. Although it presently remains unclear how often it takes place in nature, horizontal gene transfer of short and damaged DNA opens up the possibility for genetic exchange across distinct species in both time and space. In this essay, we speculate on the potential evolutionary consequences of this phenomenon. We argue that it may challenge basic assumptions in evolutionary theory; that it may have distant origins in life's history; and that horizontal gene transfer should be viewed as an evolutionary strategy not only preceding but causally underpinning the evolution of sexual reproduction. PMID- 25143191 TI - Tularemia in the Southeastern Swiss Alps at 1,700 m above sea level. AB - A 37-year-old man presented with a 4-day history of nonbloody diarrhea, fever, chills, productive cough, vomiting, and more recent sore throat. He worked for the municipality in a village in the Swiss Alps near St. Moritz. Examination showed fever (40 degrees C), hypotension, tachycardia, tachypnea, decreased oxygen saturation (90 % at room air), and bibasilar crackles and wheezing. Chest radiography and computed tomography scan showed an infiltrate in the left upper lung lobe. He responded to empiric therapy with imipenem for 5 days. After the imipenem was stopped, the bacteriology laboratory reported that 2/2 blood cultures showed growth of Francisella tularensis. He had recurrence of fever and diarrhea. He was treated with ciprofloxacin (500 mg twice daily, oral, for 14 days) and symptoms resolved. Further testing confirmed that the isolate was F. tularensis (subspecies holarctica) belonging to the subclade B.FTNF002-00 (Western European cluster). This case may alert physicians that tularemia may occur in high-altitude regions such as the Swiss Alps. PMID- 25143192 TI - No reactivation of JCV in bone marrow of follicular lymphoma patients treated front-line with rituximab plus 90y-ibritumomab tiuxetan. PMID- 25143193 TI - Risk factors for enterococcal infection and colonization by vancomycin-resistant enterococci in critically ill patients. AB - PURPOSE: Vancomycin-Resistant Enterococci (VRE) are important causes of Intensive Care Unit (ICU) infections. Our goal was to identify the prevalence and risk factors for VRE colonization upon ICU admission and during ICU stay, as well as, their impact in enterococcal infection including vancomycin-susceptible cases (VSE). METHODS: A prospective study regarding patients admitted in ICU (n = 497) was conducted during a 24-month period. Rectal swabs were collected upon admission and during hospitalization and inoculated onto selective medium. Enterococci were phenotypically characterized. van genes were investigated by PCR and clones were identified by Pulsed-Field Gel Electrophoresis and Multilocus Sequence Typing. Epidemiologic data were collected from the ICU database. RESULTS: Risk factors for VRE carriage upon ICU admission (71/497) were: duration of previous hospitalization, glycopeptide administration, chronic heart failure, malignancy, insulin-dependent diabetes mellitus, and previous enterococcal infection (VRE and/or VSE). Risk factors for VRE colonization during ICU stay (36/250) were: quinolone administration, chronic obstructive pulmonary disease, chronic renal failure, and number of VRE-positive patients in nearby beds. Risk factors for enterococcal infection during ICU stay (15/284), including VRE and VSE cases, were: administration of third- or fourth-generation cephalosporins, cortisone use before ICU admission and VRE colonization, whereas, enteral nutrition was a protective factor. CONCLUSIONS: Previous VRE colonization and antibiotic usage are essential parameters for enterococcal infection (by VRE or VSE) during ICU stay. Previous enterococcal infection, co-morbidities and antibiotic usage are associated with VRE colonization upon ICU admission, whereas, patient to patient transmission, co-morbidities and antibiotic usage constitute risk factors for VRE colonization during ICU hospitalization. PMID- 25143194 TI - What core primary health care services should be available to Australians living in rural and remote communities? AB - BACKGROUND: Australians living in rural and remote areas experience poorer access to primary health care (PHC) and poorer health outcomes compared to metropolitan populations. Current health reform in Australia aims to ensure all Australians, regardless of where they live, have access to essential PHC services. However, at a national level policy makers and health planners lack an evidence-based set of core PHC services to assist in implementing this goal. METHODS: A Delphi method was used to reach consensus on an evidence-based list of core PHC services to which all Australians should have access and their necessary support functions. Experts in rural and remote and/or Indigenous PHC, including policy-makers, academics, clinicians and consumers, were invited to consider a list of core services derived from the literature. RESULTS: Thirty nine experts agreed to participate. After three survey rounds there was a strong consensus (>=80% agreement) on core PHC services namely; 'care of the sick and injured', 'mental health', 'maternal/child health', 'allied health', 'sexual/reproductive health', 'rehabilitation', 'oral/dental health' and 'public health/illness prevention'; and on the PHC support functions of; 'management/governance/leadership', 'coordination', 'health infrastructure', 'quality systems', 'data systems', 'professional development' and 'community participation'. Themes emerging from qualitative data included challenges in providing equitable PHC in rural and remote areas, the importance of service coordination and diverse strategies to overcome access barriers. CONCLUSION: This study identifies a basket of PHC services that consumers in rural and remote communities can expect to access. It provides rigorously derived evidence that will contribute to a more systematic approach to PHC service planning and availability and will assist policy makers in the allocation of scarce resources necessary to improve the health outcomes of residents of rural and remote areas. PMID- 25143195 TI - Absorption, translocation and metabolism of bispyribac-sodium on rice seedlings under cold stress. AB - BACKGROUND: Rice production is highly affected by weed competition. The efficacy of chemical weed control and crop safety is a function of absorption, translocation and metabolism of herbicides. This study investigates the effect of cold stress 22/16 degrees C (day/night) on absorption, translocation and metabolism of (14)C-bispyribac-sodium on rice seedlings. RESULTS: Maximum (14)C bispyribac-sodium absorption occurred at 24 h after herbicide treatment and was stimulated by the warm 30/22 degrees C (day/night) temperature. A large amount of total absorbed herbicide was retained in the treated leaf, indicating that bispyribac-sodium had minimal translocation to other plant parts. Piperonyl butoxide (a P450 inhibitor) plus herbicide caused greater injury than the herbicide alone. In addition, injury on rice plants was enhanced by exposure to cold, emphasizing the negative effect on herbicide metabolism. In the thin-layer chromatography metabolism experiment, cold-grown plants had higher injury and retained more of the parent herbicide than plants grown at a warm temperature. CONCLUSION: Cold stress reduces bispyribac-sodium absorption and metabolism in rice, but has no effect on translocation. PMID- 25143197 TI - 2D or not 2D? PMID- 25143198 TI - An ode to the atomic weights. PMID- 25143196 TI - Protective effects of calycosin against CCl4-induced liver injury with activation of FXR and STAT3 in mice. AB - PURPOSE: Investigating the hepatoprotective effect of calycosin against acute liver injury in association with FXR activation and STAT3 phosphorylation. METHODS: The acute liver injury model was established by intraperitoneal injection of CCl4 in C57BL/6 mice. Serum alanine aminotransferase, aspartate aminotransferase, HE staining and TUNEL assay were used to identify the amelioration of the liver histopathological changes and hepatocytes apoptosis after calycosin treatment. ELISA kit and 5-bromo-2-deoxyuridine immunohistochemistry were used to measure the liver bile acid concentration and hepatocyte mitotic rate in vivo. The relation between calycosin and activation of FXR and STAT3 was comfirmed using the Luciferase assay, Molecular docking, Real time PCR and Western Blot in vitro. RESULTS: The liver histopathological changes, hepatocytes apoptosis, liver bile acid overload and hepatocyte mitosis showed significant changes after calycosin treatment. Calycosin promoted the expression of FXR target genes such as FoxM1B and SHP but the effect was reversed by FXR suppressor guggulsterone. Molecular docking results indicated that calycosin could be embedded into the binding pocket of FXR, thereby increasing the expressions of STAT3 tyrosine phosphorylation and its target genes, Bcl-xl and SOCS3. CONCLUSIONS: Calycosin plays a critical role in hepatoprotection against liver injury in association with FXR activation and STAT3 phosphorylation. PMID- 25143199 TI - The chemists behind the crystals. PMID- 25143205 TI - Enzyme catalysis: Evolution made easy. PMID- 25143206 TI - Two-dimensional materials: Crystallized creations in 2D. PMID- 25143207 TI - Quantum control: May the electric force be with you. PMID- 25143208 TI - Helicates: Making head-head-tails of it. PMID- 25143209 TI - Scientific conferences: A big hello to halogen bonding. PMID- 25143210 TI - The electron is a catalyst. AB - The electron is an efficient catalyst for conducting various types of radical cascade reaction that proceed by way of radical and radical ion intermediates. But because electrons are omnipresent, catalysis by electrons often passes unnoticed. In this Review, a simple analogy between acid/base catalysis and redox catalysis is presented. Conceptually, the electron is a catalyst in much the same way that a proton is a catalyst. The 'electron is a catalyst' paradigm unifies mechanistically an assortment of synthetic transformations that otherwise have little or no apparent relationship. Diverse radical cascades, including unimolecular radical substitution reactions (SRN1-type chemistry), base-promoted homolytic aromatic substitutions (BHAS), radical Heck-type reactions, radical cross-dehydrogenative couplings (CDC), direct arene trifluoromethylations and radical alkoxycarbonylations, can all be viewed as electron-catalysed reactions. PMID- 25143212 TI - Gram-scale synthesis of two-dimensional polymer crystals and their structure analysis by X-ray diffraction. AB - The rise of graphene, a natural two-dimensional polymer (2DP) with topologically planar repeat units, has challenged synthetic chemistry, and has highlighted that accessing equivalent covalently bonded sheet-like macromolecules has, until recently, not been achieved. Here we show that non-centrosymmetric, enantiomorphic single crystals of a simple-to-make monomer can be photochemically converted into chiral 2DP crystals and cleanly reversed back to the monomer. X ray diffraction established unequivocal structural proof for this synthetic 2DP, which has an all-carbon scaffold and can be synthesized on the gram scale. The monomer crystals are highly robust, can be easily grown to sizes greater than 1 mm and the resulting 2DP crystals exfoliated into nanometre-thin sheets. This unique combination of features suggests that these 2DPs could find use in membranes and nonlinear optics. PMID- 25143211 TI - A nanoporous two-dimensional polymer by single-crystal-to-single-crystal photopolymerization. AB - In contrast to the wide number and variety of available synthetic routes to conventional linear polymers, the synthesis of two-dimensional polymers and unambiguous proof of their structure remains a challenge. Two-dimensional polymers-single-layered polymers that form a tiling network in exactly two dimensions-have potential for use in nanoporous membranes and other applications. Here, we report the preparation of a fluorinated hydrocarbon two-dimensional polymer that can be exfoliated into single sheets, and its characterization by high-resolution single-crystal X-ray diffraction analysis. The procedure involves three steps: preorganization in a lamellar crystal of a rigid monomer bearing three photoreactive arms, photopolymerization of the crystalline monomers by [4 + 4] cycloaddition, and isolation of individual two-dimensional polymer sheets. This polymer is a molecularly thin (~1 nm) material that combines precisely defined monodisperse pores of ~9 A with a high pore density of 3.3 * 10(13) pores cm(-2). Atomic-resolution single-crystal X-ray structures of the monomer, an intermediate dimer and the final crystalline two-dimensional polymer were obtained and prove the single-crystal-to-single-crystal nature and molecular precision of the two-dimensional photopolymerization. PMID- 25143213 TI - Control of ultrafast molecular photodissociation by laser-field-induced potentials. AB - Experiments aimed at understanding ultrafast molecular processes are now routine, and the notion that external laser fields can constitute an additional reagent is also well established. The possibility of externally controlling a reaction with radiation increases immensely when its intensity is sufficiently high to distort the potential energy surfaces at which chemists conceptualize reactions take place. Here we explore the transition from the weak- to the strong-field regimes of laser control for the dissociation of a polyatomic molecule, methyl iodide. The control over the yield of the photodissociation reaction proceeds through the creation of a light-induced conical intersection. The control of the velocity of the product fragments requires external fields with both high intensities and short durations. This is because the mechanism by which control is exerted involves modulating the potentials around the light-induced conical intersection, that is, creating light-induced potentials. PMID- 25143214 TI - Evolution of enzyme catalysts caged in biomimetic gel-shell beads. AB - Natural evolution relies on the improvement of biological entities by rounds of diversification and selection. In the laboratory, directed evolution has emerged as a powerful tool for the development of new and improved biomolecules, but it is limited by the enormous workload and cost of screening sufficiently large combinatorial libraries. Here we describe the production of gel-shell beads (GSBs) with the help of a microfluidic device. These hydrogel beads are surrounded with a polyelectrolyte shell that encloses an enzyme, its encoding DNA and the fluorescent reaction product. Active clones in these man-made compartments can be identified readily by fluorescence-activated sorting at rates >10(7) GSBs per hour. We use this system to perform the directed evolution of a phosphotriesterase (a bioremediation catalyst) caged in GSBs and isolate a 20 fold faster mutant in less than one hour. We thus establish a practically undemanding method for ultrahigh-throughput screening that results in functional hybrid composites endowed with evolvable protein components. PMID- 25143215 TI - Asymmetric triplex metallohelices with high and selective activity against cancer cells. AB - Small cationic amphiphilic alpha-helical peptides are emerging as agents for the treatment of cancer and infection, but they are costly and display unfavourable pharmacokinetics. Helical coordination complexes may offer a three-dimensional scaffold for the synthesis of mimetic architectures. However, the high symmetry and modest functionality of current systems offer little scope to tailor the structure to interact with specific biomolecular targets, or to create libraries for phenotypic screens. Here, we report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices. Their anti-parallel head-to-head-to-tail 'triplex' strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host defence peptides and p53. The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 p53(++), causing dramatic changes in the cell cycle without DNA damage. They have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468) and, most remarkably, they show no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli. PMID- 25143216 TI - Template-directed covalent conjugation of DNA to native antibodies, transferrin and other metal-binding proteins. AB - DNA-protein conjugates are important in bioanalytical chemistry, molecular diagnostics and bionanotechnology, as the DNA provides a unique handle to identify, functionalize or otherwise manipulate proteins. To maintain protein activity, conjugation of a single DNA handle to a specific location on the protein is often needed. However, preparing such high-quality site-specific conjugates often requires genetically engineered proteins, which is a laborious and technically challenging approach. Here we demonstrate a simpler method to create site-selective DNA-protein conjugates. Using a guiding DNA strand modified with a metal-binding functionality, we directed a second DNA strand to the vicinity of a metal-binding site of His6-tagged or wild-type metal-binding proteins, such as serotransferrin, where it subsequently reacted with lysine residues at that site. This method, DNA-templated protein conjugation, facilitates the production of site-selective protein conjugates, and also conjugation to IgG1 antibodies via a histidine cluster in the constant domain. PMID- 25143217 TI - Synthesis of hydroxyphthioceranic acid using a traceless lithiation-borylation protodeboronation strategy. AB - In planning organic syntheses, disconnections are most often made adjacent to functional groups, which assist in C-C bond formation. For molecules devoid of obvious functional groups this approach presents a problem, and so functionalities must be installed temporarily and then removed. Here we present a traceless strategy for organic synthesis that uses a boronic ester as such a group in a one-pot lithiation-borylation-protodeboronation sequence. To realize this strategy, we developed a methodology for the protodeboronation of alkyl pinacol boronic esters that involves the formation of a boronate complex with a nucleophile followed by oxidation with Mn(OAc)3 in the presence of the hydrogen atom donor 4-tert-butylcatechol. Iterative lithiation-borylation protodeboronation allows the coupling of smaller fragments to build-up long alkyl chains. We employed this strategy in the synthesis of hydroxyphthioceranic acid, a key component of the cell-wall lipid of the virulent Mycobacterium tuberculosis, in just 14 steps (longest linear sequence) with full stereocontrol. PMID- 25143218 TI - Triazolinediones enable ultrafast and reversible click chemistry for the design of dynamic polymer systems. AB - With its focus on synthetic reactions that are highly specific and reliable, 'click' chemistry has become a valuable tool for many scientific research areas and applications. Combining the modular, covalently bonded nature of click chemistry linkages with an ability to reverse these linkages and reuse the constituent reactants in another click reaction, however, is a feature that is not found in most click reactions. Here we show that triazolinedione compounds can be used in click-chemistry applications. We present examples of simple and ultrafast macromolecular functionalization, polymer-polymer linking and polymer crosslinking under ambient conditions without the need for a catalyst. Moreover, when triazolinediones are combined with indole reaction partners, the reverse reaction can also be induced at elevated temperatures, and the triazolinedione reacted with a different reaction partner, reversibly or irreversibly dependent on its exact nature. We have used this 'transclick' reaction to introduce thermoreversible links into polyurethane and polymethacrylate materials, which allows dynamic polymer-network healing, reshaping and recycling. PMID- 25143219 TI - A redox hydrogel protects hydrogenase from high-potential deactivation and oxygen damage. AB - Hydrogenases are nature's efficient catalysts for both the generation of energy via oxidation of molecular hydrogen and the production of hydrogen via the reduction of protons. However, their O2 sensitivity and deactivation at high potential limit their applications in practical devices, such as fuel cells. Here, we show that the integration of an O2-sensitive hydrogenase into a specifically designed viologen-based redox polymer protects the enzyme from O2 damage and high-potential deactivation. Electron transfer between the polymer bound viologen moieties controls the potential applied to the active site of the hydrogenase and thus insulates the enzyme from excessive oxidative stress. Under catalytic turnover, electrons provided from the hydrogen oxidation reaction induce viologen-catalysed O2 reduction at the polymer surface, thus providing self-activated protection from O2. The advantages of this tandem protection are demonstrated using a single-compartment biofuel cell based on an O2-sensitive hydrogenase and H2/O2 mixed feed under anode-limiting conditions. PMID- 25143220 TI - High-performance Ag-Co alloy catalysts for electrochemical oxygen reduction. AB - The electrochemical oxygen reduction reaction is the limiting half-reaction for low-temperature hydrogen fuel cells, and currently costly Pt-based electrocatalysts are used to generate adequate rates. Although most other metals are not stable in typical acid-mediated cells, alkaline environments permit the use of less costly electrodes, such as silver. Unfortunately, monometallic silver is not sufficiently active for economical fuel cells. Herein we demonstrate the design of low-cost Ag-Co surface alloy nanoparticle electrocatalysts for oxygen reduction. Their performance relative to that of Pt is potential dependent, but reaches over half the area-specific activity of Pt nanoparticle catalysts and is more than a fivefold improvement over pure silver nanoparticles at typical operating potentials. The Ag-Co electrocatalyst was initially identified with quantum chemical calculations and then synthesized using a novel technique that generates a surface alloy, despite bulk immiscibility of the constituent materials. Characterization studies support the hypothesis that the activity improvement comes from a ligand effect, in which cobalt atoms perturb surface silver sites. PMID- 25143221 TI - Irreversible xenon insertion into a small-pore zeolite at moderate pressures and temperatures. AB - Pressure drastically alters the chemical and physical properties of materials and allows structural phase transitions and chemical reactions to occur that defy much of our understanding gained under ambient conditions. Particularly exciting is the high-pressure chemistry of xenon, which is known to react with hydrogen and ice at high pressures and form stable compounds. Here, we show that Ag16Al16Si24O8.16H2O (Ag-natrolite) irreversibly inserts xenon into its micropores at 1.7 GPa and 250 degrees C, while Ag(+) is reduced to metallic Ag and possibly oxidized to Ag(2+). In contrast to krypton, xenon is retained within the pores of this zeolite after pressure release and requires heat to desorb. This irreversible insertion and trapping of xenon in Ag-natrolite under moderate conditions sheds new light on chemical reactions that could account for the xenon deficiency relative to argon observed in terrestrial and Martian atmospheres. PMID- 25143222 TI - Californium gleaming. PMID- 25143223 TI - gammadelta T-cell-rich variants of pityriasis lichenoides and lymphomatoid papulosis: benign cutaneous disorders to be distinguished from aggressive cutaneous gammadelta T-cell lymphomas. AB - BACKGROUND: T cells with a gammadelta phenotype have been associated with aggressive lymphomas. Yet, inflammatory skin disorders and low-grade lymphoproliferative disorders have rarely been described with a predominant gammadelta T-cell infiltrate. OBJECTIVES: To review our experience and determine the clinical relevance of the gammadelta T-cell phenotype in lymphomatoid papulosis (LyP) and pityriasis lichenoides (PL). METHODS: A retrospective dermatopathology file review looking for LyP and PL characterized by a gammadelta T-cell phenotype was performed. Clinical manifestations and course, histological features and molecular data were analyzed. RESULTS: Six of 16 cases of LyP and four of 23 cases diagnosed as PL during a 5-year period (2009-14) were identified. The median follow-up for the whole group was 16 months (range 3-64), showing an indolent clinical course in all cases. CONCLUSIONS: The detection of a predominantly gammadelta T-cell phenotype in papular lymphoid-rich infiltrates in the absence of other lesions is not associated with a clinically aggressive course. gammadelta T-cell-rich variants of LyP and PL may reflect a spectrum of related conditions. This is a single academic centre retrospective chart review of a relatively small sample. PMID- 25143225 TI - Low prevalence of hepatitis B virus infection in patients with autoimmune diseases in a Chinese patient population. AB - Hepatitis B is a very common communicable disease in China but the prevalence of hepatitis B virus (HBV) infection in patients with autoimmune diseases is unknown. We retrospectively investigated the prevalence of autoimmune diseases in patients with HBV infection. The medical records of 4060 patients with autoimmune or nonautoimmune diseases were reviewed. A positive test result for hepatitis B surface antigen (HBsAg) was used to indicate the presence of HBV infection. Autoimmune diseases included autoimmune hepatitis, primary biliary cirrhosis, systemic lupus erythematosus and ulcerative colitis. Nonautoimmune conditions included inguinal hernia, appendicitis and pregnant or postpartum women. The proportion of autoimmune disease patients who were HBsAg positive (2.24%) was significantly lower than that of nonautoimmune disease patients who were HBsAg positive (4.58%; P = 0.0014). Regarding hepatic autoimmune diseases, the positivity rates for HBsAg in autoimmune hepatitis patients (0.83%) and primary biliary cirrhosis patients (1.02%) were both significantly lower than in nonautoimmune patients (4.58%; P = 0.006 and 0.004, respectively). Patients with hepatic autoimmune disease were significantly less likely to be HBsAg positive (0.93%) than patients with non-hepatic autoimmune disease (3.99%; P = 0.002). Patients with autoimmune diseases, especially those with hepatic autoimmune disease, may more efficiently clear HBV than patients with nonautoimmune diseases. PMID- 25143224 TI - Polypharmacy is associated with an increased risk of bleeding in elderly patients with venous thromboembolism. AB - BACKGROUND: Polypharmacy, defined as the concomitant use of multiple medications, is very common in the elderly and may trigger drug-drug interactions and increase the risk of falls in patients receiving vitamin K antagonists. OBJECTIVE: To examine whether polypharmacy increases the risk of bleeding in elderly patients who receive vitamin K antagonists for acute venous thromboembolism (VTE). DESIGN: We used a prospective cohort study. PARTICIPANTS: In a multicenter Swiss cohort, we studied 830 patients aged >= 65 years with VTE. MAIN MEASURES: We defined polypharmacy as the prescription of more than four different drugs. We assessed the association between polypharmacy and the time to a first major and clinically relevant non-major bleeding, accounting for the competing risk of death. We adjusted for known bleeding risk factors (age, gender, pulmonary embolism, active cancer, arterial hypertension, cardiac disease, cerebrovascular disease, chronic liver and renal disease, diabetes mellitus, history of major bleeding, recent surgery, anemia, thrombocytopenia) and periods of vitamin K antagonist treatment as a time-varying covariate. KEY RESULTS: Overall, 413 (49.8 %) patients had polypharmacy. The mean follow-up duration was 17.8 months. Patients with polypharmacy had a significantly higher incidence of major (9.0 vs. 4.1 events/100 patient-years; incidence rate ratio [IRR] 2.18, 95 % confidence interval [CI] 1.32-3.68) and clinically relevant non-major bleeding (14.8 vs. 8.0 events/100 patient-years; IRR 1.85, 95 % CI 1.27-2.71) than patients without polypharmacy. After adjustment, polypharmacy was significantly associated with major (sub-hazard ratio [SHR] 1.83, 95 % CI 1.03-3.25) and clinically relevant non-major bleeding (SHR 1.60, 95 % CI 1.06-2.42). CONCLUSIONS: Polypharmacy is associated with an increased risk of both major and clinically relevant non-major bleeding in elderly patients receiving vitamin K antagonists for VTE. PMID- 25143226 TI - Antiarrhythmic therapy of atrial fibrillation: are we treating too late? AB - Atrial fibrillation (AF) is associated with increased risk for stroke, heart failure and mortality. The causality between worse prognosis and AF is not clear at this time and AF may just be expression of underlying heart disease that by itself is associated with increased morbidity and mortality. AF is characterized by progression from rare paroxysmal episodes to permanent AF. It has been well recognized that maintenance of sinus rhythm with either antiarrhythmic drugs or catheter ablation is easier to achieve if treatment is established early on. In addition to the established indication of symptomatic improvement, the focus of AF management is shifting to earlier intervention to prevent cardiovascular complications. This concept is currently under investigation in the ongoing EAST trial. Early treatment initiation is desirable from a pathophysiologic perspective. This includes consequent prevention and treatment of AF risk factors, efforts for early diagnosis, and stroke prevention according to the CHA2DS2-VASc score. As long as no data support prognostic advantages with "aggressive" rhythm control therapy it remains reserved for symptomatic patients, since both, medication and catheter ablation, convey a significant risk for complications. PMID- 25143227 TI - [Catheter ablation of persistent atrial fibrillation : Current state]. AB - The invasive treatment of persistent atrial fibrillation (AF) is one of the biggest challenges in modern electrophysiology. Treatment strategies are diverse and include pulmonary vein isolation (PVI) alone, left atrial ablation lines, local electrogram-based ablation of complex fractionated electrograms (CFAE) or various combinations of these techniques. New approaches comprise fibrosis-guided ablation or the localisation and ablation of AF sustaining rotors. Different ablation techniques reflect a different understanding of what the most important pathophysiological mechanism of persistent AF might be. Multiple wavelets, repetitive focal discharges (mostly from the pulmonary veins), instable micro reentries, anatomically fixed slow conduction zones close to atrial scarring or (relatively stable) rotors have been proposed as AF sustaining factors. It has become evident that conventional ablation strategies often involve more than one ablation procedure to reach acceptable success rates, whereas new methods of fibrosis-guided ablation and rotor ablation are still under evaluation. PMID- 25143228 TI - [Non-invasive treatment of tachycardias during childhood]. AB - In principle tachycardias during childhood do not differ from those in adulthood but they present with a significant age-dependency. Additionally the clinical presentation has a broad spectrum related to the different ages, from the neonatal period until adolescence. If congenital heart disease is present the hemodynamic compromise may be accentuated. This paper describes the diagnostic and therapeutic approaches to pediatric tachycardias with focus upon the age dependent aspects and the presense of congenital heart disease, either native or postoperative. PMID- 25143229 TI - Long-term quality of life after radical prostatectomy: 8-year longitudinal study in Japan. AB - OBJECTIVES: To assess long-term health-related quality of life in patients undergoing radical prostatectomy. METHODS: A total of 120 patients with at least 5 years of follow up after radical prostatectomy were included in the present study. Health-related quality of life outcomes were assessed using three questionnaires, the Short Form 36-Item Health Survey, the University of California, Los Angeles Prostate Cancer Index and the International Prostate Symptom Score. RESULTS: A total of 91 patients (73%) responded at a median follow up time of 102 months (range 85-123 months). Among general health-related quality of life domains, mental and role composite summary score remained stable throughout the follow-up period. At the final survey, no significant differences were observed in any of the domains compared with the age-matched average score of the Japanese population. Although the slight decrease in urinary function scores and International Prostate Symptom Score beyond 5 years postoperatively compared with 5 years, the differences were not significant. The sexual function summary score showed a substantially lower score just after radical prostatectomy and remained at a deteriorated level (P < 0.001). Responders at the final survey were more likely to report favorable general, urinary and sexual outcomes at 60 months compared with non-responders. CONCLUSIONS: When taking age-related changes into account, general health-related quality of life seems to remain stable in the long term after radical prostatectomy: patients with favorable health-related quality of life outcomes during the first 5 years after radical prostatectomy maintain favorable outcomes thereafter. PMID- 25143230 TI - Medical journals: a disruptive technology. PMID- 25143231 TI - Biophilosophical criticisms of brain death: the need for a new paradigm. PMID- 25143232 TI - A multiplex method for the detection of serum antibodies against in silico predicted tumor antigens. AB - Humoral immune responses against tumor antigens are studied as indirect markers of antigen exposure and in cancer vaccine studies. An increasing number of tumor antigens potentially translated from mutant genes is identified by advances in genomic sequencing. They represent an interesting source for yet unknown immunogenic epitopes. We here describe a multiplex method using the Luminex technology allowing for the detection of antibodies against multiple in silico predicted linear neo-antigens in large sets of sera. The approach included 32 synthetic biotinylated peptides comprising a predicted set of frameshift mutation induced neo-antigens. The antigens were fused to a FLAG epitope to ensure monitoring antigen binding to avidin-linked microspheres in the absence of monoclonal antibodies. Analytical specificity of measured serum antibody reactivity was proven by the detection of immune responses in immunized rabbits and a colorectal cancer patient vaccinated with peptides included in the assay. The measured antibody responses were comparable to peptide ELISA, and inter-assay reproducibility of the multiplex approach was excellent (R (2) > 0.98) for 20 sera tested against all antigens. Our methodic approach represents a valuable platform to monitor antibody responses against predicted antigens. It may be used in individualized cancer vaccine studies, thereby extending the relevance beyond the model system in the presented approach. PMID- 25143235 TI - Elastic trapping of dislocation loops in cascades in ion-irradiated tungsten foils. AB - Using in situ transmission electron microscopy (TEM), we have observed nanometre scale dislocation loops formed when an ultra-high-purity tungsten foil is irradiated with a very low fluence of self-ions. Analysis of the TEM images has revealed the largest loops to be predominantly of prismatic 1/2<111> type and of vacancy character. The formation of such dislocation loops is surprising since isolated loops are expected to be highly mobile, and should escape from the foil. In this work we show that the observed size and number density of loops can be explained by the fact that the loops are not isolated-the loops formed in close proximity in the cascades interact with each other and with vacancy clusters, also formed in cascades, through long-range elastic fields, which prevent the escape of loops from the foil. We find that experimental observations are well reproduced by object Kinetic Monte Carlo simulations of evolution of cascades only if elastic interaction between the loops is taken into account. Our analysis highlights the profound effect of elastic interaction between defects on the microstructural evolution of irradiated materials. PMID- 25143234 TI - A review of the clinical evidence for complementary and alternative therapies in Parkinson's disease. AB - OPINION STATEMENT: No conventional treatment has been convincingly demonstrated to slow or stop the progression of Parkinson's disease (PD). Dopaminergic therapy is the gold standard for managing the motor disability associated with PD, but it falls short of managing all of the aspects of the disease that contribute to quality of life. Perhaps for this reason, an increasing number of patients are searching for a more holistic approach to healthcare. This is not to say that they are abandoning the standard and effective symptomatic therapies for PD, but rather are complementing them with healthy living, mind-body practices, and natural products that empower patients to be active participants in their healthcare and widen the net under which disease modification might one day be achieved. Despite high rates of utilization of complementary and alternative medicine (CAM) practices, data on efficacy is generally limited, restricting physicians in providing guidance to interested patients. Exercise is now well established as integral in the management of PD, but mind-body interventions such as Tai Chi that incorporate relaxation and mindfulness with physical activity should be routinely encouraged as well. While no comment can be made about neuroplastic or disease-modifying effects of mind-body interventions, patients should be encouraged to be as active as possible and engage with others in enjoyable and challenging activities such as dance, music therapy, and yoga. Many PD patients also choose to try herbs, vitamins, and neutraceuticals as part of a healthy lifestyle, with the added expectation that these products may lower free radical damage and protect them against further cell death. Evidence for neuroprotection is limited, but patients can be encouraged to maintain a healthy diet rich in "high-power," low-inflammatory foods, while at the same time receiving education that many promising natural products have produced disappointing results in clinical trials. It is vital that the science of holistic medicine reaches a point where all neutraceuticals are investigated with the same rigor as conventional drugs. A number of agents discussed here that have a proposed role in the treatment of neurodegenerative diseases (and PD in particular), including cannabis, mucuna pruriens, and Chinese herbals, deserve more attention from basic science researchers and clinical investigators before they can be either safely utilized or dismissed. PMID- 25143233 TI - CpG-mediated modulation of MDSC contributes to the efficacy of Ad5-TRAIL therapy against renal cell carcinoma. AB - Tumor progression occurs through the modulation of a number of physiological parameters, including the development of immunosuppressive mechanisms to prevent immune detection and response. Among these immune evasion mechanisms, the mobilization of myeloid-derived suppressor cells (MDSC) is a major contributor to the suppression of antitumor T-cell immunity. Patients with renal cell carcinoma (RCC) show increased MDSC, and methods are being explored clinically to reduce the prevalence of MDSC and/or inhibit their function. In the present study, we investigated the relationship between MDSC and the therapeutic potential of a TRAIL-encoding recombinant adenovirus (Ad5-TRAIL) in combination with CpG containing oligodeoxynucleotides (Ad5-TRAIL/CpG) in an orthotopic mouse model of RCC. This immunotherapy effectively clears renal (Renca) tumors and enhances survival, despite the presence of a high frequency of MDSC in the spleens and primary tumor-bearing kidneys at the time of treatment. Subsequent analyses revealed that the CpG component of the immunotherapy was responsible for decreasing the frequency of MDSC in Renca-bearing mice; further, treatment with CpG modulated the phenotype and function of MDSC that remained after immunotherapy and correlated with an increased T-cell response. Interestingly, the CpG-dependent alterations in MDSC frequency and function did not occur in tumor-bearing mice complicated with diet-induced obesity. Collectively, these data suggest that in addition to its adjuvant properties, CpG also enhances antitumor responses by altering the number and function of MDSC. PMID- 25143236 TI - Invertebrate community responses to a particulate- and dissolved-copper exposure in model freshwater ecosystems. AB - Historical contamination has left a legacy of high copper concentrations in the sediments of freshwater ecosystems worldwide. Previous mesocosm studies have focused on dissolved-copper exposures in the overlying waters, which, because of altered exposure pathways, may not accurately predict the effects of copper exposure on invertebrate communities at historically contaminated sites. The present study assessed the effects of copper on the establishment of invertebrate communities within a large outdoor pond mesocosm facility containing environmentally relevant copper-spiked sediments. High particulate copper concentrations (>400 mg/kg dry wt) caused a pronounced effect on the benthic community richness, abundance, and structure in the mesocosms, but particulate copper concentrations below 100 mg/kg dry weight had no effect. Furthermore, there were no effects of copper on the invertebrate communities within the water column, even in the highest copper treatment. The response of the benthic community to copper was influenced by interspecific interactions, the stage of ecological succession, and interspecies variation in sensitivity to copper. The present study demonstrates the importance of using environmentally realistic exposure scenarios that provide both particulate and dissolved exposure pathways. It also emphasizes that risk assessments for aquatic ecosystems should consider the influence of interspecific interactions and interspecies variation in driving the biotic response to contamination. PMID- 25143237 TI - Potential of Cellular and Animal Models Based on a Prion-Like Propagation of alpha-Synuclein for Assessing Antiparkinson Agents. AB - The pathological hallmark of Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies (LBs). LBs are intracellular inclusions typically found in these neurons and in noradrenergic neurons of the locus coeruleus in patients with PD. However, LBs can be found more widely in neurons of the olfactory bulb, cerebral cortex, and spinal cord. Additionally, LBs appear in neurons of the cardiac, cutaneous, and intestinal autonomic nervous systems. LBs are composed of fibrillar aggregates of alpha-synuclein (alpha-syn). The widespread distribution of LBs indicates that alpha-syn aggregation occurs in neurons in various areas, supporting the concept that PD is not only a simple movement disorder but also a complex one with nonmotor impairments. However, it is unclear how alpha-syn pathology spreads in the nervous system. Postmortem analyses of patients with PD who received transplants of fetal mesencephalic dopaminergic neurons revealed LB formation in surviving grafts, providing a crucial clue regarding the host-to-graft disease propagation. Recent experiments demonstrated that fibrillar alpha-syn is transferred from neurons to neurons in cellular and animal models, suggesting that fibrillar alpha-syn is repeatedly generated in cells by triggering the continuous conversion of normal soluble species into fibrillar ones. These findings suggest a "prion-like" mechanism for alpha-syn propagation in the pathogenesis of PD. This review summarizes the experimental findings on the prion like propagation of alpha-syn and discusses the potential of cellular and animal models for testing the protective effects of chemical agents against neurodegeneration in PD. PMID- 25143239 TI - Bio-Bentall procedure versus isolated biological aortic valve replacement: a case match study. AB - OBJECTIVES: The aim of the study was to evaluate whether a complete aortic root replacement using a composite graft with biological valve prosthesis carries a higher early or late postoperative risk than isolated valve replacement. METHODS: Between 1998 and 2008, 182 consecutive patients underwent complete aortic root and ascending aorta replacement using a self-assembled composite graft with a biological valve prosthesis located within the vascular tube (modified Bentall procedure). In the same period, 1959 patients received an isolated aortic valve replacement using a biological valve prosthesis. After matching the patients using five variables (sex, age-by 5-year increments, aortic valve defect, concomitant coronary surgery and the year of surgery), 79 perfectly matched pairs were found. Regarding other clinically essential but unmatched preoperative characteristics, there were no relevant differences between the groups. RESULTS: There was no statistically significant difference in the early postoperative mortality (30-day and/or in-hospital), which was 5.1% (4 patients) in the Root Group (RG) and 3.8% (3 patients) in the Valve Group (VG). The follow-up was complete for all patients and contained 499 patient-years in the RG versus 488 in the VG. In total, there were 23 deaths in each group during the follow-up time, which was 6.2 +/- 2.8 years for the RG and 6.2 +/- 3.2 years for the VG. Hence, the linearized death rate and actuarial survival at 10 years were almost identical. They were 4.66%/year and 63.2 +/- 8.3%, respectively, in the RG; compared with 4.71%/year and 58.5 +/- 9.3% in the VG. Also the rates of valve related morbidities were similar except for the tendency of a lower rate of cerebral embolism in the RG. CONCLUSIONS: Complete aortic root replacement with a biological composite graft can be performed by experienced surgeons with an operative risk similar to that of an isolated biological aortic valve replacement. Starting with comparable operative outcomes, both procedures offer almost identical long-term survival. The rates of valve-related events after complete aortic root replacement and isolated valve replacement are also comparable, apart from cerebral embolism, which seems to be less frequent after aortic root replacement. PMID- 25143240 TI - The left and right internal thoracic arteries may not have equivalent histological structures. PMID- 25143238 TI - The Role of Collagens in Peripheral Nerve Myelination and Function. AB - In the peripheral nervous system, myelin is formed by Schwann cells, which are surrounded by a basal lamina. Extracellular matrix (ECM) molecules in the basal lamina play an important role in regulating Schwann cell functions, including adhesion, survival, spreading, and myelination, as well as in supporting neurite outgrowth. Collagens are a major component of ECM molecules, which include 28 types that differ in structure and function. A growing body of evidence suggests that collagens are key components of peripheral nerves, where they not only provide a structural support but also affect cell behavior by triggering intracellular signals. In this review, we will summarize the main properties of collagen family, discuss the role of extensively studied collagen types (collagens IV, V, VI, and XV) in Schwann cell function and myelination, and provide a detailed overview of the recent advances with respect to these collagens in peripheral nerve function. PMID- 25143241 TI - Reply to Gomes. PMID- 25143242 TI - How impossibly difficult the whole undertaking is. PMID- 25143243 TI - Isolation and characterization of 16 polymorphic microsatellite loci for Euchiloglanis kishinouyei. AB - A total of 16 novel polymorphic microsatellite marker loci were isolated from a genomic library of Euchiloglanis kishinouyei and further characterized using a sample from a wild population consisting of 40 individuals. The number of alleles among loci ranged from three to 17 and the observed and expected heterozygosities ranged from 0.030 to 0.950 and 0.163 to 0.980, respectively. The average polymorphic information content (PIC) of all loci was 0.450. PMID- 25143244 TI - EsrC, an envelope stress-regulated repressor of the mexCD-oprJ multidrug efflux operon in Pseudomonas aeruginosa. AB - mexCD-oprJ is an envelope stress-inducible multidrug efflux operon of Pseudomonas aeruginosa. A gene encoding a homologue of the NfxB repressor of this operon, PA4596, occurs downstream of oprJ and was proposed as a second repressor of this efflux operon. Inactivation of this gene had no impact on mexCD-oprJ expression in cells not exposed to envelope stress although its loss under envelope stress conditions yielded a > 10-fold increase in mexCD-oprJ expression. Consistent with PA4596 functioning as a mexCD-oprJ repressor, the purified protein was able to bind to a DNA fragment carrying the mexCD-oprJ promoter region. Expression of PA4596 was induced under conditions of envelope stress dependent on the AlgU envelope stress sigma factor, consistent with PA4596 operating under envelope stress conditions where it possibly serves to moderate envelope stress-inducible mexCD-oprJ expression. nfxB mutants showed elevated PA4596 expression and purified NfxB bound to DNA encompassing the PA4596 upstream region, an indication that NfxB functions as a repressor of PA4596 expression. Elimination of PA4596 in P. aeruginosa lacking nfxB and hyperexpressing mexCD-oprJ had no additional impact on mexCD-oprJ expression, regardless of the presence of envelope stress, suggesting that PA4596 repressor activity may be dependent on NfxB. This envelope stress-regulated repressor of mexCD-oprJ has been renamed esrC. PMID- 25143245 TI - PAS-cal: A repetitive peptide sequence calibration standard for MALDI mass spectrometry. AB - Mass spectrometers equipped with matrix-assisted laser desorption/ionization (MALDI-MS) require frequent multipoint calibration to obtain good mass accuracy over a wide mass range and across large numbers of samples. In this study, we introduce a new synthetic peptide mass calibration standard termed PAS-cal tailored for MALDI-MS based bottom-up proteomics. This standard consists of 30 peptides between 8 and 37 amino acids long and each constructed to contain repetitive sequences of Pro, Ala and Ser as well as one C-terminal arginine residue. MALDI spectra thus cover a mass range between 750 and 3200 m/z in MS mode and between 100 and 3200 m/z in MS/MS mode. Our results show that multipoint calibration of MS spectra using PAS-cal peptides compares well to current commercial reagents for protein identification by PMF. Calibration of tandem mass spectra from LC-MALDI experiments using the longest peptide, PAS-cal37, resulted in smaller fragment ion mass errors, more matching fragment ions and more protein and peptide identifications compared to commercial standards, making the PAS-cal standard generically useful for bottom-up proteomics. PMID- 25143247 TI - Translational genomics and head and neck cancer: toward precision medicine. AB - Head and neck squamous cell carcinoma (HNSCC) comprise a wide spectrum of neoplasms with different tumor biologies, prognosis and response to therapies. Current tumor classification and traditional diagnostic methods (e.g. clinical assessment, histopathology) are limited in their capacity to determine prognosis and clinical decision-making. Despite recent improvements in treatment, the outcome for patients with HNSCC remains poor. Similar to most tumors, several patient-related factors, (e.g. genetics and environment) and disease-related factors (e.g. tumor location, TMN staging) play a significant role on survival. Thus, the problem in defining the prognosis is that the clinical course and response to treatment differ considerably among patients. Such interindividual variability is related to the heterogeneity of the tumor, genetic and epigenetic variations, thus reflecting the interaction of multiple biological components that result in a unique phenotype. Integrative genomics are developed to identify the molecular pathways leading to cancer at the individual level and find novel prognostic markers for HNSCC, hence tailoring a treatment accordingly. Such genetic-based personalized diagnosis allows tumor stratification and implementation of targeted therapy. Modern medicine includes new drugs that disrupt the implicated molecules and their signaling pathways. Here, we summarize the current state of knowledge that elucidates the translation of genetic data into clinical benefit. PMID- 25143246 TI - Dimerization of 30Kc19 protein in the presence of amphiphilic moiety and importance of Cys-57 during cell penetration. AB - Recently, the recombinant 30Kc19 protein, originating from silkworm hemolymph of Bombyx mori has attracted attention due to its cell-penetrating property and potential application as a protein delivery system. However, this observation of penetration across cell membrane has raised questions concerning the interaction of the protein-lipid bilayer. Here, we report a dimerization propensity of the 30Kc19 protein in the presence of amphiphilic moieties; sodium dodecyl sulfate (SDS) or phospholipid. Native PAGE showed that the 30Kc19 monomer formed a dimer when SDS or phospholipid was present. In the glutathione-S-transferase (GST) pull down assay, supplementation of the 30Kc19 protein to mammalian cell culture medium showed dimerization and penetration; due to phospholipids at the cell membrane, the main components of the lipid bilayer. Mutagenesis was performed, and penetration was observed by 30Kc19 C76A and not 30Kc19 C57A, which meant that the presence of cysteine at position 57 (Cys-57) is involved in dimerization of the 30Kc19 at the cell membrane during penetration. We anticipate application of the native 30Kc19 protein with high cell-penetrating efficiency for delivery of cargos to various cell types. The intracellular cargo delivery using the 30Kc19 protein is a non-virus derived (e.g. TAT) delivery method, which can open up new approaches for the delivery of therapeutics in bioindustries, such as pharma- and cosmeceuticals. PMID- 25143248 TI - Identification of three proteins involved in fertilization and parthenogenetic development of a brown alga, Scytosiphon lomentaria. AB - Metabolic pathways of cell organelles may influence the expression of nuclear genes involved in fertilization and subsequent zygote development through a retrograde regulation. In Scytosiphon lomentaria, inheritance of chloroplast is biparental but mitochondria are maternally inherited. Male and female gametes underwent different parthenogenetic outcomes. Most (>99%) male gametes did not differentiate rhizoid cells or survived beyond four-cell stage, while over 95% of female gametes grew into mature asexual plants. Proteomic analysis showed that the protein contents of male and female gametes differed by approximately 1.7%, 12 sex-specific proteins out of 700 detected proteins. Three sex-specific proteins were isolated and identified using CAF-MALDI mass spectrometry and RACE PCR. Among them, a male gamete-specific homoaconitate hydratase (HACN) and a female gamete-specific succinate semialdehyde dehydrogenase (SSADH) were predicted to be the genes involved in mitochondrial metabolic pathways. The expression level of both mitochondrial genes was dramatically changed at the fertilization event. During parthenogenetic development the male-specific HACN and GTP-binding protein were gradually down-regulated but SSADH stayed up regulated up to 48h. To observe the effect of chemicals on the expression of these genes, male and female gametes were treated with gamma-aminobutyric acid (GABA), hydrogen peroxide and L-ascorbic acid. Among them GABA treatment significantly reduced SSADH gene expression in female gamete but the same treatment induced high upregulation of the gene in male gamete. GABA treatment affected the behavior of gametes and their parthenogenetic development. Both gametes showed prolonged motile stage, retarded settlement and subsequent parthenogenetic development. Our results suggest that male and female gametes regulate mitochondrial metabolic pathways differentially during fertilization, which may be the reason for their physiological and behavioral differences. PMID- 25143249 TI - Single nucleotide polymorphisms in a cellulose synthase gene (PtoCesA3) are associated with growth and wood properties in Populus tomentosa. AB - In plants, the composition and organization of the cell wall determine cell shape, enable cell expansion, and affect the properties of woody tissues. Cellulose synthase (CesA) genes encode the enzymes involved in the synthesis of cellulose which is the major component of plant primary and secondary cell walls. Here, we isolated a full-length PtoCesA3 cDNA from the stem cambium tissue of Populus tomentosa. Tissue-specific expression profiling showed that PtoCesA3 is highly expressed during primary cell wall formation. Estimation of single nucleotide polymorphism (SNP) diversity and linkage disequilibrium (LD) revealed that PtoCesA3 harbors high SNP diversity (pi(T) = 0.00995 and theta(w) = 0.0102) and low LD (r(2) >= 0.1, within 1,280 bp). Association analysis in a P. tomentosa association population (460 individuals) showed that seven SNPs (false discovery rate Q < 0.10) and five haplotypes (Q < 0.10) were significantly associated with growth and wood properties, explaining 4.09-7.02% of the phenotypic variance. All significant marker-trait associations were validated in at least one of the three smaller subsets (climatic regions) while five associations were repeated in the linkage population. Variation in RNA transcript abundance among genotypic classes of significant loci was also confirmed in the association or linkage populations. Identification of PtoCesA3 and examining its allelic polymorphisms using association studies open an avenue to understand the mechanism of cellulose synthesis in the primary cell wall and its effects on the properties of woody tissues. PMID- 25143251 TI - An in vitro study reveals the nutraceutical potential of punicic acid relevant to diabetes via enhanced GLUT4 expression and adiponectin secretion. AB - The prevalence of diabetes and heart diseases is increasing in the world. Nutraceuticals of natural origin are gaining importance as an alternative to modern drugs for the management of metabolic syndrome. In the present study, punicic acid (PA), a major bioactive found in pomegranate seed, was subjected for biological characterization with respect to peroxisome proliferator-activated receptor gamma (PPARgamma) agonist property in an in vitro system (3T3-L1 adipocytes). We evaluated the adipogenic potential of various concentrations (5, 10 and 30 MUM) of PA by studying triglyceride accumulation and glycerol-3 phosphate dehydrogenase (GPDH) activity in adipocytes, which were found to be increased moderately compared with the positive control, i.e. rosiglitazone (RG). Glucose uptake activity (?225.93% +/- 2.55% for 30 MUM of PA), and the prevention of reactive oxygen species (ROS) generation (?57 +/- 1.83% for 30 MUM of PA) in adipocytes with PA were also evaluated. We also found that PA increased adiponectin secretion and upregulated GLUT4 expression and translocation in adipocytes. Molecular modelling studies revealed a high binding affinity of PA to the PPARgamma ligand binding domain. An in vitro ligand binding assay based on time-resolved fluorescence resonance energy transfer (TR-FRET) also proved PA as a PPARgamma agonist. Finally, we conclude that PA is a potential nutraceutical and should be encouraged for use both as a prophylactic and therapeutic agent. PMID- 25143252 TI - Development and validation of a hydrophilic interaction liquid chromatography with tandem mass spectrometry method for the simultaneous detection and quantification of etilefrine and oxilofrine in equine blood plasma and urine. AB - A sensitive hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry method was developed and validated for the simultaneous detection and quantification of etilefrine and oxilofrine in equine blood plasma and urine. The method is highly sensitive and specific with good precision and accuracy. In plasma the limit of detection and limit of quantification are 0.03 and 0.1 ng/mL, respectively, for both analytes. In urine the limit of detection and limit of quantification are 0.3 and 1 ng/mL, respectively, for both analytes. The suitability of the method for doping control analysis in equine species is demonstrated by analyzing postadministration samples collected after a single intravenous administration of 50 mg etilefrine to a standardbred mare. Etilefrine was detected up to 120 h in urine and up to 48 h in plasma. Etilefrine is highly conjugated in equine urine whereas it exists in the free form in equine plasma. Therefore, enzyme hydrolysis prior to sample preparation is recommended for the detection and quantification of etilefrine and oxilofrine in equine urine. PMID- 25143250 TI - Phenotypic plasticity of the maize root system in response to heterogeneous nitrogen availability. AB - Mineral nutrients are distributed in a non-uniform manner in the soil. Plasticity in root responses to the availability of mineral nutrients is believed to be important for optimizing nutrient acquisition. The response of root architecture to heterogeneous nutrient availability has been documented in various plant species, and the molecular mechanisms coordinating these responses have been investigated particularly in Arabidopsis, a model dicotyledonous plant. Recently, progress has been made in describing the phenotypic plasticity of root architecture in maize, a monocotyledonous crop. This article reviews aspects of phenotypic plasticity of maize root system architecture, with special emphasis on describing (1) the development of its complex root system; (2) phenotypic responses in root system architecture to heterogeneous N availability; (3) the importance of phenotypic plasticity for N acquisition; (4) different regulation of root growth and nutrients uptake by shoot; and (5) root traits in maize breeding. This knowledge will inform breeding strategies for root traits enabling more efficient acquisition of soil resources and synchronizing crop growth demand, root resource acquisition and fertilizer application during crop growing season, thereby maximizing crop yields and nutrient-use efficiency and minimizing environmental pollution. PMID- 25143253 TI - Palliative colonic stenting: a safe alternative to surgery in stage IV colorectal cancer. AB - BACKGROUND: The morbidity associated with surgery for obstructing or near obstructing stage IV colorectal cancer can be high including the frequent need for a stoma. Self-expandable metal stents (SEMS) offer an alternative to surgery. Our aim was to analyse our palliative SEMS outcomes and compare this with a palliative surgery group. METHODS: A retrospective study of a single institutions' experience with SEMS or surgery in the management of stage IV colorectal cancer was performed. RESULTS: Sixty-five patients treated with SEMS were included in the study. These were compared with an unmatched group of 63 patients who underwent surgery. Within the SEMS group was a 98.5% technical success and 100% clinical success of deployed SEMS. Overall complication rate was low at 23.1% (restenosis 7.7%, migration 7.7%, perforation 4.6% and bleeding 3.1%). Only 7.7% of patients in the SEMS group required an operation. SEMS insertion was associated with a shorter hospital stay (2.9 days versus 14.6 days; P < 0.001) and reduced requirement for a stoma (4.6% versus 44.4%; P < 0.001). There was no statistically significant difference in 30-day mortality (13.8% versus 11.1%; P = 0.640), 1-year survival (42.9% versus 41.4%; P = 0.949) or 2 year survival (24.5% versus 21.4%; P = 0.700). Overall survival was equivalent between the two groups (hazard ratio 1.27; 95% confidence interval 0.88-1.88; P = 0.212). CONCLUSION: SEMS is a safe alternative to surgery in obstructing or near obstructing stage IV colorectal cancer. It offers high success rate, a shorter hospital stay and a reduced stoma rate while not impacting overall survival. PMID- 25143254 TI - Scaling categorical spatial data for earth systems models. PMID- 25143255 TI - Barriers and facilitators to implementing the Baby-Friendly hospital initiative in neonatal intensive care units. AB - OBJECTIVE: To explore manager, educator, and clinical leader perceptions of barriers and facilitators to implementing Baby-Friendly practice in the neonatal intensive care unit (NICU). DESIGN: Qualitative, descriptive design. SETTING: Two university-affiliated level-III NICUs in Canada. PARTICIPANTS: A purposive sample of 10 medical and nursing managers, nurse educators, lactation consultants, and neonatal nurse practitioners. METHODS: In-depth, semistructured interviews transcribed and analyzed using qualitative content analysis. RESULTS: Participants valued breastfeeding and family-centered care yet identified numerous contextual barriers to Baby-Friendly care including infant health status, parent/infant separation, staff workloads and work patterns, gaps in staff knowledge and skills, and lack of continuity of breastfeeding support. Facilitators included breastfeeding education, breastfeeding champions, and interprofessional collaboration. CONCLUSION: Despite identifying numerous barriers, participants recognized the potential value of expanding the Baby Friendly Hospital Initiative (BFHI) to the NICU setting. Recommendations include promoting BFHI as a facilitator of family-centered care, interdisciplinary staff education, increasing access to lactation consultants, and establishing a group of NICU champions dedicated to BFHI implementation. PMID- 25143257 TI - Differential detection of Rhizoma coptidis by capillary electrophoresis electrospray ionization mass spectrometry with a nanospray interface. AB - A lab prototype CE-nanospray-MS platform with a high sensitivity porous sprayer was successfully applied in differential identification of Rhizoma coptidis in this paper. To obtain a stable and reliable nanospray, detailed optimizations about emitter geometry, buffer composition, emitter position, and spray voltage, as well as emitter cleanliness were discussed. Results showed that the reproducibility and sensitivity for separations of alkaloid standards were satisfactory using CE-nanospray-MS, which were also compared to ultra-HPLC (UHPLC)-MS. Their signal responds were at the same order of magnitude (intensities: 0.8 - 1.5 * 10(8) vs. 3.8 - 6.2 * 10(8) ), even though a 2 nL injection for CE was 2500-fold lower than UHPLC (5 MUL injection). The absolute LOD results of CE-MS showed a remarkable superiority (18-24 fg), equal to 1000 fold lower than that of UHPLC-MS. Principal component analysis (PCA) of adulterated R. coptidis showed that this protocol had the ability to profile and qualify complex herb medicines, which also created a great potential for evaluation and qualification of rare and valuable Chinese medicines in future. PMID- 25143258 TI - Variation in timing of ossification affects inferred heterochrony of cranial bones in Lissamphibia. AB - The evolutionary origin of Lissamphibia likely involved heterochrony, as demonstrated by the biphasic lifestyles of most extant orders, differences between Anura (with tadpole-to-froglet metamorphosis) and Urodela (which lack strongly defined metamorphosis), and the appearance of direct development among separate lineages of frogs. Patterns in the timing of appearance of skeletal elements (i.e., ossification sequence data) represent a possible source of information for understanding the origin of Lissamphibia, and with the advent of analytical methods to directly optimize these data onto known phylogenies, there has been a renewed interest in assessing the role of changes in these developmental events. However, little attention has been given to the potential impact of variation in ossification sequence data--this is particularly surprising given that different criteria for collecting these data have been employed. Herein, new and previously published ossification data are compiled and all pairs of data for same-species comparisons are selected. Analyses are run to assess the impact of using data that were collected by different methodologies: (1) wild- versus lab-raised animals; (2) different criteria for recognizing timing of ossification; and (3) randomly selecting ossification sequences for species from which multiple studies have been published, but for which the data were collected by different criteria. Parsimov-based genetic inference is utilized to map ossification sequence data onto an existing phylogeny to reconstruct ancestral sequences of ossification and infer instances of heterochrony. All analyses succeeded in optimizing sequence data on internal nodes and instances of heterochrony were identified. However, among all analyses little congruence was found in reconstructed ancestral sequences or among inferred instances of heterochrony. These results indicate a high degree of variation in timing of ossification, and suggest a cautionary note about use of these data, particularly given that in most instances issues associated with the original sources of data (e.g., wild- vs. lab-raised animals; or criteria for identification of earliest ossification) are not addressed. Potential sources of variation in the original data are discussed and may explain the incongruence observed here. PMID- 25143256 TI - Visible light-promoted metal-free sp(3)-C-H fluorination. AB - Photoexcited acetophenone can catalyze the fluorination of unactivated C(sp(3))-H groups. While acetophenone, a colorless oil, only has a trace amount of absorption in the visible light region, its photoexcitation can be achieved by irradiation with light generated by a household compact fluorescent lamp (CFL). This operational simple method provides improved substrate scope for the direct incorporation of a fluorine atom into simple organic molecules. CFL-irradiation can also be used to promote certain classic UV-promoted photoreactions of colorless monoarylketones and enones/enals. PMID- 25143259 TI - Finding off-targets, biological pathways, and target diseases for chymase inhibitors via structure-based systems biology approach. AB - Off-target binding connotes the binding of a small molecule of therapeutic significance to a protein target in addition to the primary target for which it was proposed. Progressively such off-targeting is emerging to be regular practice to reveal side effects. Chymase is an enzyme of hydrolase class that catalyzes hydrolysis of peptide bonds. A link between heart failure and chymase is ascribed, and a chymase inhibitor is in clinical phase II for treatment of heart failure. However, the underlying mechanisms of the off-target effects of human chymase inhibitors are still unclear. Here, we develop a robust computational strategy that is applicable to any enzyme system and that allows the prediction of drug effects on biological processes. Putative off-targets for chymase inhibitors were identified through various structural and functional similarity analyses along with molecular docking studies. Finally, literature survey was performed to incorporate these off-targets into biological pathways and to establish links between pathways and particular adverse effects. Off-targets of chymase inhibitors are linked to various biological pathways such as classical and lectin pathways of complement system, intrinsic and extrinsic pathways of coagulation cascade, and fibrinolytic system. Tissue kallikreins, granzyme M, neutrophil elastase, and mesotrypsin are also identified as off-targets. These off-targets and their associated pathways are elucidated for the effects of inflammation, cancer, hemorrhage, thrombosis, and central nervous system diseases (Alzheimer's disease). Prospectively, our approach is helpful not only to better understand the mechanisms of chymase inhibitors but also for drug repurposing exercises to find novel uses for these inhibitors. PMID- 25143260 TI - Collapse of the native structure caused by a single amino acid exchange in human NAD(P)H:quinone oxidoreductase(1.). AB - Human NAD(P)H: quinone oxidoreductase 1 (NQO1) is essential for the antioxidant defense system, stabilization of tumor suppressors (e.g. p53, p33, and p73), and activation of quinone-based chemotherapeutics. Overexpression of NQO1 in many solid tumors, coupled with its ability to convert quinone-based chemotherapeutics into potent cytotoxic compounds, have made it a very attractive target for anticancer drugs. A naturally occurring single-nucleotide polymorphism (C609T) leading to an amino acid exchange (P187S) has been implicated in the development of various cancers and poor survival rates following anthracyclin-based adjuvant chemotherapy. Despite its importance for cancer prediction and therapy, the exact molecular basis for the loss of function in NQO1 P187S is currently unknown. Therefore, we solved the crystal structure of NQO1 P187S. Surprisingly, this structure is almost identical to NQO1. Employing a combination of NMR spectroscopy and limited proteolysis experiments, we demonstrated that the single amino acid exchange destabilized interactions between the core and C-terminus, leading to depopulation of the native structure in solution. This collapse of the native structure diminished cofactor affinity and led to a less competent FAD binding pocket, thus severely compromising the catalytic capacity of the variant protein. Hence, our findings provide a rationale for the loss of function in NQO1 P187S with a frequently occurring single-nucleotide polymorphism. DATABASE: Structural data are available in the Protein Data Bank under the accession numbers 4cet (P187S variant with dicoumarol) and 4cf6 (P187S variant with Cibacron blue). STRUCTURED DIGITAL ABSTRACT: NQO1 P187S and NQO1 P187S bind by nuclear magnetic resonance (View interaction) NQO1 P187S and NQO1 P187S bind by x ray crystallography (1, 2) NQO1 and NQO1 bind by molecular sieving (1, 2). PMID- 25143261 TI - The prognosis of diabetic retinopathy in patients with type 2 diabetes since 1996 1998: the Skaraborg Diabetes Register. AB - Diabetes mellitus is the main reason for visual impairment among patients of working ages. The aim of this paper was to investigate the prognosis of eye complications in patients with diabetes during 10 years of follow-up and contributing risk factors. Data from ophthalmological records (occurrence of retinopathy and laser treatment and visual acuity), and clinical data (blood pressure, glycosylated hemoglobin (HbA1c), body mass index (BMI), and antihypertensive treatment) from the Skaraborg Diabetes Register were retrieved in the Skaraborg Screening Program of 1,258 patients diagnosed during 1996-1998. Kaplan Meyer survival analysis and Log Rank test were used to analyze eye complications in 773 patients with type 2 diabetes and <=70 years at diagnosis. Visual acuity was above the limit for driving license in 96 % of 548 patients and only nineteen patients were treated by laser. At diagnosis of diabetes, mean HbA1c was 6.7 +/- 1.7 % (59 +/- 7.1 mmol/mol), and systolic blood pressure was 142.9 +/- 0.7 mmHg; neither changed significantly during follow-up. Retinopathy appeared about 1 year, and maculopathy 2 years earlier, if HbA1c >= 7 % (63 mmol/mol) at diagnosis (p < 0.001 and p < 0.006). Antihypertensive treatment, higher BMI, and higher age at diagnosis were associated with less retinopathy during follow-up. Most patients with diabetes develop little retinopathy for the first 10 years after diagnosis. High HbA1c at baseline was associated with retinopathy and maculopathy during follow-up. Antihypertensive treatment, probably a proxy for regular controls and early detection of diabetes, was associated with less retinopathy. PMID- 25143262 TI - Artifactual microhemorrhage generated by susceptibility weighted image processing. AB - BACKGROUND: To report that artifactual microhemorrhages are introduced by the two dimensional (2D) homodyne filtering method of generating susceptibility weighted images (SWI) when open-ended fringelines (OEF) are present in phase data. METHODS: SWI data from 28 traumatic brain injury (TBI) patients was obtained on a 3 tesla clinical Siemens scanner using both the product 3D gradient echo sequence (GRE) with generalized autocalibrating partially parallel acquisition acceleration and an in-house developed segmented echo planar imaging (sEPI) sequence without GRAPPA acceleration. SWI processing included (i) 2D homodyne method implemented on the scanner console and (ii) a 3D Fourier-based phase unwrapping followed by 3D high pass filtering. Original and enhanced magnitude and phase images were carefully reviewed for sites of type III OEFs and microhemorrhages by a neuroradiologist on a PACS workstation. RESULTS: Nineteen of 28 (68%) phase datasets acquired using GRAPPA-accelerated GRE acquisition demonstrated type III OEFs. In SWI images, artifactual microhemorrhages were found on 17 of 19 (89%) cases generated using 2D homodyne processing. Application of a 3D Fourier-based unwrapping method prior HP filtering minimized the appearance of the phase singularities in the enhanced phase, and did not generate microhemorrhage-like artifacts in magnitude images. CONCLUSION: The 2D homodyne filtering method may introduce artifacts mimicking intracranial microhemorrhages in SWI images when type III OEFs are present in phase images. Such artifacts could lead to overestimation of pathology, e.g., TBI. This work demonstrates that 3D phase unwrapping methods minimize this artifact. However, methods to properly combine phase across coils are needed to eliminate this artifact. PMID- 25143263 TI - Molecular variants of human papilloma virus 16 E2, E4, E5, E6 and E7 genes associated with cervical neoplasia in Romanian patients. AB - The aim of this study was to identify and associate the sequence variations of human Papillomavirus 16 (HPV16) genes from women who live in two different areas of Romania and associate them with malignant progression. One hundred twenty-four HPV16-positive cervical isolates were collected, and the E2, E4, E5, E6 and E7 viral genes were sequenced. Two new missense mutations in the E6 gene (C279G and A305C) were found (together or alone, in association with other mutations) in 44 of 124 cases. The most frequently simultaneously mutated genes were E4/E2 hinge, E5 and E6 (p = 0.0004) in squamous cell carcinoma (SCC) samples. Also, for SCC patients, the best-correlated mutation patterns were obtained for E4/E2 hinge-E5 (r = 0.7984; p < 0.0001). No sample was found to have all of the investigated viral genes concurrently mutated. Phylogenetic analysis was performed to characterize the viral variants. Similar results were found for SCC and cervical intraepithelial neoplasia III (CINIII) cases. After all of the target gene sequences were assembled, all patients were found to be infected with viruses of the HPV16- European-German (EG) lineage, and two clusters were identified, the first (55/96 variants) from Moldavia and the second (41/96 variants) from Bucharest. The distinct cluster derived from EG in Moldavia could partially explain the increased frequency of SCC in this area. This study has generated a comprehensive set of sequence variation data on HPV16 circulating in Romania to join the existing data and highlight the important role of HPV16 variants during cervical carcinogenesis. PMID- 25143267 TI - Is home blood pressure monitoring useful in the management of patients with resistant hypertension? AB - BACKGROUND: Ambulatory blood pressure (BP) monitoring (ABPM) is a cornerstone in resistant hypertension (RHT) management. However, it has higher cost and lower patients' acceptance than home BP monitoring (HBPM). Our objective was to evaluate HBPM usefulness in the management of patients with RHT. METHODS: A total of 240 patients were submitted to 24-hour ABPM and 5-day HBPM (triplicate morning and evening measurements). Patients with uncontrolled office BP (>=140/90mm Hg) were classified as true RHT (daytime or home BP >=135/85mm Hg) or white-coat RHT (daytime or home BP <135/85mm Hg), and patients with controlled office BP were classified as masked RHT (daytime or home BP >=135/85mm Hg) or controlled RHT (daytime or home BP <135/85mm Hg). Sensitivity, specificity, predictive values, and likelihood ratios for HBPM were calculated. Agreement between the procedures was evaluated using kappa coefficients and the Bland-Altman method. RESULTS: Mean office BP was 157+/-26/84+/-16mm Hg, mean daytime BP was 134+/-18/77+/-13mm Hg, and mean home BP was 143+/-20/76+/-14mm Hg. The ABPM and HBPM diagnoses were 35% and 48%, respectively, for true RHT; 36% and 23%, respectively, for white-coat RHT; 7% and 17%, respectively, for masked RHT; and 22% and 13%, respectively, for controlled RHT. HBPM overestimated systolic BP by 8.8 (95% confidence interval (CI) = 6.8-10.7) mm Hg and diastolic BP by 0.2 (95% CI = -1.0 to 1.4) mm Hg. The specificity, sensitivity, and positive and negative predictive values of HBPM in detecting controlled ambulatory BP were 91%, 55%, 89%, and 59%. CONCLUSIONS: HBPM presented good agreement with ABPM and can be used as a complementary method in the follow-up of resistant hypertensive patients, particularly in those with controlled ambulatory BPs. PMID- 25143264 TI - Cytosolic DNA sensing via the stimulator of interferon genes adaptor: Yin and Yang of immune responses to DNA. AB - DNA is immunogenic and many cells express cytosolic DNA sensors that activate the stimulator of interferon genes (STING) adaptor to trigger interferon type I (IFN beta) release, a potent immune activator. DNA sensing to induce IFN-beta triggers host immunity to pathogens but constitutive DNA sensing can induce sustained IFN beta release that incites autoimmunity. Here, we focus on cytosolic DNA sensing via the STING/IFN-beta pathway that regulates immune responses. Recent studies reveal that cytosolic DNA sensing via the STING/IFN-beta pathway induces indoleamine 2,3 dioxygenase (IDO), which catabolizes tryptophan to suppress effector and helper T-cell responses and activate Foxp3-lineage CD4(+) regulatory T (Treg) cells. During homeostasis, and in some inflammatory settings, specialized innate immune cells in the spleen and lymph nodes may ingest and sense cytosolic DNA to reinforce tolerance that prevents autoimmunity. However, malignancies and pathogens may exploit DNA-induced regulatory responses to suppress natural and vaccine-induced immunity to malignant and infected cells. In this review, we discuss the biologic significance of regulatory responses to DNA and novel approaches to exploit DNA-induced immune responses for therapeutic benefit. The ability of DNA to drive tolerogenic or immunogenic responses highlights the need to evaluate immune responses to DNA in physiologic settings relevant to disease progression or therapy. PMID- 25143268 TI - Assessment of LV ejection fraction using real-time 3D echocardiography in daily practice: direct comparison of the volumetric and speckle tracking methodologies to CMR. AB - AIMS: This study is the first to directly compare two widely used real-time 3D echocardiography (RT3DE) methods of cardiac magnetic resonance imaging (CMR) and assess their reproducibility in experienced and less experienced observers. METHODS: Consecutive patients planned for CMR underwent RT3DE within 8 h of CMR with Philips (volumetric method) and Toshiba Artida (speckle tracking method). Left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were measured using RT3DE, by four trained observers, and compared with CMR values. RESULTS: Thirty-five patients were included (49.7 +/- 15.7 years; 55 % male), 30 (85.7 %) volumetric and 27 (77.1 %) speckle tracking datasets could be analysed. CMR derived LVEDV, LVESV and LVEF were 198 +/- 58 ml, 106 +/- 53 ml and 49 +/- 15 %, respectively. LVEF derived from speckle tracking was accurate and reproducible in all observers (all intra-class correlation coefficients (ICC) > 0.86). LVEF derived from the volumetric method correlated well to CMR in experienced observers (ICC 0.85 and 0.86) but only moderately in less experienced observers (ICC 0.58 and 0.77) and was less reproducible in these observers (ICC = 0.55). Volumes were significantly underestimated compared with CMR (p < 0.001). CONCLUSION: This study demonstrates that both RT3DE methodologies are sufficiently accurate and reproducible for use in daily practice. However, experience importantly influences the accuracy and reproducibility of the volumetric method, which should be considered when introducing this technique into clinical practice. PMID- 25143269 TI - Improvement in CRT: new strategies, better choices. PMID- 25143270 TI - Paraphilic coercive disorder: an unresolved issue. PMID- 25143271 TI - [The impact of polysialic acid (PSA) and polysialylated neural cell adhesion molecule (PSA-NCAM) on tumor and cell signaling pathways]. AB - The neural cell adhesion molecule (NCAM), the member of the immunoglobulin superfamily, plays an important role in regulating cell adhesion and cell communication, particularly in nervous system wiring and plasticity. Polysialic acid, which is attached to NCAM on cell surface, is a prominent regulator of neural cell migration and differentiation during nervous system development. It has been demonstrated that PSA and PSA-NCAM were re-expressed in some malignant tumors. It was indicated that PSA and PSA-NCAM were tightly associated with cell adhesion, migration and invasion, and mediated tumor development and progression through certain cell signaling pathways. Here, we summarize the functional role of PSA, PSA-NCAM and related cell signaling pathways in tumor development, progression and prognostic. PMID- 25143272 TI - [The progress of sperm functional proteins regulating the process of fertilization]. AB - The process of mammalian fertilization involves a series of sperm functional activities, including the sperm transportation, hyperactivation and capacitation, acrosome reaction and sperm-egg fusion, etc. The semen proteins play indispensable roles in these processes, and they are closely associated with the fecundity of males. So these proteins can be biomarkers to evaluate the fertilization capacity of mammalian semen. In this review, we mainly introduce some semen proteins relevant to spermatozoa functions and illustrate their important regulatory roles on the fertilization processes, involving spermatozoa motility, capacitation, acrosome reaction, penetrating the zona pellucida and sperm-egg fusion, etc. Moreover, their potential applications in the evaluation of heredity in livestock are also summarized. PMID- 25143273 TI - [Recent advances in understanding the innate immune mechanisms and developing new disease resistance breeding strategies against the rice blast fungus Magnaporthe oryzae in rice]. AB - Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is one of the most destructive diseases in rice. Utilization of resistant cultivars is the most effective and economic strategy against the disease. Recently, rice blast has become an advanced model system for elucidating the molecular mechanisms of plant fungal interactions. Significant progress has been made in the molecular biology, genomics and proteomics of the rice-M. oryzae interaction and host resistance in the last few years. In this review, we summarize the recent advances in understanding the molecular basis of PAMP-triggered immunity (PTI) and effector triggered immunity (ETI) in rice against M. oryzae, and propose the new strategies for blast resistance molecular breeding. We also discuss the new challenges for future investigations. PMID- 25143274 TI - [Regulation of pollen tube growth by reversible protein phosphorylation]. AB - The tip-growth of pollen tube is regulated by diverse signaling and metabolic processes, including Rop GTPase signaling pathway, phosphatidylinositol signaling pathway, Ca(2+) signaling, actin dynamics, vesicular trafficking, and cell wall re-modulation. These processes are regulated by reversible protein phosphorylation events: (1) The activities of Rop regulatory proteins (GEF, GDI, and GAP) that regulate Rop GTPase are variable under different protein phosphorylation states. In addition, various protein kinases function as the downstream effectors of Rop GTPase, and participate in the downstream pathways of Rop signaling. (2) Reversible protein phosphorylation can activate/inactivate the plasma membrane (PM) Ca(2+) channels and/or Ca(2+) pump, as well as control the release of intracellular Ca(2+), thereby regulating the formation of Ca(2+) gradient in pollen tube tip. In addition, protein kinases function as Ca(2+) sensors and phosphorylate the target proteins involved in the downstream regulatory pathways of Ca(2+) signaling. (3) The dynamics of actin polymerization and depolymerization are regulated by reversible phosphorylation of actin binding proteins (e.g., ADF and profilin). (4) Reversible protein phosphorylation regulates the activities of endo/exocytosis-related proteins and PM phospholipid metabolism that are involved in the membrane trafficking. (5) Reversible protein phosphorylation participates in the pollen tube cell wall re-modulation through regulating the function and subcellular distribution of cytoplasmic serine/threonine protein kinase and sucrose synthase. (6) The activities of transcription regulatory protein and eukaryotic translation initiation factor are regulated by protein phosphorylation, modulating the RNA transcription and protein synthesis. In this review, we present an overview of the functions of protein reversible phosphorylation in the aforementioned processes during the pollen tube tip-growth. PMID- 25143275 TI - [The selection of 30 ancestry informative markers and its application in ancestry inference]. AB - A panel of ancestry informative markers (AIMs) can be used to describe the genetic components of a population and infer the ancestral origin of a DNA sample. In this study, we selected 30 AIMs from 282 SNPs screened from 30 phenotype-related genes based on the genotyping data of 658 samples from nine populations in the HapMap database. Then,a multiplex assay was developed based on micro-sequencing general chip technologies, and a population allele frequency database was established. This system was utilized to ascertain the origin of subjects from East Asian, European, and African.First, 658 HapMap samples were analyzed using this panel of AIMs, and then 194 unrelated DNA samples from five populations were used for further validation of the system. Finally, population genetic components and individual genetic composition were generated using Structure software, and individual ancestry inferences were made. The 30-AIM assay was well balanced for Hardy-Weinberg equilibrium (P > 0.01), and there was no linkage disequilibrium (l < 0.1). Ancestry component analyses for the 658 HapMap samples and 194 recruited samples were consistent with their known origins. The established panel filtered and developed by the 30 AIMs can be applied to analyze the genetic components of Asian, European,and African populations, as well as individual genetic composition. PMID- 25143276 TI - [Identification of null and duplicated alleles for forensic DYS549, DYS527 and DYS459 in male infertility population]. AB - DYS549, DYS527, and DYS459 loci, located on the azoospermia factor (AZF) region and widely used in forensic and pedigree analysis, may be specifically altered in infertile patients, which will obscure the result of individual identification using Y-STR (Y chromosome short tandem repeat). In this study, we determined the AZF polymorphism by STS(-/-) (sequence tagged site) and DAZ, CDY1 gene copy numbers, and screened the samples by 14 Y-STR loci to disclose the unusual genotype of Y-STR in male infertility population. The 240 infertile males including non-obstructive azoospermia, severe oligozoospermia and congenital bilateral absence of vas deferens (CBVAD) were analyzed with a modified multiplex PCR system for AZF microdeletion STSs. AZF microdeletions were found in 40 cases (16.67%) (AZFa deletion, two cases; AZFb deletion, two cases; AZFc deletion, 30 cases; AZFb+c deletion, six cases). Further screening by the 14 Y-STR loci in samples with microdeletions, we found DYS549 allelic loss in all the cases with AZFb deletion, DYS527 and DYS459 allelic loss in all the cases with AZFc deletion, DYS549, DYS527, and DYS459 allelic loss in all the cases with AZFb+c deletion. Ten patients (4.17%) with AZFc partial duplication (one CBVAD case, two non-obstructive azoospermia cases, seven severe oligozoospermia cases) were found by DAZ and CDY1 gene dosage analysis. In conclusion, the unusual patterns of DYS549, DYS527, and DYS459 are caused by genetic defects rather than experimental bias. Revealing the locus heterogeneity in male infertility population can enrich the Y-STR database and assist in interpreting abnormal STR genotype in forensic DNA testing. PMID- 25143277 TI - [Functional analysis of Oct4 promoter in Xuhuai goat]. AB - The aim of this study was to determine the activity region of Oct4 (octamer binding transcription factor 4) promoter in Xuhuai goat, and to investigate the effect of TSA (trichostatin A) and VPA(valproicacid) on Oct4 promoter activity. Specific PCR primers of Oct4 promoter including different lengths of fragments were designed by Primer 5.0, then were amplified and cloned into PGL3-Bacic luciferase reporter vector. All the reconstruction vectors were transfected into gEF, P19 and COS7 cells, respectively. After TSA and VPA treatment, the activity of dual-luciferase reporter gene in these three transfected cells was detected. In addition, the CMV promoter of pEGFP-N1 was replaced by the -1516?+30 bp fragment of Oct4 promoter, GFP fluorescence was used to detect the activity of Oct4 promoter. The results indicated that different fragments of Oct4 promoter showed different degrees of activity in gEF, P19 and COS7 cells, and the maximal activity region of Oct4 promoter was -1516?+30 bp, the basal activity region was 238?+30 bp. Positive regulatory domains existed in the region of -1516?-946 bp and -615?-96 bp, while negative regulatory domains existed in the region of 1936?-1516 bp and -946?-615 bp. The optimum induction concentration to enhance the activity of Oct4 promoter was 1 MUmol/L of TSA and 4 mmol/L of VPA. The GFP expression can be started by the fragment of -1516?+30 bp. This study provides an experimental basis for revealing the mechanism of expression and regulation of Oct4 in goat. PMID- 25143278 TI - [Gene expression profiling of three tissues of chicken after heat stress treatment by microarray technique]. AB - In the present study, tissue samples were collected from the cerebrum, liver, and leg muscle of 8-day-old dwarf chicks that were exposed to a 3 h treatment of 28C+/- 1C (control group) or 40C+/- 1C (treatment group). Differentially expressed (DE) genes in these samples were detected using whole-genome microarray chips, and their functions were. PMID- 25143279 TI - [Bioinformatics analysis of the expansin gene family in rice]. AB - Expansin refers to a family of nonenzymatic proteins found in the plant cell wall with important roles in plant cell growth, developmental processes, and resistance to stress. Whole rice genome sequencing revealed that it contains 58 expansin genes, which belong to 4 subfamilies (A (34), B (19), LA (4) and LB (1)). All the genes were located on 10 of 12 rice chromosomes where several subfamily members clustered. Each of expansin genes ranged from 687 bp to 1128 bp in size. Sequence alignment showed that all expansins had three structural domains with two conserved amino acids of cystine in N-terminus and tryptophan in C-terminus. The amino acid identity of members among different subfamilies was less than 35%, while that among the same subfamily was more than 35%. Most genes of A subfamily had 1 or 2 introns, while genes of B, LA and LB subfamily had 3, 4 and 4 introns, respectively. Statistics analysis of codon usage showed that expansins in rice have 26 high-frequency codons which are more biased than those in other species. These bioinformatics findings will be helpful for the further study of the function and evolution of expansin genes. PMID- 25143280 TI - [Mapping of QTLs controlling Pb(2+) content in maize kernels under Pb(2+)stress]. AB - Lead (Pb(2+)) is one of the most abundant heavy-metal elements in the environment. Pb(2+) pollution has become increasingly serious in maize planting areas, especially in the southwest of China, which even threatens food security. In the present study, a RILpopulation derived from 178 (an inbred line with low accumulation of Pb(2+) in the kernels) and 9782 (a Pb(2+)-hyperaccumulator in the kernels) was used for QTL mapping. A molecular genetic map with the length of 1499.85 cM and an average inter-marker distance of 9.07 cM was constructed with 165 pairs of SSR markers. QTLs controlling Pb(2+) content in maize kernels were then analyzed to provide the basis for breeding elite maize varieties with low Pb(2+)in the kernels. Two QTLs, qPC1 and qPC4, related to Pb(2+) content in maize kernels were identified on chromosome 1 and 4, respectively. qPC1 was located between markers umc1661 and phi002, accounting for 11.13% of phenotypic variance with an additive effect value of 0.062. While qPC4 was located between markers umc1117 and nc005, explaining 5.55% of the phenotypic variance with an additive effect value of -0.044. However, there was no significant correlation observed between Pb(2+) content in the kernels and any of yield-related traits including ear length, ear diameter, kernel row number and weight of per-hundred kernels, indicating that yield-related traits would not be changed in the process of low Pb(2+)maize breeding. This suggested that the Pb(2+)content in maize kernel under Pb(2+)stress was an independent genetic trait. PMID- 25143281 TI - [Effects of histone H3 K4L and K36L mutations on the cell growth and the transcription of GAL1, SSA3 and PHO5 in Saccharomyces cerevisiae]. AB - Post-translational modifications of histones, such as acetylation and methylation, have a pivotal role in regulating gene expression and cell growth. To elucidate the different roles and importance of H3K4 and H3K36 modifications in expression of inducible genes such as Cal1, SSA3, PHO5 and the growth of yeast cell, we constructed three different yeast mutant strains carrying mutations of lysine 4, 36, or both to leucine in the histone H3 tail. Real-time PCR and sensitive assay under the conditions of high temperature, NaCl, caffeine, 6-AU, or other conditions were carried out to characterize the effects of these mutations on cell growth and transcription levels of GAL1, SSA3 and PHO5. The results showed that three histone methylation mutants exhibited more severe growth defects and slower activation of GAL1, SSA3 and PHO5 than those of wild type; H3K4L/H3K36L double mutant strain D436 has the most severe phenotype. H3K4L mutants S4 exhibited more severe defects than those of H3K36L S36 mutants, especially at high temperature and high NaCl stresses. These results show that H3K4L and H3K36L are important for the growth and survival of yeast in unfavorable conditions, and that different mutations have different effects on the expression of single inducible gene, whereas the same mutation has different effects on the activation of different inducible genes in vivo. The post translational modification of H3K4 is more important than H3K36 on the adaptation to harsh condition for yeast cell. The growth defects of histone mutant strains might arise from the slow activation of inducible gene essential for survival at harsh conditions. PMID- 25143282 TI - [Developing and applying of a parentage identification approach based on high density genetic markers]. AB - Pedigree is an important information source in the studies on human genetics and animal/plant breeding. Pedigree error is a common data error in breeding practice. It can affect the reliability of results from researches such as gene mapping, genetic or phenotypic value prediction. By using genetic markers, several approaches can identify the suspected pedigrees, but most of them are complex and the allowed number of genetic markers is limited, such as Cervus. Since the wide use of high density single nucleotide polymorphisms (SNPs) in human genetic and animal/plant breeding, a new parentage identification approach (named EasyPC, Easy Pedigree Checking) based on whole genome genetic data was proposed in this study. EasyPC was compared with Cervus on efficiency, and validated with a Chinese Holstein cattle (n=2180) and a Duroc swine (n=191) population. Results showed that EasyPC was much less time demanding than Cervus, and pedigree error rates were 20% for cattle and 6% for swine. Result from the cattle population is in accordance with previous study. By analyzing the empirical distribution of Mendelian error rate calculated in a population using all available SNPs, EasyPC not only can identify the correctness of a pedigree in a simple, fast, and accurate manner, but also can correct the wrong pedigree. EasyPC provides a promising alternative solution to traditional pedigree correction approaches and eases the data analysis of whole genome related studies. PMID- 25143283 TI - [Undergraduate teaching in life science exemplified by mycobacteriophages]. AB - An emerging theme of current biomedical study is a synthesis of multi disciplinary tools to address the complex biological issues. This trend raised the bar for undergraduate teaching and learning. The phage is an ideal material for teaching reform. Inspired by the "phage hunter" project initiated by Pittsburgh University, we present our practice in translating the mycobacteriophage research achievements into undergraduate teaching experience during the last five years. PMID- 25143284 TI - Did meiosis evolve before sex and the evolution of eukaryotic life cycles? AB - Biologists have long theorized about the evolution of life cycles, meiosis, and sexual reproduction. We revisit these topics and propose that the fundamental difference between life cycles is where and when multicellularity is expressed. We develop a scenario to explain the evolutionary transition from the life cycle of a unicellular organism to one in which multicellularity is expressed in either the haploid or diploid phase, or both. We propose further that meiosis might have evolved as a mechanism to correct for spontaneous whole-genome duplication (auto polyploidy) and thus before the evolution of sexual reproduction sensu stricto (i.e. the formation of a diploid zygote via the fusion of haploid gametes) in the major eukaryotic clades. In addition, we propose, as others have, that sexual reproduction, which predominates in all eukaryotic clades, has many different advantages among which is that it produces variability among offspring and thus reduces sibling competition. PMID- 25143285 TI - Research challenges in digital education. AB - Simulation and other forms of digital learning will occupy a place of increasing prominence in medical education in the future. However, to maximally use the potential of these media, we must go beyond a research agenda dictated by a 'Does it work?' question to one driven by careful analysis of the nature of the task to be learned and its relation to the characteristics of the technology. Secondly, we must change the focus from the characteristics of individual devices to a broader approach to design of a digital curriculum based on current understanding of the nature of human learning. PMID- 25143286 TI - A novel feature-based approach to extract drug-drug interactions from biomedical text. AB - MOTIVATION: Knowledge of drug-drug interactions (DDIs) is crucial for health-care professionals to avoid adverse effects when co-administering drugs to patients. As most newly discovered DDIs are made available through scientific publications, automatic DDI extraction is highly relevant. RESULTS: We propose a novel feature based approach to extract DDIs from text. Our approach consists of three steps. First, we apply text preprocessing to convert input sentences from a given dataset into structured representations. Second, we map each candidate DDI pair from that dataset into a suitable syntactic structure. Based on that, a novel set of features is used to generate feature vectors for these candidate DDI pairs. Third, the obtained feature vectors are used to train a support vector machine (SVM) classifier. When evaluated on two DDI extraction challenge test datasets from 2011 and 2013, our system achieves F-scores of 71.1% and 83.5%, respectively, outperforming any state-of-the-art DDI extraction system. AVAILABILITY AND IMPLEMENTATION: The source code is available for academic use at http://www.biosemantics.org/uploads/DDI.zip. PMID- 25143287 TI - OptiType: precision HLA typing from next-generation sequencing data. AB - MOTIVATION: The human leukocyte antigen (HLA) gene cluster plays a crucial role in adaptive immunity and is thus relevant in many biomedical applications. While next-generation sequencing data are often available for a patient, deducing the HLA genotype is difficult because of substantial sequence similarity within the cluster and exceptionally high variability of the loci. Established approaches, therefore, rely on specific HLA enrichment and sequencing techniques, coming at an additional cost and extra turnaround time. RESULT: We present OptiType, a novel HLA genotyping algorithm based on integer linear programming, capable of producing accurate predictions from NGS data not specifically enriched for the HLA cluster. We also present a comprehensive benchmark dataset consisting of RNA, exome and whole-genome sequencing data. OptiType significantly outperformed previously published in silico approaches with an overall accuracy of 97% enabling its use in a broad range of applications. PMID- 25143288 TI - GlycoPattern: a web platform for glycan array mining. AB - GlycoPattern is Web-based bioinformatics resource to support the analysis of glycan array data for the Consortium for Functional Glycomics. This resource includes algorithms and tools to discover structural motifs, a heatmap visualization to compare multiple experiments, hierarchical clustering of Glycan Binding Proteins with respect to their binding motifs and a structural search feature on the experimental data. AVAILABILITY AND IMPLEMENTATION: GlycoPattern is freely available on the Web at http://glycopattern.emory.edu with all major browsers supported. PMID- 25143289 TI - Acceleration of short and long DNA read mapping without loss of accuracy using suffix array. AB - HPG Aligner applies suffix arrays for DNA read mapping. This implementation produces a highly sensitive and extremely fast mapping of DNA reads that scales up almost linearly with read length. The approach presented here is faster (over 20* for long reads) and more sensitive (over 98% in a wide range of read lengths) than the current state-of-the-art mappers. HPG Aligner is not only an optimal alternative for current sequencers but also the only solution available to cope with longer reads and growing throughputs produced by forthcoming sequencing technologies. AVAILABILITY AND IMPLEMENTATION: https://github.com/opencb/hpg aligner. PMID- 25143290 TI - BioBloom tools: fast, accurate and memory-efficient host species sequence screening using bloom filters. AB - Large datasets can be screened for sequences from a specific organism, quickly and with low memory requirements, by a data structure that supports time- and memory-efficient set membership queries. Bloom filters offer such queries but require that false positives be controlled. We present BioBloom Tools, a Bloom filter-based sequence-screening tool that is faster than BWA, Bowtie 2 (popular alignment algorithms) and FACS (a membership query algorithm). It delivers accuracies comparable with these tools, controls false positives and has low memory requirements. Availability and implementaion: www.bcgsc.ca/platform/bioinfo/software/biobloomtools. PMID- 25143291 TI - Poretools: a toolkit for analyzing nanopore sequence data. AB - MOTIVATION: Nanopore sequencing may be the next disruptive technology in genomics, owing to its ability to detect single DNA molecules without prior amplification, lack of reliance on expensive optical components, and the ability to sequence long fragments. The MinIONTM from Oxford Nanopore Technologies (ONT) is the first nanopore sequencer to be commercialized and is now available to early-access users. The MinIONTM is a USB-connected, portable nanopore sequencer that permits real-time analysis of streaming event data. Currently, the research community lacks a standardized toolkit for the analysis of nanopore datasets. RESULTS: We introduce poretools, a flexible toolkit for exploring datasets generated by nanopore sequencing devices from MinIONTM for the purposes of quality control and downstream analysis. Poretools operates directly on the native FAST5 (an application of the HDF5 standard) file format produced by ONT and provides a wealth of format conversion utilities and data exploration and visualization tools. AVAILABILITY AND IMPLEMENTATION: Poretools is an open-source software and is written in Python as both a suite of command line utilities and a Python application programming interface. Source code is freely available in Github at https://www.github.com/arq5x/poretools. PMID- 25143292 TI - FACTERA: a practical method for the discovery of genomic rearrangements at breakpoint resolution. AB - For practical and robust de novo identification of genomic fusions and breakpoints from targeted paired-end DNA sequencing data, we developed Fusion And Chromosomal Translocation Enumeration and Recovery Algorithm (FACTERA). Our method has minimal external dependencies, works directly on a preexisting Binary Alignment/Map file and produces easily interpretable output. We demonstrate FACTERA's ability to rapidly identify breakpoint-resolution fusion events with high sensitivity and specificity in patients with non-small cell lung cancer, including novel rearrangements. We anticipate that FACTERA will be broadly applicable to the discovery and analysis of clinically relevant fusions from both targeted and genome-wide sequencing datasets. AVAILABILITY AND IMPLEMENTATION: http://factera.stanford.edu. PMID- 25143293 TI - Population support before and after the implementation of smoke-free laws in the United States: trends from 1992-2007. AB - INTRODUCTION: Several states implemented comprehensive smoke-free laws in workplaces (14 states), restaurants (17 states), and bars (13 states) between 2002 and 2007. We tested the hypothesis that public support for smoke-free laws increases at a higher rate in states that implemented smoke-free laws between 2002 and 2007 (group A) than in states that implemented smoke-free laws after that time or not at all (group B). The period before the implementation (1992 2001) was also considered. METHODS: Data was used from the Current Population Survey (CPS) Tobacco Use Supplements (TUS), which is representative for the U.S. adult population. Respondents were asked whether they thought smoking should not be allowed in indoor work areas, restaurants, and bars and cocktail lounges. Differences in trends were analyzed with binomial mixed effects models. RESULTS: Population support for smoke-free restaurants and bars was higher among group A than among group B before 2002. After 2002, support for smoke-free restaurants and bars increased at a higher rate among group A than among group B. Population support for smoke-free workplaces did not differ between group A and B, and the increase in support for smoke-free workplaces also did not differ between these groups. CONCLUSIONS: The positive association between the implementation of smoke free restaurant and bar laws and the rate of increase in support for these laws partly supported the hypothesis. The implementation of the laws may have caused support to increase, but also states that have higher support may have been more likely to implement smoke-free laws. PMID- 25143294 TI - Cognitive effects of very low nicotine content cigarettes, with and without nicotine replacement, in smokers with schizophrenia and controls. AB - INTRODUCTION: Beneficial effects of nicotine on cognitive functioning may contribute to the markedly high rates of smoking among people with schizophrenia. A reduction in the nicotine content of cigarettes to non-addictive levels is being considered as a regulatory strategy for reducing tobacco dependence in the United States. We examined whether switching to very low nicotine content (VLNC) cigarettes impairs cognitive functioning in smokers with and without schizophrenia, andwhether nicotine replacement reverses these effects. METHODS: Smokers with schizophrenia (SS, n = 29) and control smokers matched on smoking rate but without psychiatric illness (CS, n = 28) smoked usual-brand cigarettes, VLNC cigarettes while wearing 2 placebo patches (PLA), or VLNC cigarettes while wearing 2 nicotine patches totaling 42mg (NIC) for 5hr, and then completed computerized assessments of visual sustained attention, motor speed, visual working memory, processing speed, inhibitory control, and response variability. RESULTS: Across conditions, SS were slower than CS in tasks of motor speed and visual working memory, and had poorer target detectability on a visual sustained attention task. Across groups, functioning in domains of visual sustained attention, inhibitory control, processing speed, and response variability was impaired in the VLNC + PLA condition relative to the usual-brand and VLNC + NIC conditions. CONCLUSIONS: Dramatically reducing the nicotine content of cigarettes may impair cognitive functioning in heavy smokers with and without schizophrenia, but the use of nicotine replacement while smoking VLNC cigarettes may preserve cognitive functioning in these smokers. PMID- 25143295 TI - Framing Pictorial Cigarette Warning Labels to Motivate Young Smokers to Quit. AB - INTRODUCTION: The Family Smoking Prevention and Tobacco Control Act requires new pictorial warnings for U.S. cigarette packs, but enactment has been delayed by tobacco industry lawsuits. Research can inform implementation of the pictorial warning requirement and identify ways to optimize their public health impact post implementation. This study investigated the impact of warning label message framing on young smokers' motivation to quit, examining cessation self-efficacy, and perceived risks as moderators of message framing impact. METHODS: Smokers ages 18-30 (n = 740) completed baseline measures and were randomized to view 4 images of cigarette packs with pictorial health warnings featuring gain- or loss framed messages. Motivation to quit was assessed after participants viewed the pack images. Linear models accounting for repeated measures and adjusting for baseline covariates examined the impact of message framing and interactions with baseline self-efficacy to quit and perceived risks of smoking. RESULTS: Loss framed warnings prompted significantly greater motivation to quit among smokers with high self-efficacy compared with smokers with low self-efficacy. Among smokers with low self-efficacy, gain-framed messages were superior to loss-framed messages. Gain-framed warnings generated significantly greater motivation to quit among smokers with high perceived risks compared with smokers with low perceived risks. Among smokers with high perceived risks, gain-framed messages were superior to loss-framed messages. CONCLUSIONS: A combination of pictorial warnings featuring risk-based (i.e., loss-framed) and efficacy-enhancing (i.e., gain-framed) information may promote better public health outcomes. Research is needed to investigate how strategically framed warning messages impact smokers' behaviors based on their pre-existing attitudes and beliefs in real-world settings. PMID- 25143296 TI - Organic cation transporter variation and response to smoking cessation therapies. AB - INTRODUCTION: We evaluated chr6q25.3 organic cation transporter gene (SLC22A1, SLC22A2, SLC22A3) variation and response to smoking cessation therapies. The corresponding proteins are low-affinity transporters of choline, acetylcholine and monoamines, and smoking cessation pharmacotherapies expressed in multiple tissues. METHODS: We selected 7 common polymorphisms for mega-regression analysis. We assessed additive model association of polymorphisms with 7-day point prevalence abstinence overall and by assigned pharmacotherapy at end of treatment and at 6 months among European-ancestry participants of 7 randomized controlled trials adjusted for demographic, population genetic, and trial covariates. RESULTS: Initial results were obtained in 6 trials with 1,839 participants. Nominally statistically significant associations of 2 SLC22A2 polymorphisms were observed: (1) with rs316019 at 6 months, overall ([c.808T>G; p.Ser270Ala], OR = 1.306, 95% CI = 1.034-1.649, p = .025), and among those randomized to nicotine replacement therapy (NRT) (OR = 1.784, 95% CI = 1.072 2.970, p = .026); and (2) with rs316006 (c.1502-529A>T) among those randomized to varenicline (OR = 1.420, 95% CI = 1.038-1.944, p = .028, OR = 1.362, 95% CI = 1.001-1.853, p = .04) at end of treatment and 6 months. Individuals randomized to NRT from a seventh trial were genotyped for rs316019; rs316019 was associated with a nominally statistically significant effect on abstinence overall at 6 months among 2,233 participants (OR = 1.249, 95% CI = 1.007-1.550, p = .043). CONCLUSIONS: The functional OCT2 Ser270Ala polymorphism is nominally statistically significantly associated with abstinence among European-ancestry treatment-seeking smokers after adjustments for pharmacotherapy, demographics, population genetics, and without adjustment for multiple testing of 7 SNPs. Replication of these preliminary findings in additional randomized controlled trials of smoking cessation therapies and from multiple continental populations would describe another pharmacogenetic role for SLC22A2/OCT2. PMID- 25143297 TI - Determinants of cigarette smoking initiation in Jordanian schoolchildren: longitudinal analysis. AB - OBJECTIVE: To identify determinants of cigarette smoking initiation, by gender, among schoolchildren in Irbid, Jordan. METHODS: Between 2008 and 2011, data were collected annually using self-reported questionnaires over 4-years in a prospective cohort of 1,781 students recruited from all 7th grade classes in 19 secondary schools, selected out of a total 60, using probability-proportionate-to size method. Independent predictors of smoking initiation were identified among the cigarette naive participants (N = 1,454) with mixed-effect multivariable logistic regression. RESULTS: Participants were 12.6 years of age on average at baseline. 29.8% of the 1,454 students (37.2% of boys and 23.7% of girls) initiated cigarette smoking by 10th grade. Of those who initiated (n = 498), 47.2% of boys and 37.2% of girls initiated smoking in the 8th grade. Determinants of cigarette smoking initiation included ever smoking a waterpipe, low cigarette refusal self-efficacy, intention to start smoking cigarettes, and having friends who smoked. For girls, familial smoking was also predictive of cigarette initiation. CONCLUSION: This study shows that many Jordanian youth have an intention to initiate cigarette smoking and are susceptible to cigarette smoking modeled by peers and that girls are influenced as well by familial cigarette smoking. Prevention efforts should be tailored to address culturally relevant gender norms, help strengthen adolescents' self-efficacy to refuse cigarettes, and foster strong non-smoking social norms. PMID- 25143298 TI - Intentions to smoke cigarettes among never-smoking US middle and high school electronic cigarette users: National Youth Tobacco Survey, 2011-2013. AB - INTRODUCTION: Electronic cigarette (e-cigarette) use is increasing rapidly, and the impact on youth is unknown. We assessed associations between e-cigarette use and smoking intentions among US youth who had never smoked conventional cigarettes. METHODS: We analyzed data from the nationally representative 2011, 2012, and 2013 National Youth Tobacco Surveys of students in grades 6-12. Youth reporting they would definitely not smoke in the next year or if offered a cigarette by a friend were defined as not having an intention to smoke; all others were classified as having positive intention to smoke conventional cigarettes. Demographics, pro-tobacco advertisement exposure, ever use of e cigarettes, and ever use of other combustibles (cigars, hookah, bidis, kreteks, and pipes) and noncombustibles (chewing tobacco, snuff, dip, snus, and dissolvables) were included in multivariate analyses that assessed associations with smoking intentions among never-cigarette-smoking youth. RESULTS: Between 2011 and 2013, the number of never-smoking youth who used e-cigarettes increased 3-fold, from 79,000 to more than 263,000. Intention to smoke conventional cigarettes was 43.9% among ever e-cigarette users and 21.5% among never users. Ever e-cigarette users had higher adjusted odds for having smoking intentions than never users (adjusted odds ratio = 1.70, 95% confidence interval = 1.24 2.32). Those who ever used other combustibles, ever used noncombustibles, or reported pro-tobacco advertisement exposure also had increased odds for smoking intentions. CONCLUSION: In 2013, more than a quarter million never-smoking youth used e-cigarettes. E-cigarette use is associated with increased intentions to smoke cigarettes, and enhanced prevention efforts for youth are important for all forms of tobacco, including e-cigarettes. PMID- 25143299 TI - A phase I trial of gemcitabine, S-1 and LV combination (GSL) therapy in advanced pancreatic cancer. AB - PURPOSE: In our previous randomized controlled trial, the addition of S-1 to gemcitabine for advanced pancreatic cancer did not prolong overall survival (OS) significantly, despite its higher response rate and longer progression-free survival (PFS). Leucovorin is known to enhance efficacy of S-1, and we conducted this phase I trial of combination therapy of gemcitabine, S-1 and leucovorin (GSL). METHODS: Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Gemcitabine was administered at an escalating dose of 600, 800 and 1,000 mg/m(2) over 30 min on day 1, and oral S 1 at a dose of 40 mg/m(2) twice daily and oral leucovorin at a dose of 25 mg twice daily on days 1-7, every 2 weeks. A standard "3 + 3" phase I dose escalation design was utilized. RESULTS: Fifteen patients were enrolled across three dose levels. Three patients developed DLTs: two patients in level 1 (grade 3 anorexia in 1 and grade 3 anorexia, stomatitis and diarrhea in 1) and one patient in level 2 (grade 3 deep vein thrombosis). No DLT was observed in level 3. Response rate and the disease control rate were 33 and 93 %, respectively. The median PFS and OS were 5.4 and 16.6 months. Ten of 12 patients (83 %) with elevated CA19-9 at baseline had a >= 50 % decline. CONCLUSIONS: RD of gemcitabine in GSL was determined as 1,000 mg/m(2). GSL was well tolerable and showed promising results in advanced pancreatic cancer. PMID- 25143300 TI - Cytoprotective and regulatory functions of glutathione S-transferases in cancer cell proliferation and cell death. AB - PURPOSE: Glutathione S-transferases (GSTs) family of enzymes is best known for their cytoprotective role and their involvement in the development of anticancer drug resistance. Recently, emergence of non-detoxifying properties of GSTs has provided them with significant biological importance. Addressing the complex interactions of GSTs with regulatory kinases will help in understanding its precise role in tumor pathophysiology and in designing GST-centered anticancer strategies. METHODS: We reviewed all published literature addressing the detoxification and regulatory roles of GSTs in the altered biology of cancer and evaluating novel agents targeting GSTs for cancer therapy. RESULTS: The role of GSTs, especially glutathione S-transferase P1 isoform in tumoral drug resistance, has been the cause of intense debate. GSTs have been demonstrated to interact with different protein partners and modulate signaling pathways that control cell proliferation, differentiation and apoptosis. These specific functions of GSTs could lead to the development of new therapeutic approaches and to the identification of some interesting candidates for preclinical and clinical development. This review focuses on the crucial role played by GSTs in the development of resistance to anticancer agents and the major findings regarding the different modes of action of GSTs to regulate cell signaling. PMID- 25143301 TI - Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. AB - Astrocytoma and oligodendroglioma are histologically and genetically well-defined entities. The majority of astrocytomas harbor concurrent TP53 and ATRX mutations, while most oligodendrogliomas carry the 1p/19q co-deletion. Both entities share high frequencies of IDH mutations. In contrast, oligoastrocytomas (OA) appear less clearly defined and, therefore, there is an ongoing debate whether these tumors indeed constitute an entity or whether they represent a mixed bag containing both astrocytomas and oligodendrogliomas. We investigated 43 OA diagnosed in different institutions employing histology, immunohistochemistry and in situ hybridization addressing surrogates for the molecular genetic markers IDH1R132H, TP53, ATRX and 1p/19q loss. In all but one OA the combination of nuclear p53 accumulation and ATRX loss was mutually exclusive with 1p/19q co deletion. In 31/43 OA, only alterations typical for oligodendroglioma were observed, while in 11/43 OA, only indicators for mutations typical for astrocytomas were detected. A single case exhibited a distinct pattern, nuclear expression of p53, ATRX loss, IDH1 mutation and partial 1p/19q loss. However, this was the only patient undergoing radiotherapy prior to surgery, possibly contributing to the acquisition of this uncommon combination. In OA with oligodendroglioma typical alterations, the portions corresponding to astrocytic part were determined as reactive, while in OA with astrocytoma typical alterations the portions corresponding to oligodendroglial differentiation were neoplastic. These data provide strong evidence against the existence of an independent OA entity. PMID- 25143302 TI - Assessing biodiversity loss due to land use with Life Cycle Assessment: are we there yet? AB - Ecosystems are under increasing pressure from human activities, with land use and land-use change at the forefront of the drivers that provoke global and regional biodiversity loss. The first step in addressing the challenge of how to reverse the negative outlook for the coming years starts with measuring environmental loss rates and assigning responsibilities. Pinpointing the global pressures on biodiversity is a task best addressed using holistic models such as Life Cycle Assessment (LCA). LCA is the leading method for calculating cradle-to-grave environmental impacts of products and services; it is actively promoted by many public policies, and integrated as part of environmental information systems within private companies. LCA already deals with the potential biodiversity impacts of land use, but there are significant obstacles to overcome before its models grasp the full reach of the phenomena involved. In this review, we discuss some pressing issues that need to be addressed. LCA mainly introduces biodiversity as an endpoint category modeled as a loss in species richness due to the conversion and use of land over time and space. The functional and population effects on biodiversity are mostly absent due to the emphasis on species accumulation with limited geographic and taxonomical reach. Current land-use modeling activities that use biodiversity indicators tend to oversimplify the real dynamics and complexity of the interactions of species among each other and with their habitats. To identify the main areas for improvement, we systematically reviewed LCA studies on land use that had findings related to global change and conservation ecology. We provide suggestion as to how to address some of the issues raised. Our overall objective was to encourage companies to monitor and take concrete steps to address the impacts of land use on biodiversity on a broader geographical scale and along increasingly globalized supply chains. PMID- 25143303 TI - Bird-repellent effects on bait efficacy for control of invasive mammal pests. AB - BACKGROUND: Repellents to reduce crop damage from birds and mammals have been investigated extensively, but their efficacy in reducing risk to non-target birds in aerial poisoning operations for control of mammal pests is less known. We assessed the impact on bait acceptability, palatability and kill efficacy for captive wild rats (Rattus rattus L.) and possums (Trichosurus vulpecula Kerr) of adding bird repellents (anthraquinone and d-pulegone) to baits used for their control in food choice trials. RESULTS: For possums, anthraquinone at 0.25% reduced acceptability and palatability but not the efficacy of poison baits, whereas d-pulegone at 0.17% had no significant effects. Rats showed little response to d-pulegone, but developed a marked aversion to prefeed baits containing anthraquinone at both 0.1 and 0.25%, such that almost no exposed rats ate poison baits and mortality was reduced significantly. The aversion induced by anthraquinone was generalised to the bait, as anthraquinone-exposed rats did not eat bait with only d-pulegone. CONCLUSION: Anthraquinone is not suitable for inclusion in bait for rat control at the concentrations tested, and also presents some risk to efficacy for possum control. D-pulegone would be suitable for inclusion in bait for possums and rats, but problems related to its volatility in bait manufacture and storage would need to be overcome. Further studies should focus on an alternative secondary repellent, or on establishing the maximum anthraquinone concentration that does not reduce efficacy for rats and testing whether or not that concentration is sufficient to repel native birds from baits reliably. PMID- 25143304 TI - Morphological and morphometric evaluation of the ilium, fibula, and scapula bones for oral and maxillofacial reconstruction. AB - This study aimed to evaluate the osteometric boundaries of the ilium, fibula, and scapula beyond which reconstruction of oromandibular and craniofacial defects, using these free flaps, may not be optimal. Fibula, scapula, and iliac bones were obtained bilaterally from 33 female and 27 male European adult cadavers (n = 60). Adapting classical anthropometric methods to surgical needs by modifying the measuring bone localizations and measurement points, a measuring system of osteometry and morphometry was used, to quantify the usable bone length of the iliac crest, fibula, and lateral border of the scapula and to localize an oval region (OR) in the ilium. The thin, translucent OR of ilium was localized 62.4 +/ 5.6 mm posterior to the maximum concavity between the anterior superior (ASIS) and anterior inferior iliac spine and 26.7 +/- 6 mm caudal to the intermediate line of the iliac crest. The available iliac crest was measured from ASIS to the posterior superior iliac spine (PSIS) 247.5 +/- 12.6 mm, fibula supplied 170.2 +/ 19.1 mm harvestable bone, and the lateral border of the scapula 94.3 +/- 8.5 mm [Corrected]. The OR influenced the harvestable bone shape and volume of the ilium. Measuring of the localization points of OR, we found that the size of the OR was very variable and that the height of the neomandible reconstructed with iliac crest might alter with aging. Our findings contribute with knowledge of detailed morphometric measurements on commonly used donor bones to the planning strategies of volumetric defects in oral and maxillofacial region by precise osteometric localization method of OR and relativized length measurements. PMID- 25143305 TI - Proteomic analyses of ethanol tolerance in Lactobacillus buchneri NRRL B-30929. AB - The Lactobacillus buchneri NRRL B-30929 strain, isolated from a fuel ethanol (EtOH) production facility, exhibits high tolerance to environmental EtOH concentrations. This study aimed to identify proteins produced by B-30929 in response to environmental EtOH. Cellular proteins expressed by B-30929 growing in media with 10 versus 0% EtOH were compared by 2DE, followed by in-gel digestion and MALDI-MS analyses. Twenty EtOH responsive proteins were identified. These include a proline-specific peptidase (Lbuc_1852); a membrane protein (Lbuc_0921), two general stress-related proteins including a 10 kDa chaperonin (GroESL Lbuc_1359) and a 29 kDa member of the HK 97 family (Lbuc_1523); metabolic enzymes involving redox potential balances (Lbuc_2051 and Lbuc_0522) and carbohydrate fermentation (Lbuc_1319 and Lbuc_2157); nitrogen, amino acid, and fatty acid metabolism proteins (Lbuc_1994, Lbuc_0446, Lbuc_0858, Lbuc_0707, and Lbuc_0787). These changes suggested B-30929 cells respond to EtOH by degradation of available proteins and fatty acids and increased production of specific enzymes and molecular chaperons. These results can be used to guide genetic modifications to increase EtOH tolerance in industrial biocatalysts. The data have been deposited to World-2DPAGE (http://world-2dpage.expasy.org/repository/0068/; username liu, password 1h8d6Mg1). PMID- 25143306 TI - Alzheimer's disease and cancer: the need of putting research into context with previous published systematic reviews. PMID- 25143308 TI - Highly sensitive detection of five typical fluoroquinolones in low-fat milk by field-enhanced sample injection-based CE in bubble cell capillary. AB - Fluoroquinolones are a group of synthetic antibiotics with a broad activity spectrum against mycoplasma, Gram-positive, and Gram-negative bacteria. Due to the extensive use of fluoroquinolones in farming and veterinary science, there is a constant need in the analytical methods able to efficiently monitor their residues in food products of animal origin, regulated by Commission Regulation (European Union) no. 37/2010. Herein, field-enhanced sample injection for sample stacking prior the CZE separation was developed inside a bubble cell capillary for highly sensitive detection of five typical fluoroquinolones in bovine milk. Ethylenediamine was proposed as the main component of BGE for the antibiotics separation. The effect of BGE composition, injection parameters, and water plug length on the field-enhanced sample injection-based CE with UV detection was investigated. Under the optimized conditions, described field-enhanced sample injection-based CE-UV analysis of fluoroquinolones provides LODs varying from 0.4 to 1.3 ng/mL. These LOD values are much lower (from 460 to 1500 times) than those obtained by a conventional CE in a standard capillary without bubble cell. The developed method was finally applied for the analysis of fluoroquinolones in low fat milk from a Swiss supermarket. Sample recovery values from 93.6 to 106.0% for different fluoroquinolones, and LODs from 0.7 to 2.5 MUg/kg, were achieved. Moreover, the proposed ethylenediamine-based BGE as volatile and compatible with MS system, enabled the coupling of the field-enhanced sample injection-based CE with a recently introduced electrostatic spray ionization MS via an iontophoretic fraction collection interface for qualitative fluoroquinolones identification. PMID- 25143307 TI - Germline SMARCE1 mutations predispose to both spinal and cranial clear cell meningiomas. AB - We recently reported SMARCE1 mutations as a cause of spinal clear cell meningiomas. Here, we have identified five further cases with non-NF2 spinal meningiomas and six with non-NF2 cranial meningiomas. Three of the spinal cases and three of the cranial cases were clear cell tumours. We screened them for SMARCE1 mutations and investigated copy number changes in all point mutation negative samples. We identified two novel mutations in individuals with spinal clear cell meningiomas and three mutations in individuals with cranial clear cell meningiomas. Copy number analysis identified a large deletion of the 5' end of SMARCE1 in two unrelated probands with spinal clear cell meningiomas. Testing of affected and unaffected relatives of one of these individuals identified the same deletion in two affected female siblings and their unaffected father, providing further evidence of incomplete penetrance of meningioma disease in males. In addition, we found loss of SMARCE1 protein in three of 10 paraffin-embedded cranial clear cell meningiomas. Together, these results demonstrate that loss of SMARCE1 is relevant to cranial as well as spinal meningiomas. Our study broadens the spectrum of mutations in the SMARCE1 gene and expands the phenotype to include cranial clear cell meningiomas. PMID- 25143310 TI - Annals policy on deceptive disclosure of conflicts of interest. PMID- 25143309 TI - A Discussion on Governmental Research Grants. AB - Governmental research grants are financially supported by taxpayers to meet financial requirements of research, particularly research that is unlikely to be supported by private funds. Researchers reward donors by producing knowledge. Publishing research results in an academic journal reflects achievement by researchers; however, receiving a grant award does not. The latter only provides the researcher with the capacity to perform his/her research. Applicants may receive more financial support than they actually need because there is no strict audit on the amount of money requested by each research proposal. There are fewer opportunities to apply for a governmental grant than there are for publishing an academic article, and the application process for governmental grants is not flexible. Some potentially innovative research may be impeded by the intense competition among scientific researchers applying for financial support. Researchers face stiffer competition at this stage than at the stage of publishing results. This paper suggests that scientific foundations can improve their efficiency by giving funding preference to economic proposals. Methods for estimating the efficiency of grants are proposed. The practice followed by the Small Grants for Exploratory Research programme of the National Science Foundation validates my analysis and recommendations. PMID- 25143311 TI - Ultrasound-enhanced and microwave-assisted extraction of lipid from Dunaliella tertiolecta and fatty acid profile analysis. AB - Microalgal lipid is considered as a potential biodiesel resource due to its advantages compared to other bioresources. The production of biofuel from microalgae includes several stages like microalgae cultivation, biomass harvest, biomass treatment, lipid extraction, and the ultimate biodiesel synthesis. Lipid extraction is closely associated with the productivity and cost of energy production. In the present study, lipid of green algae Dunaliella tertiolecta was extracted by chemical agents with involvement of ultrasound and microwave. The optimization of experimental conditions was carried out by response surface methodology and orthogonal test design. Using the ultrasonic technique, an extraction rate of 45.94% was obtained under the optimum conditions of ultrasonic power 370 W, extraction time 5 min and liquid/solid ratio 125 mL/g. The extraction rate of 57.02% was obtained by the means of microwave assistance under the optimized conditions of extraction time 160 s, microwave power 490 W and liquid/solid ratio 100 mL/g. The comparison of the two results indicated microwave was more effective than ultrasound in extracting process. When the two techniques were utilized in combination, the optimized condition was ultrasonic power 320 W, ultrasonic time 4 min, microwave power 280 W, microwave time 120 s and liquid/solid ratio 100 mL/g, and the extraction rate was 49.97%. PMID- 25143312 TI - Retinal vasculitis: a novel paradoxical effect of anti-TNFalpha? AB - Retinal vasculitis (RV) is extremely rare in spondyloarthritis associated with Crohn's disease. Infliximab, a chimeric monoclonal antibody to tumour necrosis factor (TNF) alpha, is efficient in spondyloarthritis, Crohn's disease and RV. We present the case of a 41-year-old man with a known history of spondyloarthritis associated with Crohn's disease. He was under treatment with infliximab. Four days after his 12th infusion of infliximab, he presented with sudden blurred vision. Although his disease was in remission, ophthalmological examination revealed bilateral peripheral retinal occlusive vasculitis. The patient responded positively to the treatment by laser photocoagulation and peribulbar corticosteroid injection. Infliximab was not stopped. There was improvement in his eye disease. To the best of our knowledge, this is the first case of new onset of RV occurring under infliximab in a patient with Crohn's related spondyloarthritis. This case illustrates the possibility of a paradoxical effect of this kind of therapy. PMID- 25143313 TI - Sigmoid volvulus in an adolescent girl: staged management with emergency colonoscopic reduction and decompression followed by elective sigmoid colectomy. AB - A case of acute sigmoid volvulus in a 14-year-old adolescent girl presenting with acute low large bowel obstruction with a background of chronic constipation has been presented. Abdominal radiograph and CT scan helped in diagnosis. She underwent emergency colonoscopic detorsion and decompression uneventfully. Lower gastrointestinal contrast study showed very redundant sigmoid colonic loop without any transition zone and she subsequently underwent elective sigmoid colectomy with good outcome. The sigmoid volvulus should be considered in the differential diagnosis of paediatric acute abdomen presenting with marked abdominal distention, absolute constipation and pain but without vomiting. Plain abdominal radiograph and the CT scan are helpful to confirm the diagnosis. Early colonoscopic detorsion and decompression allows direct visualisation of the vascular compromise, assessment of band width of the volvulus and can reduce complications and mortality. Associated Hirschsprung's disease should be suspected if clinical and radiological features are suggestive in which case a rectal biopsy before definitive surgery should be considered. PMID- 25143314 TI - Characterization and improved quantification of left ventricular inflow using streamline visualization with 4DFlow MRI in healthy controls and patients after atrioventricular septal defect correction. AB - PURPOSE: To evaluate trans-left atrioventricular valve (LAVV) blood flow and optimize left ventricular inflow quantification in healthy controls and patients after atrioventricular septal defect (AVSD) correction. MATERIALS AND METHODS: Twenty-five patients after AVSD correction and 25 controls underwent 4DFlow MRI. Using streamline visualization in four- and two-chamber views, inflow direction at early and late filling was defined at the annulus level and at the peak inflow velocity (PIV) level. Trans-LAVV flow volume and velocity were assessed from a static 2D-multiplanar-reformat (MPR), a 4D-MPR tracking LAVV annulus and a 4D-MPR tracking the PIV-level, angulated perpendicular to the inflow. RESULTS: In patients, on average 9 degrees more laterally directed inflow was found at the PIV-level compared to controls. In controls, 4DFlow velocity mapping with LAVV annulus tracking resulted in lower absolute error with aortic flow (3 (1-8) mL) than with static 2D-MPR (7 (4-16) mL, P = 0.001). In patients, 4D-MPR tracking the PIV-level, resulted in lower absolute error with aortic flow (2 (1-4) mL) than with 4D-MPR LAVV annulus tracking (6 (2-10) mL, P = 0.003). CONCLUSION: Streamline visualization of 4DFlow MRI data revealed dynamic trans-LAVV inflow and more lateral flow after AVSD correction. Streamline visualization improved trans-LAVV flow quantification as the positioning and angulation of the measurement plane was optimized, allowing an accurate assessment of left ventricular inflow. PMID- 25143315 TI - How can I maintain my patient with diabetes and history of foot ulcer in remission? AB - Patients with diabetes and previous history of ulceration occupy the highest category of risk for reulceration and amputation. Annual recurrence rates of diabetic ulcerations have been reported as high as 34%, 61%, and 70% at 1, 3, and 5 years, respectively, with studies reporting 20% to 58% recurrence rate within 1 year. As the ever growing epidemic of diabetes expands globally, this sequelae of diabetic complication will continue to require increasing resources from the healthcare community to effectively manage. Recent data suggest that removal of preventative podiatric care from statewide reimbursement systems lead to significant and sustained increases in hospital admission (37%), charges (38%), length of stay (23%), and severe aggregate outcomes including amputation, sepsis and death (49%). The addition of comorbidities such as peripheral artery disease, poor nutrition, and non-adherence to preventive therapies not only increase a patient's likelihood for ulcer recurrence, but also cost of care and certainty of hospital admission. Currently, numerous efforts, guidelines, and industry generated products exist to prolong remission from ulceration; however, the clinical science for treating this patient population calls for much more effort. Despite this, data continue to suggest to demonstrate that appropriate follow-up care, shoe and insole modification, and patient education play a central role in reducing reulceration and amputation. Novel modalities for offloading and wearable sensor technologies offer the advantage of round-the-clock, patient specific and active response healthcare. These have the potential to detect, or even prevent, many wounds before they begin. PMID- 25143316 TI - Increased antioxidant capacity in tomato by ectopic expression of the strawberry D-galacturonate reductase gene. AB - Increasing L-ascorbic acid (AsA, vitamin C) content in fruits is a common goal in current breeding programs due to its beneficial effect on human health. Attempts to increase AsA content by genetic engineering have resulted in variable success likely due to AsA's complex regulation. Here, we report the effect of ectopically expressing in tomato the D-galacturonate reductase (FaGalUR) gene from strawberry, involved in AsA biosynthesis, either under the control of the constitutive 35S or the tomato fruit-specific polygalucturonase (PG) promoters. Although transgenic lines showed a moderate increase on AsA content, complex changes in metabolites were found in transgenic fruits. Metabolomic analyses of ripe fruits identified a decrease in citrate, glutamate, asparagine, glucose, and fructose, accompanied by an increase of sucrose, galactinol, and chlorogenic acid. Significant metabolic changes also occurred in leaves of 35S-FaGalUR lines, which showed higher non-photochemical fluorescence quenching (NPQ), indicative of a higher constitutive photo-protective capacity. Overall, overexpression of FaGalUR increased total antioxidant capacity in fruits and the results suggest a tight control of AsA content, probably linked to a complex regulation of cellular redox state and metabolic adjustment. PMID- 25143317 TI - Cellular aging in depression: Permanent imprint or reversible process?: An overview of the current evidence, mechanistic pathways, and targets for interventions. AB - Depression might be associated with accelerated cellular aging. However, does this result in an irreversible state or is the body able to slow down or recover from such a process? Telomeres are DNA-protein complexes that protect the ends of chromosomes and generally shorten with age; and therefore index cellular aging. The majority of studies indicate that persons with depression have shorter leukocyte telomeres than similarly aged non-depressed persons, which may contribute to the observed unfavorable somatic health outcomes in the depressed population. Some small-scale preliminary studies raise the possibility that behavioral or pharmacological interventions may either slow down or else reverse this accelerated telomere shortening, possibly through increasing the activity of the telomere-lengthening enzyme telomerase. This paper covers the current state of evidence in the relationship between depression and the telomere-telomerase system and debates whether depression-related cellular aging should be considered a reversible process or permanent damage. PMID- 25143318 TI - Baseline sensitivity of maize borers in India to the Bacillus thuringiensis insecticidal proteins Cry1A.105 and Cry2Ab2. AB - BACKGROUND: Among the major pests of maize in India are two stem borers, Chilo partellus (Swinhoe) and Sesamia inferens (Walker), and an earworm, Helicoverpa armigera (Hubner). As a pest control strategy, transgenic Bacillus thuringiensis (Bt) maize hybrids are undergoing regulatory trials in India. We have determined the sensitivity of the target lepidopterans to the insecticidal Bt proteins expressed in Bt maize, as this determines product efficacy and the resistance management strategy to be adopted. Maize hybrids with event MON89034 express two insecticidal Bt proteins, Cry1A.105 and Cry2Ab2. RESULTS: Sensitivity profiles of 53 populations of C. partellus, 21 populations of S. inferens and 21 populations of H. armigera, collected between 2008 and 2013 from maize-growing areas in India, to Cry1A.105 and Cry2Ab2 proteins were generated through dose-response assays. Cry1A.105 protein was the most effective to neonates of C. partellus (mean MIC90 range 0.30-1.0 ug mL(-1) ) and H. armigera (mean MIC90 range 0.71 8.22 ug mL(-1) ), whereas Cry2Ab2 (mean MIC90 range 0.65-1.70 ug mL(-1) ) was the most effective to S. inferens. CONCLUSION: Populations of C. partellus, S. inferens and H. armigera were susceptible to the Bt proteins Cry1A.105 and Cry2Ab2. The Bt sensitivity data will serve as precommercialisation benchmarks for resistance monitoring purposes. PMID- 25143319 TI - Prognosis of myocardial infarction with left ventricular dysfunction in the coronary revascularization era.Subanalysis of the Japanese Coronary Artery Disease (JCAD) Study. AB - BACKGROUND: Indications of implantable cardioverter-defibrillator (ICD) for patients with an old myocardial infarction (OMI) and left ventricular dysfunction (LVD) were expanded in Western countries after the results of MADIT II. However, the prognosis of OMI patients with LVD and the merits of prophylactic implantation of ICD, based on evidence in Japan, have not yet been clarified. This subanalysis of the Japanese Coronary Artery Disease (JCAD) Study focused on MADIT II-compatible patients to clarify the prognosis of OMI patients with LVD in Japan. METHODS AND RESULTS: Consecutive 6,868 OMI patients were prospectively followed up for 3 years or until clinical events occurred. 291 patients had left ventricular ejection fraction (LVEF) <=30%. Clinical events, congestive heart failure, cardiopulmonary arrest on arrival and vascular events were significantly more frequent in patients with LVEF <=30% than in those with better LVEF. In the LVEF <=30% group, cardiopulmonary arrest on arrival comprised 33% of all-cause deaths, and the survival curves at 2 years of the LVEF <=30% group were almost compatible with those of the MADIT II ICD group. CONCLUSIONS: In this subanalysis, LVD was less frequent than in Western countries. The annual death rate in JCAD was better than for the MADIT II ICD group. The prophylactic use of ICD seemed to be less effective than in Western countries but still expected to be useful for OMI patients with LVD in Japan. PMID- 25143320 TI - Lumbar disc herniation treated with auricular acupuncture: why the(y) wait? PMID- 25143322 TI - Cardiovascular events in pregnancy with hypertrophic cardiomyopathy. PMID- 25143321 TI - Late-phase thromboembolism after catheter ablation for paroxysmal atrial fibrillation. AB - BACKGROUND: The aim of this study was to investigate the incidence and predictors (which have not previously been fully elucidated) of late-phase thromboembolism (TE) after catheter ablation (CA) for paroxysmal atrial fibrillation (AF). METHODS AND RESULTS: We studied 1,156 consecutive patients (61+/-10 years; 891 men; CHADS2score, 0.8+/-1.0) after CA for symptomatic paroxysmal AF and examined the details of late-phase TE. During a follow-up of 49.5+/-21.9 months (median, 47 months; range, 6-113 months) after CA, 9 patients (0.78%) developed late-phase TE, all of which were ischemic stroke. Of these, 5 patients with AF recurrence experienced cardioembolism; the AF was asymptomatic at recurrence. The remaining 4 without AF recurrence experienced cardioembolism (n=1), small-vessel occlusion (n=1), large-artery atherosclerosis (n=1), and stroke of other determined etiology (n=1). On Kaplan-Meier analysis patients with structural heart disease (P=0.003), AF recurrence after the final CA (P=0.01), prior stroke (P=0.002), CHADS2score >=2 (P=0.0002), left ventricular ejection fraction <50% (P<0.0001), and spontaneous echo contrast on transesophageal echocardiogram (P=0.0004) had a significantly higher risk of late-phase TE. Multivariate analysis indicated that CHADS2score >=2 (HR, 4.49; 95% CI: 1.08-22.56; P=0.04) independently predicted late-phase TE. CONCLUSIONS: The incidence of TE was low after CA for paroxysmal AF, but CHADS2score >=2 independently increased the risk of late-phase TE. PMID- 25143323 TI - Angiotensin-converting enzyme insertion/deletion gene polymorphisms is associated with risk of glioma in a Chinese population. AB - INTRODUCTION: The insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene has recently been linked to the pathogenesis and progression of human cancers. The aim of this study was to evaluate the potential association between ACE I/D polymorphism and glioma in a Chinese population. MATERIALS AND METHODS: A case-control study involving patients with 800 glioma and 800 controls was conducted. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the ACE I/D genotypes. RESULTS: Glioma cases had a significantly higher frequency of DD genotype [odds ratio (OR) = 1.61, 95% confidence interval (CI) = 1.12, 2.32; p = 0.01] than controls. When stratified by the grade of glioma, cases with WHO IV glioma had a significantly higher frequency of DD genotype (OR = 1.51, 95% CI = 1.03, 2.21; p = 0.03). When stratified by the histology of glioma, there was no significant difference in the distribution of each genotype. CONCLUSION: Our study suggested that the ACE DD genotype was associated with a higher glioma risk in this Chinese population. To the best of our knowledge, this is the first report describing the potential association between ACE I/D polymorphism and glioma. Additional studies are needed to confirm this finding. PMID- 25143324 TI - A core promoter variant of angiotensinogen gene and interindividual variation in response to angiotensin-converting enzyme inhibitors. AB - INTRODUCTION: The polymorphic angiotensinogen (AGT) gene is one of the most promising candidates for essential hypertension. The aim of this study was to examine the association between the A-6G variant of the AGT gene and the blood pressure response to angiotensin-converting enzyme (ACE) inhibitors in hypertensive subjects. METHODS: Five hundred and nine mildly to moderately hypertensive subjects received ACE inhibitors for six weeks after a two-week run in period. AGT genotyping was performed by direct polymerase chain reaction amplification and deoxyribonucleic acid (DNA) nucleotide sequencing from peripheral blood. RESULTS: The AA genotype, AG genotype, and GG genotype were present in 301 (59.1%), 186 (36.6%), and 22 (4.3%) of patients, respectively. As compared with patients carrying the AA or AG genotype, those carrying the GG genotype had significantly greater reductions in systolic blood pressure, diastolic blood pressure, pulse pressure and mean arterial pressure (p=0.007, 0.014, 0.027 and 0.005, respectively). Moreover, stepwise multiple linear regression analysis showed that the A-6G genotype was a significant predictor of systolic blood pressure and pulse pressure reductions (p=0.040 and 0.019, respectively). CONCLUSION: Our study indicates that the A-6G variant of the AGT gene may be an important determinant of interindividual variation in the response to ACE inhibitors. PMID- 25143325 TI - The effects of siRNA-silenced TRPC6 on podocyte autophagy and apoptosis induced by AngII. AB - OBJECTIVE: the objective of this article is to evaluate the role of siRNA silenced TRPC6 on podocyte autophagy and apoptosis induced by AngII. METHODS: mouse podocyte cell lines were cultured in vitro. The apoptosis rates of each group were detected using flow cytometry. The expression of LC3-II protein and changes in distribution were detected by confocal laser, and the western blot protocol was employed for detection of protein expression of LC3-II. RESULTS: AngII-injured podocyte had a significant increase in apoptosis, while silencing TRPC6 could decrease the apoptosis induced by AngII. Autophagy remarkably increased after AngII injury. While silencing TRPC6 stabilized the autophagy expression, AngII could activate the autophagy of podocyte. Autophagy-associated protein LC3-II expression increased after AngII injury. The LC3-II mRNA and the protein level could be down regulated by 3-MA. The silencing of TRPC6 could stabilize the autophagy expression. CONCLUSION: the data suggest that AngII can lead to podocyte injury. Autophagy may have beneficial effects in preventing the progression of proteinuria. This study provides some new clues for further exploring the occurrence of podocyte injury and the development mechanism of proteinuria. PMID- 25143326 TI - Hypokalemia correlated with arterial stiffness but not microvascular endothelial function in patients with primary aldosteronism. AB - INTRODUCTION: Hypokalemia in primary aldosteronism (PA) patients correlates with higher levels of cardiovascular events and altered left ventricular geometry. However, the influence of aldosterone on microvascular endothelial function and the effect of hypokalemia on the vascular structure still remain unclear. OBJECTIVES: We investigated the peripheral arterial functions, including the endothelial function of microvasculature and arterial stiffness in PA and essential hypertension (EH) patients, and the correlation between hypokalemia and peripheral arterial function among PA patients. METHODS: Twenty patients diagnosed as EH and 37 patients with PA were enrolled in this study. Reactive hyperemia index (RHI) and the augmentation index (AI) were obtained by non invasive peripheral arterial tonometry. RESULTS: Twenty EH patients and a total of 37 PA patients, including 21 patients with normokalemia and 16 patients with hypokalemia, were enrolled and divided into groups 1, 2 and 3 respectively. PA patients had significantly higher AI (p=0.024) but not RHI than EH patients. RHI showed no difference between groups 1, 2 and 3. Group 3 had higher AI than either group 1 or group 2. In the whole study population, serum potassium level, after multivariate regression analysis testing, was the only factor associated with AI (beta= -0.102; p=0.002). In PA patients, serum potassium level was the only significant factor correlated with AI. (r= -0.458; p=0.004) CONCLUSIONS: PA patients had higher arterial stiffness but comparable microvascular endothelial function to EH patients. Hypokalemia correlated with arterial stiffness but not microvascular endothelial function in PA patients. PMID- 25143327 TI - The insertion/deletion polymorphism in the angiotensin-converting enzyme and susceptibility to schizophrenia or Parkinson's disease: A meta-analysis. AB - INTRODUCTION: The purpose of this study was to examine whether the insertion (I) and deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) confers susceptibility to schizophrenia and Parkinson's disease (PD). MATERIALS AND METHODS: A meta-analysis was performed of the associations between the ACE I/D polymorphism and schizophrenia and PD. RESULTS: Thirteen studies with 2024 cases and 2230 controls comprising eight studies on schizophrenia and five on PD were included in the meta-analysis. The meta-analysis revealed no association between the ACE D allele and schizophrenia (OR = 0.990, 95% CI = 0.889-1.102, p = 0.856) or PD (OR = 1.067, 95% CI = 0.907-1.255, p = 0.433). Stratification by ethnicity indicated no association between the ACE D allele and schizophrenia in European, Asian, or Turkish ethnic groups (OR = 0.896, 95% CI = 0.566-1.419, p = 0.640; OR = 1.057, 95% CI = 0.903-1.238, p = 0.492; OR = 1.111, 95% CI = 0.889-1.389, p = 0.354, respectively). Ethnicity-specific meta-analysis was not conducted for PD because only one ethnic PD study was available. CONCLUSIONS: This meta-analysis found no association between the ACE I/D polymorphism and schizophrenia or PD. PMID- 25143328 TI - The ratios of aldosterone / plasma renin activity (ARR) versus aldosterone / direct renin concentration (ADRR). AB - Primary aldosteronism (PA) is estimated to occur in 5-12% of patients with hypertension. Assessment of aldosterone / plasma renin activity (PRA) ratio (ARR) has been used as a screening test in patients suspected of PA. Direct determination of renin (DRC) and calculation of aldosterone / direct renin concentration ratio (ADRR) could be similarly useful for screening patients suspected of PA. The study included 62 patients with indication for evaluation of the renin-angiotensin-aldosterone system and 35 healthy volunteers. In all participants we measured concentrations of serum aldosterone, plasma direct renin, and PRA after a night's rest and again after walking for two hours. The concentrations of aldosterone, direct renin, and PRA were measured by isotopic methods (radioimmunoassay (RIA) / immunoradiometric assay (IRMA)). Correlations of ARR with ADRR in the supine position were r = 0.9162, r(2) = 0.8165 (p < 0.01); and in the up-right position were r = 0.7765, r(2) = 0.9153 (p < 0.01). The cut-off values of ARR and ADRR >= 100 presented highest specificity (99%) for the diagnosis of PA; however, quite acceptable specificity and sensitivity (> 80% and 100%, respectively) appeared for the ratios >= 30. We suggest that for practical and economic reasons ARR can be replaced by ADRR. PMID- 25143329 TI - The effect of renin-angiotensin system blockade on renal protection in chronic kidney disease patients with hyperkalemia. AB - HYPOTHESIS: The aim of this study was to determine the effects of renin angiotensin system (RAS) blockade maintenance on renal protection in chronic kidney disease (CKD) patients with hyperkalemia occurring during treatment with RAS blockade. MATERIALS AND METHODS: CKD III or IV patients, who were prescribed with RAS blockers and also had hyperkalemia, were included. The study population was divided into two groups based on maintenance or withdrawal of RAS blocker. Renal outcomes (doubling of creatinine or end-stage renal disease) and incidence of hyperkalemia were compared between the two groups. RESULTS: Out of 258 subjects who developed hyperkalemia during treatment with RAS blockers, 150 (58.1%) patients continued on RAS blockades, while RAS blockades were discontinued for more than 3 months in the remaining 108 patients. Renal event free survival was significantly higher in the maintenance group compared with the withdrawal group. Cox proportional hazard ratio for renal outcomes was 1.35 (95% CI: 1.08-1.92, p=0.04) in the withdrawal group compared with the maintenance group. However, the incidence of hyperkalemia and hyperkalemia-related hospitalization or mortality did not differ between the two groups. CONCLUSIONS: This study demonstrated that the maintenance of RAS blockade is beneficial for the preservation of renal function and relatively tolerable in patients with CKD and hyperkalemia occurring during treatment with RAS blockade. PMID- 25143330 TI - The relationship between three X-linked genes and the risk for hypertension among northeastern Han Chinese. AB - BACKGROUND AND OBJECTIVE: Incidences of hypertension are increasing and this condition is more common in men than in women. We selected six well-characterized polymorphisms from three X-linked genes (ACE2, AGTR2, apelin) aiming to investigate their interactive association with hypertension among northeastern Han Chinese. METHODS AND RESULTS: This was a case-control study involving 1009 hypertensive patients and 756 normotensive controls. All polymorphisms except rs3761581 in the apelin gene satisfied the Hardy-Weinberg equilibrium in females. The genotype and allele distributions of rs1403543 in the AGTR2 gene and rs56204867 in the apelin gene differed significantly between patients and controls for both genders, even after the Bonferroni correction (P<0.05/6). The risk prediction was significant for rs1403543 and rs56204867 under both additive and dominant models for both genders. In haplotype analysis, significance was seen for haplotype G-T-G-G-A (alleles in order of rs1978124, rs2106809, rs1403543, rs5194 and rs56204867), which was overrepresented in patients (5.15% versus 1.10% in controls, PSim=0.004). Interaction analysis indicated that all derived multifactor dimensionality reduction (MDR) models were non-significant for both genders. CONCLUSION: Our findings demonstrate that genetic defects in AGTR2 and apelin genes by themselves may play an independent leading role in determining susceptibility to hypertension in both genders. PMID- 25143331 TI - Effects of the angiotensin-(1-7)/Mas/PI3K/Akt/nitric oxide axis and the possible role of atrial natriuretic peptide in an acute atrial tachycardia canine model. AB - OBJECTIVE: To investigate the effects of the angiotensin-(1-7) signaling pathway and the possible role of atrial natriuretic peptide (ANP) on atrial electrical remodeling in canines with acute atrial tachycardia. METHODS: Forty dogs were randomly assigned to eight groups (five dogs/group): sham, paced control, paced + angiotensin-(1-7), paced + angiotensin-(1-7) + Mas inhibitor, paced + angiotensin (1-7) + Akt inhibitor, paced + angiotensin-(1-7) + PI3K inhibitor, paced + angiotensin-(1-7) + nitric oxide (NO) inhibitor, and paced + angiotensin-(1-7) + A-71915 (ANP receptor antagonist). Rapid atrial pacing was maintained at 600 bpm for 2 h for all groups, except the sham group, and angiotensin-(1-7) (6 MUg kg( 1) h(-1)), Mas inhibitor (5.83 MUg kg(-1) h(-1)), Akt inhibitor (2.14 MUg kg(-1) h(-1)), PI3K inhibitor (2.86 MUg kg(-1) h(-1)), NO synthase inhibitor (180 MUg kg(-1)h(-1)), or A-71915 (0.30 MUg kg(-1) h(-1)) were administered intravenously. Atrial effective refractory periods, inducibility, and duration of atrial fibrillation (pacing cycle lengths: 300, 250, and 200 ms), and left atrial ANP concentrations were measured. RESULTS: After pacing, the atrial effective refractory periods at the six sites shortened with increased inducibility and duration of atrial fibrillation, which was attenuated by angiotensin-(1-7), and increased ANP concentrations, which was promoted by angiotensin-(1-7) (paced control vs. sham; P < 0.05). All inhibitors and A-71915 blocked the electrophysiological effects of angiotensin-(1-7). ANP secretion induced by angiotensin-(1-7) was also blocked by all inhibitors. CONCLUSION: Angiotensin-(1 7) prevented acute electrical remodeling in canines with acute atrial tachycardia via the angiotensin-(1-7)/Mas/PI3K/Akt/NO signaling pathway. ANP was related to the anti-arrhythmic effects of angiotensin-(1-7). PMID- 25143332 TI - Retracted: Association of aldosterone synthase (CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy. AB - OBJECTIVE: This meta-analysis was conducted to assess the association of aldosterone synthase (CYP11B2) gene polymorphism with the risk of immunoglobulin A (IgA) nephropathy (IgAN) and the progression of IgAN. METHODS: The literature on associations was identified from PubMed and the Cochrane Library on 1 October 2013, and eligible reports were synthesized. RESULTS: Eligible reports were recruited into this meta-analysis for the association of CYP11B2-344C/T (rs1799998) gene polymorphism with IgAN risk, and the progression of IgAN. In this meta-analysis, the association of CYP11B2-344C/T (rs1799998) gene polymorphism with IgAN risk was not found in overall populations and in Asians. Interestingly, the C allele and CC genotype were associated with the risk of IgAN in Caucasians, but the TT genotype was not. CONCLUSION: CYP11B2-344C/T gene polymorphism is not associated with IgAN risk and IgAN progression in overall populations and in Asians, but CYP11B2 C allele and CC genotype were associated with the risk of IgAN in Caucasians. However, more studies should be performed in the future to confirm this association. PMID- 25143334 TI - Angiotensin-converting enzyme I/D polymorphism and diabetic peripheral neuropathy in type 2 diabetes mellitus: A meta-analysis. AB - BACKGROUND: Several molecular epidemiological studies have been conducted to examine the association between angiotensin-converting enzyme (ACE) I/D polymorphism and diabetic peripheral neuropathy (DPN) risk. However, the conclusions remained controversial. We therefore performed this meta-analysis. METHODS: PubMed and EMBASE were searched to identify case-control studies investigating the associations of ACE I/D polymorphism with risk of DPN. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association between ACE I/D polymorphism and risk of DPN. RESULTS: A total of seven case-control studies including 1316 cases and 1617 controls were included. ACE I/D polymorphism was associated with a significantly increased risk of DPN (OR=1.46, 95%CI 1.11-1.92, p=0.006, I(2)=48%). This result remained statistically significant when the adjusted ORs were combined (OR=1.84, 95%CI 1.14-2.99, p=0.01, I(2)=53%). In the subgroup of ethnicity, a significantly elevated risk was observed in Caucasians (OR=1.32, 95%CI 1.10-1.59, p=0.003, I(2)=43%). CONCLUSIONS: Our meta-analysis confirmed that ACE I/D polymorphism was associated with the risk of DPN. PMID- 25143335 TI - Effects of curcumin on angiotensin-converting enzyme gene expression, oxidative stress and anti-oxidant status in thioacetamide-induced hepatotoxicity. AB - INTRODUCTION: This study aimed to evaluate the protective effects of curcumin on angiotensin-converting enzyme (ACE) gene expression, oxidative stress and anti oxidant status in thioacetamide (TAA)-induced hepatotoxicity in rats. MATERIALS AND METHODS: Total 32 albino Wistar rats (male, 200-250 g) were divided into six groups (n=8). Group 1: untreated controls; Group 2: received TAA (200 mg/kg body weight (b.w.); i.p.) for 12 weeks; Group 3: received curcumin (75 mg/kg b.w.) for 24 weeks; Group 4: received TAA (200 mg/kg b.w.; i.p.) for 12 weeks+curcumin (75 mg/kg b.w.) for 12 weeks. RESULTS: A significantly higher ACE gene expression was observed in TAA-induced groups as compared with control, indicating more synthesis of ACE proteins. Treatment with curcumin suppressed ACE expression in TAA liver and reversed the toxicity produced. TAA treatment results in higher lipid peroxidation and lower GSH, SOD and CAT than the normal, and this produces oxidative stress in the liver. Cirrhotic conditions were confirmed by serum enzymes (ALT, AST and ALP) as well as histopathological observations. CONCLUSION: Curcumin treatment reduced oxidative stress in animals by scavenging reactive oxygen species, protecting the anti-oxidant enzymes from being denatured and reducing the oxidative stress marker lipid peroxidation. Curcumin treatment restores hepatocytes, damaged by TAA, and protects liver tissue approaching cirrhosis. PMID- 25143333 TI - ACE-inhibition increases podocyte number in experimental glomerular disease independent of proliferation. AB - OBJECTIVE: The objective of this article is to test the effects of angiotensin converting enzyme (ACE)-inhibition on glomerular epithelial cell number in an inducible experimental model of focal segmental glomerulosclerosis (FSGS). BACKGROUND: Although ACE-inhibition has been shown to limit podocyte loss by enhancing survival, little is known about its effect on podocyte number following an abrupt decline in disease. METHODS: Experimental FSGS was induced with cytotoxic antipodocyte antibody. Following induction, groups were randomized to receive the ACE-inhibitor enalapril, the smooth muscle relaxant hydralazine (blood pressure control) or drinking water. Blood pressure, kidney function and histology were measured seven and 14 days following disease induction. RESULTS: Both glomerulosclerosis and urinary albumin-to-creatinine ratio were less in the ACE-inhibition arm at day 14. At day 7 of disease, mean podocyte numbers were 26% and 29% lower in the enalapril and hydralazine arms, respectively, compared to normal mice in which no antibody was injected. At day 14, the mean podocyte number was only 18% lower in the enalapril arm, but was 39% lower in the hydralazine arm compared to normal mice. Podocyte proliferation did not occur at any time in any group. Compared to water- or hydralazine-treated mice with FSGS, the enalapril arm had a higher mean number of glomerular parietal epithelial cells that co-expressed the podocyte proteins WT-1 and synaptopodin, as well as phospho-ERK. CONCLUSION: The results show following an abrupt decline in podocyte number, the initiation of ACE-inhibition but not hydralazine, was accompanied by higher podocyte number in the absence of proliferation. This was accompanied by a higher number of parietal epithelial cells that co-express podocyte proteins. Increasing podocyte number appears to be accompanied by reduced glomerulosclerosis. PMID- 25143336 TI - Efficacy and safety of combination therapy of high-dose losartan and hydrochlorothiazide in patients with hypertension. AB - OBJECTIVE: We analyzed the efficacy and safety of combination therapy of high dose losartan (100 mg/day) and hydrochlorothiazide (HCTZ, 12.5 mg/day) compared with those of the combination of high-dose telmisartan (80 mg/day) and HCTZ (12.5 mg/day). METHODS: Forty hypertensive patients who received a combination of high dose telmisartan and HCTZ were enrolled. We applied a changeover strategy with switching from a combination of high-dose telmisartan and HCTZ to high-dose losartan and HCTZ. We divided the patients into two groups; those who achieved the target blood pressure (controlled group) and those who did not reach the target blood pressure (uncontrolled group) before the changeover and performed further analysis. RESULTS: The uncontrolled group showed a significant decrease in systolic blood pressure (SBP) (143+/-12 mmHg to 126+/-11 mmHg at three months). In addition, serum uric acid significantly decreased in all subjects, and in each of the controlled and uncontrolled groups. There were no significant changes in other biochemical parameters, such as potassium and hemoglobin A1c, at three months after the changeover in all subjects. CONCLUSION: Combination therapy with high-dose losartan and HCTZ was superior to the combination of telmisartan and HCTZ with respect to significant decreases in systolic blood pressure and serum uric acid in hypertensive patients. PMID- 25143337 TI - Serum concentrations of interleukin-2 and tumour necrosis factor-alpha under cyclosporine versus acitretin treatment in plaque-type psoriasis. AB - OBJECTIVE: A prospective, randomized clinical study to compare the short-term effects of cyclosporin and acitretin on psoriasis severity, and serum interleukin (IL)-2 and tumour necrosis factor (TNF)-alpha concentrations. METHODS: Patients with moderate-to-severe plaque-type psoriasis were randomly assigned to receive either 3 mg/kg per day cyclosporine or 0.3-0.5 mg/kg per day acitretin for 8 weeks. Disease severity (psoriasis area severity index [PASI] score) and serum IL 2 and TNF-alpha concentrations were determined before and after treatment. RESULTS: PASI scores and serum IL-2 and TNF-alpha concentrations were significantly decreased after treatment with either cyclosporine (n = 21) or acitretin (n = 25). There were no statistically significant between-group differences in any parameter. CONCLUSIONS: Acitretin and cyclosporine are equally effective in the treatment of moderate-to-severe plaque-type psoriasis. PMID- 25143338 TI - Detection of antibodies to the biofilm exopolysaccharide of Histophilus somni following infection in cattle by enzyme-linked immunosorbent assay. AB - An enzyme-linked immunosorbent assay (ELISA) was developed to detect bovine antibodies to Histophilus somni exopolysaccharide (EPS), which is created during biofilm formation. When an index value of 0.268 was used, the sensitivity of the assay for infected calves was 90.5% at 3 weeks postinfection, but the number of positive animals increased by week 4. The specificity of the assay for healthy calves was 92.5%. The EPS ELISA may aid in identifying calves with H. somni diseases. PMID- 25143339 TI - Fusion protein comprising factor H domains 6 and 7 and human IgG1 Fc as an antibacterial immunotherapeutic. AB - The emergence of antimicrobial resistance among several medically important pathogens represents a serious threat to human health globally and necessitates the development of novel therapeutics. Complement forms a key arm of innate immune defenses against invading pathogens. A mechanism of complement evasion employed by many pathogens is binding of complement inhibitors, including factor H (FH), a key downregulator of the alternative pathway. Most FH-binding bacteria engage FH through regions in FH spanned by domains 6 and 7 and/or 18 through 20. We created a chimeric protein that comprised human FH domains 6 and 7 fused to human IgG1 Fc (FH6,7/HuFc) and tested its activity as an immunotherapeutic against Neisseria meningitidis, which binds FH through domains 6 and 7. FH6,7/HuFc bound to meningococci and effectively blocked FH binding to bacteria. FH6,7/HuFc enhanced human C3 and C4 deposition and facilitated complement mediated killing in a dose-responsive manner; complement activation and killing were classical pathway dependent. To investigate in vivo efficacy, infant Wistar rats were treated intraperitoneally (IP) with different doses of FH6,7/HuFc and challenged 2 h later with serogroup C strain 4243 given IP. At 8 to 9 h after the challenge, the FH6,7/HuFc-treated rats had >100-fold fewer CFU per ml of blood than control animals pretreated with phosphate-buffered saline (PBS) or FH18 20/HuFc, which does not bind to meningococci (P < 0.0001). These data provide proof of concept of the utility of FH/Fc fusion proteins as anti-infective immunotherapeutics. Because many microbes share a common binding region(s) in FH, FH/Fc chimeric proteins may be a promising candidate for adjunctive therapy against drug-resistant pathogens. PMID- 25143341 TI - Assisted suicide: Models of legal regulation in selected European countries and the case law of the European Court of Human Rights. AB - This paper presents three different models of the legal regulation of assisted suicide in European countries. First, the current legal regime governing assisted suicide in the Netherlands is described where both euthanasia and assisted suicide have been legalised. This section also includes some empirical data on euthanasia and assisted-suicide practices in the Netherlands, as well as a comparison with the current legal legislation in Belgium and Luxembourg. Next, Switzerland is presented as a country where euthanasia is punishable by law but assisted suicide is legally allowed, provided it is not carried out with selfish motives. This section also focuses on the assisted-suicide-related case law of the Swiss Federal Supreme Court and the European Court of Human Rights. Last, the current legal situation regarding assisted suicide in Austria and Germany is described. While the Austrian Penal Code explicitly prohibits assisted suicide, assistance with suicide is not specifically regulated by the German Penal Code. However, medical doctors are not allowed to assist suicides according to the professional codes of conduct drawn up by the German medical associations under the supervision of the health authorities. PMID- 25143340 TI - Intranasal administration of Mycobacterium bovis BCG induces superior protection against aerosol infection with Mycobacterium tuberculosis in mice. AB - Despite the widespread use of Mycobacterium bovis BCG, the only licensed vaccine against tuberculosis (TB), TB remains a global epidemic. To assess whether more direct targeting of the lung mucosa by respiratory immunization would enhance the potency and longevity of BCG-induced anti-TB protective immunity, the long-term impact of intranasal (i.n.) BCG vaccination was compared to conventional subcutaneous (s.c.) immunization by using a mouse model of pulmonary tuberculosis. Although significantly improved protection in the lung was seen at early time points (2 and 4 months postvaccination) in i.n. BCG-immunized mice, no differences in pulmonary protection were seen 8 and 10 months postvaccination. In contrast, in all of the study periods, i.n. BCG vaccination induced significantly elevated protective splenic responses relative to s.c. immunization. At five of nine time points, we observed a splenic protective response exceeding 1.9 log10 protection relative to the s.c. route. Furthermore, higher frequencies of CD4 T cells expressing gamma interferon (IFN-gamma) and IFN-gamma/tumor necrosis factor alpha, as well as CD8 T cells expressing IFN-gamma, were detected in the spleens of i.n. vaccinated mice. Using PCR arrays, significantly elevated levels of IFN gamma, interleukin-9 (IL-9), IL-11, and IL-21 expression were also seen in the spleen at 8 months after respiratory BCG immunization. Overall, while i.n. BCG vaccination provided short-term enhancement of protection in the lung relative to s.c. immunization, potent and extremely persistent splenic protective responses were seen for at least 10 months following respiratory immunization. PMID- 25143342 TI - Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. AB - BACKGROUND: In-home iron fortification for infants in developing countries is recommended for control of anaemia, but low absorption typically results in >80% of the iron passing into the colon. Iron is essential for growth and virulence of many pathogenic enterobacteria. We determined the effect of high and low dose in home iron fortification on the infant gut microbiome and intestinal inflammation. METHODS: We performed two double-blind randomised controlled trials in 6-month old Kenyan infants (n=115) consuming home-fortified maize porridge daily for 4 months. In the first, infants received a micronutrient powder (MNP) containing 2.5 mg iron as NaFeEDTA or the MNP without iron. In the second, they received a different MNP containing 12.5 mg iron as ferrous fumarate or the MNP without the iron. The primary outcome was gut microbiome composition analysed by 16S pyrosequencing and targeted real-time PCR (qPCR). Secondary outcomes included faecal calprotectin (marker of intestinal inflammation) and incidence of diarrhoea. We analysed the trials separately and combined. RESULTS: At baseline, 63% of the total microbial 16S rRNA could be assigned to Bifidobacteriaceae but there were high prevalences of pathogens, including Salmonella Clostridium difficile, Clostridium perfringens, and pathogenic Escherichia coli. Using pyrosequencing, +FeMNPs increased enterobacteria, particularly Escherichia/Shigella (p=0.048), the enterobacteria/bifidobacteria ratio (p=0.020), and Clostridium (p=0.030). Most of these effects were confirmed using qPCR; for example, +FeMNPs increased pathogenic E. coli strains (p=0.029). +FeMNPs also increased faecal calprotectin (p=0.002). During the trial, 27.3% of infants in +12.5 mgFeMNP required treatment for diarrhoea versus 8.3% in -12.5 mgFeMNP (p=0.092). There were no study-related serious adverse events in either group. CONCLUSIONS: In this setting, provision of iron-containing MNPs to weaning infants adversely affects the gut microbiome, increasing pathogen abundance and causing intestinal inflammation. TRIAL REGISTRATION NUMBER: NCT01111864. PMID- 25143344 TI - Oral antiviral therapy for HBeAg negative chronic hepatitis B: better stop or continue? PMID- 25143345 TI - The nursing discipline and self-realization. AB - BACKGROUND: It is obvious from literature within the nursing discipline that nursing is related to moral or moral-philosophical related ideas which are other oriented. The socio-cultural process of change in modern society implies that more self-oriented ideas have been found to be significant. AIM: The overall aim of this article is to highlight self-oriented moral or moral-philosophical related ideas as an important part of the nursing discipline. This is achieved by (a) exploring self-realization as a significant self-oriented moral or moral philosophical related idea based on a philosophical anthropological perspective, (b) demonstrating how moral or moral-philosophical related ideas are expressed by nurses, (c) discussing the relevance of self-realization for the nursing discipline, and (d) pointing out possible consequences for the future development of the discipline of nursing. RESEARCH DESIGN: This theoretical study draws empirical examples from interviews. PARTICIPANTS AND RESEARCH CONTEXT: Data consisted of interviews with 13 nurses with varying work experience within the primary and secondary somatic and psychiatric health service, from inside as well as outside institutions. ETHICAL CONSIDERATIONS: The empirical study was approved by the Norwegian Social Science Data Services. Information was given and consent was obtained from the study participants. FINDINGS: Findings are presented in two themes: (a) other-oriented ideas and (b) self-oriented ideas. More concretely, the findings show that nurses hope to make life as good as possible for the patient and they have a wish to improve themselves as human beings, to become better persons. DISCUSSION: The relevance of self-realization for the nursing discipline is discussed along two lines, first, by connecting nurses' self understanding to a horizon of identity and second, by considering what self realization could offer. CONCLUSION: It is of ultimate concern for the nursing discipline to highlight self-realization connected to the positive view of freedom understood as an exercise-concept. Further identifying and articulating the contribution of self-realization to nurses and nursing practice is of particular importance. PMID- 25143343 TI - A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration. AB - OBJECTIVE: The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression. DESIGN: We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1 mg/dL) and platelet count (<100,000/mm(3)), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10 years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8 years). RESULTS: In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001). CONCLUSIONS: A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions. PMID- 25143346 TI - Probiotic Bifidobacterium species stimulate human SLC26A3 gene function and expression in intestinal epithelial cells. AB - SLC26A3, or downregulated in adenoma (DRA), plays a major role in mediating Cl(-) absorption in the mammalian intestine. Disturbances in DRA function and expression have been implicated in intestinal disorders such as congenital Cl(-) diarrhea and gut inflammation. We previously showed that an increase in DRA function and expression by Lactobacillus acidophilus and its culture supernatant (CS) might underlie antidiarrheal effects of this probiotic strain. However, the effects of Bifidobacterium species, important inhabitants of the human colon, on intestinal Cl(-)/HCO3 (-) exchange activity are not known. Our current results demonstrate that CS derived from Bifidobacterium breve, Bifidobacterium infantis, and Bifidobacterium bifidum increased anion exchange activity in Caco-2 cells (~1.8- to 2.4-fold). Consistent with the increase in DRA function, CS also increased the protein, as well as the mRNA, level of DRA (but not putative anion transporter 1). CS of all three Bifidobacterium sp. increased DRA promoter activity (-1,183/+114 bp) in Caco-2 cells (1.5- to 1.8-fold). Furthermore, the increase in DRA mRNA expression by CS of B. breve and B. infantis was blocked in the presence of the transcription inhibitor actinomycin D (5 MUM) and the ERK1/2 MAPK pathway inhibitor U0126 (10 MUM). Administration of live B. breve, B. infantis, and B. bifidum by oral gavage to mice for 24 h increased DRA mRNA and protein levels in the colon. These data demonstrate an upregulation of DRA via activation of the ERK1/2 pathway that may underlie potential antidiarrheal effects of Bifidobacterium sp. PMID- 25143348 TI - Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 1. An overview. AB - Increased demand on the protein folding capacity of the endoplasmic reticulum (ER) engages an adaptive reaction known as the unfolded protein response (UPR). The UPR regulates protein translation and the expression of numerous target genes that contribute to restore ER homeostasis or induce apoptosis of irreversibly damaged cells. UPR signaling is highly regulated and dynamic and integrates information about the type, intensity, and duration of the stress stimuli, thereby determining cell fate. Recent advances highlight novel physiological outcomes of the UPR beyond specialized secretory cells, particularly in innate immunity, metabolism, and cell differentiation. Here we discuss studies on the fine-tuning of the UPR and its physiological role in diverse organs and diseases. PMID- 25143347 TI - A highly potent agonist to protease-activated receptor-2 reveals apical activation of the airway epithelium resulting in Ca2+-regulated ion conductance. AB - The airway epithelium provides a barrier that separates inhaled air and its various particulates from the underlying tissues. It provides key physiological functions in both sensing the environment and initiating appropriate innate immune defenses to protect the lung. Protease-activated receptor-2 (PAR2) is expressed both apically and basolaterally throughout the airway epithelium. One consequence of basolateral PAR2 activation is the rapid, Ca(2+)-dependent ion flux that favors secretion in the normally absorptive airway epithelium. However, roles for apically expressed PAR2 activation have not been demonstrated, in part due to the lack of specific, high-potency PAR2 ligands. In the present study, we used the newly developed PAR2 ligand 2at-LIGRLO(PEG3-Pam)-NH2 in combination with well-differentiated, primary cultured airway epithelial cells from wild-type and PAR2 (-/-) mice to examine the physiological role of PAR2 in the conducting airway after apical activation. Using digital imaging microscopy of intracellular Ca(2+) concentration changes, we verified ligand potency on PAR2 in primary cultured airway cells. Examination of airway epithelial tissue in an Ussing chamber showed that apical activation of PAR2 by 2at-LIGRLO(PEG3-Pam)-NH2 resulted in a transient decrease in transepithelial resistance that was due to increased apical ion efflux. We determined pharmacologically that this increase in ion conductance was through Ca(2+)-activated Cl(-) and large-conductance K(+) channels that were blocked with a Ca(2+)-activated Cl(-) channel inhibitor and clotrimazole, respectively. Stimulation of Cl(-) efflux via PAR2 activation at the airway epithelial surface can increase airway surface liquid that would aid in clearing the airway of noxious inhaled agents. PMID- 25143349 TI - Differential regulation of placental amino acid transport by saturated and unsaturated fatty acids. AB - Fatty acids are critical for normal fetal development but may also influence placental function. We have previously reported that oleic acid (OA) stimulates amino acid transport in primary human trophoblasts (PHTs). In other tissues, saturated and unsaturated fatty acids have distinct effects on cellular signaling, for instance, palmitic acid (PA) but not OA reduces IkappaBalpha expression. We hypothesized that saturated and unsaturated fatty acids differentially affect trophoblast amino acid transport and cellular signaling. To test this hypothesis, PHTs were cultured in docosahexaenoic acid (DHA; 50 MUM), OA (100 MUM), or PA (100 MUM). DHA and OA were also combined to test whether DHA could counteract the OA stimulatory effect on amino acid transport. The effects of fatty acids were compared against a vehicle control. Amino acid transport was measured by isotope-labeled tracers. Activation of inflammatory-related signaling pathways and the mechanistic target of rapamycin (mTOR) pathway were determined by Western blot analysis. Exposure of PHTs to DHA for 24 h reduced amino acid transport and phosphorylation of p38 MAPK, STAT3, mTOR, eukaryotic initiation factor 4E-binding protein 1, and ribosomal protein (rp)S6. In contrast, OA increased amino acid transport and phosphorylation of ERK, mTOR, S6 kinase 1, and rpS6. The combination of DHA with OA increased amino acid transport and rpS6 phosphorylation. PA did not affect amino acid transport but reduced IkappaBalpha expression. In conclusion, these fatty acids differentially regulated placental amino acid transport and cellular signaling. Taken together, these findings suggest that dietary fatty acids could alter the intrauterine environment by modifying placental function, thereby having long-lasting effects on the developing fetus. PMID- 25143351 TI - Proteasome inhibition in skeletal muscle cells unmasks metabolic derangements in type 2 diabetes. AB - Two-dimensional difference gel electrophoresis (2-D DIGE)-based proteome analysis has revealed intrinsic insulin resistance in myotubes derived from type 2 diabetic patients. Using 2-D DIGE-based proteome analysis, we identified a subset of insulin-resistant proteins involved in protein turnover in skeletal muscle of type 2 diabetic patients, suggesting aberrant regulation of the protein homeostasis maintenance system underlying metabolic disease. We then validated the role of the ubiquitin-proteasome system (UPS) in myotubes to investigate whether impaired proteasome function may lead to metabolic arrest or insulin resistance. Myotubes derived from muscle biopsies obtained from people with normal glucose tolerance (NGT) or type 2 diabetes were exposed to the proteasome inhibitor bortezomib (BZ; Velcade) without or with insulin. BZ exposure increased protein carbonylation and lactate production yet impaired protein synthesis and UPS function in myotubes from type 2 diabetic patients, marking the existence of an insulin-resistant signature that was retained in cultured myotubes. In conclusion, BZ treatment further exacerbates insulin resistance and unmasks intrinsic features of metabolic disease in myotubes derived from type 2 diabetic patients. Our results highlight the existence of a confounding inherent abnormality in cellular protein dynamics in metabolic disease, which is uncovered through concurrent inhibition of the proteasome system. PMID- 25143350 TI - Pericyte contractility controls endothelial cell cycle progression and sprouting: insights into angiogenic switch mechanics. AB - Microvascular stability and regulation of capillary tonus are regulated by pericytes and their interactions with endothelial cells (EC). While the RhoA/Rho kinase (ROCK) pathway has been implicated in modulation of pericyte contractility, in part via regulation of the myosin light chain phosphatase (MLCP), the mechanisms linking Rho GTPase activity with actomyosin-based contraction and the cytoskeleton are equivocal. Recently, the myosin phosphatase RhoA-interacting protein (MRIP) was shown to mediate the RhoA/ROCK-directed MLCP inactivation in vascular smooth muscle. Here we report that MRIP directly interacts with the beta-actin-specific capping protein betacap73. Furthermore, manipulation of MRIP expression influences pericyte contractility, with MRIP silencing inducing cytoskeletal remodeling and cellular hypertrophy. MRIP knockdown induces a repositioning of betacap73 from the leading edge to stress fibers; thus MRIP-silenced pericytes increase F-actin-driven cell spreading twofold. These hypertrophied and cytoskeleton-enriched pericytes demonstrate a 2.2-fold increase in contractility upon MRIP knockdown when cells are plated on a deformable substrate. In turn, silencing pericyte MRIP significantly affects EC cycle progression and angiogenic activation. When MRIP-silenced pericytes are cocultured with capillary EC, there is a 2.0-fold increase in EC cycle entry. Furthermore, in three-dimensional models of injury and repair, silencing pericyte MRIP results in a 1.6-fold elevation of total tube area due to EC network formation and increased angiogenic sprouting. The pivotal role of MRIP expression in governing pericyte contractile phenotype and endothelial growth should lend important new insights into how chemomechanical signaling pathways control the "angiogenic switch" and pathological angiogenic induction. PMID- 25143353 TI - The gametic synapse: RNA transfer to the bovine oocyte. AB - Even after several decades of quiescent storage in the ovary, the female germ cell is capable of reinitiating transcription to build the reserves that are essential to support early embryonic development. In the current model of mammalian oogenesis, there exists bilateral communication between the gamete and the surrounding cells that is limited to paracrine signaling and direct transfer of small molecules via gap junctions existing at the end of the somatic cells' projections that are in contact with the oolemma. The purpose of this work was to explore the role of cumulus cell projections as a means of conductance of large molecules, including RNA, to the mammalian oocyte. By studying nascent RNA with confocal and transmission electron microscopy in combination with transcript detection, we show that the somatic cells surrounding the fully grown bovine oocyte contribute to the maternal reserves by actively transferring large cargo, including mRNA and long noncoding RNA. This occurrence was further demonstrated by the reconstruction of cumulus-oocyte complexes with transfected cumulus cells transferring a synthetic transcript. We propose selective transfer of transcripts occurs, the delivery of which is supported by a remarkable synapselike vesicular trafficking connection between the cumulus cells and the gamete. This unexpected exogenous contribution to the maternal stores offers a new perspective on the determinants of female fertility. PMID- 25143352 TI - The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT TCF pathway responses in human cancer. AB - Constitutive activation of canonical WNT-TCF signaling is implicated in multiple diseases, including intestine and lung cancers, but there are no WNT-TCF antagonists in clinical use. We have performed a repositioning screen for WNT-TCF response blockers aiming to recapitulate the genetic blockade afforded by dominant-negative TCF. We report that Ivermectin inhibits the expression of WNT TCF targets, mimicking dnTCF, and that its low concentration effects are rescued by direct activation by TCF(VP16). Ivermectin inhibits the proliferation and increases apoptosis of various human cancer types. It represses the levels of C terminal beta-CATENIN phosphoforms and of CYCLIN D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases. In vivo, Ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without obvious side effects. Analysis of single semi-synthetic derivatives highlights Selamectin, urging its clinical testing and the exploration of the macrocyclic lactone chemical space. Given that Ivermectin is a safe anti parasitic agent used by > 200 million people against river blindness, our results suggest its additional use as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers. PMID- 25143354 TI - Cellular microenvironment dictates androgen production by murine fetal Leydig cells in primary culture. AB - Despite the fact that fetal Leydig cells are recognized as the primary source of androgens in male embryos, the mechanisms by which steroidogenesis occurs within the developing testis remain unclear. A genetic approach was used to visualize and isolate fetal Leydig cells from remaining cells within developing mouse testes. Cyp11a1-Cre mice were bred to mT/mG dual reporter mice to target membrane tagged enhanced green fluorescent protein (GFP) within steroidogenic cells, whereas other cells expressed membrane-tagged tandem-dimer tomato red. Fetal Leydig cell identity was validated using double-labeled immunohistochemistry against GFP and the steroidogenic enzyme 3beta-HSD, and cells were successfully isolated as indicated by qPCR results from sorted cell populations. Because fetal Leydig cells must collaborate with neighboring cells to synthesize testosterone, we hypothesized that the fetal Leydig cell microenvironment defined their capacity for androgen production. Microfluidic culture devices were used to measure androstenedione and testosterone production of fetal Leydig cells that were cultured in cell-cell contact within a mixed population, were isolated but remained in medium contact via compartmentalized co-culture with other testicular cells, or were isolated and cultured alone. Results showed that fetal Leydig cells maintained their identity and steroidogenic activity for 3-5 days in primary culture. Microenvironment dictated proficiency of testosterone production. As expected, fetal Leydig cells produced androstenedione but not testosterone when cultured in isolation. More testosterone accumulated in medium from mixed cultures than from compartmentalized co-cultures initially; however, co-cultures maintained testosterone synthesis for a longer time. These data suggest that a combination of cell-cell contact and soluble factors constitute the ideal microenvironment for fetal Leydig cell activity in primary culture. PMID- 25143355 TI - Progressive obesity alters ovarian folliculogenesis with impacts on pro inflammatory and steroidogenic signaling in female mice. AB - Diet-induced obesity induces immune cell infiltration and inflammation in peri ovarian adipose tissue and mRNA expression of inflammatory markers in ovarian tissue. Whether these changes are associated with obesity-related ovarian dysfunction remains unknown. In the present study, qRT-PCR and Western blotting techniques were used to compare mRNA and protein abundance of ovarian immune cell and inflammation markers, along with NF-kappaB and steroidogenic pathway members in normal wild-type non-agouti (a/a; lean) and lethal yellow mice (KK.CG-A(y/)J; obese) at 6, 12, 18, or 24 wk of age. Our data revealed that, beginning at 12 wk of age, NF-kappaB inflammatory signaling members were elevated (P < 0.05) in obese females. Interestingly obesity had opposing and temporal effects on the steroidogenic enzyme pathway. Obesity decreased (P < 0.05) STAR protein at 12, 18, and 24 wk of age. CYP11A1 and CYP19A1 proteins were increased (P < 0.05) at 12 wk but were decreased (P < 0.05) at 18 and 24 wk. Interestingly, CYP19A1 was increased in lethal yellow mouse ovaries at 6 wk of age, potentially indicating early puberty onset. These data demonstrate that obesity alters expression of ovarian inflammatory and steroidogenic pathway genes in ways which could adversely affect ovarian function. PMID- 25143357 TI - Maintenance of potential spermatogonial stem cells in vitro by GDNF treatment in a chondrichthyan model (Scyliorhinus canicula L.). AB - Previous work in dogfish, Scyliorhinus canicula, has identified the testicular germinative area as the spermatogonial stem cell niche. In the present study, an in vitro co-culture system of spermatogonia and somatic cells from the germinative area was developed. Long-term maintenance of spermatogonia has been successful, and addition of GDNF has promoted the development of clones of spermatogonia expressing stem cell characteristics such as alkaline phosphatase activity and has allowed maintenance of self-renewal in spermatogonia for at least 5 mo under culture conditions, notably by decreasing cell apoptosis. Furthermore, clones of spermatogonia expressed the receptor of GDNF, GFRalpha1, which is consistent with the effect of GDNF on cells despite the lack of identification of a GDNF sequence in the dogfish's transcriptome. However, a sequence homologous to artemin has been identified, and in silico analysis supports the hypothesis that artemin could replace GDNF in the germinative area in dogfish. This study, as the first report on long-term in vitro maintenance of spermatogonia in a chondrichthyan species, suggests that the GFRalpha1 signaling function in self-renewal of spermatogonial stem cells is probably conserved in gnathostomes. PMID- 25143356 TI - Retinoic acid biosynthesis is impaired in human and murine endometriosis. AB - Endometriosis is characterized by the presence of endometrial glands and stroma in extrauterine sites. Our objective was to determine whether endometriotic lesions (ELs) from women with endometriosis have altered retinoid levels compared with their eutopic endometrium, and to test the hypothesis that defects in all trans retinoic acid (ATRA) biosynthesis in EL is related to reduced expression of cellular retinol-binding protein type 1 (RBP1). Retinoids were evaluated by liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography in eutopic endometrial biopsies (EBs) and ELs from 42 patients with pathologically confirmed endometriosis. The ATRA levels were reduced, whereas the retinol and retinyl ester concentrations were elevated in EL compared with EB tissue. Similar results were found in a mouse model of endometriosis that used green fluorescent protein-positive endometrial tissue injected into the peritoneum of syngeneic hosts to mimic retrograde menses. The ATRA biosynthesis in vitro in retinol-treated primary human endometrial stromal cell (ESC) cultures derived from ELs was reduced compared with that of ESCs derived from patient matched EBs. Correspondingly, RBP1 expression was reduced in tissue and ESCs derived from EL versus EB. Rbp1(-/-) mice showed reduced endometrial ATRA concentrations compared with wild type, associated with loss of tissue organization and hypercellularity. These findings provide the first quantitative measurements of ATRA in human endometrium and endometriosis, demonstrating reduced ATRA in ectopic tissue and corresponding ESC cultures. Quantitation of retinoids in murine endometriosis and in Rbp1(-/-) mice supports the contention that impaired ATRA synthesis caused by reduced RBP1 promotes an "endometriosis phenotype" that enables cells to implant and grow at ectopic sites. PMID- 25143358 TI - Extragonadal FSH receptor: is it real? PMID- 25143359 TI - Racial comparison of receptor-defined breast cancer in Southern African women: subtype prevalence and age-incidence analysis of nationwide cancer registry data. AB - BACKGROUND: Receptor-defined breast cancer proportions vary across Africa. They have important implications for survival prospects and research priorities. METHODS: We studied estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor statuses in two multiracial Southern African countries with routine diagnostic immunohistochemistry. A total of 12,361 women with histologically confirmed breast cancer diagnosed at age >=20 years during (i) 2009-2011 from South Africa's national cancer registry (public sector) and (ii) 2011-2013 from Namibia's only cancer hospital were included. Crude, age, and age + laboratory adjusted ORs of receptor status were analyzed using logistic regression, and age incidence curves were analyzed using Poisson regression. RESULTS: A total of 10,047 (81%) women had known ER status. Ranking of subtypes was consistent across races: ER(+)/PR(+)HER2(-) was most common (race-specific percentage range, 54.6% 64.8%), followed by triple-negative (17.4%-21.9%), ER(+)/PR(+)HER2(+) (9.6% 13.9%), and ER(-)PR(-)HER2(+) (7.8%-10.9%). Percentages in black versus white women were 33.8% [95% confidence (CI), 32.5-35.0] versus 26.0% (24.0-27.9) ER(-); 20.9% (19.7-22.1) versus 17.5% (15.4-19.6) triple-negative; and 10.7% (9.8-11.6) versus 7.8% (6.3-9.3) ER(-)PR(-)HER2(+). Indian/Asian and mixed-ancestry women had intermediate values. Age-incidence curves had similar shapes across races: rates increased by 12.7% per year (12.2-13.1) across ER subtypes under the age of 50 years, and thereafter slowed for ER(+) (1.95%) and plateaued for ER(-) disease (-0.1%). CONCLUSIONS: ER(+) breast cancer dominates in all Southern African races, but black women have a modest excess of aggressive subtypes. IMPACT: On the basis of the predominant receptor-defined breast tumors in Southern Africa, improving survival for the growing breast cancer burden should be achievable through earlier diagnosis and appropriate treatment. PMID- 25143361 TI - Bench-to-bench bottlenecks in translation. AB - Transfer of biopharmaceutical inventions between firms has bottlenecks in upstream development that suggest a role for repurposing mechanisms well before the clinical trials stage. PMID- 25143360 TI - Prolactin determinants in healthy women: A large cross-sectional study within the EPIC cohort. AB - BACKGROUND: Experimental and epidemiologic data suggest that higher circulating prolactin is associated with breast cancer risk; however, how various risk factors for breast cancer influence prolactin levels in healthy women is not clear. METHODS: We analyzed cross-sectional associations between several suggested reproductive and lifestyle risk factors for breast cancer and circulating prolactin among pre- and postmenopausal women, taking into account the use of current postmenopausal hormone therapy, among 2,560 controls from a breast cancer nested case-control study within the EPIC cohort. RESULTS: Adjusted geometric mean prolactin levels were significantly higher among premenopausal women, and among postmenopausal women using hormone therapy compared with nonusers (8.2, 7.0, and 6.3 ng/mL, respectively; Pcat = <0.0001). Furthermore, prolactin levels were significantly higher among users of combined estrogen progestin hormone therapy compared with users of estrogen-alone hormone therapy (6.66 vs. 5.90 ng/mL; Pcat = 0.001). Prolactin levels were lower among parous women compared with nulliparous women (8.61 vs. 10.95 ng/mL; Pcat = 0.0002, premenopausal women); the magnitude of this difference depended on the number of full-term pregnancies (22.1% lower, >=3 vs. 1 pregnancy, Ptrend = 0.01). Results for parity were similar but lower in magnitude among postmenopausal women. Prolactin did not vary by other studied factors, with the exception of lower levels among postmenopausal smokers compared with never smokers. CONCLUSIONS: Our study shows that current hormone therapy use, especially the use of combined hormone therapy, is associated with higher circulating prolactin levels in postmenopausal women, and confirms prior findings of lower circulating prolactin in parous women. IMPACT: Our study extends the knowledge linking various breast cancer risk factors with circulating prolactin. PMID- 25143362 TI - Proteasome inhibitors increase missense mutated dysferlin in patients with muscular dystrophy. AB - No treatment is available for patients affected by the recessively inherited, progressive muscular dystrophies caused by a deficiency in the muscle membrane repair protein dysferlin. A marked reduction in dysferlin in patients harboring missense mutations in at least one of the two pathogenic DYSF alleles encoding dysferlin implies that dysferlin is degraded by the cell's quality control machinery. In vitro evidence suggests that missense mutated dysferlin might be functional if salvaged from degradation by the proteasome. We treated three patients with muscular dystrophy due to a homozygous Arg555Trp mutation in dysferlin with the proteasome inhibitor bortezomib and monitored dysferlin expression in monocytes and in skeletal muscle by repeated percutaneous muscle biopsy. Expression of missense mutated dysferlin in the skeletal muscle and monocytes of the three patients increased markedly, and dysferlin was correctly localized to the sarcolemma of muscle fibers on histological sections. Salvaged missense mutated dysferlin was functional in a membrane resealing assay in patient-derived muscle cells treated with three different proteasome inhibitors. We conclude that interference with the proteasomal system increases expression of missense mutated dysferlin, suggesting that this therapeutic strategy may benefit patients with dysferlinopathies and possibly other genetic diseases. PMID- 25143363 TI - Pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for hereditary pulmonary alveolar proteinosis. AB - Hereditary pulmonary alveolar proteinosis (herPAP) is a rare lung disease caused by mutations in the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor genes, resulting in disturbed alveolar macrophage differentiation, massive alveolar proteinosis, and life-threatening respiratory insufficiency. So far, the only effective treatment for herPAP is repetitive whole-lung lavage, a merely symptomatic and highly invasive procedure. We introduce pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for herPAP. In a murine disease model, intrapulmonary transplanted macrophage progenitors displayed selective, long-term pulmonary engraftment and differentiation into functional alveolar macrophages. A single transplantation ameliorated the herPAP phenotype for at least 9 months, resulting in significantly reduced alveolar proteinosis, normalized lung densities in chest computed tomography, and improved lung function. A significant and sustained disease resolution was also observed in a second, humanized herPAP model after intrapulmonary transplantation of human macrophage progenitors. The therapeutic effect was mediated by long-lived, lung-resident macrophages, which displayed functional and phenotypical characteristics of primary human alveolar macrophages. Our findings present the concept of organotopic transplantation of macrophage progenitors as an effective and long-lasting therapy of herPAP and may also serve as a proof of principle for other diseases, expanding current stem cell-based strategies toward potent concepts using the transplantation of differentiated cells. PMID- 25143364 TI - IL-32 is a molecular marker of a host defense network in human tuberculosis. AB - Tuberculosis is a leading cause of infectious disease-related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-gamma- and IL-15-induced "defense response" genes. IL-32 induced the vitamin D-dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. In addition, the IL-15-induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent compared with active tuberculosis or healthy controls and a coexpression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15-induced gene network. As maintaining M. tuberculosis in a latent state and preventing transition to active disease may represent a form of host resistance, these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis. PMID- 25143367 TI - Combined anticoagulation and antiplatelet therapy in AF patients: why do we not follow guidelines? PMID- 25143365 TI - Denervation suppresses gastric tumorigenesis. AB - The nervous system plays an important role in the regulation of epithelial homeostasis and has also been postulated to play a role in tumorigenesis. We provide evidence that proper innervation is critical at all stages of gastric tumorigenesis. In three separate mouse models of gastric cancer, surgical or pharmacological denervation of the stomach (bilateral or unilateral truncal vagotomy, or local injection of botulinum toxin type A) markedly reduced tumor incidence and progression, but only in the denervated portion of the stomach. Vagotomy or botulinum toxin type A treatment also enhanced the therapeutic effects of systemic chemotherapy and prolonged survival. Denervation-induced suppression of tumorigenesis was associated with inhibition of Wnt signaling and suppression of stem cell expansion. In gastric organoid cultures, neurons stimulated growth in a Wnt-mediated fashion through cholinergic signaling. Furthermore, pharmacological inhibition or genetic knockout of the muscarinic acetylcholine M3 receptor suppressed gastric tumorigenesis. In gastric cancer patients, tumor stage correlated with neural density and activated Wnt signaling, whereas vagotomy reduced the risk of gastric cancer. Together, our findings suggest that vagal innervation contributes to gastric tumorigenesis via M3 receptor-mediated Wnt signaling in the stem cells, and that denervation might represent a feasible strategy for the control of gastric cancer. PMID- 25143366 TI - Marburg virus infection in nonhuman primates: Therapeutic treatment by lipid encapsulated siRNA. AB - Marburg virus (MARV) and the closely related filovirus Ebola virus cause severe and often fatal hemorrhagic fever (HF) in humans and nonhuman primates with mortality rates up to 90%. There are no vaccines or drugs approved for human use, and no postexposure treatment has completely protected nonhuman primates against MARV-Angola, the strain associated with the highest rate of mortality in naturally occurring human outbreaks. Studies performed with other MARV strains assessed candidate treatments at times shortly after virus exposure, before signs of disease are detectable. We assessed the efficacy of lipid nanoparticle (LNP) delivery of anti-MARV nucleoprotein (NP)-targeting small interfering RNA (siRNA) at several time points after virus exposure, including after the onset of detectable disease in a uniformly lethal nonhuman primate model of MARV-Angola HF. Twenty-one rhesus monkeys were challenged with a lethal dose of MARV-Angola. Sixteen of these animals were treated with LNP containing anti-MARV NP siRNA beginning at 30 to 45 min, 1 day, 2 days, or 3 days after virus challenge. All 16 macaques that received LNP-encapsulated anti-MARV NP siRNA survived infection, whereas the untreated or mock-treated control subjects succumbed to disease between days 7 and 9 after infection. These results represent the successful demonstration of therapeutic anti-MARV-Angola efficacy in nonhuman primates and highlight the substantial impact of an LNP-delivered siRNA therapeutic as a countermeasure against this highly lethal human disease. PMID- 25143368 TI - Joint analysis of differential gene expression in multiple studies using correlation motifs. AB - The standard methods for detecting differential gene expression are mostly designed for analyzing a single gene expression experiment. When data from multiple related gene expression studies are available, separately analyzing each study is not ideal as it may fail to detect important genes with consistent but relatively weak differential signals in multiple studies. Jointly modeling all data allows one to borrow information across studies to improve the analysis. However, a simple concordance model, in which each gene is assumed to be differential in either all studies or none of the studies, is incapable of handling genes with study-specific differential expression. In contrast, a model that naively enumerates and analyzes all possible differential patterns across studies can deal with study-specificity and allow information pooling, but the complexity of its parameter space grows exponentially as the number of studies increases. Here, we propose a correlation motif approach to address this dilemma. This approach searches for a small number of latent probability vectors called correlation motifs to capture the major correlation patterns among multiple studies. The motifs provide the basis for sharing information among studies and genes. The approach has flexibility to handle all possible study-specific differential patterns. It improves detection of differential expression and overcomes the barrier of exponential model complexity. PMID- 25143369 TI - Methylmalonic acid quantified in dried blood spots provides a precise, valid, and stable measure of functional vitamin B-12 status in healthy women. AB - Methylmalonic acid (MMA) is a sensitive and specific functional biomarker of vitamin B-12 status, commonly assessed in plasma or serum. Dried blood spots (DBSs) allow simpler and more cost-efficient blood sampling than plasma. To facilitate convenient testing for vitamin B-12 deficiency in large-scale surveys and in population groups from remote areas, we developed a method for MMA quantification in DBSs and tested its applicability as well as the long-term stability of MMA in DBSs at various temperatures. MMA was extracted from an 8-mm DBS punch with water:methanol (95:5, v:v) and methyl-d3-malonic acid as the internal standard. After sample cleanup by ultrafiltration and hexane extraction, MMA was quantified by using reversed-phase LC-tandem mass spectrometry. Extraction conditions were optimized to maximize the detection signal and achieve DBS extract concentrations above the lowest limit of quantification (signal-to noise ratio >= 10) of 10 nmol/L. Recovery was between 93% and 96%. Intra- and interassay variation (CV%) for DBS MMA was 0.49% and 2.3%, respectively. Calibrators showed linearity (R(2) = 0.998) between 10 and 10,000 nmol/L. In 94 healthy women, MMA concentrations in DBS extract (min-max: 10.2-80.5 nmol/L) and plasma (min-max: 68-950 nmol/L) were correlated (rho = 0.90) (P < 0.001). MMA concentrations in DBSs were stable at room temperature for 1 wk, in the refrigerator for 8 wk, and at -80 degrees C for at least 1 y. This simple and robust method allows quantification of MMA in DBSs of healthy individuals. The linear relation between plasma and DBS MMA suggests that DBS MMA could predict plasma MMA, the current reference indicator for functional vitamin B-12 deficiency. With the advantages of minimally invasive specimen collection and no need for laborious blood processing steps, this method has the potential to be a reliable, convenient, and field-applicable alternative for assessment of vitamin B-12 status. PMID- 25143370 TI - Evidence for an association of dietary flavonoid intake with breast cancer risk by estrogen receptor status is limited. AB - BACKGROUND: Results from preclinical studies suggest that flavonoids, which are ubiquitous in plant-based diets, lower breast cancer risk. Epidemiologic studies of flavonoid intake and breast cancer risk, however, are limited, and few investigated associations with the more aggressive estrogen receptor (ER) negative (ER-) tumors. OBJECTIVE: We examined the associations between 7 subclasses of dietary flavonoids and invasive postmenopausal breast cancer risk overall and by ER status in a U.S. prospective cohort. METHODS: In 1999-2000, 56,630 postmenopausal women completed detailed self-administered questionnaires, among whom 2116 invasive breast cancers were verified during a mean follow-up period of 8.5 y. Cox proportional hazards regression was used to calculate multivariable-adjusted HRs and 95% CIs. RESULTS: Total flavonoid intake was not associated with breast cancer risk. However, there was a modest inverse association between flavone intake and overall breast cancer risk (fifth vs. first quintile HR: 0.88; 95% CI: 0.76, 1.01; P-trend = 0.04) and between flavan-3 ol intake and risk of ER- breast cancer (for an increment of 40 mg/d; HR: 0.81; 95% CI: 0.67, 0.97) but not for ER-positive (ER+) breast cancer risk. CONCLUSION: The inverse association of flavan-3-ol intake with ER- but not ER+ breast cancer is consistent with other studies that suggest a beneficial role of plant-based diets in ER- breast cancer risk. PMID- 25143371 TI - The relative bioavailability of the calcium salt of beta-hydroxy-beta methylbutyrate is greater than that of the free fatty acid form in rats. AB - BACKGROUND: beta-Hydroxy-beta-methylbutyrate (HMB) supplementation has been demonstrated to enhance muscle protein synthesis and attenuate loss of muscle mass by multiple pathways. The beneficial effects of HMB have been studied by using either the calcium salt, monohydrate, of HMB (CaHMB) or the free acid form (FAHMB). OBJECTIVE: The present study was designed to compare the pharmacokinetics and relative bioavailability of the 2 forms of HMB administered as a liquid suspension in male Sprague-Dawley rats. METHODS: CaHMB at 30, 100, and 300 mg/kg and equivalent doses of FAHMB at 24.2, 80.8, and 242 mg/kg were administered orally as a liquid suspension to male Sprague-Dawley rats. A single i.v. dose of 5 mg/kg CaHMB, corresponding to an equivalent dose of 4.04 mg/kg FAHMB, was also administered. Plasma concentrations of HMB were analyzed by liquid chromatography tandem mass spectrometry, and pharmacokinetic variables and relative bioavailability of the 2 forms of HMB were determined. RESULTS: After oral administration, the area under the plasma concentration time curve (AUC) from time 0 to time t (0-t) and from time 0 to infinity (0-infinity) and the maximum (peak) plasma concentration (Cmax) for CaHMB were significantly greater than for FAHMB, whereas the time to reach Cmax did not differ from that of FAHMB. The relative bioavailability of CaHMB was 49%, 54%, and 27% greater than that of FAHMB for the 3 respective oral doses tested. After i.v. administration, the AUCs 0-t and 0-infinity of the calcium salt were significantly greater than those of FAHMB. The relative bioavailability of CaHMB was 80% greater than that of FAHMB. The higher relative bioavailability of CaHMB may be attributable to its low systemic clearance compared with FAHMB. CONCLUSIONS: This study demonstrates the enhanced relative bioavailability of CaHMB compared with FAHMB. Further studies are warranted to understand the physiologic mechanisms contributing to the differences in systemic clearance. PMID- 25143372 TI - Program impact pathway analysis of a social franchise model shows potential to improve infant and young child feeding practices in Vietnam. AB - By mapping the mechanisms through which interventions are expected to achieve impact, program impact pathway (PIP) analysis lays out the theoretical causal links between program activities, outcomes, and impacts. This study examines the pathways through which the Alive & Thrive (A&T) social franchise model is intended to improve infant and young child feeding (IYCF) practices in Vietnam. Mixed methods were used, including qualitative interviews with franchise management board members (n = 12), surveys with health providers (n = 120), counseling observations (n = 160), and household surveys (n = 2045). Six PIP components were assessed: 1) franchise management, 2) training and IYCF knowledge of health providers, 3) service delivery, 4) program exposure and utilization, 5) maternal behavioral determinants (knowledge, beliefs, and intentions) toward optimal IYCF practices, and 6) IYCF practices. Data were collected from A&T intensive areas (A&T-I; mass media + social franchise) and A&T-nonintensive areas (A&T-NI; mass media only) by using a cluster-randomized controlled trial design. Data from 2013 were compared with baseline where similar measures were available. Results indicate that mechanisms are in place for effective management of the franchise system, despite challenges to routine monitoring. A&T training was associated with increased capacity of providers, resulting in higher-quality IYCF counseling (greater technical knowledge and communication skills during counseling) in A&T-I areas. Franchise utilization increased from 10% in 2012 to 45% in 2013 but fell below the expected frequency of 9-15 contacts per mother child dyad. Improvements in breastfeeding knowledge, beliefs, intentions, and practices were greater among mothers in A&T-I areas than among those in A&T-NI areas. In conclusion, there are many positive changes along the impact pathway of the franchise services, but challenges in utilization and demand creation should be addressed to achieve the full intended impact. PMID- 25143373 TI - Food insecurity in children but not in their mothers is associated with altered activities, school absenteeism, and stunting. AB - Household food insecurity has substantial detrimental effects on children, but little is known about the mechanisms through which these effects occur. This study investigated some possible mechanisms by examining associations of food insecurity reported by children and mothers with daily activities, school absenteeism, and stunting. We conducted a cross-sectional study in a nonprobabilistic sample of 131 mother-child pairs from a poor peri-urban area in Miranda State, Venezuela. We assessed food insecurity in children by using an instrument developed through a naturalistic approach that had 10 items for food insecurity and 9 items for management strategies. To obtain mothers' reports of food insecurity, a previously validated 12-item instrument was used. Children's daily activities, school absenteeism, and stunting were measured. Chi-square tests for contingency tables and logistic and multiple regression analyses were used to test associations of food insecurity with outcomes. There was no association between mothers' reports of food-insecurity and any child outcome. Children's reports of food insecurity were associated with higher odds of doing passive home chores (OR: 1.17; 95% CI: 1.02, 1.32), cooking at home (OR: 1.21; 95% CI: 1.05, 1,38), taking care of siblings (OR: 1.15; 95% CI: 1.01, 1.31), and doing labor (OR: 1.22; 95% CI: 1.04, 1.42) and lower odds of playing video games (OR: 0.86; 95% CI: 0.76, 0.98) (all P < 0.03). Children's reports of management strategies were associated with 5 of 7 work activities measured. Labor in food insecure children was the main activity that explained school absenteeism. Food insecurity reported by children can be assessed by pediatricians, school personnel, and other practitioners by using a simple instrument to identify food insecure children and to respond to mitigate their food insecurity and its consequences. PMID- 25143374 TI - A 22-element micronutrient powder benefits language but not cognition in Bangladeshi full-term low-birth-weight children. AB - BACKGROUND: Low-birth-weight children are known to be at risk of both anemia and cognitive/language deficits in their early years. OBJECTIVE: The aim of the current study was to examine the effects of a 22-element multiple micronutrient powder (MNP) on the cognitive and language development of full-term low-birth weight (LBW-T) children in Bangladesh. METHODS: The current study was a follow-up of children who were enrolled in a randomized cluster trial at 7-12 mo of age. Children in 12 intervention clusters (communities) were administered a daily 22 element MNP sachet with their food for 5 mo, and both intervention and control groups (also 12 clusters) received nutrition, health, and hygiene education. The current study involved the assessment of children at 16-22 mo of age (22-element MNP group: n = 96; control group: n = 82) on 3 subtests of the Bayley Scales of Infant and Toddler Development III test to measure cognitive, receptive language, and expressive language development. RESULTS: There was a significant effect of the 22-element MNP on children's expressive language scores (d = 0.39), and stunting moderated the effect on receptive language scores; there was no effect on cognitive development (d = 0.08). CONCLUSION: An MNP may thus offer one feasible solution to improve language development of LBW-T children in low resource community settings. This trial was registered at clinicaltrials.gov as NCT01455636. PMID- 25143375 TI - Prepregnancy healthy dietary pattern is inversely associated with depressive symptoms among pregnant Brazilian women. AB - Dietary patterns before pregnancy may be associated with depressive symptomatology during pregnancy. The aim of this study was to identify dietary patterns before pregnancy and to examine the association between these dietary patterns and depressive symptoms during pregnancy. A prospective cohort of 248 healthy pregnant women were followed at 5-13, 20-26, and 30-36 gestational weeks. Dietary intake was obtained by using a food-frequency questionnaire administered between 5 and 13 gestational weeks, which referred to the 6 mo preceding gestation, and factor analysis (principal components) was applied to identify dietary patterns. The Edinburgh Postnatal Depressive Scale (EPDS) was used to evaluate depressive symptoms during 3 follow-up pregnancy points. A multiple linear mixed-effects model was applied to verify the association between dietary patterns and depressive symptoms adjusted for obstetric factors, socioeconomic status, and energy intake. Three prepregnancy dietary patterns were identified: common-Brazilian, healthy, and processed. Together, these patterns explained 36.1% of the total percentage of variance; the eigenvalues were 2.88, 2.12, and 1.86, respectively. Mean depressive symptom scores were 9.0 (95% CI: 8.4, 9.6), 7.2 (95% CI: 6.5, 7.8), and 7.0 (95% CI: 6.4, 7.7) for trimesters 1, 2, and 3, respectively. The rate of decrease in depressive symptoms was -0.088/wk (95% CI: 0.115, -0.061; P < 0.001). In the multiple longitudinal linear regression model, the healthy dietary pattern before pregnancy was inversely associated with depressive symptoms (beta:-0.723; 95% CI: -1.277, -0.169; P = 0.011). High adherence to the healthy pattern before pregnancy was associated with lower EPDS scores during pregnancy in women from Rio de Janeiro, Brazil. PMID- 25143376 TI - Short-chain fructo-oligosaccharide and inulin modulate inflammatory responses and microbial communities in Caco2-bbe cells and in a mouse model of intestinal injury. AB - BACKGROUND: Few studies have focused on the ability of prebiotics to prevent pathogen-induced cellular changes or alter the composition of the intestinal microbiota in complimentary relevant cell and animal models of inflammatory bowel disease. OBJECTIVE: The objective of this study was to determine if pretreatment with inulin and a short-chain fructo-oligosaccharide (sc-FOS) prevents enterohemorrhagic Escherichia coli (EHEC) O157:H7 infection in Caco2-bbe epithelial cells and what effect 10% wt:v sc-FOS or inulin has on C57BL/6 mice under sham conditions or pretreatment with prebiotics before Citrobacter rodentium infection (10(8) colony-forming units). METHODS: Actin rearrangement and tight junction protein (zona occludin-1) were examined with immunofluorescence. Barrier function was assessed by a fluorescent probe and by measuring transepithelial electrical resistance (TER). Alterations in cytokine gene expression and microbiome were assessed with quantitative reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization. Short-chain fatty acids (SCFAs) were measured by GC. RESULTS: sc-FOS added to monolayers altered actin polymerization without affecting TER or permeability to a fluorescein isothiocyanate (FITC) probe, whereas inulin increased TER (P < 0.005) and altered actin arrangement without affecting FITC permeability. Neither prebiotic attenuated EHEC-induced decreases in barrier function. Prebiotics increased interleukin 10 (Il10) and transforming growth factor-beta (Tgfbeta) cytokine responses alone (P < 0.05) or with EHEC O157:H7 infection (P < 0.05) in vitro. Increases in tumor necrosis factor-alpha (Tnfalpha) (P < 0.05) and decreases in chemokine CXC motif ligand 8 (Cxcl8) (P < 0.05) expression were observed with prebiotic treatment prior to EHEC infection. No differences were noted in barrier function or cytokine responses in the absence or presence of C. rodentium in vivo. Alterations in microbiome were evident at 6 d and 10 d postinfection in treatment groups, but a change in C. rodentium load was not observed. Inulin and sc-FOS (P < 0.05) increased fecal SCFAs in the absence of infection. CONCLUSION: This study provides new insights as to how prebiotics act in complementary in vitro and in vivo models of intestinal injury. PMID- 25143377 TI - Tyrosine-based signal mediates LRP6 receptor endocytosis and desensitization of Wnt/beta-catenin pathway signaling. AB - Wnt/beta-catenin signaling orchestrates a number of critical events including cell growth, differentiation, and cell survival during development. Misregulation of this pathway leads to various human diseases, specifically cancers. Endocytosis and phosphorylation of the LDL receptor-related protein 6 (LRP6), an essential co-receptor for Wnt/beta-catenin signaling, play a vital role in mediating Wnt/beta-catenin signal transduction. However, its regulatory mechanism is not fully understood. In this study, we define the mechanisms by which LRP6 endocytic trafficking regulates Wnt/beta-catenin signaling activation. We show that LRP6 mutant with defective tyrosine-based signal in its cytoplasmic tail has an increased cell surface distribution and decreased endocytosis rate. These changes in LRP6 endocytosis coincide with an increased distribution to caveolae, increased phosphorylation, and enhanced Wnt/beta-catenin signaling. We further demonstrate that treatment of Wnt3a ligands or blocking the clathrin-mediated endocytosis of LRP6 leads to a redistribution of wild-type receptor to lipid rafts. The LRP6 tyrosine mutant also exhibited an increase in signaling activation in response to Wnt3a stimulation when compared with wild-type LRP6, and this activation is suppressed when caveolae-mediated endocytosis is blocked. Our results reveal molecular mechanisms by which LRP6 endocytosis routes regulate its phosphorylation and the strength of Wnt/beta-catenin signaling, and have implications on how this pathway can be modulated in human diseases. PMID- 25143378 TI - Inflammatory monocytes determine endothelial nitric-oxide synthase uncoupling and nitro-oxidative stress induced by angiotensin II. AB - Endothelial nitric-oxide synthase (eNOS) uncoupling and increased inducible NOS (iNOS) activity amplify vascular oxidative stress. The role of inflammatory myelomonocytic cells as mediators of these processes and their impact on tetrahydrobiopterin availability and function have not yet been defined. Angiotensin II (ATII, 1 mg/kg/day for 7 days) increased Ly6C(high) and CD11b(+)/iNOS(high) leukocytes and up-regulated levels of eNOS glutathionylation in aortas of C57BL/6 mice. Vascular iNOS-dependent NO formation was increased, whereas eNOS-dependent NO formation was decreased in aortas of ATII-infused mice as assessed by electron paramagnetic resonance (EPR) spectroscopy. Diphtheria toxin-mediated ablation of lysozyme M-positive (LysM(+)) monocytes in ATII infused LysM(iDTR) transgenic mice prevented eNOS glutathionylation and eNOS derived N(omega)-nitro-L-arginine methyl ester-sensitive superoxide formation in the endothelial layer. ATII increased vascular guanosine triphosphate cyclohydrolase I expression and biopterin synthesis in parallel, which was reduced in monocyte-depleted LysM(iDTR) mice. Vascular tetrahydrobiopterin was increased by ATII infusion but was even higher in monocyte-depleted ATII-infused mice, which was paralleled by a strong up-regulation of dihydrofolate reductase expression. EPR spectroscopy revealed that both vascular iNOS- and eNOS-dependent NO formation were normalized in ATII-infused mice following monocyte depletion. Additionally, deletion as well as pharmacologic inhibition of iNOS prevented ATII induced endothelial dysfunction. In summary, ATII induces an inflammatory cell dependent increase of iNOS, guanosine triphosphate cyclohydrolase I, tetrahydrobiopterin, NO formation, and nitro-oxidative stress as well as eNOS uncoupling in the vessel wall, which can be prevented by ablation of LysM(+) monocytes. PMID- 25143379 TI - Dissection of structural and functional requirements that underlie the interaction of ERdj3 protein with substrates in the endoplasmic reticulum. AB - ERdj3, a mammalian endoplasmic reticulum (ER) Hsp40/DnaJ family member, binds unfolded proteins, transfers them to BiP, and concomitantly stimulates BiP ATPase activity. However, the requirements for ERdj3 binding to and release from substrates in cells are not well understood. We found that ERdj3 homodimers that cannot stimulate the ATPase activity of BiP (QPD mutants) bound to unfolded ER proteins under steady state conditions in much greater amounts than wild-type ERdj3. This was due to reduced release from these substrates as opposed to enhanced binding, although in both cases dimerization was strictly required for substrate binding. Conversely, heterodimers consisting of one wild-type and one mutant ERdj3 subunit bound substrates at levels comparable with wild-type ERdj3 homodimers, demonstrating that release requires only one protomer to be functional in stimulating BiP ATPase activity. Co-expressing wild-type ERdj3 and a QPD mutant, which each exclusively formed homodimers, revealed that the release rate of wild-type ERdj3 varied according to the relative half-lives of substrates, suggesting that ERdj3 release is an important step in degradation of unfolded client proteins in the ER. Furthermore, pulse-chase experiments revealed that the binding of QPD mutant homodimers remained constant as opposed to increasing, suggesting that ERdj3 does not normally undergo reiterative binding cycles with substrates. PMID- 25143380 TI - A reciprocal shift in transient receptor potential channel 1 (TRPC1) and stromal interaction molecule 2 (STIM2) contributes to Ca2+ remodeling and cancer hallmarks in colorectal carcinoma cells. AB - We have investigated the molecular basis of intracellular Ca(2+) handling in human colon carcinoma cells (HT29) versus normal human mucosa cells (NCM460) and its contribution to cancer features. We found that Ca(2+) stores in colon carcinoma cells are partially depleted relative to normal cells. However, resting Ca(2+) levels, agonist-induced Ca(2+) increases, store-operated Ca(2+) entry (SOCE), and store-operated currents (ISOC) are largely enhanced in tumor cells. Enhanced SOCE and depleted Ca(2+) stores correlate with increased cell proliferation, invasion, and survival characteristic of tumor cells. Normal mucosa cells displayed small, inward Ca(2+) release-activated Ca(2+) currents (ICRAC) mediated by ORAI1. In contrast, colon carcinoma cells showed mixed currents composed of enhanced ICRAC plus a nonselective ISOC mediated by TRPC1. Tumor cells display increased expression of TRPC1, ORAI1, ORAI2, ORAI3, and STIM1. In contrast, STIM2 protein was nearly depleted in tumor cells. Silencing data suggest that enhanced ORAI1 and TRPC1 contribute to enhanced SOCE and differential store-operated currents in tumor cells, whereas ORAI2 and -3 are seemingly less important. In addition, STIM2 knockdown decreases SOCE and Ca(2+) store content in normal cells while promoting apoptosis resistance. These data suggest that loss of STIM2 may underlie Ca(2+) store depletion and apoptosis resistance in tumor cells. We conclude that a reciprocal shift in TRPC1 and STIM2 contributes to Ca(2+) remodeling and tumor features in colon cancer. PMID- 25143381 TI - Biochemical and biophysical investigation of the brain-derived neurotrophic factor mimetic 7,8-dihydroxyflavone in the binding and activation of the TrkB receptor. AB - 7,8-dihydroxyflavone (7,8-DHF), a newly identified small molecular TrkB receptor agonist, rapidly activates TrkB in both primary neurons and the rodent brain and mimics the physiological functions of the cognate ligand BDNF. Accumulating evidence supports that 7,8-DHF exerts neurotrophic effects in a TrkB-dependent manner. Nonetheless, the differences between 7,8-DHF and BDNF in activating TrkB remain incompletely understood. Here we show that 7,8-DHF and BDNF exhibit different TrkB activation kinetics in which TrkB maturation may be implicated. Employing two independent biophysical approaches, we confirm that 7,8-DHF interacts robustly with the TrkB extracellular domain, with a Kd of ~10 nm. Although BDNF transiently activates TrkB, leading to receptor internalization and ubiquitination/degradation, in contrast, 7,8-DHF-triggered TrkB phosphorylation lasts for hours, and the internalized receptors are not degraded. Notably, primary neuronal maturation may be required for 7,8-DHF but not for BDNF to elicit the full spectrum of TrkB signaling cascades. Hence, 7,8-DHF interacts robustly with the TrkB receptor, and its agonistic effect may be mediated by neuronal development and maturation. PMID- 25143382 TI - Structural insights into amyloid oligomers of the Parkinson disease-related protein alpha-synuclein. AB - The presence of intraneuronal deposits mainly formed by amyloid fibrils of the presynaptic protein alpha-synuclein (AS) is a hallmark of Parkinson disease. Currently, neurotoxicity is attributed to prefibrillar oligomeric species rather than the insoluble aggregates, although their mechanisms of toxicity remain elusive. Structural details of the supramolecular organization of AS oligomers are critically needed to decipher the structure-toxicity relationship underlying their pathogenicity. In this study, we employed site-specific fluorescence to get a deeper insight into the internal architecture of AS oligomeric intermediates. We demonstrate that AS oligomers are ordered assemblies possessing a well defined pattern of intermolecular contacts. Some of these contacts involve regions that form the beta-sheet core in the fibrillar state, although their spatial arrangement may differ in the two aggregated forms. However, even though the two termini are excluded from the fibrillar core, they are engaged in a number of intermolecular interactions within the oligomer. Therefore, substantial structural remodeling of early oligomeric interactions is essential for fibril growth. The intermolecular contacts identified in AS oligomers can serve as targets for the rational design of anti-amyloid compounds directed at preventing oligomeric interactions/reorganizations. PMID- 25143384 TI - The aromatic and charge pairs of the thin extracellular gate of the gamma aminobutyric acid transporter GAT-1 are differently impacted by mutation. AB - GAT-1 is a sodium- and chloride-coupled GABA transporter and a member of the neurotransmitter:sodium:symporters, which are crucial for synaptic transmission. The structure of bacterial homologue LeuT shows a thin extracellular gate consisting of a charge and an aromatic pair. Here we addressed the question of whether mutation of the aromatic and charge pair residues of GAT-1 has similar consequences. In contrast to charge pair mutants, significant radioactive GABA transport was retained by mutants of the aromatic pair residue Phe-294. Moreover, the magnitude of maximal transport currents induced by GABA by these mutants was comparable with those by wild type GAT-1. However, the apparent affinity of the nonconserved mutants for GABA was reduced up to 20-fold relative to wild type. The voltage dependence of the sodium-dependent transient currents of the Phe-294 mutants was similar to that of the wild type. On the other hand, the conserved charge pair mutant D451E exhibited a right-shifted voltage dependence, indicating an increased apparent affinity for sodium. In further contrast to D451E, whereas the extracellular aqueous accessibility of an endogenous cysteine residue to a membrane-impermeant sulfhydryl reagent was increased relative to wild type, this was not the case for the aromatic pair mutants. Our data indicate that, in contrast to the charge pair, the aromatic pair is not essential for gating. Instead they are compatible with the idea that they serve to diminish dissociation of the substrate from the binding pocket. PMID- 25143383 TI - Gene targeting study reveals unexpected expression of brain-expressed X-linked 2 in endocrine and tissue stem/progenitor cells in mice. AB - Identification of genes specifically expressed in stem/progenitor cells is an important issue in developmental and stem cell biology. Genome-wide gene expression analyses in liver cells performed in this study have revealed a strong expression of X-linked genes that include members of the brain-expressed X-linked (Bex) gene family in stem/progenitor cells. Bex family genes are expressed abundantly in the neural cells and have been suggested to play important roles in the development of nervous tissues. However, the physiological role of its individual members and the precise expression pattern outside the nervous system remain largely unknown. Here, we focused on Bex2 and examined its role and expression pattern by generating knock-in mice; the enhanced green fluorescence protein (EGFP) was inserted into the Bex2 locus. Bex2-deficient mice were viable and fertile under laboratory growth conditions showing no obvious phenotypic abnormalities. Through an immunohistochemical analysis and flow cytometry-based approach, we observed unique EGFP reporter expression patterns in endocrine and stem/progenitor cells of the liver, pyloric stomach, and hematopoietic system. Although Bex2 seems to play redundant roles in vivo, these results suggest the significance and potential applications of Bex2 in studies of endocrine and stem/progenitor cells. PMID- 25143385 TI - Metal bridges illuminate transmembrane domain movements during gating of the cystic fibrosis transmembrane conductance regulator chloride channel. AB - Opening and closing of the cystic fibrosis transmembrane conductance regulator are controlled by ATP binding and hydrolysis by the cytoplasmic nucleotide binding domains. Different conformational changes in the channel pore have been described during channel opening and closing; however, the relative importance of these changes to the process of gating the pore is not known. We have used patch clamp recording to identify high affinity Cd(2+) bridges formed between pairs of pore-lining cysteine residues introduced into different transmembrane alpha helices (TMs). Seven Cd(2+) bridges were identified forming between cysteines in TMs 6 and 12. Interestingly, each of these Cd(2+) bridges apparently formed only in closed channels, and their formation stabilized the closed state. In contrast, a single Cd(2+) bridge identified between cysteines in TMs 1 and 12 stabilized the channel open state. Analysis of the pattern of Cd(2+) bridge formation in different channel states suggests that lateral separation and convergence of different TMs, rather than relative rotation or translation of different TMs, is the key conformational change that causes the channel pore to open and close. PMID- 25143386 TI - Stress-dependent proteolytic processing of the actin assembly protein Lsb1 modulates a yeast prion. AB - Yeast prions are self-propagating amyloid-like aggregates of Q/N-rich protein that confer heritable traits and provide a model of mammalian amyloidoses. [PSI(+)] is a prion isoform of the translation termination factor Sup35. Propagation of [PSI(+)] during cell division under normal conditions and during the recovery from damaging environmental stress depends on cellular chaperones and is influenced by ubiquitin proteolysis and the actin cytoskeleton. The paralogous yeast proteins Lsb1 and Lsb2 bind the actin assembly protein Las17 (a yeast homolog of human Wiskott-Aldrich syndrome protein) and participate in the endocytic pathway. Lsb2 was shown to modulate maintenance of [PSI(+)] during and after heat shock. Here, we demonstrate that Lsb1 also regulates maintenance of the Sup35 prion during and after heat shock. These data point to the involvement of Lsb proteins in the partitioning of protein aggregates in stressed cells. Lsb1 abundance and cycling between actin patches, endoplasmic reticulum, and cytosol is regulated by the Guided Entry of Tail-anchored proteins pathway and Rsp5 dependent ubiquitination. Heat shock-induced proteolytic processing of Lsb1 is crucial for prion maintenance during stress. Our findings identify Lsb1 as another component of a tightly regulated pathway controlling protein aggregation in changing environments. PMID- 25143387 TI - Fbxo45 inhibits calcium-sensitive proteolysis of N-cadherin and promotes neuronal differentiation. AB - Fbxo45 is an atypical E3 ubiquitin ligase, which specifically targets proteins for ubiquitin-mediated degradation. Fbxo45 ablation results in defective neuronal differentiation and abnormal formation of neural connections; however, the mechanisms underlying these defects are poorly understood. Using an unbiased mass spectrometry-based proteomic screen, we show here that N-cadherin is a novel interactor of Fbxo45. N-cadherin specifically interacts with Fbxo45 through two consensus motifs overlapping the site of calcium-binding and dimerization of the cadherin molecule. N-cadherin interaction with Fbxo45 is significantly abrogated by calcium treatment. Surprisingly, Fbxo45 depletion by RNAi-mediated silencing results in enhanced proteolysis of N-cadherin. Conversely, ectopic expression of Fbxo45 results in decreased proteolysis of N-cadherin. Fbxo45 depletion results in dramatic reduction in N-cadherin expression, impaired neuronal differentiation, and diminished formation of neuronal processes. Our studies reveal an unanticipated role for an F-box protein that inhibits proteolysis in the regulation of a critical biological process. PMID- 25143388 TI - Single expressed glycine receptor domains reconstitute functional ion channels without subunit-specific desensitization behavior. AB - Cys loop receptors are pentameric arrangements of independent subunits that assemble into functional ion channels. Each subunit shows a domain architecture. Functional ion channels can be reconstituted even from independent, nonfunctional subunit domains, as shown previously for GlyRalpha1 receptors. Here, we demonstrate that this reconstitution is not restricted to alpha1 but can be transferred to other members of the Cys loop receptor family. A nonfunctional GlyR subunit, truncated at the intracellular TM3-4 loop by a premature stop codon, can be complemented by co-expression of the missing tail portion of the receptor. Compared with alpha1 subunits, rescue by domain complementation was less efficient when GlyRalpha3 or the GABAA/C subunit rho1 was used. If truncation disrupted an alternative splicing cassette within the intracellular TM3-4 loop of alpha3 subunits, which also regulates receptor desensitization, functional rescue was not possible. When alpha3 receptors were restored by complementation using domains with and without the spliced insert, no difference in desensitization was found. In contrast, desensitization properties could even be transferred between alpha1/alpha3 receptor chimeras harboring or lacking the alpha3 splice cassette proving that functional rescue depends on the integrity of the alternative splicing cassette in alpha3. Thus, an intact alpha3 splicing cassette in the TM3-4 loop environment is indispensable for functional rescue, and the quality of receptor restoration can be assessed from desensitization properties. PMID- 25143389 TI - Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors. AB - The antidiabetic drug metformin exhibits both chemopreventive and chemotherapeutic activity for multiple cancers including pancreatic cancer; however, the underlying mechanism of action of metformin is unclear. A recent study showed that metformin down-regulated specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells and tumors, and this was accompanied by down-regulation of several pro-oncogenic Sp-regulated genes. Treatment with metformin or down-regulation of Sp TFs by RNAi also inhibits two major pro-oncogenic pathways in pancreatic cancer cells, namely mammalian target of rapamycin (mTOR) signaling and epidermal growth factor (EGFR)-dependent activation of Ras. Metformin and Sp knockdown by RNAi decreased expression of the insulin-like growth factor-1 receptor (IGF-1R), resulting in inhibition of mTOR signaling. Ras activity was also decreased by metformin and Sp knockdown of EGFR, another Sp-regulated gene. Thus, the antineoplastic activities of metformin in pancreatic cancer are due, in part, to down-regulation of Sp TFs and Sp-regulated IGF-1R and EGFR, which in turn results in inhibition of mTOR and Ras signaling, respectively. PMID- 25143390 TI - Epithelial splicing regulatory proteins 1 (ESRP1) and 2 (ESRP2) suppress cancer cell motility via different mechanisms. AB - ESRP1 (epithelial splicing regulatory protein 1) and ESRP2 regulate alternative splicing events associated with epithelial phenotypes of cells, and both are down regulated during the epithelial-mesenchymal transition. However, little is known about their expression and functions during carcinogenesis. In this study, we found that expression of both ESRP1 and ESRP2 is plastic: during oral squamous cell carcinogenesis, these proteins are up-regulated relative to their levels in normal epithelium but down-regulated in invasive fronts. Importantly, ESRP1 and ESRP2 are re-expressed in the lymph nodes, where carcinoma cells metastasize and colonize. In head and neck carcinoma cell lines, ESRP1 and ESRP2 suppress cancer cell motility through distinct mechanisms: knockdown of ESRP1 affects the dynamics of the actin cytoskeleton through induction of Rac1b, whereas knockdown of ESRP2 attenuates cell-cell adhesion through increased expression of epithelial mesenchymal transition-associated transcription factors. Down-regulation of ESRP1 and ESRP2 is thus closely associated with a motile phenotype of cancer cells. PMID- 25143391 TI - Trends in bacterial and fungal keratitis in South India, 2002-2012. AB - OBJECTIVE: To assess the trends in microbiological organisms identified from corneal scrapings from patients with infectious keratitis at a tertiary care medical centre in South India. METHODS: We reviewed the records of the microbiology laboratory at Aravind Eye Hospital in Madurai, India, from 2002 until 2012. We identified the microbiological causes of all corneal ulcers from the culture and smear results, and assessed for trends in bacterial and fungal keratitis over time. RESULTS: Of 23 897 corneal patients with ulcer with a corneal smear from 2002 to 2012 a fungal organism was identified in 34.3%, a bacterial organism in 24.7% and no organism in 38.3%. During this period, the annual number of keratitis cases due to bacteria decreased from 677 to 412, and the annual number due to fungus increased from 609 to 863. In analyses accounting for the total number of outpatients seen each year, the decline in number of smears positive for bacteria was statistically significant (p<0.001) but the increase in the number positive for fungus was not (p=0.73). The relative frequency of individual bacterial or fungal organisms remained relatively stable over this time. CONCLUSIONS: At a tertiary eye care centre in South India, there has been a reduction in the numbers of smear-positive bacterial keratitis over the past 11 years. This decline likely reflects economic development in India and increased access to antibiotics. PMID- 25143393 TI - Susceptibility allele-specific loss of miR-1324-mediated silencing of the INO80B chromatin-assembly complex gene in pre-eclampsia. AB - In humans, the elucidation of the genetics underlying multifactorial diseases such as pre-eclampsia remains complex. Given the current day availability of genome-wide linkage- and expression data pools, we applied pathway-guided genome wide meta-analysis guided by the premise that the functional network underlying these multifactorial syndromes is under selective genetic pressure. This approach drastically reduced the genomic region of interest, i.e. 2p13 linked with pre eclampsia in Icelandic families, from 8 679 641 bp (region with linkage) to 45 264 bp (coding exons of prioritized genes) (0.83%). Mutation screening of the candidate genes (n = 13) rapidly reduced the minimal critical region and showed the INO80B gene, encoding a novel winged helix domain (pfam14465) and part of the chromatin-remodeling complex, to be linked to pre-eclampsia. The functional defect in placental cells involved a susceptibility allele-dependent loss-of-gene silencing due to increased INO80B RNA stability as a consequence of differential binding of miR-1324 to the susceptibility allele of rs34174194. This risk allele is located at position 1 in an absolutely conserved 7-mer (UUGUCUG) in the 3-UTR of INO80B immediately downstream of a variant Pumillio Recognition Element (UGUANAAG). These data support that pre-eclampsia genes affect a conserved fundamental mechanism that evolved as a consequence of hemochorial placentation. Functionally, this involves founder-dependent, placentally expressed paralogous genes that regulate an essential trophoblast differentiation pathway but act at different entry points. PMID- 25143392 TI - Dominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells. AB - The physiological function of Ataxin-3 (ATXN3), a deubiquitylase (DUB) involved in Machado-Joseph Disease (MJD), remains elusive. In this study, we demonstrate that ATXN3 is required for neuronal differentiation and for normal cell morphology, cytoskeletal organization, proliferation and survival of SH-SY5Y and PC12 cells. This cellular phenotype is associated with increased proteasomal degradation of alpha5 integrin subunit (ITGA5) and reduced activation of integrin signalling and is rescued by ITGA5 overexpression. Interestingly, silencing of ATXN3, overexpression of mutant versions of ATXN3 lacking catalytic activity or bearing an expanded polyglutamine (polyQ) tract led to partially overlapping phenotypes. In vivo analysis showed that both Atxn3 knockout and MJD transgenic mice had decreased levels of ITGA5 in the brain. Furthermore, abnormal morphology and reduced branching were observed both in cultured neurons expressing shRNA for ATXN3 and in those obtained from MJD mice. Our results show that ATXN3 rescues ITGA5 from proteasomal degradation in neurons and that polyQ expansion causes a partial loss of this cellular function, resulting in reduced integrin signalling and neuronal cytoskeleton modifications, which may be contributing to neurodegeneration. PMID- 25143394 TI - Mutant huntingtin alters Tau phosphorylation and subcellular distribution. AB - Tau abnormalities play a central role in several neurodegenerative diseases, collectively known as tauopathies. In the present study, we examined whether mutant huntingtin (mHtt), which causes Huntington's disease (HD), modifies Tau phosphorylation and subcellular localization using cell and mouse HD models. Initially, we used novel bimolecular fluorescence complementation assays in live cells to evaluate Tau interactions with either wild type (25QHtt) or mutant huntingtin (103QHtt). While 25QHtt and Tau interacted at the level of the microtubule network, 103QHtt and Tau interacted and formed 'ring-like' inclusions localized in the vicinity of the microtubular organizing center (MTOC). Fluorescence recovery after photobleaching experiments also indicated that, whereas homomeric 103QHtt/103QHtt pairs rapidly re-entered into inclusions, heteromeric 103QHtt/Tau pairs remained excluded from the 'ring-like' inclusions. Interestingly, in vitro Tau relocalization was associated to Tau hyperphosphorylation. Consistent with this observation, we found strong Tau hyperphosphorylation in brain samples from two different mouse models of HD, R6/2 and 140CAG knock-in. This was associated with a significant reduction in the levels of Tau phosphatases (PP1, PP2A and PP2B), with no apparent involvement of major Tau kinases. Thus, the present study strongly suggests that expression of mHtt leads to Tau hyperphosphorylation, relocalization and sequestration through direct protein-protein interactions in inclusion-like compartments in the vicinity of the MTOC. Likewise, our data also suggest that Tau alterations may also contribute to HD pathogenesis. PMID- 25143395 TI - Local and global analysis of endocytic patch dynamics in fission yeast using a new "temporal superresolution" realignment method. AB - Quantitative microscopy is a valuable tool for inferring molecular mechanisms of cellular processes such as clathrin-mediated endocytosis, but, for quantitative microscopy to reach its potential, both data collection and analysis needed improvement. We introduce new tools to track and count endocytic patches in fission yeast to increase the quality of the data extracted from quantitative microscopy movies. We present a universal method to achieve "temporal superresolution" by aligning temporal data sets with higher temporal resolution than the measurement intervals. These methods allowed us to extract new information about endocytic actin patches in wild-type cells from measurements of the fluorescence of fimbrin-mEGFP. We show that the time course of actin assembly and disassembly varies <600 ms between patches. Actin polymerizes during vesicle formation, but we show that polymerization does not participate in vesicle movement other than to limit the complex diffusive motions of newly formed endocytic vesicles, which move faster as the surrounding actin meshwork decreases in size over time. Our methods also show that the number of patches in fission yeast is proportional to cell length and that the variability in the repartition of patches between the tips of interphase cells has been underestimated. PMID- 25143396 TI - Calpain cleavage within dysferlin exon 40a releases a synaptotagmin-like module for membrane repair. AB - Dysferlin and calpain are important mediators of the emergency response to repair plasma membrane injury. Our previous research revealed that membrane injury induces cleavage of dysferlin to release a synaptotagmin-like C-terminal module we termed mini-dysferlinC72. Here we show that injury-activated cleavage of dysferlin is mediated by the ubiquitous calpains via a cleavage motif encoded by alternately spliced exon 40a. An exon 40a-specific antibody recognizing cleaved mini-dysferlinC72 intensely labels the circumference of injury sites, supporting a key role for dysferlinExon40a isoforms in membrane repair and consistent with our evidence suggesting that the calpain-cleaved C-terminal module is the form specifically recruited to injury sites. Calpain cleavage of dysferlin is a ubiquitous response to membrane injury in multiple cell lineages and occurs independently of the membrane repair protein MG53. Our study links calpain and dysferlin in the calcium-activated vesicle fusion of membrane repair, placing calpains as upstream mediators of a membrane repair cascade that elicits cleaved dysferlin as an effector. Of importance, we reveal that myoferlin and otoferlin are also cleaved enzymatically to release similar C-terminal modules, bearing two C2 domains and a transmembrane domain. Evolutionary preservation of this feature highlights its functional importance and suggests that this highly conserved C terminal region of ferlins represents a functionally specialized vesicle fusion module. PMID- 25143397 TI - Quantitative analysis and modeling of katanin function in flagellar length control. AB - Flagellar length control in Chlamydomonas reinhardtii provides a simple model system in which to investigate the general question of how cells regulate organelle size. Previous work demonstrated that Chlamydomonas cytoplasm contains a pool of flagellar precursor proteins sufficient to assemble a half-length flagellum and that assembly of full-length flagella requires synthesis of additional precursors to augment the preexisting pool. The regulatory systems that control the synthesis and regeneration of this pool are not known, although transcriptional regulation clearly plays a role. We used quantitative analysis of length distributions to identify candidate genes controlling pool regeneration and found that a mutation in the p80 regulatory subunit of katanin, encoded by the PF15 gene in Chlamydomonas, alters flagellar length by changing the kinetics of precursor pool utilization. This finding suggests a model in which flagella compete with cytoplasmic microtubules for a fixed pool of tubulin, with katanin mediated severing allowing easier access to this pool during flagellar assembly. We tested this model using a stochastic simulation that confirms that cytoplasmic microtubules can compete with flagella for a limited tubulin pool, showing that alteration of cytoplasmic microtubule severing could be sufficient to explain the effect of the pf15 mutations on flagellar length. PMID- 25143398 TI - TGF-beta regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion. AB - Recent studies implicate a role for cell mechanics in cancer progression. The epithelial-to-mesenchymal transition (EMT) regulates the detachment of cancer cells from the epithelium and facilitates their invasion into stromal tissue. Although classic EMT hallmarks include loss of cell-cell adhesions, morphology changes, and increased invasion capacity, little is known about the associated mechanical changes. Previously, force application on integrins has been shown to initiate cytoskeletal rearrangements that result in increased cell stiffness and a stiffening response. Here we demonstrate that transforming growth factor beta (TGF-beta)-induced EMT results in decreased stiffness and loss of the normal stiffening response to force applied on integrins. We find that suppression of the RhoA guanine nucleotide exchange factors (GEFs) LARG and GEF-H1 through TGF beta/ALK5-enhanced proteasomal degradation mediates these changes in cell mechanics and affects EMT-associated invasion. Taken together, our results reveal a functional connection between attenuated stiffness and stiffening response and the increased invasion capacity acquired after TGF-beta-induced EMT. PMID- 25143399 TI - Loss of gamma-cytoplasmic actin triggers myofibroblast transition of human epithelial cells. AB - Transdifferentiation of epithelial cells into mesenchymal cells and myofibroblasts plays an important role in tumor progression and tissue fibrosis. Such epithelial plasticity is accompanied by dramatic reorganizations of the actin cytoskeleton, although mechanisms underlying cytoskeletal effects on epithelial transdifferentiation remain poorly understood. In the present study, we observed that selective siRNA-mediated knockdown of gamma-cytoplasmic actin (gamma-CYA), but not beta-cytoplasmic actin, induced epithelial-to-myofibroblast transition (EMyT) of different epithelial cells. The EMyT manifested by increased expression of alpha-smooth muscle actin and other contractile proteins, along with inhibition of genes responsible for cell proliferation. Induction of EMyT in gamma-CYA-depleted cells depended on activation of serum response factor and its cofactors, myocardial-related transcriptional factors A and B. Loss of gamma-CYA stimulated formin-mediated actin polymerization and activation of Rho GTPase, which appear to be essential for EMyT induction. Our findings demonstrate a previously unanticipated, unique role of gamma-CYA in regulating epithelial phenotype and suppression of EMyT that may be essential for cell differentiation and tissue fibrosis. PMID- 25143400 TI - The actin regulators Enabled and Diaphanous direct distinct protrusive behaviors in different tissues during Drosophila development. AB - Actin-based protrusions are important for signaling and migration during development and homeostasis. Defining how different tissues in vivo craft diverse protrusive behaviors using the same genomic toolkit of actin regulators is a current challenge. The actin elongation factors Diaphanous and Enabled both promote barbed-end actin polymerization and can stimulate filopodia in cultured cells. However, redundancy in mammals and Diaphanous' role in cytokinesis limited analysis of whether and how they regulate protrusions during development. We used two tissues driving Drosophila dorsal closure--migratory leading-edge (LE) and nonmigratory amnioserosal (AS) cells--as models to define how cells shape distinct protrusions during morphogenesis. We found that nonmigratory AS cells produce filopodia that are morphologically and dynamically distinct from those of LE cells. We hypothesized that differing Enabled and/or Diaphanous activity drives these differences. Combining gain- and loss-of-function with quantitative approaches revealed that Diaphanous and Enabled each regulate filopodial behavior in vivo and defined a quantitative "fingerprint"--the protrusive profile--which our data suggest is characteristic of each actin regulator. Our data suggest that LE protrusiveness is primarily Enabled driven, whereas Diaphanous plays the primary role in the AS, and reveal each has roles in dorsal closure, but its robustness ensures timely completion in their absence. PMID- 25143401 TI - A Vps21 endocytic module regulates autophagy. AB - In autophagy, the double-membrane autophagosome delivers cellular components for their degradation in the lysosome. The conserved Ypt/Rab GTPases regulate all cellular trafficking pathways, including autophagy. These GTPases function in modules that include guanine-nucleotide exchange factor (GEF) activators and downstream effectors. Rab7 and its yeast homologue, Ypt7, in the context of such a module, regulate the fusion of both late endosomes and autophagosomes with the lysosome. In yeast, the Rab5-related Vps21 is known for its role in early- to late-endosome transport. Here we show an additional role for Vps21 in autophagy. First, vps21? mutant cells are defective in selective and nonselective autophagy. Second, fluorescence and electron microscopy analyses show that vps21? mutant cells accumulate clusters of autophagosomal structures outside the vacuole. Third, cells with mutations in other members of the endocytic Vps21 module, including the GEF Vps9 and factors that function downstream of Vps21, Vac1, CORVET, Pep12, and Vps45, are also defective in autophagy and accumulate clusters of autophagosomes. Finally, Vps21 localizes to PAS. We propose that the endocytic Vps21 module also regulates autophagy. These findings support the idea that the two pathways leading to the lysosome--endocytosis and autophagy--converge through the Vps21 and Ypt7 GTPase modules. PMID- 25143402 TI - Regulation of microtubule-based transport by MAP4. AB - Microtubule (MT)-based transport of organelles driven by the opposing MT motors kinesins and dynein is tightly regulated in cells, but the underlying molecular mechanisms remain largely unknown. Here we tested the regulation of MT transport by the ubiquitous protein MAP4 using Xenopus melanophores as an experimental system. In these cells, pigment granules (melanosomes) move along MTs to the cell center (aggregation) or to the periphery (dispersion) by means of cytoplasmic dynein and kinesin-2, respectively. We found that aggregation signals induced phosphorylation of threonine residues in the MT-binding domain of the Xenopus MAP4 (XMAP4), thus decreasing binding of this protein to MTs. Overexpression of XMAP4 inhibited pigment aggregation by shortening dynein-dependent MT runs of melanosomes, whereas removal of XMAP4 from MTs reduced the length of kinesin-2 dependent runs and suppressed pigment dispersion. We hypothesize that binding of XMAP4 to MTs negatively regulates dynein-dependent movement of melanosomes and positively regulates kinesin-2-based movement. Phosphorylation during pigment aggregation reduces binding of XMAP4 to MTs, thus increasing dynein-dependent and decreasing kinesin-2-dependent motility of melanosomes, which stimulates their accumulation in the cell center, whereas dephosphorylation of XMAP4 during dispersion has an opposite effect. PMID- 25143403 TI - Failure of cell cleavage induces senescence in tetraploid primary cells. AB - Tetraploidy can arise from various mitotic or cleavage defects in mammalian cells, and inheritance of multiple centrosomes induces aneuploidy when tetraploid cells continue to cycle. Arrest of the tetraploid cell cycle is therefore potentially a critical cellular control. We report here that primary rat embryo fibroblasts (REF52) and human foreskin fibroblasts become senescent in tetraploid G1 after drug- or small interfering RNA (siRNA)-induced failure of cell cleavage. In contrast, T-antigen-transformed REF52 and p53+/+ HCT116 tumor cells rapidly become aneuploid by continuing to cycle after cleavage failure. Tetraploid primary cells quickly become quiescent, as determined by loss of the Ki-67 proliferation marker and of the fluorescent ubiquitination-based cell cycle indicator/late cell cycle marker geminin. Arrest is not due to DNA damage, as the gamma-H2AX DNA damage marker remains at control levels after tetraploidy induction. Arrested tetraploid cells finally become senescent, as determined by SA-beta-galactosidase activity. Tetraploid arrest is dependent on p16INK4a expression, as siRNA suppression of p16INK4a bypasses tetraploid arrest, permitting primary cells to become aneuploid. We conclude that tetraploid primary cells can become senescent without DNA damage and that induction of senescence is critical to tetraploidy arrest. PMID- 25143404 TI - Cdc42 controls the dilation of the exocytotic fusion pore by regulating membrane tension. AB - Membrane fusion underlies multiple processes, including exocytosis of hormones and neurotransmitters. Membrane fusion starts with the formation of a narrow fusion pore. Radial expansion of this pore completes the process and allows fast release of secretory compounds, but this step remains poorly understood. Here we show that inhibiting the expression of the small GTPase Cdc42 or preventing its activation with a dominant negative Cdc42 construct in human neuroendocrine cells impaired the release process by compromising fusion pore enlargement. Consequently the mode of vesicle exocytosis was shifted from full-collapse fusion to kiss-and-run. Remarkably, Cdc42-knockdown cells showed reduced membrane tension, and the artificial increase of membrane tension restored fusion pore enlargement. Moreover, inhibiting the motor protein myosin II by blebbistatin decreased membrane tension, as well as fusion pore dilation. We conclude that membrane tension is the driving force for fusion pore dilation and that Cdc42 is a key regulator of this force. PMID- 25143405 TI - Arrestins function in cAR1 GPCR-mediated signaling and cAR1 internalization in the development of Dictyostelium discoideum. AB - Oscillation of chemical signals is a common biological phenomenon, but its regulation is poorly understood. At the aggregation stage of Dictyostelium discoideum development, the chemoattractant cAMP is synthesized and released at 6 min intervals, directing cell migration. Although the G protein-coupled cAMP receptor cAR1 and ERK2 are both implicated in regulating the oscillation, the signaling circuit remains unknown. Here we report that D. discoideum arrestins regulate the frequency of cAMP oscillation and may link cAR1 signaling to oscillatory ERK2 activity. Cells lacking arrestins (adcB(-)C(-)) display cAMP oscillations during the aggregation stage that are twice as frequent as for wild- type cells. The adcB(-)C(-) cells also have a shorter period of transient ERK2 activity and precociously reactivate ERK2 in response to cAMP stimulation. We show that arrestin domain-containing protein C (AdcC) associates with ERK2 and that activation of cAR1 promotes the transient membrane recruitment of AdcC and interaction with cAR1, indicating that arrestins function in cAR1-controlled periodic ERK2 activation and oscillatory cAMP signaling in the aggregation stage of D. discoideum development. In addition, ligand-induced cAR1 internalization is compromised in adcB(-)C(-) cells, suggesting that arrestins are involved in elimination of high-affinity cAR1 receptors from cell surface after the aggregation stage of multicellular development. PMID- 25143406 TI - Two Dictyostelium tyrosine kinase-like kinases function in parallel, stress induced STAT activation pathways. AB - When Dictyostelium cells are hyperosmotically stressed, STATc is activated by tyrosine phosphorylation. Unusually, activation is regulated by serine phosphorylation and consequent inhibition of a tyrosine phosphatase: PTP3. The identity of the cognate tyrosine kinase is unknown, and we show that two tyrosine kinase-like (TKL) enzymes, Pyk2 and Pyk3, share this function; thus, for stress induced STATc activation, single null mutants are only marginally impaired, but the double mutant is nonactivatable. When cells are stressed, Pyk2 and Pyk3 undergo increased autocatalytic tyrosine phosphorylation. The site(s) that are generated bind the SH2 domain of STATc, and then STATc becomes the target of further kinase action. The signaling pathways that activate Pyk2 and Pyk3 are only partially overlapping, and there may be a structural basis for this difference because Pyk3 contains both a TKL domain and a pseudokinase domain. The latter functions, like the JH2 domain of metazoan JAKs, as a negative regulator of the kinase domain. The fact that two differently regulated kinases catalyze the same phosphorylation event may facilitate specific targeting because under stress, Pyk3 and Pyk2 accumulate in different parts of the cell; Pyk3 moves from the cytosol to the cortex, whereas Pyk2 accumulates in cytosolic granules that colocalize with PTP3. PMID- 25143407 TI - Synergies between Aip1p and capping protein subunits (Acp1p and Acp2p) in clathrin-mediated endocytosis and cell polarization in fission yeast. AB - Aip1p cooperates with actin-depolymerizing factor (ADF)/cofilin to disassemble actin filaments in vitro and in vivo, and is proposed to cap actin filament barbed ends. We address the synergies between Aip1p and the capping protein heterodimer Acp1p/Acp2p during clathrin-mediated endocytosis in fission yeast. Using quantitative microscopy and new methods we have developed for data alignment and analysis, we show that heterodimeric capping protein can replace Aip1p, but Aip1p cannot replace capping protein in endocytic patches. Our quantitative analysis reveals that the actin meshwork is organized radially and is compacted by the cross-linker fimbrin before the endocytic vesicle is released from the plasma membrane. Capping protein and Aip1p help maintain the high density of actin filaments in meshwork by keeping actin filaments close enough for cross-linking. Our experiments also reveal new cellular functions for Acp1p and Acp2p independent of their capping activity. We identified two independent pathways that control polarization of endocytic sites, one depending on acp2(+) and aip1(+) during interphase and the other independent of acp1(+), acp2(+), and aip1(+) during mitosis. PMID- 25143410 TI - Improved Knowledge, Attitudes, and Behaviors After Implementation of TeamSTEPPS Training in an Academic Emergency Department: A Pilot Report. AB - TeamSTEPPS is a validated, formal patient safety curriculum created by the Agency for Healthcare Research and Quality (AHRQ) for the development of high functioning multidisciplinary teams. TeamSTEPPS was implemented in an academic emergency department (ED), including all ED hospital staff as well as physicians and residents. It was hypothesized that extensive interprofessional education combined with implementation of specific tools would increase knowledge of TeamSTEPPS principles, attitudes, and behaviors. The TeamSTEPPS knowledge test and the AHRQ Hospital Survey attitude test were administered at 0, 45, and 90 days after training. Behaviors were evaluated using an observation tool that was developed to document huddle occurrence. Knowledge and attitudes significantly improved 45 days from baseline (P < .05) and were sustained by day 90. In this pilot study, the implementation of TeamSTEPPS training in a multidisciplinary team in an academic ED led to increased knowledge and improved communication attitudes. Adoption of a specific behavior, the huddle, also was observed. PMID- 25143409 TI - Caenorhabditis elegans chaperonin CCT/TRiC is required for actin and tubulin biogenesis and microvillus formation in intestinal epithelial cells. AB - Intestinal epithelial cells have unique apical membrane structures, known as microvilli, that contain bundles of actin microfilaments. In this study, we report that Caenorhabditis elegans cytosolic chaperonin containing TCP-1 (CCT) is essential for proper formation of microvilli in intestinal cells. In intestinal cells of cct-5(RNAi) animals, a substantial amount of actin is lost from the apical area, forming large aggregates in the cytoplasm, and the apical membrane is deformed into abnormal, bubble-like structures. The length of the intestinal microvilli is decreased in these animals. However, the overall actin protein levels remain relatively unchanged when CCT is depleted. We also found that CCT depletion causes a reduction in the tubulin levels and disorganization of the microtubule network. In contrast, the stability and localization of intermediate filament protein IFB-2, which forms a dense filamentous network underneath the apical surface, appears to be superficially normal in CCT-deficient cells, suggesting substrate specificity of CCT in the folding of filamentous cytoskeletons in vivo. Our findings demonstrate physiological functions of CCT in epithelial cell morphogenesis using whole animals. PMID- 25143408 TI - Systematic lipidomic analysis of yeast protein kinase and phosphatase mutants reveals novel insights into regulation of lipid homeostasis. AB - The regulatory pathways required to maintain eukaryotic lipid homeostasis are largely unknown. We developed a systematic approach to uncover new players in the regulation of lipid homeostasis. Through an unbiased mass spectrometry-based lipidomic screening, we quantified hundreds of lipid species, including glycerophospholipids, sphingolipids, and sterols, from a collection of 129 mutants in protein kinase and phosphatase genes of Saccharomyces cerevisiae. Our approach successfully identified known kinases involved in lipid homeostasis and uncovered new ones. By clustering analysis, we found connections between nutrient sensing pathways and regulation of glycerophospholipids. Deletion of members of glucose- and nitrogen-sensing pathways showed reciprocal changes in glycerophospholipid acyl chain lengths. We also found several new candidates for the regulation of sphingolipid homeostasis, including a connection between inositol pyrophosphate metabolism and complex sphingolipid homeostasis through transcriptional regulation of AUR1 and SUR1. This robust, systematic lipidomic approach constitutes a rich, new source of biological information and can be used to identify novel gene associations and function. PMID- 25143412 TI - Commentary on: development of our TAVI protocol for emergency initiation of cardiopulmonary bypass. PMID- 25143411 TI - Development of a Quality Improvement Bundle to Reduce Tracheal Intubation Associated Events in Pediatric ICUs. AB - Advanced airway management in the pediatric intensive care unit (PICU) is hazardous, with associated adverse outcomes. This report describes a methodology to develop a bundle to improve quality and safety of tracheal intubations. A prospective observational cohort study was performed with expert consensus opinion of 1715 children undergoing tracheal intubation at 15 PICUs. Baseline process and outcomes data in tracheal intubation were collected using the National Emergency Airway Registry for Children reporting system. Univariate analysis was performed to identify risk factors associated with adverse tracheal intubation-associated events. A multidisciplinary quality improvement committee was formed. Workflow analysis of tracheal intubation and pilot testing were performed to develop the Airway Bundle Checklist with 4 parts: (1) risk factor assessment, (2) plan generation, (3) preprocedure time-out to ensure that providers, equipment, and plans are prepared, (4) postprocedure huddle to identify improvement opportunities. The Airway Bundle Checklist developed may lead to improvement in airway management. PMID- 25143413 TI - The impact of haemodilution and bypass pump flow on cerebral oxygen desaturation during cardiopulmonary bypass--A comparison of two systems of cardiopulmonary bypass. AB - OBJECTIVE: To determine the influence of haemodilution, bypass flow rates and calculated oxygen delivery during cardiopulmonary bypass (CPB) with either a conventional CPB (C-CPB) circuit or a miniaturised (Mini-CPB) circuit on cerebral oxygen desaturation. The effect of minimal haemodilution with a Mini-CPB was investigated. PARTICIPANTS: Eighty patients scheduled for elective cardiac surgery. INTERVENTION: Oxygenated haemoglobin (O2Hb) and tissue oxygenation index (TOI) were measured with near-infrared spectroscopy (NIRS). RESULTS: The average indexed bypass pump flow was significantly lower with Mini-CPB. When combined with haemoglobin concentration, the average oxygen delivery was the same between groups. Patients in the C-CPB group had a greater duration and severity of cerebral desaturation to a level <20% below baseline values, but none reached the depth and duration of the cerebral desaturation associated with poor outcome. Cerebral oxygen desaturation with C-CPB was significantly associated with low flows during bypass, whereas desaturation with Mini-CPB was associated with low perioperative haemoglobin concentration. PMID- 25143415 TI - Development of our TAVI protocol for emergency initiation of cardiopulmonary bypass. AB - All transcatheter aortic valve implantation (TAVI) cases are done in our hybrid operating room with a multidisciplinary team and a primed cardiopulmonary bypass (CPB) circuit on pump stand-by. We decided that we would resuscitate all patients undergoing a TAVI procedure via a transfemoral, transapical or transaortic approach, if required. Perfusion plays an essential role in providing rescue CPB for patient salvage when catastrophic complications occur. To coordinate the multidisciplinary effort, we have developed a written safety checklist that assigns a pre-determined role for team members for the rapid sequence initiation of CPB. Although many TAVI patients are not candidates for conventional aortic valve replacements, we feel strongly that rescue CPB should be offered to all TAVI patients to allow the correction of potentially reversible complications. This protocol is included in every surgical "Time Out" involving a TAVI procedure (Figure 1). The protocol has led to rapid and safe CPB initiation in less than five minutes of cardiac arrest. It has also led to a coordinated and consistent team, with pre-specified roles and improved communication. We discuss a case series of four TAVI patients who required emergent use of CPB. The first few cases did not have a written protocol. The experience from these cases led to the development of our protocol. We identified a lack of coordination, wasted movements, unnecessary delayed resuscitation and overall chaos, each of which was targeted for correction with the protocol. We will discuss the merits of the protocol in two recent TAVI cases which required emergent CPB. PMID- 25143416 TI - Photo quiz: a 69-year-old man with aortic native valve endocarditis. PMID- 25143417 TI - Faropenem disks for screening of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae. PMID- 25143418 TI - Molecular diagnosis of rifampin-monoresistant tuberculosis in Indian patients: problems with a discordance analysis. PMID- 25143419 TI - Reply to "molecular diagnosis of rifampin-monoresistant tuberculosis in Indian patients: problems with a discordance analysis". PMID- 25143420 TI - Not over yet: fungal infections following methyl prednisolone injections smoulder on. PMID- 25143421 TI - Reply to "not over yet: fungal infections following methyl prednisolone injections smoulder on". PMID- 25143422 TI - Classification of emergent U.S. strains of porcine epidemic diarrhea virus by phylogenetic analysis of nucleocapsid and ORF3 genes. PMID- 25143423 TI - Reply to "classification of emergent U.S. strains of porcine epidemic diarrhea virus by phylogenetic analysis of nucleocapsid and ORF3 genes". PMID- 25143424 TI - Detection of multiple fungal species in blood samples by real-time PCR: an interpretative challenge. PMID- 25143425 TI - Reply to "detection of multiple fungal species in blood samples by real-time PCR: an interpretative challenge". PMID- 25143426 TI - Optimization of standard 24-locus variable-number tandem-repeat typing of Mycobacterium tuberculosis isolates: a multicenter perspective. PMID- 25143429 TI - Rising inequality in mortality among working-age men and women in Sweden: a national registry-based repeated cohort study, 1990-2007. AB - BACKGROUND: In the past two decades, health inequality has persisted or increased in states with comprehensive welfare. METHODS: We conducted a national registry based repeated cohort study with a 3-year follow-up between 1990 and 2007 in Sweden. Information on all-cause mortality in all working-age Swedish men and women aged between 30 and 64 years was collected. Data were subjected to temporal trend analysis using joinpoint regression to statistically confirm the trajectories observed. RESULTS: Among men, age-standardised mortality rate decreased by 38.3% from 234.9 to 145 (per 100 000 population) over the whole period in the highest income quintile, whereas the reduction was only 18.3% (from 774.5 to 632.5) in the lowest quintile. Among women, mortality decreased by 40% (from 187.4 to 112.5) in the highest income group, but increased by 12.1% (from 280.2 to 314.2) in the poorest income group. Joinpoint regression identified that the differences in age-standardised mortality between the highest and the lowest income quintiles decreased among men by 18.85 annually between 1990 and 1994 (p trend=0.02), whereas it increased later, with a 2.88 point increase per year (p trend <0.0001). Among women, it continuously increased by 9.26/year (p trend <0.0001). In relative terms, age-adjusted mortality rate ratios showed a continuous increase in both genders. CONCLUSIONS: Income-based inequalities among working-age male and female Swedes have increased since the late 1990s, whereas in absolute terms the increase was less remarkable among men. Structural and behavioural factors explaining this trend, such as the economic recession in the early 1990s, should be studied further. PMID- 25143431 TI - Asymmetrical social mach bands: exaggeration of social identities on the more esteemed side of group borders. AB - Perceptual processes generally enhance borders, because of their high information value. Mach bands are an example in vision. In the social world, borders are also of special significance; one side of a border is generally more esteemed or valued than the other. We claim that entities (individuals, groups) that are just over the border on the positive side tend to exaggerate their membership on the positive side (asymmetrical social Mach bands). We demonstrate this by showing that (a) master's-degree universities use the word university to describe themselves more than major graduate universities do, (b) small international airports use the word international to describe themselves more than major airports do, and (c) University of Pennsylvania students, who are affiliated with a "marginal" Ivy League school, use the word Ivy to describe their school more than Harvard students do. PMID- 25143430 TI - Genes influence young children's human figure drawings and their association with intelligence a decade later. AB - Drawing is ancient; it is the only childhood cognitive behavior for which there is any direct evidence from the Upper Paleolithic. Do genes influence individual differences in this species-typical behavior, and is drawing related to intelligence (g) in modern children? We report on the first genetically informative study of children's figure drawing. In a study of 7,752 pairs of twins, we found that genetic differences exert a greater influence on children's figure drawing at age 4 than do between-family environmental differences. Figure drawing was as heritable as g at age 4 (heritability of .29 for both). Drawing scores at age 4 correlated significantly with g at age 4 (r = .33, p < .001, n = 14,050) and with g at age 14 (r = .20, p < .001, n = 4,622). The genetic correlation between drawing at age 4 and g at age 14 was .52, 95% confidence interval = [.31, .75]. Individual differences in this widespread behavior have an important genetic component and a significant genetic link with g. PMID- 25143432 TI - BIRO1, a cell-permeable BH3 peptide, promotes mitochondrial fragmentation and death of retinoblastoma cells. AB - Retinoblastoma is the most common pediatric intraocular neoplasm. While retinoblastoma development requires the inactivation of both alleles of the retinoblastoma tumor suppressor gene (RB1) in the developing retina, additional genomic changes are involved in tumor progression, which progressively lead to resistance of tumor cells to death. Therapeutics acting at very downstream levels of death signaling pathways should therefore be interesting in killing retinoblastoma cells. The BH3-only proteins promote apoptosis by modulating the interaction between the pro- and antiapoptotic members of the BCL2 protein family, and this effect can be recapitulated by the BH3 domains. This report analyzes the effect of various BH3 peptides, corresponding to different BH3-only proteins, on two retinoblastoma cell lines, Y79 and WERI-Rb, as well as on the photoreceptor cell line 661W. The BH3 peptide BIRO1, derived from the BCL2L11 death domain, was very effective in promoting Y79 and WERI-Rb cell death without affecting the 661W photoreceptor cells. This cell death was efficient even in absence of BAX and was shown to be caspase independent. While ROS production or AIF release was not detected from mitochondria of treated cells, BIRO1 initiated mitochondria fragmentation in a short period of time following treatment. IMPLICATIONS: The BIRO1 peptide is highly effective at killing retinoblastoma cells and has potential as a peptidomimetic. PMID- 25143433 TI - Constitutively active ErbB2 regulates cisplatin-induced cell death in breast cancer cells via pro- and antiapoptotic mechanisms. AB - Despite the frequent expression of N-terminally truncated ErbB2 (DeltaNErbB2/p95HER2) in breast cancer and its association with Herceptin resistance and poor prognosis, it remains poorly understood how DeltaNErbB2 affects chemotherapy-induced cell death. Previously it was shown that DeltaNErbB2 upregulates acid extrusion from MCF-7 breast cancer cells and that inhibition of the Na(+)/H(+) exchanger (SLC9A1/NHE1) strongly sensitizes DeltaNErbB2-expressing MCF-7 cells to cisplatin chemotherapy. The aim of this study was to identify the mechanism through which DeltaNErbB2 regulates cisplatin-induced breast cancer cell death, and determine how NHE1 regulates this process. Cisplatin treatment elicited apoptosis, ATM phosphorylation, upregulation of p53, Noxa (PMAIP1), and PUMA (BBC3), and cleavage of caspase-9, -7, fodrin, and PARP-1 in MCF-7 cells. Inducible DeltaNErbB2 expression strongly reduced cisplatin-induced ATM- and p53 phosphorylation, augmented Noxa upregulation and caspase-9 and -7 cleavage, doubled p21(WAF1/Cip1) (CDKN1A) expression, and nearly abolished Bcl-2 expression. LC3-GFP analysis demonstrated that autophagic flux was reduced by cisplatin in a manner augmented by DeltaNErbB2, yet did not contribute to cisplatin-induced death. Using knockdown approaches, it was shown that cisplatin induced caspase-7 cleavage in DeltaNErbB2-MCF-7 cells was Noxa- and caspase-9 dependent. This pathway was augmented by NHE1 inhibition, while the Na(+)/HCO3 ( ) cotransporter (SLC4A7/NBCn1) was internalized following cisplatin exposure. IMPLICATIONS: This work reveals that DeltaNErbB2 strongly affects several major pro- and antiapoptotic pathways and provides mechanistic insight into the role of NHE1 in chemotherapy resistance. These findings have relevance for defining therapy regimens in breast cancers with DeltaNErbB2 and/or NHE1 overexpression. PMID- 25143435 TI - Examining Specialization Among Sex Offenders Released From Prison. AB - A prevailing cultural stereotype about sex offenders is that they tend to specialize in sexual offending. Many recent policy developments-mainly aimed to restrict the liberties of sex offenders-are rooted in this idea. We examined the correctional and arrest records of a sample of 312 sex offenders released on parole in Colorado to determine the prevalence of sexual specialization among these offenders, and to compare the legal and social characteristics of specialists and versatile sex offenders. Overall we found that very few participants officially classified as sex offenders fit the specialist stereotype. Study participants generally displayed versatile histories of criminal offending. We also found that specialists were distinguishable from versatile offenders on certain indices of social integration and mental health, and they were more likely to have had a history of offending against children. PMID- 25143436 TI - An exploration of protective factors supporting desistance from sexual offending. AB - This article considers factors that support or assist desistance from sexual offending in those who have previously offended. Current risk assessment tools for sexual offending focus almost exclusively on assessing factors that raise the risk for offending. The aim of this study was to review the available literature on protective factors supporting desistance from sexual offending. This article discusses the potential value of incorporating protective factors into the assessment process, and examines the literature on this topic to propose a list of eight potential protective domains for sexual offending. The inclusion of notions of desistance and strengths may provide additional guidance to the assessment and treatment of those who sexually offend. Further research investigations are recommended to consolidate the preliminary conclusions from this study regarding the nature and influence of protective factors in enabling individuals to desist from further offending. PMID- 25143434 TI - SIRT1 inactivation evokes antitumor activities in NSCLC through the tumor suppressor p27. AB - P27(Kip1) (CDKN1B) regulates cellular proliferation and senescence, and p27(Kip1) deficiency in cancer is strongly correlated with poor prognosis of multiple cancer types. Understanding the mechanism of p27(Kip1) loss in cancer and the consequences of restoring p27(Kip1) levels is therefore critical for effective management during therapy. Here, SIRT1, a class III histone deacetylase (HDAC), is identified as an important regulator of p27(Kip1) expression. Mechanistically, SIRT1 reduces p27(Kip1) expression by decreasing p27(Kip1) protein stability through the ubiquitin-proteasome pathway. In addition, SIRT1 silencing suppresses non-small cell lung cancer (NSCLC) proliferation and induces senescence in a p27(Kip1)-dependent manner. Furthermore, SIRT1 silencing dramatically suppresses tumor formation and proliferation in two distinct NSCLC xenograft mouse models. Collectively, these data demonstrate that not only SIRT1 is an important regulator of p27(Kip1) but also SIRT inhibition induces senescence and antigrowth potential in lung cancer in vivo. IMPLICATIONS: SIRT1 is a key regulator of p27 protein levels and SIRT1 inhibition is a viable strategy for NSCLC therapy by means of p27 reactivation. PMID- 25143437 TI - Anxious Attachment, Social Isolation, and Indicators of Sex Drive and Compulsivity: Predictors of Child Sexual Abuse Perpetration in Adolescent Males? AB - It has been suggested that child sexual abuse is related to poor attachment to parents, which is associated with an inability to form intimate relationships. Seto and Lalumiere indicated that there were too few studies of adolescent males to determine whether poor attachment was associated with perpetration. This study was designed to follow up on a previous study and further explored the association between insecure attachment to parents, social isolation, and interpersonal adequacy to child sexual abuse perpetration in adolescents. We compared two samples of adolescent males who had committed sexual offenses, those who committed offenses against children (n = 140) and those who committed offenses against peer or adults (n = 92), with a sample of similarly aged males in treatment for mental health or substance use issues (n = 93). Data were collected using a semi-structured interview and computer-administered questionnaire. We found an indirect association between anxious attachment and sexual offenses against child victims, which was accounted for by measures of social involvement and social isolation. These involvement and isolation measures also did not have a direct association with sexual offenses against child victims, in that their contribution was accounted for by a measure of Masculine Adequacy. This Masculine Adequacy, combined with decreased levels of Sexual Preoccupation and Hypersexuality and increased Sexual Compulsivity, was associated with commission of child sexual abuse. The interpersonal variables did not enter a model predicting sexual offending against peers/adults, which seemed solely associated with the interaction between Sexual Compulsivity and Hypersexuality. PMID- 25143439 TI - A novel percutaneous technique for treating complete rectal prolapse in adults. AB - PURPOSE: To evaluate a new technique for treating complete rectal prolapse in adults that combines injection sclerotherapy with anal encirclement. METHODS: From 2008 to 2012, 20 patients were treated using combined perirectal injection sclerotherapy with anal encirclement. The primary outcome was recurrent full thickness/mucosal rectal prolapse. RESULTS: The mean age of the patients was 39 years. The mean operating time was 17 minutes. Patients had short hospital stays (range = 2-4 days) and rapid recovery with no serious postoperative complications. After a mean follow-up of 22 months, recurrence occurred in 9 patients, and was complete in 6 cases and mucosal in 3 patients. Recurrent mucosal prolapse was treated with a mucosectomy, while recurrent complete rectal prolapse was treated with an open rectopexy with mesh. CONCLUSION: The combination of perirectal sclerotherapy and anal encirclement for treating complete rectal prolapse in adults is a simple and safe procedure with reasonable outcome. These findings call for confirmatory trials in larger series. PMID- 25143440 TI - Understanding the diffusion of ambulatory surgery centers. AB - BACKGROUND: Outpatient surgery is increasingly delivered at freestanding ambulatory surgery centers (ASCs), which are thought to deliver quality care at lower costs per episode. The objective of this study was to understand potential facilitators and/or barriers to the introduction of freestanding ASCs in the United States. METHODS: This is an observational study conducted from 2008 to 2010 using a 20% sample of Medicare claims. Potential determinants of ASC dissemination, including population, system, and legal factors, were compared between markets that always had ASCs, never had ASCs, and those that had new ASCs open during the study. Multivariable logistic regression was used to determine characteristics of markets associated with the opening of a new facility in a previously naive market. RESULTS: New ASCs opened in 67 previously naive markets between 2008 and 2010. ASCs were more likely to open in hospital service areas that were urban (adjusted odds ratio [OR], 4.10; 95% confidence interval [CI], 1.51-10.96), had higher per capita income (adjusted OR, 3.83; 95% CI, 1.43 10.45), and had less competition for outpatient surgery (adjusted OR, 2.13; 95% CI, 1.02-4.45). Legal considerations and latent need, as measured by case volumes of hospital-based outpatient surgery in 2007, were not associated with the opening of a new ASC. CONCLUSIONS: Freestanding ASCs opened in advantageous socioeconomic environments with the least amount of competition. Because of their associated efficiency advantages, policy makers might consider strategies to promote ASC diffusion in disadvantaged markets to potentially improve access and reduce costs. PMID- 25143441 TI - The survival and differentiation of pro-B and pre-B cells in the bone marrow is dependent on IL-7Ralpha Tyr449. AB - IL-7 is critical for murine T and B cell development and survival and plays a significant role in lymphoblastic leukemia in both humans and mice. We evaluated the role of the IL-7Ralpha Tyr(449) cytoplasmic SH2-binding motif in IL-7 mediated B cell development using a knock-in mouse with a Tyr to Phe mutation (IL 7Ralpha(449F/449F) mouse). IL-7Ralpha(449F/449F) and IL-7Ralpha(-/-) mice showed no defect in the number of pre-pro-B cells, although IL-7Ralpha(449F/449F) mice had decreased Ebf1 in pre-pro-B cells and impairment in B cell-committed CLPs. We identified that IL-7Ralpha Tyr(449) was critical for both pro-B and pre-B stages of development in the bone marrow. IL-7Ralpha(449F/449F) and IL-7Ralpha(-/-) mice had comparable precursor B cell defects, indicating that signaling from the IL 7Ralpha required this motif. Although the defect in IL-7Ralpha(449F/449F) pro-B cells was associated with loss of STAT5 activation and diminished expression of Mcl1, this was not rescued by overexpression of Bcl-2. IL-7Ralpha(449F/449F) and IL-7Ralpha(-/-) pre-B cells also showed defective cyto-IgMU and CD25 expression, associated with reduced levels of Rag1, Rag2, and Irf4. Pre-B cells from IL 7Ralpha(449F/449F) mice also failed to proliferate, perhaps as a result of the failure to rearrange IgMU. Our data suggest that IL-7Ralpha Tyr(449) was essential for IL-7Ralpha signaling in bone marrow B cell development and survival. PMID- 25143442 TI - Live simian immunodeficiency virus vaccine correlate of protection: immune complex-inhibitory Fc receptor interactions that reduce target cell availability. AB - Principles to guide design of an effective vaccine against HIV are greatly needed, particularly to protect women in the pandemic's epicenter in Africa. We have been seeking these principles by identifying correlates of the robust protection associated with SIVmac239Deltanef vaccination in the SIV-rhesus macaque animal model of HIV-1 transmission to women. We identified one correlate of SIVmac239Deltanef protection against vaginal challenge as a resident mucosal system for SIV-gp41 trimer Ab production and neonatal FcR-mediated concentration of these Abs on the path of virus entry to inhibit establishment of infected founder populations at the portal of entry. In this study, we identify blocking CD4(+) T cell recruitment to thereby inhibit local expansion of infected founder populations as a second correlate of protection. Virus-specific immune complex interactions with the inhibitory FcgammaRIIb receptor in the epithelium lining the cervix initiate expression of genes that block recruitment of target cells to fuel local expansion. Immune complex-FcgammaRIIb receptor interactions at mucosal frontlines to dampen the innate immune response to vaginal challenge could be a potentially general mechanism for the mucosal immune system to sense and modulate the response to a previously encountered pathogen. Designing vaccines to provide protection without eliciting these transmission-promoting innate responses could contribute to developing an effective HIV-1 vaccine. PMID- 25143443 TI - Fungal beta-glucan, a Dectin-1 ligand, promotes protection from type 1 diabetes by inducing regulatory innate immune response. AB - beta-Glucans are naturally occurring polysaccharides in cereal grains, mushrooms, algae, or microbes, including bacteria, fungi, and yeast. Immune cells recognize these beta-glucans through a cell surface pathogen recognition receptor called Dectin-1. Studies using beta-glucans and other Dectin-1 binding components have demonstrated the potential of these agents in activating the immune cells for cancer treatment and controlling infections. In this study, we show that the beta glucan from Saccharomyces cerevisiae induces the expression of immune regulatory cytokines (IL-10, TGF-beta1, and IL-2) and a tolerogenic enzyme (IDO) in bone marrow-derived dendritic cells as well as spleen cells. These properties can be exploited to modulate autoimmunity in the NOD mouse model of type 1 diabetes (T1D). Treatment of prediabetic NOD mice with low-dose beta-glucan resulted in a profound delay in hyperglycemia, and this protection was associated with increase in the frequencies of Foxp3(+), LAP(+), and GARP(+) T cells. Upon Ag presentation, beta-glucan-exposed dendritic cells induced a significant increase in Foxp3(+) and LAP(+) T cells in in vitro cultures. Furthermore, systemic coadministration of beta-glucan plus pancreatic beta cell Ag resulted in an enhanced protection of NOD mice from T1D as compared with treatment with beta glucan alone. These observations demonstrate that the innate immune response induced by low-dose beta-glucan is regulatory in nature and can be exploited to modulate T cell response to beta cell Ag for inducing an effective protection from T1D. PMID- 25143444 TI - IL-33-induced hematopoietic stem and progenitor cell mobilization depends upon CCR2. AB - IL-33 has been implicated in the pathogenesis of asthma, atopic allergy, anaphylaxis, and other inflammatory diseases by promoting the production of proinflammatory cytokines and chemokines or Th2 immune responses. In this study, we analyzed the in vivo effect of IL-33 administration. IL-33 markedly promoted myelopoiesis in the bone marrow and myeloid cell emigration. Concomitantly, IL-33 induced hematopoietic stem and progenitor cell (HSPC) mobilization and extramedullary hematopoiesis. HSPC mobilization was mediated mainly through increased levels of CCL7 produced by vascular endothelial cells in response to IL 33. In vivo treatment of IL-33 rapidly induced phosphorylation of ERK, JNK, and p38, and inhibition of these signaling molecules completely blocked the production of CCL7 induced by IL-33. Consistently, inhibitor of CCR2 markedly reduced IL-33-mediated HSPC mobilization in vivo and migration of HSPCs in response to CCL7 in vitro. IL-33-mobilized HSPCs were capable of homing to, and of long-term reconstitution in, the bone marrow of irradiated recipients. Immune cells derived from these recipients had normal antifungal activity. The ability of IL-33 to promote migration of HSPCs and myeloid cells into the periphery and to regulate their antifungal activity represents a previously unrecognized role of IL-33 in innate immunity. These properties of IL-33 have clinical implications in hematopoietic stem cell transplantation. PMID- 25143445 TI - Tuberculin skin test negativity is under tight genetic control of chromosomal region 11p14-15 in settings with different tuberculosis endemicities. AB - A substantial proportion of subjects exposed to a contagious tuberculosis case display lack of tuberculin skin test (TST) reactivity. We previously mapped a major locus (TST1) controlling lack of TST reactivity in families from an area in South Africa where tuberculosis is hyperendemic. Here, we conducted a household tuberculosis contact study in a French area where the endemicity of tuberculosis is low. A genome-wide analysis of TST negativity identified a significant linkage signal (P < 3 * 10(-5)) in close vicinity of TST1. Combined analysis of the 2 samples increased evidence of linkage (P = 2.4 * 10(-6)), further implicating genetic factors located on 11p14-15. This region overlaps the TNF1 locus controlling mycobacteria-driven tumor necrosis factor alpha production. PMID- 25143447 TI - Longitudinal time-dependent effects of irradiation on multidrug resistance in a non-small lung cancer cell line. AB - Multidrug resistance (MDR) in cancer is known to decrease the therapeutic efficacy of chemotherapy. The effects of irradiation on MDR in cancer cells remain unclear. Tc-99m methoxyisobutylisonitrile (MIBI) exhibits the same ATP binding cassette (ABC) transporter kinetics as the chemotherapeutic compound doxorubicin. In this study, we investigated the synergistic effects of chemotherapeutics and irradiation [0 Gy: C (control) group; 3, 6, 9, 12 Gy: I (irradiation) group] in the human non-small lung cancer cell line H1299 exhibiting MDR, on MIBI and doxorubicin ABC transporter kinetics, in vitro and in vivo, respectively. In vitro, inhibition of H1299 cell proliferation by irradiation was found to be irradiation dose dependent. The degree and duration of MDR inhibition in vitro in H1299 were also dose dependent. In the cells of both the C group and 3-Gy I group, no significant difference of MIBI accumulation was observed. In the 6-Gy I group, a higher MIBI accumulation was observed at only 7 days after irradiation relative to the C group. A higher MIBI accumulation in the 9- and 12-Gy I groups with a significant difference from the C group was observed at 4 to 14 days after irradiation. A significant negative correlation between intracellular MIBI accumulation and cell replication was found. In vivo, high accumulation and retention of doxorubicin were observed in irradiated tumors in the H1299 xenograft mice group at 4 to 14 days after 9-Gy irradiation compared with the control mice group. These results provide evidence for a synergistic effect of concurrent chemotherapy and radiotherapy. PMID- 25143448 TI - Tissue penetration and activity of camptothecins in solid tumor xenografts. AB - The ability of a panel of camptothecin derivatives to access the tumor compartment was evaluated to determine the mechanisms by which the architecture of solid tumors may act to limit their activity. Microregional localization and activity of members of the camptothecin class of topoisomerase I targeting agents, including topotecan, irinotecan, and irinophore C, a lipid-based nanoparticulate formulation of irinotecan, were evaluated over time in HCT116 and HT29 colorectal tumor xenografts. Using native drug fluorescence, their distributions in tissue cryosections were related to the underlying tumor vasculature, tumor cell proliferation, and apoptosis. Topotecan exhibited a relatively uniform tumor distribution; in tissue 100 MUm away from vessels, it reached 94% +/- 5% of levels seen around blood vessels, whereas irinotecan and irinophore C were found to reach only 41% +/- 10% and 5% +/- 2%, respectively. Surprisingly, all three agents were able to initially inhibit proliferation uniformly throughout the tumors, and it was their rate of washout (topotecan > irinotecan > irinophore C) that correlated with activity. To explain this discrepancy, we looked at SN38, the active metabolite of irinotecan, and found it to penetrate tissue similarly to topotecan. Hence, the poor access to the tumor compartment of irinotecan and irinophore C could be offset by their systemic conversion to SN38. It was concluded that all three agents were effective at reaching tumor cells, and that despite the poor access to the extravascular compartment of irinophore C, its extended plasma exposure and systemic conversion to the diffusible metabolite SN38 enabled it to effectively target solid tumors. PMID- 25143450 TI - Nutrition in the 21st century: riding the U-shaped wave. PMID- 25143449 TI - Anti-MET immunoPET for non-small cell lung cancer using novel fully human antibody fragments. AB - MET, the receptor of hepatocyte growth factor, plays important roles in tumorigenesis and drug resistance in numerous cancers, including non-small cell lung cancer (NSCLC). As increasing numbers of MET inhibitors are being developed for clinical applications, antibody fragment-based immunopositron emission tomography (immunoPET) has the potential to rapidly quantify in vivo MET expression levels for drug response evaluation and patient stratification for these targeted therapies. Here, fully human single-chain variable fragments (scFvs) isolated from a phage display library were reformatted into bivalent cys diabodies (scFv-cys dimers) with affinities to MET ranging from 0.7 to 5.1 nmol/L. The candidate with the highest affinity, H2, was radiolabeled with (89)Zr for immunoPET studies targeting NSCLC xenografts: low MET-expressing Hcc827 and the gefitinib-resistant Hcc827-GR6 with 4-fold MET overexpression. ImmunoPET at as early as 4 hours after injection produced high-contrast images, and ex vivo biodistribution analysis at 20 hours after injection showed about 2-fold difference in tracer uptake levels between the parental and resistant tumors (P < 0.01). Further immunoPET studies using a larger fragment, the H2 minibody (scFv CH3 dimer), produced similar results at later time points. Two of the antibody clones (H2 and H5) showed in vitro growth inhibitory effects on MET-dependent gefitinib-resistant cell lines, whereas no effects were observed on resistant lines lacking MET activation. In conclusion, these fully human antibody fragments inhibit MET-dependent cancer cells and enable rapid immunoPET imaging to assess MET expression levels, showing potential for both therapeutic and diagnostic applications. PMID- 25143451 TI - Effect of preemptive treatment with human umbilical cord blood-derived mesenchymal stem cells on the development of renal ischemia-reperfusion injury in mice. AB - Human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) have been studied in several models of immune-mediated disease because of their unique immunomodulatory properties. We hypothesized that HUCB-MSCs could suppress the inflammatory response in postischemic kidneys and attenuate early renal injury. In 8- to 10-wk-old male C57BL/6 mice, bilateral ischemia-reperfusion injury (IRI) surgery was performed, and 1 * 10(6) HUCB-MSCs were injected intraperitoneally 24 h before surgery and during reperfusion. Renal functional and histological changes, HUCB-MSC trafficking, leukocyte infiltration, and cytokine expression were analyzed. Renal functional decline and tubular injury after IRI were attenuated by HUCB-MSC treatment. PKH-26-labeled HUCB-MSCs trafficked into the postischemic kidney. Although numbers of CD45-positive leukocytes in the postischemic kidney were comparable between groups, the expression of interferon gamma in the postischemic kidney was suppressed by HUCB-MSC treatment. The rapid decrease in intrarenal VEGF after IRI was markedly mitigated by HUCB-MSC treatment. In inflammatory conditions simulated in a cell culture experiment, VEGF secretion from HUCB-MSCs was substantially enhanced. VEGF inhibitor abolished the renoprotective effect of HUCB-MSCs after IRI. Flow cytometry analysis revealed the decreased infiltration of natural killer T cells and increased number of regulatory T cells in postischemic kidneys. In addition, these effects of HUCB-MSCs on kidney infiltrating mononuclear cells after IRI were attenuated by VEGF inhibitor. HUCB-MSCs attenuated renal injury in mice in the early injury phase after IRI, mainly by humoral effects and secretion of VEGF. Our results suggest a promising role for HUCB-MSCs in the treatment of renal IRI. PMID- 25143452 TI - Decreasing podocyte number during human kidney intrauterine development. AB - Nephron number at birth has relevant clinical importance with implications for long-term renal health. In recent years, the podocyte depletion hypothesis has emerged as an important concept in kidney pathology. This study was aimed at verifying whether human podocyte number changes significantly during intrauterine life. To this end, 62 subjects with gestational ages ranging from 20 to 41 wk were examined. Kidney sections were stained with hematoxylin and eosin and digitally scanned at *400 magnification. Subjects were subdivided into fetuses (gestational age<=24 wk, n=5), preterms (gestational age>=25 and <=36 wk, n=39), and full-term newborns (gestational age>=37 wk, n=18). The average podocyte number of 1,908+/-645, 1,394+/-498, and 1,126+/-256 was, respectively, observed in fetuses, preterms, and full-term newborns. A significant main effect (P=0.0051) of gestational age on podocyte number was observed with a significantly lower number in full-term newborns than in fetuses (P<0.01). Intragroup variability was also observed. We speculate that variations in podocyte number could be correlated with factors such as drugs and maternal diet occurring during intrauterine life. In conclusion, this study shows, for the first time, a decreasing trend in podocyte number during gestation. PMID- 25143454 TI - Restoring multidrug resistance-associated protein 3 attenuates cell proliferation in the polycystic kidney. AB - Autosomal dominant polycystic kidney disease (ADPKD) is characterized by abnormal proliferation of renal tubular epithelial cells, resulting in the loss of renal function. Despite identification of the genes responsible for ADPKD, few effective drugs are currently available for the disease. Thus finding additional effective drug targets is necessary. The functions of multidrug- resistance associated protein 3 (MRP3) have been reported only in the field of drug resistance, and the renal functions of MRP3 are mostly unknown. In this study, we found that MRP3 was significantly downregulated in kidneys of human patients with ADPKD and polycystic kidney disease (PKD) mouse models. Our results suggest that downregulated MRP3 stimulated renal epithelial cell proliferation through the B Raf/MEK/ERK signaling pathway. In contrast, we found that restoring MRP3 reduced cell proliferation and cystogenesis in vitro. These results suggest that the renal function of MRP3 is related to renal cell proliferation and cyst formation and that restoring MRP3 may be an effective therapeutic approach for PKD. PMID- 25143453 TI - Carbonic anhydrase 2 deficiency leads to increased pyelonephritis susceptibility. AB - Carbonic anhydrase 2 regulates acid-base homeostasis, and recent findings have indicated a correlation between cellular control of acid-base status and the innate defense of the kidney. Mice deficient in carbonic anhydrase 2 (Car2(-/-) mice) have metabolic acidosis, impaired urine acidification, and are deficient in normal intercalated cells. The objective of the present study was to evaluate the biological consequences of carbonic anhydrase 2 deficiency in a murine model of pyelonephritis. Infection susceptibility and transcription of bacterial response components in Car2(-/-) mice were compared with wild-type littermate controls. Car2(-/-) mice had increased kidney bacterial burdens along with decreased renal bacterial clearance after inoculation compared with wild-type mice. Standardization of the urine pH and serum HCO(3)(-) levels did not substantially alter kidney infection susceptibility between wild-type and Car2(-/-) mice; thus, factors other than acid-base status are responsible. Car2(-/-) mice had significantly increased neutrophil-gelatinase-associated lipocalin mRNA and protein and expression at baseline and a marked decreased ability to upregulate key bacterial response genes during pyelonephritis. Our findings provide in vivo evidence that supports a role for carbonic anhydrase 2 and intercalated cells in promoting renal bacterial clearance. Decreased carbonic anhydrase expression results in increased antimicrobial peptide production by cells other than renal intercalated cells, which is not sufficient to prevent infection after a bacterial challenge. PMID- 25143455 TI - Renal medullary cyclooxygenase-2 and (pro)renin receptor expression during angiotensin II-dependent hypertension. AB - The (pro)renin receptor [(P)RR] upregulates cyclooxygenase-2 (COX-2) in inner medullary collecting duct (IMCD) cells through ERK1/2. Intrarenal COX-2 and (P)RR are upregulated during chronic ANG II infusion. However, the duration of COX-2 and (P)RR upregulation has not been determined. We hypothesized that during the early phase of ANG II-dependent hypertension, membrane-bound (P)RR and COX-2 are augmented in the renal medulla, serving to buffer the hypertensinogenic and vasoconstricting effects of ANG II. In Sprague-Dawley rats infused with ANG II (0.4 MUg.min(-1).kg(-1)), systolic blood pressure (BP) increased by day 7 (162 +/ 5 vs. 114 +/- 10 mmHg) and continued to increase by day 14 (198 +/- 15 vs. 115 +/- 13 mmHg). Membrane-bound (P)RR was augmented at day 3 coincident with phospho ERK1/2 levels, COX-2 expression, and PGE2 in the renal medulla. In contrast, membrane-bound (P)RR was reduced and COX-2 protein levels were not different from controls by day 14. In cultured IMCD cells, ANG II increased secretion of the soluble (P)RR. In anesthetized rats, COX-2 inhibition decreased the glomerular filtration rate (GFR) and renal blood flow (RBF) during the early phase of ANG II infusion without altering BP. However, at 14 days of ANG II infusions, COX-2 inhibition decreased mean arterial BP (MABP), RBF, and GFR. Thus, during the early phase of ANG II-dependent hypertension, the increased (P)RR and COX-2 expression in the renal medulla may contribute to attenuate the vasoconstrictor effects of ANG II on renal hemodynamics. In contrast, at 14 days the reductions in RBF and GFR caused by COX-2 inhibition paralleled the reduced MABP, suggesting that vasoconstrictor COX-2 metabolites contribute to ANG II hypertension. PMID- 25143456 TI - A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation. AB - Electrical stimulation of pudendal afferents can inhibit bladder contractions and increase bladder capacity. Recent results suggest that stimulation-evoked bladder inhibition is mediated by a mechanism other than activation of sympathetic bladder efferents in the hypogastric nerve, generating alpha-adrenergic receptor mediated inhibition at the vesical ganglia and/or beta-adrenergic receptor mediated direct inhibition of the detrusor muscle. We investigated several inhibitory neurotransmitters that may instead be necessary for stimulation-evoked inhibition and found that intravenous picrotoxin, a noncompetitive GABAA antagonist, significantly and reversibly blocked pudendal afferent stimulation evoked inhibition of bladder contractions in a dose-dependent manner. Similarly, intravenous picrotoxin also blocked pudendal afferent stimulation-evoked inhibition of nociceptive bladder contractions evoked by acetic acid infusion. Furthermore, intrathecal administration of picrotoxin at the lumbosacral spinal cord also blocked bladder inhibition by pudendal afferent stimulation. On the other hand, glycinergic, adrenergic, or opioidergic mechanisms were not necessary for bladder inhibition evoked by pudendal afferent stimulation. These results identify a lumbosacral spinal GABAergic mechanism of bladder inhibition evoked by pudendal afferent stimulation. PMID- 25143457 TI - Comparison of serum creatinine and serum cystatin C as biomarkers to detect sepsis-induced acute kidney injury and to predict mortality in CD-1 mice. AB - Acute kidney injury (AKI) dramatically increases sepsis mortality, but AKI diagnosis is delayed when based on serum creatinine (SCr) changes, due in part, to decreased creatinine production. During experimental sepsis, we compared serum cystatin C (sCysC), SCr, and blood urea nitrogen (BUN) to inulin glomerular filtration rate (iGFR) before or 3-18 h after cecal ligation and puncture (CLP) induced sepsis in CD-1 mice. sCysC had a faster increase and reached peak levels more rapidly than SCr in both sepsis and bilateral nephrectomy (BiNx) models. sCysC was a better surrogate of iGFR than SCr during sepsis. Combining sCysC with SCr values into a composite biomarker improved correlation with iGFR better than any biomarker alone or any other combination. We determined the renal contribution to sCysC handling with BiNx. sCysC and SCr were lower post-BiNx/CLP than post-BiNx alone, despite increased inflammatory and nonrenal organ damage biomarkers. Sepsis decreased CysC production in nephrectomized mice without changing body weight or CysC space. Sepsis decreased sCysC production and increased nonrenal clearance, similar to effects of sepsis on SCr. sCysC, SCr, and BUN were measured 6 h postsepsis to link AKI with mortality. Mice with above median sCysC, BUN, or SCr values 6 h postsepsis died earlier than mice with below median values, corresponding to a substantial AKI association with sepsis mortality in this model. sCysC performs similarly to SCr in classifying mice at risk for early mortality. We conclude that sCysC detects AKI early and better reflects iGFR in CLP-induced sepsis. This study shows that renal biomarkers need to be evaluated in specific contexts. PMID- 25143459 TI - Semicarbazide-sensitive amine oxidase (SSAO) inhibition ameliorates kidney fibrosis in a unilateral ureteral obstruction murine model. AB - Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme known for its dual function in mediating inflammation and reactive oxygen species production. However, the role of SSAO inhibitors in limiting kidney fibrosis is unclear. We aimed to determine the effectiveness of a SSAO inhibitor (SSAOi; PXS4728A) as an antifibrotic agent using a 7-day unilateral ureteric obstruction (UUO) model of acute kidney fibrosis in 6- to 8-wk-old mice. The experimental groups were 1) Sham operated; 2) UUO; 3) UUO+SSAOi (2 mg/kg); 4) UUO+telmisartan, an angiotensin receptor blocker (3 mg/kg); and 5) UUO+SSAOi+telmisartan. Kidney tissue was analyzed for histological evidence of tubulointerstitial fibrosis, nitrotyrosine staining, and mRNA expression of markers associated with fibrosis and inflammation. Kidney SSAO activity was determined by radiometric [(14)C]benzylamine methodology. Our results show that SSAOi effectively suppresses UUO-mediated SSAO activity. Extracellular matrix markers, namely, fibronectin, collagen IV protein, and nitrotyrosine staining, were lower in UUO+SSAOi mice compared with untreated UUO mice. This was consistent with the attenuated mRNA expression of collagen IV and fibronectin. SSAOi effectively inhibited transforming growth factor-beta1 (TGF-beta1) and monocyte chemoattractant protein-1 (MCP-1) expression to a similar extent to that observed with telmisartan. Individually, SSAOi and telmisartan induced a reduction in interstitial leukocyte and macrophage accumulation. However, the combination of SSAOi and telmisartan was more effective at reducing inflammatory cell infiltration. These results demonstrate that SSAO inhibition significantly suppresses profibrotic and proinflammatory cytokine secretion, reduces oxidative stress, and limits inflammatory cell accumulation and extracellular matrix expression in an acute model of renal fibrosis. PMID- 25143458 TI - A current understanding of vascular calcification in CKD. AB - Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) have significant cardiovascular morbidity and mortality that is in part due to the development of vascular calcification. Vascular calcification is an active, highly regulated process that shares many similarities with normal bone formation. New discoveries related to extracellular vesicles, microRNAs, and calciprotein particles continue to reveal the mechanisms that are involved in the initiation and progression of vascular calcification in CKD. Further innovations in these fields are critical for the development of biomarkers and therapeutic options for patients with CKD and ESRD. PMID- 25143460 TI - Sestrin 2: a regulator of the glomerular parietal epithelial cell phenotype. PMID- 25143461 TI - Maternally-derived zinc transporters ZIP6 and ZIP10 drive the mammalian oocyte-to egg transition. AB - Rapid cellular zinc influx regulates early mammalian development during the oocyte-to-egg transition through modulation of the meiotic cell cycle. Despite the physiological necessity of this zinc influx, the molecular mechanisms that govern such accumulation are unknown. Here we show that the fully grown mammalian oocyte does not employ a transcriptionally based mechanism of zinc regulation involving metal response element-binding transcription factor-1 (MTF-1), as demonstrated by a lack of MTF-1 responsiveness to environmental zinc manipulation. Instead, the mammalian oocyte controls zinc uptake through two maternally derived and cortically distributed zinc transporters, ZIP6 and ZIP10. Targeted disruption of these transporters using several approaches during meiotic maturation perturbs the intracellular zinc quota and results in a cell cycle arrest at a telophase I-like state. This arrest phenocopies established models of zinc insufficiency during the oocyte-to-egg transition, indicating the essential function of these maternally expressed transporters. Labile zinc localizes to punctate cytoplasmic structures in the human oocyte, and ZIP6 and ZIP10 are enriched in the cortex. Altogether, we demonstrate a mechanism of metal regulation required for female gamete development that may be evolutionarily conserved. PMID- 25143464 TI - Long-term care: multiple methods and multiple perspectives. PMID- 25143462 TI - Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine. AB - Immunization with homologous malondialdehyde (MDA)-modified LDL (MDA-LDL) leads to atheroprotection in experimental models supporting the concept that a vaccine to oxidation-specific epitopes (OSEs) of oxidized LDL could limit atherogenesis. However, modification of human LDL with OSE to use as an immunogen would be impractical for generalized use. Furthermore, when MDA is used to modify LDL, a wide variety of related MDA adducts are formed, both simple and more complex. To define the relevant epitopes that would reproduce the atheroprotective effects of immunization with MDA-LDL, we sought to determine the responsible immunodominant and atheroprotective adducts. We now demonstrate that fluorescent adducts of MDA involving the condensation of two or more MDA molecules with lysine to form malondialdehyde-acetaldehyde (MAA)-type adducts generate immunodominant epitopes that lead to atheroprotective responses. We further demonstrate that a T helper (Th) 2-biased hapten-specific humoral and cellular response is sufficient, and thus, MAA-modified homologous albumin is an equally effective immunogen. We further show that such Th2-biased humoral responses per se are not atheroprotective if they do not target relevant antigens. These data demonstrate the feasibility of development of a small-molecule immunogen that could stimulate MAA-specific immune responses, which could be used to develop a vaccine approach to retard or prevent atherogenesis. PMID- 25143463 TI - High-resolution imaging of dietary lipids in cells and tissues by NanoSIMS analysis. AB - Nanoscale secondary ion MS (NanoSIMS) imaging makes it possible to visualize stable isotope-labeled lipids in cells and tissues at 50 nm lateral resolution. Here we report the use of NanoSIMS imaging to visualize lipids in mouse cells and tissues. After administering stable isotope-labeled fatty acids to mice by gavage, NanoSIMS imaging allowed us to visualize neutral lipids in cytosolic lipid droplets in intestinal enterocytes, chylomicrons at the basolateral surface of enterocytes, and lipid droplets in cardiomyocytes and adipocytes. After an injection of stable isotope-enriched triglyceride-rich lipoproteins (TRLs), NanoSIMS imaging documented delivery of lipids to cytosolic lipid droplets in parenchymal cells. Using a combination of backscattered electron (BSE) and NanoSIMS imaging, it was possible to correlate the chemical data provided by NanoSIMS with high-resolution BSE images of cell morphology. This combined imaging approach allowed us to visualize stable isotope-enriched TRLs along the luminal face of heart capillaries and the lipids within heart capillary endothelial cells. We also observed examples of TRLs within the subendothelial spaces of heart capillaries. NanoSIMS imaging provided evidence of defective transport of lipids from the plasma LPs to adipocytes and cardiomyocytes in mice deficient in glycosylphosphatidylinositol-anchored HDL binding protein 1. PMID- 25143465 TI - The value of resident choice during daily care: do staff and families differ? AB - Allowing long-term care (LTC) residents to make choices about their daily life activities is a central tenet of resident-centered care. This study examined whether staff and family rated care episodes involving choice differently from care episodes not involving choice. Seventeen nurse aide and 15 family participants were shown paired video vignettes of care interactions. Participants were asked to rate their preferred care vignette using a standardized forced choice questionnaire. Focus groups were held separately for staff and family members following this rating task to determine reasons for their preferences. Both staff and family rated the vignettes depicting choice as "strongly" preferred to the vignettes without choice. Reasons provided for the preference ratings during the focus group discussions related to resident well-being, sense of control, and respondents' own personal values. These findings have implications for LTC staff training related to resident-centered care to promote choice. PMID- 25143466 TI - Heat shock protein 90.1 plays a role in Agrobacterium-mediated plant transformation. PMID- 25143467 TI - Individual variation in size and fecundity is correlated with differences in global DNA cytosine methylation in the perennial herb Helleborus foetidus (Ranunculaceae). AB - * PREMISE OF THE STUDY: Few studies have examined how epigenetic modifications of DNA may influence individual plant phenotypes and ecological processes in wild plant populations. We investigated natural variation in global DNA cytosine methylation and its phenotypic correlates in the perennial herb Helleborus foetidus.* METHODS: We focused specifically on individual differences in size- and fecundity-related traits and used HPLC to quantify percentage of total cytosines in the genome of young full-grown leaves that were methylated.* KEY RESULTS: About one third of all cytosines in H. foetidus genome were methylated. Methylation level differed significantly among individual plants (range = 26.4 36.6%; n = 60 plants), and this variation was significantly related to most size- and fecundity-related traits considered. Relatively hypomethylated plants bore more vegetative, reproductive, and total ramets, produced more flowers, larger inflorescences and more seed-bearing follicles, and their ramets remained vegetative for fewer years before reproducing sexually, than relatively hypermethylated ones. Taken together, results revealed that individual differences in size and reproductive output were inversely related to global cytosine methylation.* CONCLUSIONS: These results confirm, in a natural scenario, the association between DNA methylation and size- and fecundity-related traits that was previously found by experimental studies. Variations in global cytosine methylation were predictably related to individual differences in sexual reproduction through significant effects on flower and fruit production, which might ultimately influence patterns of selection and population dynamics in this species. This study provides novel insights on the potential ecological significance of epigenetic heterogeneity in wild plant populations. PMID- 25143468 TI - Drivers of a riparian forest specialist (Carex remota, Cyperaceae): it is not only a matter of soil moisture. AB - * PREMISE OF THE STUDY: Plants respond to the prevailing conditions in the surrounding environment, but since they are dynamic systems this response may vary during their life. Thus, the identification of key aspects for the maintenance of plant populations requires the consideration of plant performance across environmental gradients and along life stages. This study examines how abiotic conditions and biotic interactions and processes determine the spatial distribution of two life-story stages that play a key role in the functioning of a representative population of Carex remota.* METHODS: We used structural equation modeling (SEM) to test for direct and indirect influences of abiotic and biotic factors on seedlings and adults of Carex remota. The variables used in the analysis were number of seedlings, cover of adults, soil moisture, leaf litter cover, relative light, and topographic position.* KEY RESULTS: Population patterns partially depend on direct and indirect effects of abiotic conditions. Whereas adult individuals were only affected by topsoil moisture, seedling emergence was largely affected by multiple environmental conditions. The number of seedlings increased with high topsoil moisture, low leaf-litter values, high light values as well as in low parts of the study area. The importance of adult individuals in determining seedling success is also highlighted: higher abundance provides seed rain in the surroundings and modifies the microenvironmental conditions favoring high seedling establishment.* CONCLUSIONS: As hypothesized, adults and seedlings responded to the environmental conditions differently. Seedling emergence was a critical aspect in C. remota performance, and abrupt changes in the environment during this stage may strongly influence population performance. PMID- 25143469 TI - Effectiveness of PhysioDirect telephone assessment and advice services for patients with musculoskeletal problems. AB - STUDY QUESTION: Are PhysioDirect services, based on initial telephone assessment and advice from a physiotherapist, as effective as usual care involving patients waiting for a face-to-face appointment? SUMMARY ANSWER: Patients allocated to PhysioDirect received treatment more quickly than those allocated to usual care, and had equivalent clinical outcomes. PMID- 25143470 TI - Republished editorial: Autologous blood products in musculoskeletal medicine. PMID- 25143472 TI - Bisphenol A enhances adipogenic differentiation of human adipose stromal/stem cells. AB - Exposure of humans to the endocrine disrupter bisphenol A (BPA) has been associated with increased weight and obesity. However, the mechanism(s) by which BPA increases adipose tissue in humans remains to be determined. The goal of this study was to determine the effects of BPA on adipogenesis of cultured human adipose stromal/stem cells (ASCs), precursors to mature adipocytes. ASCs from three donors were cultured for either 14 or 21 days in adipogenic differentiation media containing increasing concentrations of BPA (100 pM-10 MUM). The extent of adipogenic differentiation in the ASCs was assessed by staining with Oil Red O to visualize adipogenic differentiation and then quantified by extraction and optical density measurement of the retained dye. BPA significantly enhanced adipogenesis at a concentration of 1 MUM after 21 days of culture. Additionally, we found that BPA increased transcription of the estrogen receptor (ER (ESR1)) and that treatment with the ER antagonist ICI 182 780, blocked the effects of BPA, indicating that BPA may act via an ER-mediated pathway. The results of molecular analyses indicated that the expression of the adipogenesis-associated genes dual leucine zipper-bearing kinase (DLK (MAP3K12)), IGF1, CCAAT/enhancer binding protein alpha (C/EBPalpha (CEBPA)), peroxisome proliferator-activated receptor gamma (PPARgamma (PPARG)), and lipoprotein lipase (LPL) was temporally accelerated and increased by BPA. In summary, these results indicate that BPA significantly enhances adipogenesis in ASCs through an ER-mediated pathway at physiologically relevant concentrations. PMID- 25143473 TI - The insulin-sensitivity sulphonylurea receptor variant is associated with thyrotoxic paralysis. AB - Thyrotoxicosis is the most common cause of the acquired flaccid muscle paralysis in adults called thyrotoxic periodic paralysis (TPP) and is characterised by transient hypokalaemia and hypophosphataemia under high thyroid hormone levels that is frequently precipitated by carbohydrate load. The sulphonylurea receptor 1 (SUR1 (ABCC8)) is an essential regulatory subunit of the beta-cell ATP sensitive K(+) channel that controls insulin secretion after feeding. Additionally, the SUR1 Ala1369Ser variant appears to be associated with insulin sensitivity. We examined the ABCC8 gene at the single nucleotide level using PCR restriction fragment length polymorphism (RFLP) analysis to determine its allelic variant frequency and calculated the frequency of the Ala1369Ser C-allele variant in a cohort of 36 Brazilian TPP patients in comparison with 32 controls presenting with thyrotoxicosis without paralysis (TWP). We verified that the frequency of the alanine 1369 C-allele was significantly higher in TPP patients than in TWP patients (61.1 vs 34.4%, odds ratio (OR)=3.42, P=0.039) and was significantly more common than the minor allele frequency observed in the general population from the 1000 Genomes database (61.1 vs 29.0%, OR=4.87, P<0.005). Additionally, the C-allele frequency was similar between TWP patients and the general population (34.4 vs 29%, OR=1.42, P=0.325). We have demonstrated that SUR1 alanine 1369 variant is associated with allelic susceptibility to TPP. We suggest that the hyperinsulinaemia that is observed in TPP may be linked to the ATP-sensitive K(+)/SUR1 alanine variant and, therefore, contribute to the major feedforward precipitating factors in the pathophysiology of TPP. PMID- 25143474 TI - Dietary fiber intake and total mortality: a meta-analysis of prospective cohort studies. AB - Greater intake of dietary fiber has been associated with lower risk of several chronic diseases. Some observational studies have examined the association between dietary fiber intake and total mortality, but the results were inconclusive. We conducted a meta-analysis of data from prospective cohort studies to quantitatively assess the association. Eligible studies were identified by searching the PubMed and Embase databases for all articles published through November 30, 2013, and by reviewing the reference lists of retrieved articles. Study-specific estimates adjusting for potential confounders were combined to calculate a pooled relative risk and 95% confidence interval using a random-effects model. Seven prospective cohort studies of dietary fiber intake and total mortality, including 62,314 deaths among 908,135 participants, were identified. The pooled adjusted relative risk of total mortality for the highest category of dietary fiber intake versus the lowest was 0.77 (95% confidence interval: 0.74, 0.80). In a dose-response meta-analysis, the pooled adjusted relative risk for a 10-g/day increment of dietary fiber intake was 0.89 (95% confidence interval: 0.85, 0 92). By source of fiber, cereal and, to a lesser extent, vegetable fiber were significantly associated with lower total mortality, while fruit fiber showed no association. In conclusion, high dietary fiber intake may reduce the risk of total mortality. PMID- 25143475 TI - The role of prediction modeling in propensity score estimation: an evaluation of logistic regression, bCART, and the covariate-balancing propensity score. AB - The covariate-balancing propensity score (CBPS) extends logistic regression to simultaneously optimize covariate balance and treatment prediction. Although the CBPS has been shown to perform well in certain settings, its performance has not been evaluated in settings specific to pharmacoepidemiology and large database research. In this study, we use both simulations and empirical data to compare the performance of the CBPS with logistic regression and boosted classification and regression trees. We simulated various degrees of model misspecification to evaluate the robustness of each propensity score (PS) estimation method. We then applied these methods to compare the effect of initiating glucagonlike peptide-1 agonists versus sulfonylureas on cardiovascular events and all-cause mortality in the US Medicare population in 2007-2009. In simulations, the CBPS was generally more robust in terms of balancing covariates and reducing bias compared with misspecified logistic PS models and boosted classification and regression trees. All PS estimation methods performed similarly in the empirical example. For settings common to pharmacoepidemiology, logistic regression with balance checks to assess model specification is a valid method for PS estimation, but it can require refitting multiple models until covariate balance is achieved. The CBPS is a promising method to improve the robustness of PS models. PMID- 25143477 TI - Zombie bugs? The fungus Purpureocillium cf. lilacinum may manipulate the behavior of its host bug Edessa rufomarginata. AB - Just before dying, Edessa rufomarginata (Hemiptera, Pentotomidae) individuals that are infected with the fungus Purpureocillium cf. lilacinum (Ascomycota: Ophiocordycipitaceae) move from the leaves onto the stems of their Solanum sp. host and firmly grasp the stems in ways seldom employed by uninfected bugs. These alterations in host behavior probably improve the chances that the subsequently produced fungal spores will be dispersed aerially. Purpureocillium cf. lilacinum is a member of the Ophiocordycipitaceae, a group in which other species also modify the behavior of their hosts. As in the case of newly distinguished relatives of Ophiocordyceps unilateralis associated with "zombie ants" the discovery of P. cf. lilacinum infecting bugs reveals that P. lilacinum may be more diverse than previously appreciated. PMID- 25143478 TI - Fodinomyces uranophilus gen. nov. sp. nov. and Coniochaeta fodinicola sp. nov., two uranium mine-inhabiting Ascomycota fungi from northern Australia. AB - Seven acidophilic/acidotolerant fungal strains were characterized from samples of process waters (raffinate) at one of Australia's largest uranium mines, the Ranger Mine in Northern Territory. They were isolated from raffinate, which typically were very acidic (pH 1.7-1.8) and contained high concentrations of total dissolved/colloidal salts (> 100 g/L). Five of the isolates correspond to two new acidotolerant Ascomycota fungi. The first is a member of a new genus, here described as Fodinomyces (Teratosphaeriaceae, Capnodiales, Dothideomycetes) and does not show clear close affiliation with any other described fungus in the scientific literature. The second belongs to the genus Coniochaeta (Coniochaetaceae, Coniochaetales, Sordariomycetes) and is closely related to Coniochaeta hansenii. PMID- 25143479 TI - Irineochytrium, a new genus in Chytridiales having zoospores and aplanospores. AB - Many described chytrids exhibit distinct morphological features that permit positive identification by light microscopy. Chytriomyces annulatus is one such species. It has a flap-like operculum and its sporangial wall is ornamented with multiple collar-like annulations proximal to the rhizoidal axis, features that, in combination, do not occur in any other described chytrid. Recent molecular phylogenies placed C. annulatus in the Chytridiaceae (Chytridiales) lineage, which is characterized by a Group II zoospore. Here we use light microscopy and transmission electron microscopy to examine thallus morphology of an isolate (JEL 729) of C. annulatus to confirm its identity and transmission electron microscopy to examine zoospore ultrastructure to confirm its phylogenetic placement. Light microscopic examinations confirmed its identity, and transmission electron microscopy analysis revealed both motile spores (zoospores) and nonmotile spores (aplanospores). Zoospores had a unique suite of ultrastructural features characteristic of the Group II zoospore; aplanospores had similar ultrastructure minus a flagellum. Chytriomyces annulatus does not group with the Chytriomycetaceae (Chytridiales) lineage containing the type of Chytriomyces, C. hyalinus, nor does it have a zoospore typical of that lineage. These arguments support the recognition of a distinct genus in Chytridiaceae, including one species, Irineochytrium annulatum. PMID- 25143480 TI - Acute pseudotumoral hemicerebellitis in a child: a rare and distinct entity? AB - A pseudotumoral presentation of acute hemicerebellitis is rare in pediatric age. The authors report a new single case study of a 7-year-old child with pseudotumoral unilateral cerebellitis mimicking an intracranial tumor, which clinically presented itself with signs of intracranial hypertension and mild contralateral hemiparesis, completely recovered after anti-inflammatory therapy. Brain magnetic resonance imaging (MRI) was essential for the differential diagnosis between inflammatory and neoplastic processes. The literature highlighting specific clues about pseudotumoral hemicerebellitis as a distinct clinical and radiological entity is reviewed. PMID- 25143481 TI - Everolimus Treatment for an Early Infantile Subependymal Giant Cell Astrocytoma With Tuberous Sclerosis Complex. AB - Subependymal giant cell astrocytomas are benign tumors often observed with tuberous sclerosis complex. These tumors are rarely diagnosed during fetal life or early infancy. Until recently, the only available treatment has been surgical resection. Current clinical research has demonstrated that everolimus can induce these tumors' regression. We report a 19-month-old boy with tuberous sclerosis complex. At 2 months of age, he presented with congenital subependymal giant cell astrocytoma that was complicated by refractory epilepsy and severe mental retardation. Treatment with everolimus was started when he was 10 months old. Three months after initiating everolimus, the tumor was significantly reduced in size, and the reduction was subsequently maintained. His seizures decreased and he showed cognitive and developmental improvement. No severe adverse events have been observed to date. Everolimus has promise as an effective alternative to surgery for subependymal giant cell astrocytomas during early infancy. PMID- 25143482 TI - How do you keto? Survey of North American pediatric ketogenic diet centers. AB - We surveyed ketogenic diet centers in North America about their practices surrounding the ketogenic diet. An internet survey was disseminated via REDCap((c)) to North American ketogenic diet centers identified from the Charlie Foundation and Ketocal((c)) websites. Fifty-six centers responded. In addition to physicians, nurses and dieticians, ketogenic teams included social workers (39%), feeding specialists (14%), educational liaisons (4%), psychologists (5%), and pharmacists (36%). A child attending school (2%), non-English speaking family (19%), single-parent family (0%), and oral feeding (6%) were rarely considered barriers. Overall, the diet was considered the first or second (0%), third or fourth (67%), fifth or sixth (29%), and last resort treatment (4%) by centers. It was considered the first or second treatment for GLUT1 disease (86%) and third or fourth for Dravet (63%), West (71%), and Doose (65%) syndromes. Ketogenic diet is no longer a last resort option. Traditional barriers do not influence its use. PMID- 25143483 TI - Does gender matter? Differences in social-emotional behavior among infants and toddlers before and after mild traumatic brain injury: a preliminary study. AB - Traumatic brain injury is a common cause of acquired disability in childhood. While much is known about cognitive sequelae of brain trauma, gender-specific social-emotional problems in children with mild traumatic brain injury is far less understood. The aims of the study were to investigate gender differences in social-emotional behavior before and after mild traumatic brain injury. Thirty five 3- to 65-month-old children with mild traumatic brain injury and 70 controls were assessed with Ages and Stages Questionnaires: Social-Emotional. Nine months later, 27 of 35 patients and 54 of 70 controls were reassessed. We found that before injury, boys had more self-regulation and autonomy difficulties and girls had problems with adaptive functioning. Nine months after injury, boys continued to struggle with self-regulation and autonomy and new difficulties with interaction had emerged, whereas in girls, problems in interaction had evolved. Even mild traumatic brain injury in early childhood disrupts normal social emotional development having especially devastating influence on interaction skills. PMID- 25143484 TI - Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma. AB - Myc oncogenic transcription factors (c-Myc, N-Myc, and L-Myc) coordinate the control of cell growth, division, and metabolism. In cancer, Myc overexpression is often associated with aggressive disease, which is in part due to the destruction of select targets by the ubiquitin-proteasome system (eg, SCF(Skp2) directed destruction of the Cdk inhibitor p27(Kip1)). We reasoned that Myc would also regulate SUMOylation, a related means of posttranslational modification of proteins, and that this circuit would play essential roles in Myc-dependent tumorigenesis. Here, we report marked increases in the expression of genes that encode regulators and components of the SUMOylation machinery in mouse and human Myc-driven lymphomas, resulting in hyper-SUMOylation in these tumors. Further, inhibition of SUMOylation by genetic means disables Myc-induced proliferation, triggering G2/M cell-cycle arrest, polyploidy, and apoptosis. Using genetically defined cell models and conditional expression systems, this response was shown to be Myc specific. Finally, in vivo loss-of-function and pharmacologic studies demonstrated that inhibition of SUMOylation provokes rapid regression of Myc driven lymphoma. Thus, targeting SUMOylation represents an attractive therapeutic option for lymphomas with MYC involvement. PMID- 25143485 TI - JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation. AB - Megakaryopoiesis is a 2-step differentiation process, regulated by thrombopoietin (TPO), on binding to its cognate receptor myeloproliferative leukemia (MPL). This receptor associates with intracytoplasmic tyrosine kinases, essentially janus kinase 2 (JAK2), which regulates MPL stability and cell-surface expression, and mediates TPO-induced signal transduction. We demonstrate that JAK2 and MPL mediate TPO-induced proliferation arrest and megakaryocytic differentiation of the human megakaryoblastic leukemia cell line UT7-MPL. A decrease in JAK2 or MPL protein expression, and JAK2 chemical inhibition, suppress this antiproliferative action of TPO. The expression of JAK2 and MPL, which progressively increases along normal human megakaryopoiesis, is decreased in platelets of patients diagnosed with JAK2- or MPL-mutated essential thrombocytemia and primary myelofibrosis, 2 myeloproliferative neoplasms in which megakaryocytes (MKs) proliferate excessively. Finally, low doses of JAK2 chemical inhibitors are shown to induce a paradoxical increase in MK production, both in vitro and in vivo. We propose that JAK2 and MPL expression levels regulate megakaryocytic proliferation vs differentiation in both normal and pathological conditions, and that JAK2 chemical inhibitors could promote a paradoxical thrombocytosis when used at suboptimal doses. PMID- 25143487 TI - Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. AB - GAUGUIN evaluated the safety and efficacy of obinutuzumab (GA101) monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In phase 1 (dose escalation), 13 patients received obinutuzumab 400 to 1200 mg (days 1 and 8 of cycle 1; day 1 of cycles 2-8). In phase 2, 20 patients received a fixed dose of 1000 mg (days 1, 8, and 15 of cycle 1; day 1 of cycles 2-8). Infusion-related reactions occurred in nearly all patients, but few were grade 3/4. Grade 3/4 neutropenia occurred in 7 patients in phase 1 (but was not dose-related) and in 4 patients in phase 2. Overall end-of-treatment response (all partial responses) was 62% (phase 1) and 15% (phase 2); best overall response was 62% and 30%, respectively. Phase 2 median progression-free survival was 10.7 months and median duration of response was 8.9 months. In summary, obinutuzumab monotherapy is active in patients with heavily pretreated relapsed/refractory CLL. PMID- 25143486 TI - Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice. AB - Evidence is emerging that platelets are major contributors to innate immune responses in conditions such as acute lung injury (ALI). Platelets form heterotypic aggregates with neutrophils, and we hypothesized that lipoxin mediators regulate formation of neutrophil-platelet aggregates (NPA) and that NPA significantly contribute to ALI. Lipopolysaccharide (LPS)-induced lung injury was accompanied by platelet sequestration, activation, intra-alveolar accumulation, and NPA formation within both blood and alveolar compartments. Using lung intravital microscopy, we observed the dynamic formation of NPA during physiologic conditions, which sharply increased with ALI. Aspirin (ASA) treatment significantly reduced lung platelet sequestration and activation, NPA formation, and lung injury. ASA treatment increased levels of ASA-triggered lipoxin (ATL; 15 epi-lipoxin A4), and blocking the lipoxin A4 receptor (ALX) with a peptide antagonist (Boc2) or using ALX knockouts (Fpr2/3(-/-)) reversed this protection. LPS increased NPA formation in vitro, which was reduced by ATL, and engagement of ALX by ATL on both neutrophils and platelets was necessary to prevent aggregation. In a model of transfusion-related acute lung injury (TRALI), Boc2 also reversed ASA protection, and treatment with ATL in both LPS and TRALI models protected from ALI. We conclude that ATL regulates neutrophil-platelet aggregation and that platelet-neutrophil interactions are a therapeutic target in lung injury. PMID- 25143488 TI - Radiographic identification of the anterior and posterior root attachments of the medial and lateral menisci. AB - BACKGROUND: Anatomic root placement is necessary to restore native meniscal function during meniscal root repair. Radiographic guidelines for anatomic root placement are essential to improve the accuracy and consistency of anatomic root repair and to optimize outcomes after surgery. PURPOSE: To define quantitative radiographic guidelines for identification of the anterior and posterior root attachments of the medial and lateral menisci on anteroposterior (AP) and lateral radiographic views. STUDY DESIGN: Descriptive laboratory study. METHODS: The anterior and posterior roots of the medial and lateral menisci were identified in 12 human cadaveric specimens (average age, 51.3 years; age range, 39-65 years) and labeled using 2-mm radiopaque spheres. True AP and lateral radiographs were obtained, and 2 raters independently measured blinded radiographs in relation to pertinent landmarks and radiographic reference lines. RESULTS: On AP radiographs, the anteromedial and posteromedial roots were, on average, 31.9 +/- 5.0 mm and 36.3 +/- 3.5 mm lateral to the edge of the medial tibial plateau, respectively. The anterolateral and posterolateral roots were, on average, 37.9 +/- 5.2 mm and 39.3 +/- 3.8 mm medial to the edge of the lateral tibial plateau, respectively. On lateral radiographs, the anteromedial and anterolateral roots were, on average, 4.8 +/- 3.7 mm and 20.5 +/- 4.3 mm posterior to the anterior margin of the tibial plateau, respectively. The posteromedial and posterolateral roots were, on average, 18.0 +/- 2.8 mm and 19.8 +/- 3.5 mm anterior to the posterior margin of the tibial plateau, respectively. The intrarater and interrater intraclass correlation coefficients (ICCs) were >0.958, demonstrating excellent reliability. CONCLUSION: The meniscal root attachment sites were quantitatively and reproducibly defined with respect to anatomic landmarks and superimposed radiographic reference lines. The high ICCs indicate that the measured radiographic relationships are a consistent means for evaluating meniscal root positions. CLINICAL RELEVANCE: This study demonstrated consistent and reproducible radiographic guidelines for the location of the meniscal roots. These measurements may be used to assess root positions on intraoperative fluoroscopy and postoperative radiographs. PMID- 25143489 TI - Early Versus Delayed Passive Range of Motion Exercise for Arthroscopic Rotator Cuff Repair: A Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: Postoperative shoulder stiffness complicates functional recovery after arthroscopic rotator cuff repair. PURPOSE: To compare early passive range of motion (ROM) exercise with a delayed rehabilitation protocol with regard to the effectiveness of stiffness reduction and functional improvements and rates of improper healing in patients undergoing arthroscopic repair for torn rotator cuffs. STUDY DESIGN: Systematic review and meta-analysis. METHODS: Randomized controlled trials (RCTs) comparing both rehabilitation approaches were identified in PubMed and Scopus. Between-group differences in shoulder function were transformed to effect sizes for comparisons, whereas the effectiveness against stiffness and the risk of tendon failure were reported using standardized mean differences of ROM degrees and odds ratios (ORs) of recurrent tears, respectively. RESULTS: Six RCTs were included, consisting of 482 patients. No significant difference in shoulder function existed across both protocols. The early ROM group demonstrated more improvement in shoulder forward flexion than the delayed rehabilitation group, with a standardized mean difference of 7.45 degrees (95% CI, 3.20 degrees -11.70 degrees ) at 6 months and 3.51 degrees (95% CI, 0.31 degrees -6.71 degrees ) at 12 months. Early ROM exercise tended to cause a higher rate of recurrent tendon tears (OR, 1.43; 95% CI, 0.90-2.28), and the effect became statistically significant (OR, 1.93; 95% CI, 1.04-3.60) after excluding 2 RCTs that recruited only those patients with small to medium-sized tears. CONCLUSION: Early ROM exercise accelerated recovery from postoperative stiffness for patients after arthroscopic rotator cuff repair but was likely to result in improper tendon healing in shoulders with large-sized tears. The choice of either protocol should be based on an accommodation of the risks of recurrent tears and postoperative shoulder stiffness. PMID- 25143491 TI - Soft-tissue allografts terminally sterilized with an electron beam are biomechanically equivalent to aseptic, nonsterilized tendons. AB - BACKGROUND: Allograft safety is contingent on effective sterilization. However, current sterilization methods have been associated with decreased biomechanical strength and higher failure rates of soft-tissue allografts. In this study, electron beam (e-beam) sterilization was explored as an alternative sterilization method to preserve biomechanical integrity. We hypothesized that e-beam sterilization would not significantly alter the biomechanical properties of tendon allograft compared with aseptic, nonsterilized controls and gamma irradiated grafts. METHODS: Separate sets of forty fresh-frozen tibialis tendon allografts (four from each of ten donors) and forty bisected bone-patellar tendon bone (BTB) allografts (four from each of ten donors) were randomly assigned to four study groups. One group received a 17.1 to 21.0-kGy gamma radiation dose; two other groups were sterilized with an e-beam at either a high (17.1 to 21.0 kGy) or low (9.2 to 12.2-kGy) dose. A fourth group served as nonsterilized controls. Each graft was cyclically loaded to 200 N of tension for 2000 cycles at a frequency of 2 Hz, allowed to relax for five minutes, and then tested in tension until failure at a 100%/sec strain rate. One-way analysis of variance testing was used to identify significant differences. RESULTS: Tibialis tendons sterilized with both e-beam treatments and with gamma irradiation exhibited values for cyclic tendon elongation, maximum load, maximum displacement, stiffness, maximum stress, maximum strain, and elastic modulus that were not significantly different from those of nonsterilized controls. BTB allografts sterilized with the high e-beam dose and with gamma irradiation were not significantly different in cyclic tendon elongation, maximum load, maximum displacement, stiffness, maximum stress, maximum strain, and elastic modulus from nonsterilized controls. BTB allografts sterilized with the e-beam at the lower dose were significantly less stiff than nonsterilized controls (p = 0.014) but did not differ from controls in any other properties. The difference in stiffness likely resulted from variations in tendon size rather than the treatments, as the elastic moduli of the groups were similar. CONCLUSIONS: The biomechanical properties of tibialis and BTB allografts sterilized with use of an e-beam at a dose range of 17.1 to 21.0 kGy were not different from those of aseptic, nonsterilized controls or gamma-irradiated allografts. CLINICAL RELEVANCE: E-beam sterilization can be a viable method to produce safe and biomechanically uncompromised soft-tissue allografts. PMID- 25143490 TI - Fluoroquinolones impair tendon healing in a rat rotator cuff repair model: a preliminary study. AB - BACKGROUND: Recent studies suggest that fluoroquinolone antibiotics predispose tendons to tendinopathy and/or rupture. However, no investigations on the reparative capacity of tendons exposed to fluoroquinolones have been conducted. HYPOTHESIS: Fluoroquinolone-treated animals will have inferior biochemical, histological, and biomechanical properties at the healing tendon-bone enthesis compared with controls. STUDY DESIGN: Controlled laboratory study. METHODS: Ninety-two rats underwent rotator cuff repair and were randomly assigned to 1 of 4 groups: (1) preoperative (Preop), whereby animals received fleroxacin for 1 week preoperatively; (2) pre- and postoperative (Pre/Postop), whereby animals received fleroxacin for 1 week preoperatively and for 2 weeks postoperatively; (3) postoperative (Postop), whereby animals received fleroxacin for 2 weeks postoperatively; and (4) control, whereby animals received vehicle for 1 week preoperatively and for 2 weeks postoperatively. Rats were euthanized at 2 weeks postoperatively for biochemical, histological, and biomechanical analysis. All data were expressed as mean +/- standard error of the mean (SEM). Statistical comparisons were performed using either 1-way or 2-way ANOVA, with P < .05 considered significant. RESULTS: Reverse transcriptase quantitative polymerase chain reaction (RTqPCR) analysis revealed a 30-fold increase in expression of matrix metalloproteinase (MMP)-3, a 7-fold increase in MMP-13, and a 4-fold increase in tissue inhibitor of metalloproteinases (TIMP)-1 in the Pre/Postop group compared with the other groups. The appearance of the healing enthesis in all treated animals was qualitatively different than that in controls. The tendons were friable and atrophic. All 3 treated groups showed significantly less fibrocartilage and poorly organized collagen at the healing enthesis compared with control animals. There was a significant difference in the mode of failure, with treated animals demonstrating an intrasubstance failure of the supraspinatus tendon during testing. In contrast, only 1 of 10 control samples failed within the tendon substance. The healing enthesis of the Pre/Postop group displayed significantly reduced ultimate load to failure compared with the Preop, Postop, and control groups. There was no significant difference in load to failure in the Preop group compared with the Postop group. Pre/Postop animals demonstrated significantly reduced cross-sectional area compared with the Postop and control groups. There was also a significant reduction in area between the Preop and control groups. CONCLUSION: In this preliminary study, fluoroquinolone treatment negatively influenced tendon healing. CLINICAL RELEVANCE: These findings indicate that there was an active but inadequate repair response that has potential clinical implications for patients who are exposed to fluoroquinolones before tendon repair surgery. PMID- 25143492 TI - Evaluation of the first-generation AAOS clinical guidelines on the prophylaxis of venous thromboembolic events in patients undergoing total joint arthroplasty: experience with 3289 patients from a single institution. AB - BACKGROUND: Patients undergoing total hip or total knee arthroplasty have risks that include venous thromboembolism. The American Academy of Orthopaedic Surgeons has promulgated guidelines for the preoperative assessment of patients with the primary objective of preventing pulmonary embolism. We aimed to evaluate and establish the utility of the first-generation American Academy of Orthopaedic Surgeons guidelines for the prophylaxis of venous thromboembolism in patients undergoing total joint arthroplasty at a single institution. METHODS: A prospective analysis of 3289 consecutive patients managed with total hip or total knee arthroplasty at the Connecticut Joint Replacement Institute between June 1, 2009, and April 30, 2011, was conducted. Data on age, sex, body mass index, American Society of Anesthesiologists classification, and a personal or family history of blood clots requiring long-term warfarin use were analyzed, as were data on a personal history of a malignant tumor, a bleeding disorder, gastrointestinal bleeding, or a hemorrhagic cerebrovascular accident. All patients were managed prophylactically with a specific algorithm based on the American Academy of Orthopaedic Surgeons guidelines. All of the patients were mobilized on postoperative day one, and pneumatic foot-pump compression was used for the duration of the hospitalization. RESULTS: Thirty-six major venous thromboembolic events were documented with Doppler ultrasound or computed tomography angiography, for a ninety-day incidence of 1.1% (95% confidence interval, 0.8% to 1.5%). A personal history of blood clots was significantly associated with a blood clot in the proximal part of the thigh or a pulmonary embolism, but a family history of blood clots and a personal history of a malignant tumor did not show a significant relationship with venous thromboembolism. The ninety-day incidence of venous thromboembolism was significantly different between total hip arthroplasty patients (0.56%; 95% confidence interval, 0.30% to 1.15%) and total knee arthroplasty patients (1.46%; 95% confidence interval, 1.01% to 2.10%). The risk was greater in high-risk total knee arthroplasty patients compared with high-risk total hip arthroplasty patients despite comparable prophylaxis with enoxaparin sodium for twenty-eight days. CONCLUSIONS: The prospective use of the first-generation American Academy of Orthopaedic Surgeons guidelines resulted in a low incidence of clinically important thromboembolic events in total hip and total knee arthroplasty patients. When properly used in these patients, the guidelines to minimize adverse outcomes are executable and effective. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25143493 TI - The effect of surgeon experience on outcomes of surgery for adolescent idiopathic scoliosis. AB - BACKGROUND: Single-surgeon series investigating the learning curve involved in surgery for spinal deformity may be confounded by changes in technology and techniques. Our objective with this multicenter, prospective study was to present a cross-sectional analysis of the impact of surgeon experience on surgery for adolescent idiopathic scoliosis. METHODS: All posterior-only surgical procedures for adolescent idiopathic scoliosis performed in the 2007 to 2008 academic year, with a minimum of two years of patient follow-up, were included. Two groups were created on the basis of surgeon experience: a young surgeons' group, which included patients of surgeons with less than five years of experience, and an experienced surgeons' group, which included patients of surgeons with five or more years of experience. RESULTS: Nine surgeons (four young and five experienced) operated on a total of one hundred and sixty-five patients with adolescent idiopathic scoliosis. The surgeons' experience ranged from less than one year to thirty-six years in practice. The two groups had similar preoperative curve-magnitude measurements, SRS-22 (Scoliosis Research Society-22) scores, and distribution by Lenke curve type. There were significant operative and postoperative differences. The young surgeons fused an average of 1.2 levels more than the experienced surgeons (p = 0.045). The mean intraoperative estimated blood loss (EBL) of the young surgeons' group was more than twice that of the experienced surgeons' group (2042 mL compared with 1013 mL; p < 0.001). The duration of surgery was 458 minutes for the young surgeons compared with 265 minutes for the experienced surgeons (p < 0.001). The overall SRS-22 scores were significantly worse in the young surgeons' group (a mean of 4.1 compared with 4.5; p = 0.001). The difference between groups was also significant for the domains of pain (p = 0.016), self-image (p = 0.008), and function (p < 0.001). Complication rates did not differ significantly between the groups. CONCLUSIONS: Operative results and health-related quality of life following surgery for adolescent idiopathic scoliosis were significantly and positively correlated with surgeon experience. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25143494 TI - The Bristow and Latarjet procedures: why these techniques should not be considered synonymous. AB - BACKGROUND: Recurrent shoulder instability is commonly associated with glenoid bone defects. Coracoid transfer procedures, such as the Bristow and Latarjet procedures, are frequently used to address these bone deficiencies. Despite the frequent synonymous labeling of these transfers as the "Bristow-Latarjet" procedure, their true equivalence has not been demonstrated. Therefore, our purpose was to compare the biomechanical effects of these two procedures. METHODS: Eight cadaveric specimens were tested on a custom shoulder simulator capable of loading nine muscle groups and of accurately orienting the joint throughout shoulder motion. The specimens were tested in the intact state, following Bristow and Latarjet reconstructions of a capsulolabral injury (0% glenoid defect), and following each procedure after creation of 15% and 30% glenoid bone defects. The reconstruction order was randomized. In each condition, joint stiffness (anterior stability) and occurrence of dislocation were assessed in shoulder adduction and abduction with neutral and external rotation. RESULTS: No significant differences (p < 0.05) in joint stiffness or stability were found between the Bristow and Latarjet reconstructions for the 0% glenoid defect in any joint position. However, substantially greater joint stiffness occurred following the Latarjet procedure, as compared with the Bristow procedure, for the 15% and 30% glenoid bone-loss conditions in adduction with neutral rotation, adduction with external rotation, and abduction with external rotation (average across the three joint positions: 8.6 +/- 4.4 N/mm versus 3.9 +/- 1.26.7 N/mm [p = 0.034] with 15% bone loss and 7.5 +/- 4.4 N/mm versus 3.4 +/- 1.5 N/mm [p = 0.045] with 30% bone loss). The Latarjet reconstruction restored the stiffness that had been measured in the intact state in eleven of the twelve tested conditions, whereas the Bristow procedure was successful in only four of the twelve conditions. In addition, during instability testing, three more specimens dislocated following the Bristow reconstruction, compared with the Latarjet procedure, in the 15% defect condition and five more dislocated in the 30% defect condition. CONCLUSIONS: The Bristow and Latarjet procedures are not equivalent in terms of their effects on glenohumeral joint stiffness and stability in cases of glenoid osseous deficiency. CLINICAL RELEVANCE: The Bristow and Latarjet procedures have equivalent stabilizing effects in unstable shoulders with preserved glenoid osseous anatomy. However, the Latarjet procedure confers superior stabilization in the setting of substantial glenoid bone loss. PMID- 25143495 TI - The effect of timing of manipulation under anesthesia to improve range of motion and functional outcomes following total knee arthroplasty. AB - BACKGROUND: Manipulation under anesthesia has been reported to improve range of motion when other rehabilitative efforts fail to obtain adequate motion after total knee arthroplasty. The purpose of this study was to evaluate the effects of the timing of the manipulation on knee range of motion and clinical outcomes. METHODS: All 2128 total knee arthroplasties performed at our institution from 2005 to 2011 were reviewed to determine the number of patients who had undergone manipulation under anesthesia. A total of 144 manipulations in eighty-eight women and forty-five men were reviewed. Manipulations under anesthesia that were performed within the first twelve weeks after total knee arthroplasty were considered early and those after that period were considered late. Patients were further substratified according to the timing of the manipulation: Group I included those who had the manipulation within six weeks; Group II, at seven to twelve weeks; Group III, at thirteen to twenty-six weeks; and Group IV, after twenty-six weeks. Outcomes evaluated included gains in flexion and final range of motion, and Knee Society objective and function scores between early and late manipulation, using various adjusted multivariable regression models and at a mean follow-up of fifty-one months (range, twelve to eighty-one months). Mediation analysis was used to investigate whether gains in range of motion from the manipulations under anesthesia alone had mediated the effect between the timing of the manipulation and the clinical outcomes. RESULTS: Patients who underwent early manipulation had a significantly higher mean gain in flexion (36.5 degrees versus 17 degrees ), higher final range of motion (119 degrees versus 95 degrees ), and higher Knee Society objective (89 versus 84 points) and function scores (88 versus 83 points) than those who had late manipulation under anesthesia. There were no significant differences in the outcomes of Groups I and II. Manipulations after twenty-six weeks resulted in unsatisfactory clinical outcomes. Multivariable regression analyses confirmed significantly better clinical outcomes with early manipulation. Mediation analysis showed that the timing of manipulation independently had significantly contributed to the outcomes. CONCLUSIONS: Orthopaedic surgeons should have a low threshold for performing early manipulations with the patient under anesthesia within twelve weeks after an arthroplasty, to achieve higher knee range of motion and improved clinical outcomes. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25143496 TI - Development and initial validation of the Classification of Early-Onset Scoliosis (C-EOS). AB - BACKGROUND: Early-onset scoliosis is a heterogeneous condition, with highly variable manifestations and natural history. No standardized classification system exists to describe and group patients, to guide optimal care, or to prognosticate outcomes within this population. A classification system for early onset scoliosis is thus a necessary prerequisite to the timely evolution of care of these patients. METHODS: Fifteen experienced surgeons participated in a nominal group technique designed to achieve a consensus-based classification system for early-onset scoliosis. A comprehensive list of factors important in managing early-onset scoliosis was generated using a standardized literature review, semi-structured interviews, and open forum discussion. Three group meetings and two rounds of surveying guided the selection of classification components, subgroupings, and cut-points. Initial validation of the system was conducted using an interobserver reliability assessment based on the classification of a series of thirty cases. RESULTS: Nominal group technique was used to identify three core variables (major curve angle, etiology, and kyphosis) with high group content validity scores. Age and curve progression ranked slightly lower. Participants evaluated the cases of thirty patients with early onset scoliosis for reliability testing. The mean kappa value for etiology (0.64) was substantial, while the mean kappa values for major curve angle (0.95) and kyphosis (0.93) indicated almost perfect agreement. The final classification consisted of a continuous age prefix, etiology (congenital or structural, neuromuscular, syndromic, and idiopathic), major curve angle (1, 2, 3, or 4), and kyphosis (-, N, or +) variables, and an optional progression modifier (P0, P1, or P2). CONCLUSIONS: Utilizing formal consensus-building methods in a large group of surgeons experienced in treating early-onset scoliosis, a novel classification system for early-onset scoliosis was developed with all core components demonstrating substantial to excellent interobserver reliability. This classification system will serve as a foundation to guide ongoing research efforts and standardize communication in the clinical setting. PMID- 25143497 TI - Comparison of two percutaneous volar approaches for screw fixation of scaphoid waist fractures: radiographic and biomechanical study of an osteotomy-simulated model. AB - BACKGROUND: When a surgeon uses a percutaneous volar approach to treat scaphoid waist fractures, central screw placement is complicated by the shape of the scaphoid and by obstruction by the trapezium. In this study, we used radiographs and biomechanical tests to compare the standard volar percutaneous approach with the transtrapezial approach, with regard to central screw placement at the distal pole of the scaphoid. METHODS: Fourteen matched pairs of cadaveric wrists were randomly assigned to two treatment groups. Under fluoroscopic control, a guidewire was drilled into the scaphoid, either through a transtrapezial approach or through a standard volar approach that avoided the trapezium. Guidewire position was measured in the coronal and sagittal planes. A transverse osteotomy was performed along the scaphoid waist, and this was followed by the insertion of the longest possible cannulated headless bone screw. Each specimen was placed into a fixture with a pneumatically driven plunger resting on the surface of the distal pole. Load was applied by using a load-controlled test protocol in a hydraulic testing machine. RESULTS: All guidewires were inside the central one third of the proximal pole. The guidewire positions at the distal pole differed significantly between the transtrapezial and standard volar approach groups (p < 0.001). The load to 2 mm of displacement and the load to failure averaged, respectively, 324.4 N (standard error of the mean [SEM] = 73.5 N) and 386.4 N (SEM = 65.6 N) for the transtrapezial approach group compared with 125.7 N (SEM = 22.6 N) (p = 0.002) and 191.4 N (SEM = 36.30 N) (p = 0.005) for the standard volar approach group. CONCLUSIONS: The data suggest that, in a cadaveric osteotomy-simulated scaphoid waist fracture model, the transtrapezial approach reliably achieves central positioning of a screw in the proximal and distal poles. This position offers a biomechanical advantage compared with central placement in only the proximal pole. PMID- 25143498 TI - Negative-pressure wound therapy after fasciotomy reduces muscle-fiber regeneration in a pig model. AB - BACKGROUND: Negative-pressure wound therapy (NPWT) can improve fasciotomy wound closure, but its effects on skeletal muscle are largely unknown. The purpose of this study was to evaluate NPWT effects on skeletal muscle after fasciotomy for compartment syndrome in an animal model and to assess regional variability in muscle fiber regeneration. METHODS: Compartment syndrome was induced in the hindlimb of twenty-two adult female pigs with use of a continuous intracompartmental serum-infusion model. Fasciotomy was performed after six hours, and animals were randomized to receive either wet-to-dry gauze dressings (control group) or NPWT dressings (-125 mm Hg, continuous suction) for seven days. Delayed primary wound closure was attempted at seven days, and the peroneus tertius was harvested for analysis seven days or twenty-one days after fasciotomy. Muscles were weighed, and hematoxylin and eosin-stained samples from four regions of the muscle (superficial central, deep central, lateral, and proximal) were mapped for different cellular morphologies. RESULTS: Muscle weight was greater in the affected limb at all time points with no difference between treatment groups. At seven days, only the deep central samples in the NPWT group had a significantly greater cross-sectional area containing normal fibers as compared with that found in the controls. By twenty-one days, the deep central, lateral, and proximal regions of the NPWT-treated muscles had a smaller cross sectional area containing normal fiber morphology and a greater cross-sectional area containing only mononucleated cells as compared with the controls. CONCLUSIONS: NPWT did not decrease muscle weight. At twenty-one days, the extent of muscle fiber regeneration after fasciotomy for compartment syndrome was reduced in muscles treated with NPWT for seven days compared with the values in the control group treated with wet-to-dry gauze dressings. CLINICAL RELEVANCE: NPWT may be harmful to skeletal muscle after compartment syndrome requiring fasciotomy and local wound care. PMID- 25143499 TI - Differences in short-term complications between unicompartmental and total knee arthroplasty: a propensity score matched analysis. AB - BACKGROUND: Knee arthroplasty has emerged as an effective treatment for end-stage gonarthrosis. Although total knee arthroplasty remains the gold standard, unicompartmental knee arthroplasty is an appropriate alternative for select patients. We sought to use a large, heterogeneous national database to identify differences in thirty-day complication rates between unicompartmental and total knee arthroplasty as well as to identify risk factors for complications. METHODS: Patients in the ACS NSQIP (American College of Surgeons National Surgical Quality Improvement Program) database who had undergone total or unicompartmental knee arthroplasty from 2005 to 2011 were identified. CPT (Current Procedural Terminology) codes were used to select cases of elective primary knee arthroplasty. Statistical models employing univariate and multivariate logistic regression identified risk factors associated with the thirty-day incidence of morbidity and mortality after total and unicompartmental knee arthroplasty. Propensity score matching addressed demographic differences between the total and unicompartmental knee arthroplasty cohorts. RESULTS: A total of 29,333 patients were identified; 27,745 (94.6%) underwent total knee arthroplasty and 1588 (5.41%) underwent unicompartmental knee arthroplasty. Prior to matching, the total knee arthroplasty cohort was 63.7% female and had a mean BMI of 32.8 +/- 7.3 kg/m(2), whereas the values for the unicompartmental cohort were 55.3% and 31.5 +/- 6.5 kg/m(2) (p < 0.0001). The mean ages of these cohorts were 67.2 +/- 10.1 and 64.0 +/- 10.7 years, respectively (p < 0.0001). A previously developed and implemented propensity score matching algorithm was used to address the demographic differences. Following matching, the total complication rate did not differ significantly between the total and unicompartmental knee arthroplasty cohorts (5.29% compared with 4.16%, p = 0.35), whereas the rate of deep venous thrombosis (1.50% compared with 0.50%, p = 0.02) and the duration of hospital stay (3.4 compared with 2.2 days, p < 0.0001) were significantly higher in the total knee arthroplasty cohort. CONCLUSIONS: Comparison of total and unicompartmental knee arthroplasty revealed no differences in overall short-term (thirty-day) morbidity and mortality. Although this study does not address long term subjective outcomes or implant survival, these findings should provide helpful information for surgeons counseling patients considering total and/or unicompartmental knee arthroplasty. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25143500 TI - Arthroscopic partial meniscectomy was not better than sham surgery for medial meniscal tear. PMID- 25143501 TI - Open reduction and plate fixation reduced nonunion after displaced midshaft clavicular fracture. PMID- 25143502 TI - Immobilization with an external rotation brace was similar to an internal rotation sling for shoulder dislocation. PMID- 25143503 TI - What's new in limb-lengthening and deformity correction. PMID- 25143504 TI - Weight-bearing compared with non-weight-bearing following osteochondral autograft transfer for small defects in weight-bearing areas in the femoral articular cartilage of the knee. AB - BACKGROUND: Patients are routinely kept non-weight-bearing for four to eight weeks following osteochondral autograft transfer to repair cartilage defects of the medial and/or lateral femoral condyle. Therefore, the objective of this novel study was to investigate whether postoperative weight-bearing restrictions affect the outcomes of cartilage repair when an osteochondral autograft transfer system is used to repair small defects in weight-bearing areas of femoral articular cartilage. METHODS: This a retrospective comparative study. Following review of the charts on 567 consecutive arthroscopic osteochondral autograft transfers, three homogeneous groups of patients with consecutive cases were identified: group A, cases of patients who were non-weight-bearing following the procedure (n = 68); group B, cases of those who were non-weight-bearing following the procedure with concomitant anterior cruciate ligament reconstruction (n = 29); and group C, cases of those who were weight-bearing as tolerated following the procedure (n = 437). The cases of patients whose knees underwent second-look (repeat) arthroscopy were stratified into two subgroups: non-weight-bearing (n = 20) and weight-bearing as tolerated (n = 42). Graft position and manifestation of a repair-adjacent defect (Outerbridge grade-III or IV cartilage defect that develops adjacent to the original osteochondral autograft transfer repair) were assessed during second-look arthroscopy. Cartilage repair was retrospectively assessed from second-look arthroscopy pictures by a blinded, independent orthopaedic surgeon with use of the International Cartilage Repair Society macroscopic cartilage-repair assessment tool. Postoperative complication rates were compared among the three primary groups. RESULTS: The mean grafted area was 0.72 cm(2) (range, 0.16 to 1.45 cm(2)) and 0.73 cm(2) (range, 0.16 to 1.80 cm(2)) for the non-weight-bearing and weight-bearing-as-tolerated second-look subgroups, respectively. The mean International Cartilage Repair Society score was 11.12 and 11.25 points (near-normal cartilage) for the non-weight-bearing and weight bearing-as-tolerated subgroups (p = 0.71) at a mean follow-up of 42.7 and 33.0 months, respectively. There was no significant difference in the duration of follow-up (p = 0.58), repair-adjacent defect prevalence (p = 0.94), or graft position (p = 0.99) between the two subgroups. Weight-bearing-as-tolerated patients (group C) experienced significantly fewer deep vein thrombosis and arthrofibrosis complications compared with non-weight-bearing patients (groups A and B) (p < 0.001). CONCLUSIONS: Postoperative weight-bearing restrictions did not affect mid-term cartilage repair outcomes in patients who underwent second look arthroscopy when an osteochondral autograft transfer system was used to repair small defects in weight-bearing areas of cartilage of the medial and/or lateral femoral condyle. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25143505 TI - Can neonatal pelvic osteotomies permanently change pelvic shape in patients with exstrophy? Understanding late rediastasis. AB - BACKGROUND: Pelvic osteotomies are frequently used as part of the surgical management of bladder exstrophy. The outcomes are often measured on the basis of the residual symphyseal diastasis. The aims of this study were to evaluate and validate a more reliable radiographic measure of ischiopubic rotation, to utilize this measure in analyzing pelves from patients with exstrophy and controls, and to propose a model for rediastasis in a pelvis with exstrophy. METHODS: Pelvic radiographs of 164 normal children two months to eighteen years of age were used to determine the changes in interpubic and interischial distances and in the interischial/interpubic (IS/IP) ratio with age. Twenty-one pelvic CT (computed tomography) studies of normal children, two to sixteen years of age, were also used to study the change in the ischiopubic divergence angle. The same parameters were measured on radiographs or CT or magnetic resonance imaging studies of seventy-three patients with classic bladder exstrophy who were followed for two to nineteen years after exstrophy closure with or without pelvic osteotomies. RESULTS: In normal children, the interpubic distance and the ischiopubic divergence angle had a narrow range and were constant with age, whereas the interischial distance and the IS/IP ratio increased progressively and were strongly correlated with age. In the patients with exstrophy, the interpubic distance was positively correlated with the interischial distance, whereas the IS/IP ratio was lower than that in normal controls and was not correlated with age. CONCLUSIONS: The IS/IP ratio is a useful measure of ischiopubic rotation and can be used to characterize pelvic growth, including the phenomenon of rediastasis in patients with exstrophy. Pelvic rediastasis is a progressive increase in interpubic distance resulting from growth without loss of rotational correction, as shown by the constancy of the IS/IP ratio with age in these patients. A better rotational position at the time of osteotomy may lead to a better pelvic shape at maturity. CLINICAL RELEVANCE: Symphyseal rediastasis following neonatal pelvic osteotomies in patients with exstrophy is not due to loss of correction and progressive derotation of the hemipelves but is a consequence of the normal three-dimensional growth of the pelvis. The best correction of the pelvic deformity should always be the aim even in neonatal pelvic osteotomies because this will permanently change the pelvic shape. PMID- 25143506 TI - A comparison of concentric and eccentric glenospheres in reverse shoulder arthroplasty: a randomized controlled trial. AB - BACKGROUND: Inferior scapular notching following reverse shoulder arthroplasty is due to mechanical impingement and, in some studies, has been associated with poorer functional scores, lower patient satisfaction, and more limited shoulder motion. We aimed to test the hypothesis that inferior positioning of the center of rotation with eccentric glenosphere designs decreases the adduction deficit before impingement occurs and improves clinical outcome. METHODS: A randomized, controlled, double-blinded trial was performed. According to the results of a power analysis, fifty patients undergoing reverse shoulder arthroplasty for the diagnosis of cuff tear arthropathy were randomized intraoperatively to receive either a concentric or eccentric glenosphere. The glenoid baseplate was positioned flush to the inferior border of the glenoid before the glenosphere was then attached. Notching was assessed using an anteroposterior radiograph, and clinical outcome was assessed using the visual analog pain scale score, shoulder function rating, American Shoulder and Elbow Surgeons score, and Oxford shoulder score. Active forward elevation and external rotation were assessed. The outcome assessor was blinded to the treatment group. The mean follow-up period for the groups was forty-three and forty-seven months. RESULTS: Patient demographics and preoperative scores were similar between the groups. At the time of the final follow-up, four patients (14.8%) in the concentric group had developed inferior scapular notching (two with Nerot grade I and two with Nerot grade II), ranging in size from 1.1 to 7.4 mm, compared with one patient (4.3%; Nerot grade I) in the eccentric group (p = 0.36). No notching occurred in any patient with glenoid overhang of >3.5 mm. No significant difference between the groups was seen with respect to functional outcome scores, patient satisfaction, or shoulder motion. CONCLUSIONS: There were no differences in notching rates or clinical outcomes between concentric and eccentric glenospheres following reverse shoulder arthroplasty. Inferior glenosphere overhang of >3.5 mm, however, prevented notching. This may be achieved with a modified surgical technique, but eccentric glenospheres provide an additional option. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 25143507 TI - Prevalence of rotator cuff tears in adults with traumatic brachial plexus injuries. AB - BACKGROUND: Restoration of shoulder function is a primary goal when treating patients with traumatic brachial plexus injury. A concomitant rotator cuff tear may alter the treatment approach and prognosis for these individuals. The purpose of this study was to define the prevalence of rotator cuff tears in patients with traumatic brachial plexus injuries. METHODS: This is a retrospective review of 280 adult patients with traumatic brachial plexus injury treated at a single institution over a twelve-year period. An upper-extremity magnetic resonance imaging (MRI) scan was acquired for all patients as part of the initial evaluation for posttraumatic brachial plexus injury. The radiographic and clinical data on these patients were reviewed to document partial or full thickness rotator cuff tears, mechanism and location of the brachial plexus injury, and age. RESULTS: Twenty-three patients (8.2%) had a full-thickness rotator cuff tear: one patient had tears involving three tendons, eight patients had tears involving two tendons, twelve patients had a single-tendon tear, one patient had a single-tendon tear in each shoulder, and one patient had a single tendon tear in one shoulder and a two-tendon tear in the other. Twenty-one tears involved the supraspinatus, eight involved the infraspinatus, and seven involved the subscapularis. Thirteen patients underwent surgical repair of the rotator cuff. The average age of the patients in this cohort was 33.4 years, and older age was associated with an increased risk of full-thickness rotator cuff tears (odds ratio [OR], 1.06 per year). Patients with infraclavicular brachial plexus injury had a significantly higher rate of full-thickness rotator cuff tears. CONCLUSIONS: Concomitant rotator cuff tears are present in approximately one in ten patients with traumatic brachial plexus injury. These injuries may contribute to shoulder dysfunction; therefore, evaluation of the rotator cuff with imaging studies is appropriate when formulating treatment strategies. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25143508 TI - A surgical skills training curriculum for PGY-1 residents: AAOS exhibit selection. PMID- 25143509 TI - The effect of the Massachusetts healthcare reform on the uninsured rate of the orthopaedic trauma population. AB - BACKGROUND: The 2006 Massachusetts Healthcare Reform (MHR) has resulted in health coverage for 98.1% of residents in Massachusetts. The purpose of this study was to evaluate the effect of MHR on the actual rate of uninsured individuals in the orthopaedic trauma population in the largest metropolitan area of Massachusetts. We also sought to measure the change in uncompensated care following the implementation of MHR. METHODS: We performed a retrospective review of all patients treated by the orthopaedic trauma services at three of the four level-I trauma centers in Boston from 2003 to 2010. The primary study cohort consisted of all uninsured patients, while the remaining patients were considered to have insurance. The study population was divided into two groups to compare the uninsured rate before and after MHR. Patients from 2006 to 2007 were excluded from the analysis to allow for an enrollment period in subsidized health insurance. RESULTS: A total of 16,338 patients with extremity and pelvic fractures and dislocations were treated from 2003 to 2010. There was a significant decrease in the uninsured rate from 23.8% to 14.4% following MHR (p < 0.001). The post-MHR risk of being uninsured is approximately 0.6 times the pre MHR risk, with a 95% confidence interval of 0.56 to 0.65. There was also a reduction in the proportion of uncompensated care from 16.7% to 11.5% after MHR. CONCLUSIONS: There was an estimated 40% reduction in risk of uninsured individuals in the orthopaedic trauma population in the metropolitan Boston area following MHR. Despite a significant improvement, these results reveal a rate of uninsured individuals fivefold greater than currently reported by the state of Massachusetts and the U.S. government. PMID- 25143510 TI - Cautious optimism: commentary on an article by Egleide Y. Elenes, MS, and Shawn A. Hunter, PhD: "soft-tissue allografts terminally sterilized with an electron beam are biomechanically equivalent to aseptic, nonsterilized tendons". PMID- 25143511 TI - Who Will Guard the Guardians? Commentary on an article by Courtland G. Lewis, MD, et al.: "evaluation of the first-generation AAOS clinical guidelines on the prophylaxis of venous thromboembolic events in patients undergoing total joint arthroplasty. Experience with 3289 patients from a single institution". PMID- 25143512 TI - It may be more than age and experience: commentary on an article by Patrick J. Cahill, MD, et al.: "the effect of surgeon experience on outcomes of surgery for adolescent idiopathic scoliosis". PMID- 25143513 TI - Multi-lineage MSC differentiation via engineered morphogen fields. AB - Tissue loss due to oral diseases requires the healing and regeneration of tissues of multiple lineages. While stem cells are native to oral tissues, a current major limitation to regeneration is the ability to direct their lineage-specific differentiation. This work utilizes polymeric scaffold systems with spatiotemporally controlled morphogen cues to develop precise morphogen fields to direct mesenchymal stem cell differentiation. First, a simple three-layer scaffold design was developed that presented two spatially segregated, lineage specific cues (Dentinogenic TGF-beta1 and Osteogenic BMP4). However, this system resulted in diffuse morphogen fields, as assessed by the in vitro imaging of cell signaling pathways triggered by the morphogens. Mathematical modeling was then exploited, in combination with incorporation of specific inhibitors (neutralizing antibodies or a small molecule kinase inhibitor) into each morphogen in an opposing spatial pattern as the respective morphogen, to design a five-layer scaffold that was predicted to yield distinct, spatially segregated zones of morphogen signaling. To validate this system, undifferentiated MSCs were uniformly seeded in these scaffold systems, and distinct mineralized tissue differentiation were noted within these morphogen zones. Finally, to demonstrate temporal control over morphogen signaling, latent TGF-beta1 was incorporated into one region of a concentric scaffold design, and laser treatment was used to activate the morphogen on-demand and to induce dentin differentiation solely within that specific spatial zone. This study demonstrates a significant advance in scaffold design to generate precise morphogen fields that can be used to develop in situ models to explore tissue differentiation and may ultimately be useful in engineering multi-lineage tissues in clinical dentistry. PMID- 25143515 TI - A review and meta-analysis of cancer risks in relation to Portland cement exposure. AB - Workers engaged in the production of Portland cement may come into contact with potential occupational hazards, but existing epidemiological studies show wide variation in risk estimates for cancer incidence and mortality in relation to cement exposure. This report identified studies of cement workers and associations with cancer incidence and mortality in a systematic review and meta analysis. A systematic review according to the PRISMA guidelines was conducted to identify studies of Portland cement workers and cancer outcomes. Meta-analyses were performed using random effects models for all cancers combined and for each cancer site with three or more reported measures of risk. A total of 26 studies were included in the review (14 occupational cohort studies and 12 case-control studies). Overall, the meta-relative risks did not provide convincing evidence for increased risks of any cancers in relation to cement exposure. Meta-SMR and 95% CIs were 0.94 (0.76 to 1.16) for six studies reporting all cancers combined, 0.93 (0.62 to 1.39) for seven studies reporting on lung cancer, 1.07 (0.72 to 1.59) for five studies reporting on stomach cancer, and 1.05 (0.79 to 1.40) for four studies reporting on colorectal cancer. Meta-relative risks for cancer incidence were similarly null for all sites with the exception of colorectal cancer which had a borderline statistically significant elevated risk (SIR=1.38, 95% CI 1.02 to 1.88). Overall, the meta-relative risks calculated across 26 published studies do not provide evidence of increased risks for cancer in relation to cement exposure. PMID- 25143516 TI - GPs feel pressurised to prescribe unnecessary antibiotics, survey finds. PMID- 25143514 TI - ENAM mutations with incomplete penetrance. AB - Amelogenesis imperfecta (AI) is a genetic disease affecting tooth enamel formation. AI can be an isolated entity or a phenotype of syndromes. To date, more than 10 genes have been associated with various forms of AI. We have identified 2 unrelated Turkish families with hypoplastic AI and performed mutational analysis. Whole-exome sequencing identified 2 novel heterozygous nonsense mutations in the ENAM gene (c.454G>T p.Glu152* in family 1, c.358C>T p.Gln120* in family 2) in the probands. Affected individuals were heterozygous for the mutation in each family. Segregation analysis within each family revealed individuals with incomplete penetrance or extremely mild enamel phenotype, in spite of having the same mutation with the other affected individuals. We believe that these findings will broaden our understanding of the clinical phenotype of AI caused by ENAM mutations. PMID- 25143517 TI - Benchmarking of a Markov multizone model of contaminant transport. AB - A Markov chain model previously applied to the simulation of advection and diffusion process of gaseous contaminants is extended to three-dimensional transport of particulates in indoor environments. The model framework and assumptions are described. The performance of the Markov model is benchmarked against simple conventional models of contaminant transport. The Markov model is able to replicate elutriation predictions of particle deposition with distance from a point source, and the stirred settling of respirable particles. Comparisons with turbulent eddy diffusion models indicate that the Markov model exhibits numerical diffusion in the first seconds after release, but over time accurately predicts mean lateral dispersion. The Markov model exhibits some instability with grid length aspect when turbulence is incorporated by way of the turbulent diffusion coefficient, and advection is present. However, the magnitude of prediction error may be tolerable for some applications and can be avoided by incorporating turbulence by way of fluctuating velocity (e.g. turbulence intensity). PMID- 25143518 TI - Microscopic colitis occurring in association with hyperplastic polyps and tubulovillous adenomas: observations in 10 cases. PMID- 25143519 TI - Private provider's contract is terminated after half of cataract patients experience complications. PMID- 25143520 TI - Appeals from candidates in MRCP(UK) examinations. PMID- 25143521 TI - Response to: 'IL-23 expression and activation of autophagy in synovium and PBMCs of HLA-B27 positive patients with ankylosing spondylitis' by Neerinckx et al. PMID- 25143522 TI - How much does Disease Activity Score in 28 joints ESR and CRP calculations underestimate disease activity compared with the Simplified Disease Activity Index? AB - OBJECTIVES: Disease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) is used instead of erythrocyte sedimentation rate (DAS28-ESR) to assess rheumatoid arthritis disease activity; however, values for remission and low disease activity (LDA) for DAS28-CRP have not been validated. American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) guidelines suggest remission should be calculated by Simplified Disease Activity Index (SDAI) rather than DAS28-ESR. We examined values of remission and LDA of DAS28 CRP that correspond to the respective cut-off points for DAS28-ESR and SDAI from five clinical trials. METHODS: DAS28-CRP cut-offs that best correspond to DAS28 ESR remission <2.6 and LDA <=3.2 were obtained by cumulative distribution plots, receiver operating curves and maximum concordance and averaged for each approach, treatment group and study. Level of agreement between DAS28-CRP and DAS28-ESR remission and LDA cut-offs was compared against each other and versus SDAI remission <=3.3 and LDA <=11. RESULTS: Percentage of patients who achieved remission and LDA by DAS28-ESR cut-offs was greater for DAS28-CRP versus DAS28 ESR regardless of patient population or treatment group. Discordance between CRP and ESR cut-offs ranged from 4%-26% and 8%-23% for remission and LDA, respectively, and 19%-40% and 6%-11% for DAS28-CRP versus SDAI, respectively. Estimated (range) remission and LDA thresholds were 2.4 (2.2-2.6) and 2.9 (2.6 3.3), 1.9 (1.6-2.2) and 3.1 (3.1-3.3) and 2.2 (1.1-2.9) and 3.6 (3.4-4.0) for DAS28-CRP versus DAS28-ESR, DAS28-CRP versus SDAI and DAS28-ESR versus SDAI, respectively. CONCLUSIONS: DAS28-CRP underestimates disease activity when using cut-off points validated for DAS28-ESR; therefore, DAS28-ESR cut-off values should not be applied to DAS28-CRP. Although DAS28-CRP and DAS28-ESR cut-offs for LDA <=3.2 correspond to SDAI LDA, neither corresponds well to SDAI remission. PMID- 25143524 TI - The BMJ's cover line on calcaneal fractures is misleading. PMID- 25143525 TI - Electronic health records may threaten blinding in trials of statins. PMID- 25143523 TI - B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease. AB - OBJECTIVES: Fibrosis is a predominant feature of IgG4-related disease (IgG4-RD). B-cell depletion induces a prompt clinical and immunological response in patients with IgG4-RD, but the effects of this intervention on fibrosis in IgG4-RD are unknown. We used the enhanced liver fibrosis (ELF) score to address the impact of rituximab on fibroblast activation. The ELF score is an algorithm based on serum concentrations of procollagen-III aminoterminal propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid. METHODS: Ten patients with active, untreated IgG4-RD were enrolled. ELF scores were measured and correlated with the IgG4-RD Responder Index, serum IgG4, circulating plasmablasts and imaging studies. Through immunohistochemical stains for CD3, CD20, IgG4 and alpha smooth muscle actin, we assessed the extent of the lymphoplasmacytic infiltration and the degree of fibroblast activation in one patient with tissue biopsies before and after rituximab. RESULTS: The ELF score was increased in patients with IgG4-RD compared with healthy controls (8.3+/-1.4 vs 6.2+/-0.9; p=0.002) and correlated with the number of organs involved (R(2)=0.41; p=0.04). Rituximab induced significant reductions in the ELF score, the number of circulating plasmablasts and the IgG4-RD Responder Index (p<0.05 for all three parameters). Rituximab reduced both the lymphoplasmacytic infiltrate and myofibroblast activation. IgG4-RD relapse coincided with recurrent increases in the ELF score, indicating reactivation of collagen deposition. CONCLUSIONS: The ELF score may be a clinically useful indicator of active fibrosis and the extent of disease in IgG4-RD. B-cell depletion has the potential to halt continued collagen deposition by attenuating the secretory phenotype of myofibroblasts in IgG4-RD lesions. PMID- 25143526 TI - School health in Malaysia: where are we now? PMID- 25143527 TI - Global School-based Student Health Survey, Malaysia. PMID- 25143528 TI - Potential for genomic instability associated with retrotranspositionally incompetent L1 loci. AB - Expression of the L1 retrotransposon can damage the genome through insertional mutagenesis and the generation of DNA double-strand breaks (DSBs). The majority of L1 loci in the human genome are 5'-truncated and therefore incapable of retrotransposition. While thousands of full-length L1 loci remain, most are retrotranspositionally-incompetent due to inactivating mutations. However, mutations leading to premature stop codons within the L1 ORF2 sequence may yield truncated proteins that retain a functional endonuclease domain. We demonstrate that some truncated ORF2 proteins cause varying levels of toxicity and DNA damage when chronically overexpressed in mammalian cells. Furthermore, transfection of some ORF2 constructs containing premature stop codons supported low levels of Alu retrotransposition, demonstrating the potential for select retrotranspositionally incompetent L1 loci to generate genomic instability. This result suggests yet another plausible explanation for the relative success of Alu elements in populating the human genome. Our data suggest that a subset of retrotranspositionally-incompetent L1s, previously considered to be harmless to genomic integrity, may have the potential to cause chronic DNA damage by introducing DSBs and mobilizing Alu. These results imply that the number of known L1 loci in the human genome that potentially threaten its stability may not be limited to the retrotranspositionally active loci. PMID- 25143529 TI - Translational stalling at polyproline stretches is modulated by the sequence context upstream of the stall site. AB - The polymerization of amino acids into proteins occurs on ribosomes, with the rate influenced by the amino acids being polymerized. The imino acid proline is a poor donor and acceptor for peptide-bond formation, such that translational stalling occurs when three or more consecutive prolines (PPP) are encountered by the ribosome. In bacteria, stalling at PPP motifs is rescued by the elongation factor P (EF-P). Using SILAC mass spectrometry of Escherichia coli strains, we identified a subset of PPP-containing proteins for which the expression patterns remained unchanged or even appeared up-regulated in the absence of EF-P. Subsequent analysis using in vitro and in vivo reporter assays revealed that stalling at PPP motifs is influenced by the sequence context upstream of the stall site. Specifically, the presence of amino acids such as Cys and Thr preceding the stall site suppressed stalling at PPP motifs, whereas amino acids like Arg and His promoted stalling. In addition to providing fundamental insight into the mechanism of peptide-bond formation, our findings suggest how the sequence context of polyproline-containing proteins can be modulated to maximize the efficiency and yield of protein production. PMID- 25143530 TI - Zinc finger oxidation of Fpg/Nei DNA glycosylases by 2-thioxanthine: biochemical and X-ray structural characterization. AB - DNA glycosylases from the Fpg/Nei structural superfamily are base excision repair enzymes involved in the removal of a wide variety of mutagen and potentially lethal oxidized purines and pyrimidines. Although involved in genome stability, the recent discovery of synthetic lethal relationships between DNA glycosylases and other pathways highlights the potential of DNA glycosylase inhibitors for future medicinal chemistry development in cancer therapy. By combining biochemical and structural approaches, the physical target of 2-thioxanthine (2TX), an uncompetitive inhibitor of Fpg, was identified. 2TX interacts with the zinc finger (ZnF) DNA binding domain of the enzyme. This explains why the zincless hNEIL1 enzyme is resistant to 2TX. Crystal structures of the enzyme bound to DNA in the presence of 2TX demonstrate that the inhibitor chemically reacts with cysteine thiolates of ZnF and induces the loss of zinc. The molecular mechanism by which 2TX inhibits Fpg may be generalized to all prokaryote and eukaryote ZnF-containing Fpg/Nei-DNA glycosylases. Cell experiments show that 2TX can operate in cellulo on the human Fpg/Nei DNA glycosylases. The atomic elucidation of the determinants for the interaction of 2TX to Fpg provides the foundation for the future design and synthesis of new inhibitors with high efficiency and selectivity. PMID- 25143531 TI - Shape matters: size-exclusion HPLC for the study of nucleic acid structural polymorphism. AB - In recent years, an increasing number of reports have been focused on the structure and biological role of non-canonical nucleic acid secondary structures. Many of these studies involve the use of oligonucleotides that can often adopt a variety of structures depending on the experimental conditions, and hence change the outcome of an assay. The knowledge of the structure(s) formed by oligonucleotides is thus critical to correctly interpret the results, and gain insight into the biological role of these particular sequences. Herein we demonstrate that size-exclusion HPLC (SE-HPLC) is a simple yet surprisingly powerful tool to quickly and effortlessly assess the secondary structure(s) formed by oligonucleotides. For the first time, an extensive calibration and validation of the use of SE-HPLC to confidently detect the presence of different species displaying various structure and/or molecularity, involving >110 oligonucleotides forming a variety of secondary structures (antiparallel, parallel, A-tract bent and mismatched duplexes, triplexes, G-quadruplexes and i motifs, RNA stem loops), is performed. Moreover, we introduce simple metrics that allow the use of SE-HPLC without the need for a tedious calibration work. We show that the remarkable versatility of the method allows to quickly establish the influence of a number of experimental parameters on nucleic acid structuration and to operate on a wide range of oligonucleotide concentrations. Case studies are provided to clearly illustrate the all-terrain capabilities of SE-HPLC for oligonucleotide secondary structure analysis. Finally, this manuscript features a number of important observations contributing to a better understanding of nucleic acid structural polymorphism. PMID- 25143532 TI - A view through a chromatin loop: insights into the ecdysone activation of early genes in Drosophila. AB - The early genes are a key group of ecdysone targets that function at the top of the signaling hierarchy. In the presence of ecdysone, early genes exhibit a highly characteristic rapid and powerful induction that represents a primary response. Multiple isoforms encoded by early genes then coordinate the activation of a larger group of late genes. While the general mechanism of ecdysone dependent transcription is well characterized, it is not known whether a distinct mechanism governs the hormonal response of early genes. We previously found that one of the Drosophila early genes, E75, harbors multiple functional ecdysone response elements (EcREs). In this study we extended the analysis to Broad and E74 and found that EcRE multiplicity is a general feature of the early genes. Since most of the EcREs within early gene loci are situated distantly from promoters, we employed the chromosome conformation capture method to determine whether higher order chromatin structure facilitates hormonal activation. For each early gene we detected chromatin loops that juxtapose their promoters and multiple distant EcREs prior to ecdysone activation. Our findings suggest that higher order chromatin structure may serve as an important mechanism underlying the distinct response of early genes to ecdysone. PMID- 25143533 TI - Mechanism by which a LINE protein recognizes its 3' tail RNA. AB - LINEs mobilize their own copies via retrotransposition. LINEs can be divided into two types. One is a stringent type, which constitutes a majority of LINEs. The other is a relaxed type. To elucidate the molecular mechanism of retrotransposition, we used here two different zebrafish LINEs belonging to the stringent type. By using retrotransposition assays, we demonstrated that proteins (ORF2) encoded by an individual LINE recognize the cognate 3' tail sequence of the LINE RNA strictly. By conducting in vitro binding assays with a variety of ORF2 proteins, we demonstrated that the region between the endonuclease and reverse transcriptase domains in ORF2 is the site at which the proteins bind the stem-loop structure of the 3' tail RNA, showing that the strict recognition of the stem-loop structure by the cognate ORF2 protein is an important step in retrotransposition. This recognition can be bipartite, involving the general recognition of the stem by cTBR (conserved tail-binding region) of ORF2 and the specific recognition of the loop by vTBR (variable tail-binding region). This is the first report that clearly characterized the RNA-binding region in ORF2, providing the generality for the recognition mechanism of the RNA tail by the ORF2 protein encoded by LINEs. PMID- 25143536 TI - Israel's health minister stuns experts by ending mandatory fluoridation. PMID- 25143534 TI - Transcriptional landscape and essential genes of Neisseria gonorrhoeae. AB - The WHO has recently classified Neisseria gonorrhoeae as a super-bacterium due to the rapid spread of antibiotic resistant derivatives and an overall dramatic increase in infection incidences. Genome sequencing has identified potential genes, however, little is known about the transcriptional organization and the presence of non-coding RNAs in gonococci. We performed RNA sequencing to define the transcriptome and the transcriptional start sites of all gonococcal genes and operons. Numerous new transcripts including 253 potentially non-coding RNAs transcribed from intergenic regions or antisense to coding genes were identified. Strikingly, strong antisense transcription was detected for the phase-variable opa genes coding for a family of adhesins and invasins in pathogenic Neisseria, that may have regulatory functions. Based on the defined transcriptional start sites, promoter motifs were identified. We further generated and sequenced a high density Tn5 transposon library to predict a core of 827 gonococcal essential genes, 133 of which have no known function. Our combined RNA-Seq and Tn-Seq approach establishes a detailed map of gonococcal genes and defines the first core set of essential gonococcal genes. PMID- 25143535 TI - Retinoid acid-related orphan receptor gamma, RORgamma, participates in diurnal transcriptional regulation of lipid metabolic genes. AB - The hepatic circadian clock plays a pivotal role in regulating major aspects of energy homeostasis and lipid metabolism. In this study, we show that RORgamma robustly regulates the rhythmic expression of several lipid metabolic genes, including the insulin-induced gene 2a, Insig2a, elongation of very long chain fatty acids-like 3, Elovl3 and sterol 12alpha-hydroxylase, Cyp8b1, by enhancing their expression at ZT20-4. The time-dependent increase in their expression correlates with the rhythmic expression pattern of RORgamma. The enhanced recruitment of RORgamma to ROREs in their promoter region, increased histone acetylation, and reporter and mutation analysis support the concept that RORgamma regulates the transcription of several lipid metabolic genes directly by binding ROREs in their promoter regulatory region. Consistent with the disrupted expression of a number of lipid metabolic genes, loss of RORgamma reduced the level of several lipids in liver and blood in a ZT-preferred manner. Particularly the whole-body bile acid pool size was considerably reduced in RORgamma(-/-) mice in part through its regulation of several Cyp genes. Similar observations were made in liver-specific RORgamma-deficient mice. Altogether, our study indicates that RORgamma functions as an important link between the circadian clock and the transcriptional regulation of several metabolic genes. PMID- 25143539 TI - Differential modulation of descending signals from the reticulospinal system during reaching and locomotion. AB - We tested the hypothesis that the same spinal interneuronal pathways are activated by the reticulospinal system during locomotion and reaching. If such were the case, we expected that microstimulation within the pontomedullary reticular formation (PMRF) would evoke qualitatively similar responses in muscles active during both behaviors. To test this, we stimulated in 47 sites within the PMRF during both tasks. Stimulation during locomotion always produced a strongly phase-dependent, bilateral pattern of activity in which activity in muscles was generally facilitated or suppressed during one phase of activity (swing or stance) and was unaffected in the other. During reaching, stimulation generally activated the same muscles as during locomotion, although the modulation of the magnitude of the evoked responses was less limb dependent than during locomotion. An exception was found for some forelimb flexor muscles that were strongly facilitated by stimulation during the swing phase of locomotion but were not influenced by stimulation during the transport phase of the reach. We suggest that during locomotion the activity in interneuronal pathways mediating signals from the reticulospinal system is subject to strong modulation by the central pattern generator for locomotion. During reach, we suggest that, for most muscles, the same spinal interneuronal pathways are used to modify muscle activity but are not as strongly gated according to limb use as during locomotion. Finally, we propose that the command for movement during discrete voluntary movements suppresses the influence of the reticulospinal system on selected forelimb flexor muscles, possibly to enhance fractionated control of movement. PMID- 25143538 TI - Flocculus Purkinje cell signals in mouse Cacna1a calcium channel mutants of escalating severity: an investigation of the role of firing irregularity in ataxia. AB - Mutation of the Cacna1a gene for the P/Q (CaV2.1) calcium channel invariably leads to cerebellar dysfunction. The dysfunction has been attributed to disrupted rhythmicity of cerebellar Purkinje cells, but the hypothesis remains unproven. If irregular firing rates cause cerebellar dysfunction, then the irregularity and behavioral deficits should covary in a series of mutant strains of escalating severity. We compared firing irregularity in floccular and anterior vermis Purkinje cells in the mildly affected rocker and moderately affected tottering Cacna1a mutants and normal C57BL/6 mice. We also measured the amplitude and timing of modulations of floccular Purkinje cell firing rate during the horizontal vestibuloocular reflex (VOR, 0.25-1 Hz) and the horizontal and vertical optokinetic reflex (OKR, 0.125-1 Hz). We recorded Purkinje cells selective for rotational stimulation about the vertical axis (VAPCs) and a horizontal axis (HAPCs). Irregularity scaled with behavioral deficit severity in the flocculus but failed to do so in the vermis, challenging the irregularity hypothesis. Mutant VAPCs exhibited unusually strong modulation during VOR and OKR, the response augmentation scaling with phenotypic severity. HAPCs exhibited increased OKR modulation but in tottering only. The data contradict prior claims that modulation amplitude is unaffected in tottering but support the idea that attenuated compensatory eye movements in Cacna1a mutants arise from defective transfer of Purkinje cell signals to downstream circuitry, rather than attenuated synaptic transmission within the cerebellar cortex. Shifts in the relative sizes of the VAPC and HAPC populations raise the possibility that Cacna1a mutations influence the development of floccular zone architecture. PMID- 25143537 TI - Reversible deactivation of higher-order posterior parietal areas. II. Alterations in response properties of neurons in areas 1 and 2. AB - The role that posterior parietal (PPC) and motor cortices play in modulating neural responses in somatosensory areas 1 and 2 was examined with reversible deactivation by transient cooling. Multiunit recordings from neurons in areas 1 and 2 were collected from six anesthetized adult monkeys (Macaca mulatta) before, during, and after reversible deactivation of areas 5L or 7b or motor cortex (M1/PM), while select locations on the hand and forelimb were stimulated. Response changes were quantified as increases and decreases to stimulus-driven activity relative to baseline and analyzed during three recording epochs: during deactivation ("cool") and at two time points after deactivation ("rewarm 1," "rewarm 2"). Although the type of response change observed was variable, for neurons at the recording sites tested >90% exhibited a significant change in response during cooling of 7b while cooling area 5L or M1/PM produced a change in 75% and 64% of sites, respectively. These results suggest that regions in the PPC, and to a lesser extent motor cortex, shape the response characteristics of neurons in areas 1 and 2 and that this kind of feedback modulation is necessary for normal somatosensory processing. Furthermore, this modulation appears to happen on a minute-by-minute basis and may serve as the substrate for phenomena such as somatosensory attention. PMID- 25143540 TI - Single tactile afferents outperform human subjects in a vibrotactile intensity discrimination task. AB - We simultaneously compared the sensitivity of single primary afferent neurons supplying the glabrous skin of the hand and the psychophysical amplitude discrimination thresholds in human subjects for a set of vibrotactile stimuli delivered to the receptive field. All recorded afferents had a dynamic range narrower than the range of amplitudes across which the subjects could discriminate. However, when the vibration amplitude was chosen to be within the steepest part of the afferent's stimulus-response function the response of single afferents, defined as the spike count over the vibration duration (500 ms), was often more sensitive in discriminating vibration amplitude than the perceptual judgment of the participants. We quantified how the neuronal performance depended on the integration window: for short windows the neuronal performance was inferior to the performance of the subject. The neuronal performance progressively improved with increasing spike count duration and reached a level significantly above that of the subjects when the integration window was 250 ms or longer. The superiority in performance of individual neurons over observers could reflect a nonoptimal integration window or be due to the presence of noise between the sensory periphery and the cortical decision stage. Additionally, it could indicate that the range of perceptual sensitivity comes at the cost of discrimination through pooling across neurons with different response functions. PMID- 25143541 TI - Roles of GABAA and GABAB receptors in regulating thalamic activity by the zona incerta: a computational study. AB - The posterior thalamic nucleus (PO) is a higher order nucleus heavily implicated in the processing of somatosensory information. We have previously shown in rodent models that activity in PO is tightly regulated by inhibitory inputs from a GABAergic nucleus known as the zona incerta (ZI). The level of incertal inhibition varies under both physiological and pathological conditions, leading to concomitant changes in PO activity. These changes are causally linked to variety of phenomena from altered sensory perception to pathological pain. ZI regulation of PO is mediated by GABAA and GABAB receptors (GABAAR and GABABR) that differ in their binding kinetics and their electrophysiological properties, suggesting that each may have distinct roles in incerto-thalamic regulation. We developed a computational model to test this hypothesis. We created a two-cell Hodgkin-Huxley model representing PO and ZI with kinetically realistic GABAAR- and GABABR-mediated synapses. We simulated spontaneous and evoked firing in PO and observed how these activities were affected by inhibition mediated by each receptor type. Our model predicts that spontaneous PO activity is preferentially regulated by GABABR-mediated mechanisms, while evoked activity is preferentially regulated by GABAAR. Our model also predicts that modulation of ZI firing rate and synaptic GABA concentrations is an effective means to regulate the incerto thalamic circuit. The coupling of distinct functions to GABAAR and GABABR presents an opportunity for the development of therapeutics, as particular aspects of incerto-thalamic regulation can be targeted by manipulating the corresponding receptor class. Thus these findings may provide interventions for pathologies of sensory processing. PMID- 25143543 TI - The organization and dynamics of corticostriatal pathways link the medial orbitofrontal cortex to future behavioral responses. AB - Accurately making a decision in the face of incongruent options increases the efficiency of making similar congruency decisions in the future. Contextual factors like reward can modulate this adaptive process, suggesting that networks associated with monitoring previous success and failure outcomes might contribute to this form of behavioral updating. To evaluate this possibility, a group of healthy adults (n = 30) were tested with functional MRI (fMRI) while they performed a color-word Stroop task. In a conflict-related region of the medial orbitofrontal cortex (mOFC), stronger BOLD responses predicted faster response times (RTs) on the next trial. More importantly, the degree of behavioral adaptation of RTs was correlated with the magnitude of mOFC-RT associations on the previous trial, but only after accounting for network-level interactions with prefrontal and striatal regions. This suggests that congruency sequencing effects may rely on interactions between distributed corticostriatal circuits. This possibility was evaluated by measuring the convergence of white matter projections from frontal areas into the striatum with diffusion-weighted imaging. In these pathways, greater convergence of corticostriatal projections correlated with stronger functional mOFC-RT associations that, in turn, provided an indirect pathway linking anatomical structure to behavior. Thus distributed corticostriatal processing may mediate the orbitofrontal cortex's influence on behavioral updating, even in the absence of explicit rewards. PMID- 25143542 TI - Persistent beneficial impact of H-reflex conditioning in spinal cord-injured rats. AB - Operant conditioning of a spinal cord reflex can improve locomotion in rats and humans with incomplete spinal cord injury. This study examined the persistence of its beneficial effects. In rats in which a right lateral column contusion injury had produced asymmetric locomotion, up-conditioning of the right soleus H-reflex eliminated the asymmetry while down-conditioning had no effect. After the 50-day conditioning period ended, the H-reflex was monitored for 100 [+/-9 (SD)] (range 79-108) more days and locomotion was then reevaluated. After conditioning ended in up-conditioned rats, the H-reflex continued to increase, and locomotion continued to improve. In down-conditioned rats, the H-reflex decrease gradually disappeared after conditioning ended, and locomotion at the end of data collection remained as impaired as it had been before and immediately after down conditioning. The persistence (and further progression) of H-reflex increase but not H-reflex decrease in these spinal cord-injured rats is consistent with the fact that up-conditioning improved their locomotion while down-conditioning did not. That is, even after up-conditioning ended, the up-conditioned H-reflex pathway remained adaptive because it improved locomotion. The persistence and further enhancement of the locomotor improvement indicates that spinal reflex conditioning protocols might supplement current therapies and enhance neurorehabilitation. They may be especially useful when significant spinal cord regeneration becomes possible and precise methods for retraining the regenerated spinal cord are needed. PMID- 25143544 TI - A system for the determination of planar force vectors from spontaneously active chicken embryos. AB - Generally, a combination of kinematic, electromyographic (EMG), and force measurements are used to understand how an organism generates and controls movement. The chicken embryo has been a very useful model system for understanding the early stages of embryonic motility in vertebrates. Unfortunately, the size and delicate nature of embryos makes studies of motility during embryogenesis very challenging. Both kinematic and EMG recordings have been achieved in embryonic chickens, but two-dimensional force vector recordings have not. Here, we describe a dual-axis system for measuring force generated by the leg of embryonic chickens. The system employs two strain gauges to measure planar forces oriented with the plane of motion of the leg. This system responds to forces according to the principles of Pythagorean geometry, which allows a simple computational program to determine the force vector (magnitude and direction) generated during spontaneous motor activity. The system is able to determine force vectors for forces >0.5 mN accurately and allows for simultaneous kinematic and EMG recordings. This sensitivity is sufficient for force vector measurements encompassing most embryonic leg movements in midstage chicken embryos allowing for a more complete understanding of embryonic motility. Variations on this system are discussed to enable nonideal or alternative sensor arrangements and to allow for translation of this approach to other delicate model systems. PMID- 25143545 TI - Differential contribution of Kv4-containing channels to A-type, voltage-gated potassium currents in somatic and visceral dorsal root ganglion neurons. AB - Little is known about electrophysiological differences of A-type transient K(+) (KA) currents in nociceptive afferent neurons that innervate somatic and visceral tissues. Staining with isolectin B4 (IB4)-FITC classifies L6-S1 dorsal root ganglion (DRG) neurons into three populations with distinct staining intensities: negative to weak, moderate, and intense fluorescence signals. All IB4 intensely stained cells are negative for a fluorescent dye, Fast Blue (FB), injected into the bladder wall, whereas a fraction of somatic neurons labeled by FB, injected to the external urethral dermis, is intensely stained with IB4. In whole-cell, patch-clamp recordings, phrixotoxin 2 (PaTx2), a voltage-gated K(+) (Kv)4 channel blocker, exhibits voltage-independent inhibition of the KA current in IB4 intensely stained cells but not the one in bladder-innervating cells. The toxin also shows voltage-independent inhibition of heterologously expressed Kv4.1 current, whereas its inhibition of Kv4.2 and Kv4.3 currents is voltage dependent. The swapping of four amino acids at the carboxyl portion of the S3 region between Kv4.1 and Kv4.2 transfers this characteristic. RT-PCRs detected Kv4.1 and the long isoform of Kv4.3 mRNAs without significant Kv4.2 mRNA in L6-S1 DRGs. Kv4.1 and Kv4.3 mRNA levels were higher in laser-captured, IB4-stained neurons than in bladder afferent neurons. These results indicate that PaTx2 acts differently on channels in the Kv4 family and that Kv4.1 and possibly Kv4.3 subunits functionally participate in the formation of KA channels in a subpopulation of somatic C-fiber neurons but not in visceral C-fiber neurons innervating the bladder. PMID- 25143546 TI - Reversible deactivation of higher-order posterior parietal areas. I. Alterations of receptive field characteristics in early stages of neocortical processing. AB - Somatosensory processing in the anesthetized macaque monkey was examined by reversibly deactivating posterior parietal areas 5L and 7b and motor/premotor cortex (M1/PM) with microfluidic thermal regulators developed by our laboratories. We examined changes in receptive field size and configuration for neurons in areas 1 and 2 that occurred during and after cooling deactivation. Together the deactivated fields and areas 1 and 2 form part of a network for reaching and grasping in human and nonhuman primates. Cooling area 7b had a dramatic effect on receptive field size for neurons in areas 1 and 2, while cooling area 5 had moderate effects and cooling M1/PM had little effect. Specifically, cooling discrete locations in 7b resulted in expansions of the receptive fields for neurons in areas 1 and 2 that were greater in magnitude and occurred in a higher proportion of sites than similar changes evoked by cooling the other fields. At some sites, the neural receptive field returned to the precooling configuration within 5-22 min of rewarming, but at other sites changes in receptive fields persisted. These results indicate that there are profound top down influences on sensory processing of early cortical areas in the somatosensory cortex. PMID- 25143548 TI - Duifhuis pitch: neuromagnetic representation and auditory modeling. AB - When a high harmonic is removed from a cosine-phase harmonic complex, we hear a sine tone pop out of the perception; the sine tone has the pitch of the high harmonic, while the tone complex has the pitch of its fundamental frequency, f0. This phenomenon is commonly referred to as Duifhuis Pitch (DP). This paper describes, for the first time, the cortical representation of DP observed with magnetoencephalography. In experiment 1, conditions that produce the perception of a DP were observed to elicit a classic onset response in auditory cortex (P1m, N1m, P2m), and an increment in the sustained field (SF) established in response to the tone complex. Experiment 2 examined the effect of the phase spectrum of the complex tone on the DP activity: Schroeder-phase negative waves elicited a transient DP complex with a similar shape to that observed with cosine-phase waves but with much longer latencies. Following the transient DP activity, the responses of the negative and positive Schroeder-phase waves converged, and the increment in the SF slowly died away. In the absence of DP, the two Schroeder phase conditions with low peak factors both produced larger SFs than cosine-phase waves with large peak factors. A model of the auditory periphery that includes coupling between adjacent frequency channels is used to explain the early neuromagnetic activity observed in auditory cortex. PMID- 25143549 TI - Interest of active posturography to detect age-related and early Parkinson's disease-related impairments in mediolateral postural control. AB - Patients with Parkinson's disease display impairments of postural control most particularly in active, challenging conditions. The objective of the present study was to analyze early signs of disease-related and also age-related impairments in mediolateral body extension and postural control. Fifty-five participants (18 Hoehn and Yahr stage 2 patients in the off-drug condition, 18 healthy elderly control subjects, and 19 young adults) were included in the study. The participants performed a quiet stance task and two active tasks that analyzed the performance in mediolateral body motion: a limit of stability and a rhythmic weight shift task. As expected, the patients displayed significantly lower and slower body displacement (head, neck, lower back, center of pressure) than elderly control subjects when performing the two body excursion tasks. However, the behavioral variability in both tasks was similar between the groups. Under these active conditions, the patients showed significantly lower contribution of the hip postural control mechanisms compared with the elderly control subjects. Overall, the patients seemed to lower their performance in order to prevent a mediolateral postural instability. However, these patients, at an early stage of their disease, were not unstable in quiet stance. Complementarily, elderly control subjects displayed slower body performance than young adults, which therefore showed an additional age-related impairment in mediolateral postural control. Overall, the study illustrated markers of age related and Parkinson's disease impairments in mediolateral postural control that may constrain everyday activities in elderly adults and even more in patients with Parkinson's disease. PMID- 25143547 TI - An acetylcholinesterase inhibitor, eserine, induces long-term depression at CA3 CA1 synapses in the hippocampus of adult rats. AB - Studies in humans and rodents support a role for muscarinic ACh receptor (mAChR) and nicotinic AChR in learning and memory, and both regulate hippocampal synaptic plasticity using complex and often times opposing mechanisms. Acetylcholinesterase (AChE) inhibitors are commonly prescribed to enhance cholinergic signaling in Alzheimer's disease in hopes of rescuing cognitive function, caused, in part, by degeneration of cholinergic innervation to the hippocampus and cortex. Unfortunately, therapeutic efficacy is moderate and inconsistent, perhaps due to unanticipated mechanisms. M1 mAChRs bidirectionally control synaptic strength at CA3-CA1 synapses; weak pharmacological activation using carbachol (CCh) facilitates potentiation, whereas strong agonism induces muscarinic long-term depression (mLTD) via an ERK-dependent mechanism. Here, we tested the prediction that accumulation of extracellular ACh via inhibition of AChE is sufficient to induce LTD at CA3-CA1 synapses in hippocampal slices from adult rats. Although AChE inhibition with eserine induces LTD, it unexpectedly does not share properties with mLTD induced by CCh, as reported previously. Eserine-LTD was prevented by the M3 mAChR-preferring antagonist 1,1-dimethyl-4 diphenylacetoxypiperidinium iodide (4-DAMP), and pharmacological inhibition of MEK was completely ineffective. Additionally, pharmacological inhibition of p38 MAPK prevents mLTD but has no effect on eserine-LTD. Finally, long-term expression of eserine-LTD is partially dependent on a decrease in presynaptic release probability, likely caused by tonic activation of mAChRs by the sustained increase in extracellular ACh. Thus these findings extend current literature by showing that pharmacological AChE inhibition causes a prolonged decrease in presynaptic glutamate release at CA3-CA1 synapses, in addition to inducing a likely postsynaptic form of LTD. PMID- 25143550 TI - A new electronic diary tool for mapping and tracking spatial and temporal head pain patterns in migraine. AB - AIM: We present an electronic tool for collecting data on the patterns of migraine headache onset and progression. METHODS: A digitized map consisting of 44 color-coded segments was defined based on previous reports of migraine pain and the distribution of nerves in the face, head and neck. The map was overlaid on a schematic map of the face, head and neck nerves. Thirty-six patients (N = 36, 28 female/eight male), who met ICDH-II criteria for episodic migraine and had headaches for at least three years, identified all regions where pain typically started and how pain spread and subsequently progressed. RESULTS: Consistent with previous findings, throbbing was the most prevalent quality of migraine pain, always present in 70% of patients surveyed. For the 70% of the patients with throbbing pain, the temple was the onset site of throbbing pain, with no significant difference in the laterality of onset site (58.3% on the right vs. 55.6% on the left hemisphere). The tool was able to capture patterns of pain distribution for throbbing and pressure headache pain and also may be used to assess the change in the pattern of the pain distribution as the disease progresses. DISCUSSION: The pain map survey may be a useful tool for recording and tracking the temporal pattern of migraine onset both for clinical and research purposes. The tool could be used to create maps of pain locations on a large population scale and thus will be a very useful tool in correlating the temporal nature of headache symptoms with potential mechanisms of disease evolution. PMID- 25143551 TI - Reduced cranial parasympathetic tone during the remission phase of cluster headache. AB - BACKGROUND: Cluster headache (CH) attacks are accompanied by cranial autonomic symptoms indicative of parasympathetic hyperactivity and sympathetic dysfunction ipsilateral to the pain. We aimed to assess cranial autonomic function in CH patients during the remission phase of cluster headache. MATERIALS AND METHODS: During a remission phase, 38 episodic CH patients underwent the following: dynamic pupillometry, measurement of the superficial temporal artery diameter by ultrasound, and measurement of the retinal vessel diameters from digital retinal photographs. Pupillometry was also performed on 30 age- and sex-matched healthy controls. RESULTS: Thirty patients were included (27 men, three women, mean age 50.2 years +/- 12.6). Seven patients reported occasional side shift of their headache, but with a clear predominating side. Significantly reduced average pupillary constriction velocity and retinal venular diameter on the CH pain side were found. There was no asymmetry of the superficial temporal artery diameters. Compared to healthy controls, cluster patients displayed bilaterally reduced pupillary average and maximum constriction velocities, reduced constriction in percentage and increased latency of the light reflex. CONCLUSIONS: The present findings indicate a bilaterally reduced cranial parasympathetic tone in CH patients in remission phase, with significant lateralization to the CH pain side. This implies a central origin, and a central pathophysiological model of CH is discussed. PMID- 25143552 TI - Surgical treatment for migraine: Time to fight against the knife. PMID- 25143553 TI - A clinical interview versus prospective headache diaries in the diagnosis of menstrual migraine without aura. AB - OBJECTIVES: The objective of this article is to compare the diagnosis of menstrual migraine without aura (MM) from a clinical interview with prospective headache diaries in a population-based study. MATERIAL AND METHODS: A total of 237 women with self-reported migraine in at least half of menstruations were interviewed by a neurologist about headache and diagnosed according to the International Classification of Headache Disorders II (ICHD II). Additionally, the MM criteria were expanded to include other types of migraine related to menstruation. Subsequently, all women were asked to complete three month prospective headache diaries. RESULTS: A total of 123 (52%) women completed both clinical interview and diaries. Thirty-eight women were excluded from the analyses: Two had incomplete diaries and 36 women recorded <=1 menstruation, leaving 85 diaries eligible for analysis. Sensitivity, specificity, positive and negative predictive value and Kappa for the diagnosis of MM in clinical interview vs. headache diary were 82%, 83%, 90%, 71% and 0.62 (95% CI 0.45-0.79). Using a broader definition of MM, Kappa was 0.64 (95% CI 0.47-0.83). CONCLUSION: A thorough clinical interview is valid for the diagnosis of MM. When this is undertaken, prospective headache diaries should not be mandatory to diagnose MM but may be necessary to exclude a chance association. PMID- 25143554 TI - How to enhance patient experiences of decision-making about kidney transplantation? PMID- 25143555 TI - FGF23: more a matter of the heart than of the vessels? PMID- 25143557 TI - Finding the evidence is all in the methodology. PMID- 25143556 TI - Antiproteinuric effect of add-on paricalcitol in Fabry disease patients: a prospective observational study. AB - BACKGROUND: Proteinuria is the predominant risk factor for renal disease progression in Fabry disease (FD). When urine protein excretion is controlled to <0.50 g/24 h, the rate loss of glomerular filtration rate (GFR) is not significantly different from 0. However, enzyme replacement therapy (ERT) alone does not decrease proteinuria and it has been recommended that patients receiving ERT also receive anti-renin-angiotensin system (RAS) therapy. Emerging evidence show that paricalcitol (PCT) reduces proteinuria in the presence of intensified inhibition of RAS; however, there is no evidence in FD. We evaluated the antiproteinuric effect of PCT in FD patients with proteinuria >0.50 g/24 h persisting despite ERT and anti-RAS therapy titrated to maximum tolerated dosage. METHODS: Fifteen FD patients were selected and studied in the first 6 months of add-on oral PCT (1 ug/day) and, in order to verify the dependence of proteinuria reduction on PCT, 3 months after drug withdrawal. RESULTS: At baseline, proteinuria was 1.3 +/- 0.6 g/24 h. Six months of add-on PCT significantly decreased proteinuria to 0.4 +/- 0.3 g/24 h, with levels <0.50 g/24 h achieved in four patients at Month 1, six at Month 3, and in 12 by Month 6, in the absence of changes to BP and GFR. Proteinuria recovered to basal value after drug withdrawal. CONCLUSIONS: In conclusion, our study is the first evidence that PCT is effective in reducing proteinuria in FD patients in the presence of ERT and anti-RAS therapy. PMID- 25143559 TI - The impact of surface preparation on shear bond strength of metallic orthodontic brackets bonded with a resin-modified glass ionomer cement. AB - AIM: The aim of this study was to assess the effects of four enamel preparation techniques on shear bond strength (SBS) of brackets bonded with a resin-modified glass ionomer cement (RMGIC). Adhesive Remnant Index (ARI) and enamel surface roughness (Ra) were also investigated after cement removal. MATERIALS AND METHODS: One hundred and forty-four human premolars were divided into four groups (n = 36 in each group) as follows: Group 1, 37% phosphoric acid (i.e. conventional); Group 2, sandblasting; Group 3, sodium hypochlorite and 37% phosphoric acid; and Group 4, sodium hypochlorite and sandblasting. Twenty-four hours after bonding, the brackets were debonded with an Instron machine using a crosshead speed of 1.0 mm/min; the ARI was evaluated by an image analyser system; the Ra was measured by profilometry; and the morphology of the tooth enamel surface was observed by scanning electron microscope evaluation. Data were submitted to ANOVA and the Kruskal-Wallis test (alpha = 0.05). RESULTS: Mean SBS values for Groups 1-4 were 13.86, 9.08, 17 and 9.63 MPa, respectively. Mean ARI for Groups 1-4 were 11.16, 2.06, 20.66 and 3.73%. The SBS and ARI showed statistically significant differences between the four groups (P<0.001). The Ra (MUm) showed no significant differences between groups. CONCLUSIONS: Bracket bonding using RMGIC showed adequate adhesion for clinical use, and the type of enamel preparation had a significant influence. PMID- 25143562 TI - Letter to the editor: case report by Drs. Al-Musfir and Morris. PMID- 25143563 TI - Authors' response to Letter to the Editor. PMID- 25143564 TI - Light Detection and Signal Transduction in the BLUF Photoreceptors. PMID- 25143565 TI - Highly sensitive detection of small ruminant bovine spongiform encephalopathy within transmissible spongiform encephalopathy mixes by serial protein misfolding cyclic amplification. AB - It is assumed that sheep and goats consumed the same bovine spongiform encephalopathy (BSE)-contaminated meat and bone meal that was fed to cattle and precipitated the BSE epidemic in the United Kingdom that peaked more than 20 years ago. Despite intensive surveillance for cases of BSE within the small ruminant populations of the United Kingdom and European Union, no instances of BSE have been detected in sheep, and in only two instances has BSE been discovered in goats. If BSE is present within the small ruminant populations, it may be at subclinical levels, may manifest as scrapie, or may be masked by coinfection with scrapie. To determine whether BSE is potentially circulating at low levels within the European small ruminant populations, highly sensitive assays that can specifically detect BSE, even within the presence of scrapie prion protein, are required. Here, we present a novel assay based on the specific amplification of BSE PrP(Sc) using the serial protein misfolding cyclic amplification assay (sPMCA), which specifically amplified small amounts of ovine and caprine BSE agent which had been mixed into a range of scrapie-positive brain homogenates. We detected the BSE prion protein within a large excess of classical, atypical, and CH1641 scrapie isolates. In a blind trial, this sPMCA based assay specifically amplified BSE PrP(Sc) within brain mixes with 100% specificity and 97% sensitivity when BSE agent was diluted into scrapie-infected brain homogenates at 1% (vol/vol). PMID- 25143566 TI - Phenotypic and genotypic changes over time and across facilities of serial colonizing and infecting Escherichia coli isolates recovered from injured service members. AB - Escherichia coli is the most common colonizing and infecting organism isolated from U.S. service members injured during deployment. Our objective was to evaluate the phenotypic and genotypic changes of infecting and colonizing E. coli organisms over time and across facilities to better understand their transmission patterns. E. coli isolates were collected via surveillance cultures and infection workups from U.S. military personnel injured during deployment (June 2009 to May 2011). The isolates underwent antimicrobial susceptibility testing, pulsed-field gel electrophoresis, and multiplex PCR for phylotyping to determine their resistance profiles and clonality. A total of 343 colonizing and 136 infecting E. coli isolates were analyzed, of which 197 (57%) and 109 (80%) isolates, respectively, produced extended-spectrum beta-lactamases (ESBL). Phylogroup A was predominant among both colonizing (38%) and infecting isolates (43%). Although 188 unique pulsed-field types (PFTs) were identified from the colonizing isolates, and 54 PFTs were identified from the infecting isolates, there was a lack of PFT overlap between study years, combat zones, and military treatment facilities. On a per-subject basis, 26% and 32% of the patients with serial colonizing isolates and 10% and 21% with serial infecting isolates acquired changes in their phylogroup and PFT profiles, respectively, over time. The production of ESBL remained high over time and across facilities, with no substantial changes in antimicrobial susceptibilities. Overall, our results demonstrated an array of genotypic and phenotypic differences for the isolates without large clonal clusters; however, the same PFTs were occasionally observed in the colonizing and infecting isolates, suggesting that the source of infections may be endogenous host organisms. PMID- 25143567 TI - Reassessment of genotype 1 hepatitis C virus subtype misclassification by LiPA 2.0: implications for direct-acting antiviral treatment. AB - The accuracy of LiPA 2.0 for hepatitis C virus 1 (HCV-1) subtype classification was analyzed. LiPA 2.0 genotype results from 101 HCV-1-infected patients were compared to genotype findings determined by direct core sequencing. Eleven (11%) samples were misclassified. Given the influence of the HCV-1-subtype in the anti HCV therapy response, an alternative classification method is warranted. PMID- 25143568 TI - Isolation of Salmonella enterica serovar Kentucky strain ST 198 and its H2S negative variant from a patient: implications for diagnosis. AB - H2S-producing multiresistant Salmonella enterica serovar Kentucky strain sequence type (ST) 198 and its non-H2S-producing variant were isolated from a patient. Whole-genome comparison showed a base addition in the gene encoding molybdenum cofactor biosynthesis protein C, which could affect H2S production in the variant. Lack of H2S production has implications for diagnosis of salmonella. PMID- 25143569 TI - Precision of vancomycin and daptomycin MICs for methicillin-resistant Staphylococcus aureus and effect of subculture and storage. AB - The reproducibility of vancomycin and daptomycin MICs, measured by broth microdilution (BMD) and Etest, was prospectively assessed for 10 methicillin resistant Staphylococcus aureus (MRSA) isolates from the blood samples from patients on vancomycin therapy. The isolates were tested at the time of isolation from blood and following 5, 10, and 20 subcultures and at 1, 3, 6, and 12 months of storage at -70 degrees C. The MICs were determined by Etest and BMD using two different manufacturers (BBL and Difco) of cation-adjusted Mueller-Hinton broth (CA-MHB), and using three different drug powders: vancomycin from Sigma, vancomycin from Novation, and daptomycin from Cubist. The antimicrobial concentrations tested were 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, and 4.0 MUg/ml. Two isolates were vancomycin intermediate and daptomycin nonsusceptible, and two isolates had reduced susceptibility to vancomycin (BMD MIC, 1.5 or 2.0 MUg/ml). The vancomycin MICs were significantly higher in the BBL CA-MHB than those in the Difco CA-MHB, and with Sigma versus Novation vancomycin powder. The daptomycin MICs were also significantly higher in the BBL CA-MHB. The Etest MICs were significantly higher than those obtained by BMD for vancomycin but not for daptomycin. The average precision of the vancomycin BMD MICs when analyzing 20 results was +/- 1.10-fold log2 dilutions, and it was +/- 1.67-fold for daptomycin (10 results). The average precision for Etest was +/- 1.11-fold for vancomycin and +/- 1.16-fold for daptomycin. No significant change in MICs was noted following 5, 10, or 20 subcultures or at up to 6 months of frozen storage. However, the vancomycin MICs alone were significantly lower (0.74-fold) following 12 months of frozen storage. From these data, despite variations in CA-MHB and antimicrobial powder, the MIC result precision was <0.5 log2 dilutions in a single laboratory, suggesting that testing interdilution MICs (e.g., MICs between serial 2-fold dilutions) is a possibility. A more accurate method for measuring vancomycin MIC results is thus possible, but further standardization of BMD testing would be required to achieve this goal. PMID- 25143570 TI - Updating the PGMY primers and probes for improved detection of HPV68a: validation of version 2 of the PGMY-CHUV assay. AB - HPV68a is not efficiently detected by PCR with the PGMY primers. Version 2 of the PGMY-CHUV assay (PGv2) was developed from version 1 (PGv1) to evaluate HPV68 discordant results with the Anyplex II HPV28 assay. We now report that PGv2 is significantly more sensitive than PGv1 for HPV68a and as sensitive and specific for the other HPV genotypes during a 1-year prospective validation (n = 714 samples). PMID- 25143571 TI - Comparison of five chromogenic media for recovery of vancomycin-resistant enterococci from fecal samples. AB - Five chromogenic agars, evaluated using 400 stool specimens, were found to be superior in sensitivity (range, 89.9 to 93.9%) to bile esculin azide agar with vancomycin (BEAV) agar (84.8%) for detecting vancomycin-resistant enterococci (VRE), and the results were available 24 to 48 h sooner. The time to detection, need for supplemental testing, color distinction, and breakthrough of non-VRE organisms vary among the chromogenic media tested and may factor into the decision to use a particular medium. PMID- 25143572 TI - Rapid time to results and high sensitivity of the CarbaNP test on early cultures. AB - For rapid results, we adapted the CarbaNP test by using 5-hour-old cultures; the sensitivity and specificity for detection of carbapenemase production were 100% for non-OXA-producing organisms. The sensitivity from early cultures was 94% for detection of carbapenemase production in Enterobacteriaceae strains. Utilizing younger cultures allows the test to be incorporated into a single day's workflow, facilitating timely patient care and antimicrobial stewardship. PMID- 25143573 TI - Molecular and clinical diagnosis of group A streptococcal pharyngitis in children. AB - Group A Streptococcus (GAS) pharyngitis is a very common condition causing significant morbidity in children. Accurate diagnosis followed by appropriate antimicrobial therapy is recommended to prevent postinfectious sequelae. Diagnosis of GAS pharyngitis by a rapid antigen detection test (RADT) or culture in the absence of discriminating clinical findings remains challenging. Validation of new sensitive rapid diagnostic tests is therefore a priority. The performance of a loop-mediated isothermal amplification (LAMP) assay (illumigene assay) for the diagnosis of GAS pharyngitis was compared with that of a RADT and standard culture in 361 pediatric throat swab samples. Discrepant results were resolved using an alternate molecular assay. Test results were correlated with clinical presentations in patients positive by either method. The closest estimate of the true prevalence of GAS pharyngitis was 19.7% (71/361 samples). The illumigene assay alone detected 70/71 GAS-positive samples; RADT and culture detected 35/71 and 55/71 samples, respectively. RADT followed by culture confirmation of RADT-negative specimens detected 58/71 cases. The illumigene assay increased identification among children eligible for testing by American College of Physicians (ACP)/American Academy of Family Physicians (AAFP) criteria from 31 to 39 positive cases, five of which were false positives. Analysis of clinical data in GAS-positive patients indicated that a significantly greater proportion of children with McIsaac scores of >= 4 tested positive by the illumigene assay versus RADT and culture. Overall, the illumigene assay was much more sensitive and was similarly specific for GAS detection, compared to culture alone, RADT alone, or the ACP/AAFP RADT/culture algorithm. Combining high sensitivity with rapidly available results, the illumigene GAS assay is an appropriate alternative to culture for the laboratory diagnosis of GAS pharyngitis in patients for whom testing is clinically indicated. PMID- 25143574 TI - Major intercontinentally distributed sequence types of Kingella kingae and development of a rapid molecular typing tool. AB - Although Kingella kingae is the most common etiology of osteoarticular infections in young children, is a frequent cause of bacteremia in those younger than 4 years, and has been involved in clusters of invasive infections among daycare center attendees, the population structure of the species has not been systematically studied. Using multilocus sequence typing, we investigated the genetic diversity of the largest intercontinental collection of K. kingae strains to date. To facilitate typing of bacterial isolates, we developed a novel genotyping tool that targets the DNA uptake sequence (DUS). Among 324 strains isolated from asymptomatic carriers and patients from Israel, Europe, North America, and Australia with various invasive forms of the disease from 1960 to 2013, we identified 64 sequence types (STs) and 12 ST complexes (STcs). Five predominant STcs, comprising 72.2% of all strains, were distributed intercontinentally. ST-6 was the most frequent, showing a worldwide distribution, and appeared genotypically isolated by exhibiting few neighboring STs, suggesting an optimal fitness. ST-14 and ST-23 appeared to be the oldest groups of bacteria, while ST-25 probably emerged more recently from the highly evolutive ST-23. Using the DUS typing method, randomly chosen isolates were correctly classified to one of the major STcs. The comprehensive description of K. kingae evolution would help to detect new emerging clones and decipher virulence and fitness mechanisms. The rapid and reproducible DUS typing method may serve in the initial investigation of K. kingae outbreaks. PMID- 25143575 TI - Characterization of a novel thermostable nuclease homolog (NucM) in a highly divergent Staphylococcus aureus clade. AB - A thermostable nuclease homologue (NucM) in an animal-associated divergent clade of Staphylococcus aureus in sub-Saharan Africa has a highly divergent nucleotide sequence compared to those of the classical nuc1 and nuc2 genes of S. aureus. Its deduced amino acid sequences, tertiary structures, and nuclease activities, however, are similar. PMID- 25143576 TI - Klebsiella pneumoniae ST147 coproducing NDM-7 carbapenemase and RmtF 16S rRNA methyltransferase in Minnesota. PMID- 25143577 TI - Sensitivity of surveillance testing for multidrug-resistant Gram-negative bacteria in the intensive care unit. AB - We tested intensive care unit patients for colonization with multidrug-resistant Gram-negative bacilli (MDR GNB) and compared the results with those of concurrent clinical cultures. The sensitivity of the surveillance test for detecting MDR GNB was 58.8% (95% confidence interval, 48.6 to 68.5%). Among 133 patients with positive surveillance tests, 61% had no prior clinical culture with MDR GNB. PMID- 25143578 TI - In vitro activity of ceftolozane-tazobactam as determined by broth dilution and agar diffusion assays against recent U.S. Escherichia coli isolates from 2010 to 2011 carrying CTX-M-type extended-spectrum beta-lactamases. AB - Ceftolozane MIC(50)/MIC(90)s were 4/8 MUg/ml when tested against 26 CTX-M-14-type producing isolates and 64/>64 MUg/ml against 219 CTX-M-15-type-producing isolates. The addition of 4 MUg/ml tazobactam lowered the ceftolozane MIC50/MIC9(0)s to <= 0.25/0.5 MUg/ml by broth microdilution and Etest. The zone diameters for the ceftolozane-tazobactam disks were 23 to 29 mm for 92.2% of the isolates. PMID- 25143579 TI - Limited utility of dried-blood- and plasma spot-based screening for antiretroviral treatment failure with Cobas Ampliprep/TaqMan HIV-1 version 2.0. AB - The 2013 WHO antiretroviral therapy (ART) guidelines recommend dried blood spots (DBS) as an alternative specimen type for viral load (VL) monitoring. We assessed the programmatic utility of screening for antiretroviral (ARV) treatment failure (TF) at 5,000 and 1,000 copies/ml using DBS and dried plasma spots (DPS) with a commonly used VL assay, the Roche Cobas Ampliprep/Cobas TaqMan V.2.0 (CAP/CTM). Plasma, DBS, and DPS were prepared from 839 whole-blood specimens collected from patients on ART for >= 6 months at three public facilities in Namibia. Using the CAP/CTM test, VL were measured in plasma, DBS, and DPS, and the results were compared using the plasma VL as the reference standard. The clinical sensitivities, specificities, and positive (PPV) and negative predictive values (NPV) of DBS at ARV TF diagnostic thresholds of 5,000 copies/ml and 1,000 copies/ml were 0.99, 0.55, 0.33, and 0.99 and 0.99, 0.26, 0.29, and 0.99, respectively, and for DPS at TF diagnostic thresholds of 5,000 copies/ml and 1,000 copies/ml, they were 0.88, 0.98, 0.92, and 0.97 and 0.91, 0.96, 0.89, and 0.97, respectively. The prevalences of TF were overestimated in DBS by 33% and 57% at these two thresholds, respectively. A high rate of false-positive results would occur if the CAP/CTM with DBS were to be used to screen for ARV TF. WHO recommendations for DBS-based VL monitoring should be specific to the VL assay version and type. Despite the better performance of DPS, the programmatic utility for TF screening may be limited by requirements for processing the whole blood at the collection site. PMID- 25143580 TI - Development and validation of a sensitive and specific sodB-based quantitative PCR assay for molecular detection of Ehrlichia species. AB - We developed a sensitive and specific sodB-based quantitative PCR assay to detect Ehrlichia spp. The assay's limit of detection was 5 copies/reaction, and it did not amplify nonspecific DNA. Compared with a 16S rRNA gene PCR target, the sodB target may offer an improved molecular diagnostic assay to detect Ehrlichia spp. PMID- 25143581 TI - Molecular typing of Escherichia coli O157:H7 isolates from Swedish cattle and human cases: population dynamics and virulence. AB - While all verotoxin-producing Escherichia coli O157:H7 bacteria are considered potential pathogens, their genetic subtypes appear to differ in their levels of virulence. The aim of this study was to compare the distribution of subtypes of E. coli O157:H7 in the cattle reservoir and in human cases with and without severe complications in order to gain clues about the relationship between subtype and relative virulence. A lineage-specific polymorphism assay (LSPA-6), multilocus variable-number tandem-repeat analysis (MLVA), and a novel real-time PCR assay to identify clade 8 were applied to a large and representative set of isolates from cattle from 1996 to 2009 (n = 381) and human cases from 2008 to 2011 (n = 197) in Sweden. Draft genome sequences were produced for four selected isolates. The E. coli O157:H7 isolates in Swedish cattle generally belonged to four groups with the LSPA-6 profiles 211111 (clade 8/non-clade 8), 213111, and 223323. The subtype composition of the cattle isolates changed dramatically during the study period with the introduction and rapid spread of the low virulence 223323 subtype. The human cases presumed to have been infected within the country predominantly carried isolates with the profiles 211111 (clade 8) and 213111. Cases progressing to hemolytic-uremic syndrome (HUS) were mostly caused by clade 8, with MLVA profiles consistent with Swedish cattle as the source. In contrast, infections contracted abroad were caused by diverse subtypes, some of which were associated with a particular region. The work presented here confirms the high risk posed by the clade 8 variant of E. coli O157:H7. It also highlights the dynamic nature of the E. coli O157:H7 subtype composition in animal reservoirs and the importance of this composition for the human burden of disease. PMID- 25143583 TI - Characterization of multiple cytomegalovirus drug resistance mutations detected in a hematopoietic stem cell transplant recipient by recombinant phenotyping. AB - Cytomegalovirus resistance to antivirals is a major problem in transplant recipients. We evaluated the impact of five mutations (A594V, L595F, and E655K in the UL97 gene and V526L and E756K in the UL54 gene), detected in a blood sample from a stem cell transplant recipient, on drug susceptibilities and replicative capacities of recombinant viruses. PMID- 25143582 TI - Single-molecule long-read 16S sequencing to characterize the lung microbiome from mechanically ventilated patients with suspected pneumonia. AB - In critically ill patients, the development of pneumonia results in significant morbidity and mortality and additional health care costs. The accurate and rapid identification of the microbial pathogens in patients with pulmonary infections might lead to targeted antimicrobial therapy with potentially fewer adverse effects and lower costs. Major advances in next-generation sequencing (NGS) allow culture-independent identification of pathogens. The present study used NGS of essentially full-length PCR-amplified 16S ribosomal DNA from the bronchial aspirates of intubated patients with suspected pneumonia. The results from 61 patients demonstrated that sufficient DNA was obtained from 72% of samples, 44% of which (27 samples) yielded PCR amplimers suitable for NGS. Out of the 27 sequenced samples, only 20 had bacterial culture growth, while the microbiological and NGS identification of bacteria coincided in 17 (85%) of these samples. Despite the lack of bacterial growth in 7 samples that yielded amplimers and were sequenced, the NGS identified a number of bacterial species in these samples. Overall, a significant diversity of bacterial species was identified from the same genus as the predominant cultured pathogens. The numbers of NGS identifiable bacterial genera were consistently higher than identified by standard microbiological methods. As technical advances reduce the processing and sequencing times, NGS-based methods will ultimately be able to provide clinicians with rapid, precise, culture-independent identification of bacterial, fungal, and viral pathogens and their antimicrobial sensitivity profiles. PMID- 25143584 TI - Oxidative stress contributes to autophagy induction in response to endoplasmic reticulum stress in Chlamydomonas reinhardtii. AB - The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) results in the activation of stress responses, such as the unfolded protein response or the catabolic process of autophagy to ultimately recover cellular homeostasis. ER stress also promotes the production of reactive oxygen species, which play an important role in autophagy regulation. However, it remains unknown whether reactive oxygen species are involved in ER stress-induced autophagy. In this study, we provide evidence connecting redox imbalance caused by ER stress and autophagy activation in the model unicellular green alga Chlamydomonas reinhardtii. Treatment of C. reinhardtii cells with the ER stressors tunicamycin or dithiothreitol resulted in up-regulation of the expression of genes encoding ER resident endoplasmic reticulum oxidoreductin1 oxidoreductase and protein disulfide isomerases. ER stress also triggered autophagy in C. reinhardtii based on the protein abundance, lipidation, cellular distribution, and mRNA levels of the autophagy marker ATG8. Moreover, increases in the oxidation of the glutathione pool and the expression of oxidative stress-related genes were detected in tunicamycin-treated cells. Our results revealed that the antioxidant glutathione partially suppressed ER stress-induced autophagy and decreased the toxicity of tunicamycin, suggesting that oxidative stress participates in the control of autophagy in response to ER stress in C. reinhardtii In close agreement, we also found that autophagy activation by tunicamycin was more pronounced in the C. reinhardtii sor1 mutant, which shows increased expression of oxidative stress-related genes. PMID- 25143585 TI - CD1d-unrestricted NKT cells are endowed with a hybrid function far superior than that of iNKT cells. AB - Invariant natural killer T (iNKT) cells to date represent the best example of cells known to have a hybrid function, representing both innate and adaptive immunity. Shared phenotypic similarities with NK cells together with a rapid response to a cytokine stimulus and a productive TCR engagement are the features that underline the hybrid nature of iNKT cells. Using these criteria, we provide molecular and functional evidence demonstrating that CD1d-independent (CD1d(ind)) NKT cells, a population of CD1d-unrestricted NKT cells, are endowed with a hybrid function far superior to that of iNKT cells: (i) an extensive shared program with NK cells, (ii) a closer Euclidian distance with NK cells, and (iii) the ability to respond to innate stimuli (Poly:IC) with cytotoxic potential in the same manner as NK cells identify a hybrid feature in CD1d(ind)NKT cells that truly fulfills the dual function of an NK and a T cell. Our finding that CD1d(ind)NKT cells are programmed to act like NK cells in response to innate signals while being capable of adaptive responses is unprecedented, and thus might reemphasize CD1d-unrestricted NKT cells as a subset of lymphocytes that could affect biological processes of antimicrobial and tumor immunity in a unique way. PMID- 25143590 TI - Age at obesity and association with subsequent dementia: record linkage study. AB - OBJECTIVE: Obesity in mid-life may increase the risk of subsequent dementia. Our objective was to study this risk, focusing on differences by age at the time of recording of obesity, in a large defined population. METHODS: A record linkage cohort study was undertaken using national administrative statistical data on hospital care and mortality in England, 1999-2011. A cohort of 451 232 people with obesity and a control cohort was constructed. Results were expressed as age specific risk ratios comparing the two cohorts. RESULTS: The risk ratio for dementia in people admitted to hospital with obesity aged 30-39 years was significantly increased at 3.5 (95% CI 2.1 to 5.6). Risk ratios for dementia then gradually reduced with increasing age at obesity from 1.7 (95% CI 1.3 to 2.2) in people aged 40-49 years when obesity was first recorded to 1.4 (95% CI 1.3 to 1.5) in those aged 60-69 years. People in their 70s when obesity was recorded had neither an increased nor a reduced risk of subsequent dementia at 0.97 (95% CI 0.93 to 1.01), and those aged >=80 years had a reduced risk of subsequent dementia at 0.78 (95% CI 0.74 to 0.82). CONCLUSIONS: Obesity is associated with a risk of dementia in a way that appears to vary with age. Investigation of the mechanisms mediating this association might give insights into the biology of both conditions. PMID- 25143588 TI - Primary cilia signaling mediates intraocular pressure sensation. AB - Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-alpha, TGF-beta, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in how the eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems. PMID- 25143589 TI - Shewanella oneidensis MR-1 nanowires are outer membrane and periplasmic extensions of the extracellular electron transport components. AB - Bacterial nanowires offer an extracellular electron transport (EET) pathway for linking the respiratory chain of bacteria to external surfaces, including oxidized metals in the environment and engineered electrodes in renewable energy devices. Despite the global, environmental, and technological consequences of this biotic-abiotic interaction, the composition, physiological relevance, and electron transport mechanisms of bacterial nanowires remain unclear. We report, to our knowledge, the first in vivo observations of the formation and respiratory impact of nanowires in the model metal-reducing microbe Shewanella oneidensis MR 1. Live fluorescence measurements, immunolabeling, and quantitative gene expression analysis point to S. oneidensis MR-1 nanowires as extensions of the outer membrane and periplasm that include the multiheme cytochromes responsible for EET, rather than pilin-based structures as previously thought. These membrane extensions are associated with outer membrane vesicles, structures ubiquitous in Gram-negative bacteria, and are consistent with bacterial nanowires that mediate long-range EET by the previously proposed multistep redox hopping mechanism. Redox-functionalized membrane and vesicular extensions may represent a general microbial strategy for electron transport and energy distribution. PMID- 25143591 TI - Dietary calcium, phosphorus, and phytase effects on bird performance, intestinal morphology, mineral digestibility, and bone ash during a natural necrotic enteritis episode. AB - The objective of this study was to evaluate the effects of dietary Ca, P, and phytase on performance, intestinal morphology, bone ash, and Ca and P digestibility during a necrotic enteritis (NE) outbreak. The 35-d trial was designed as a 2 * 2 * 2 factorial, which included 2 Ca levels (0.6 and 0.9%), 2 P levels (0.3 and 0.45%), and 2 levels of phytase [0 and 1,000 phytase units (FTU)/kg]. Birds were placed on litter from a previous flock that exhibited clinical signs of NE. Birds and feed were weighed on d 12, 19, and 35, and BW gain, feed intake, and feed conversion were calculated. Mortality was recorded daily, and gastrointestinal pH was measured. Tibias and ileal digesta were also collected. Birds began exhibiting clinical signs of NE on d 9, and NE-associated mortality persisted until d 26. Dietary Ca supplemented at 0.9% or inclusion of 1,000 FTU/kg of phytase significantly increased mortality compared with 0.6% Ca or 0 FTU/kg of phytase, respectively. From d 0 to 12, birds fed 0.9% Ca and 0.45% available P with phytase had greater BW gain compared with birds fed 0.6% Ca, 0.45% available P, and phytase. From d 0 to 19, birds fed diets with 0.9% Ca and 0.3% available P had decreased feed intake and improved feed conversion compared with birds fed 0.9% Ca and 0.45% available P. Calcium at 0.9% increased gizzard (d 19) and jejunum (d 12) pH. Phytase supplementation significantly increased Ca digestibility regardless of Ca and P levels of the diets. In addition, diets containing 0.6% Ca and 1,000 FTU/kg of phytase resulted in a significant increase in P digestibility. The results suggest that dietary Ca level may influence NE associated mortality. In addition, bird performance was affected by interactions of Ca, P, and phytase during the exposure to Clostridium perfringens and the subsequent NE outbreak. Results showed improvements in bird performance when birds were fed 0.6% Ca and 0.3% P in diets supplemented with phytase, which was likely consequent to the influence of Ca in NE pathogenesis. PMID- 25143592 TI - Effect of high-dose irradiation on quality characteristics of ready-to-eat broiler breast fillets stored at room temperature. AB - The effect of high-dose irradiation on the physical, chemical, and bacteriological parameters of ready-to-eat vacuum-packed broiler breast meat after 430 d of storage at room temperature was investigated. Ready-to-eat broiler breast fillets were immersed in brine with garlic powder and then drained, grilled, and vacuum-packed (primary packaging). The high-dose irradiation used was approximately 48 kGy. The treatments were designated as A (irradiated samples stored at room temperature), B (irradiated samples stored at -25 degrees C), and C (nonirradiated samples stored at -25 degrees C). All samples were packaged in polyethylene bags containing aluminum to exclude light (secondary packaging). Proximate composition, pH, 2-thiobarbituric acid reactive substance (TBARS), and heterotrophic aerobic mesophilic bacteria were analyzed during 430 d of storage. Results were analyzed using 1-way ANOVA and the Tukey test. Linear regression was used to analyze the correlation between the results for each parameter and storage time of the different treatments. The gamma radiation caused slight changes (P < 0.05) in the moisture and fat content, regardless of storage temperature. After storage d 110, TBARS values remained stable (P > 0.05) in all the treatments. The preservation methods used were effective in maintaining the mesophilic counts below the detection level during the entire storage period. We concluded that, among the treatments studied, high-dose irradiation with storage at room temperature showed potential for the preservation of ready-to-eat products made from poultry meat, to provide foods safe for consumption. PMID- 25143593 TI - Cell bioenergetics in Leghorn male hepatoma cells and immortalized chicken liver cells in response to 4-hydroxy 2-nonenal-induced oxidative stress. AB - The major objectives of this study were to compare cell bioenergetics in 2 avian liver cell lines under control conditions and in response to oxidative stress imposed by 4-hydroxy 2-nonenal (4-HNE). Cells in this study were from a chemically immortalized Leghorn male hepatoma (LMH) cell line and a spontaneously immortalized chicken liver (CELi) cell line. Oxygen consumption rate (OCR) was monitored in specialized microtiter plates using an XF24 Flux Analyzer (Seahorse Bioscience, Billerica, MA). Cell bioenergetics was assessed by sequential additions of oligomycin, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), and antimycin-A that enables the determination of a) OCR linked to adenosine triphosphate (ATP) synthase activity, b) mitochondrial oxygen reserve capacity, c) proton leak, and d) nonmitochondrial cytochrome c oxidase activity. Under control (unchallenged) conditions, LMH cells exhibited higher basal OCR and higher OCR attributed to each of the bioenergetic components listed above compared with CELi cells. When expressed as a percentage of maximal OCR (following uncoupling with FCCP), LMH cells exhibited higher OCR due to ATP synthase and proton leak activity, but lower mitochondrial oxygen reserve capacity compared with CELi cells; there were no differences in OCR associated with nonmitochondrial cytochrome c oxidase activity. Whereas the LMH cells exhibited robust ATP synthase activity up to 50 MUM 4-HNE, CELi cells exhibited a progressive decline in ATP synthase activity with 10, 20, and 30 MUM 4-HNE. The CELi cells exhibited higher mitochondrial oxygen reserve capacity compared with LMH cells with 0 and 20 MUM 4-HNE but not with 30 MUM 4-HNE. Both cell lines exhibited inducible proton leak in response to increasing levels of 4-HNE that was evident with 30 MUM 4-HNE for CELi cells and with 40 and 50 MUM 4-HNE in LMH cells. The results of these studies demonstrate fundamental differences in cell bioenergetics in 2 avian liver-derived cell lines under control conditions and in response to oxidative challenge due to 4-HNE. PMID- 25143594 TI - Influence of particle size and calcium source on production performance, egg quality, and bone parameters in laying ducks. AB - The influence of calcium source (limestone and oyster shell) and particle size (<0.1 mm; 0.85 to 2 mm) on laying performance, egg quality, and bone properties were examined in laying ducks by a 2 * 2 factorial arrangement of treatments. Longyan females (288) with similar BW at 24 wk of age were randomly allotted into 4 treatments, each with 6 replicates of 12 individually caged birds and studied over the following 12 wk. Particle size affected egg weight and feed conversion (P < 0.05). Large particle size increased shell breaking strength, albumen height, Haugh unit, and shell content of phosphorus and magnesium (P < 0.05), but had no effect on egg shape, yolk color, shell thickness, or the weight proportion of shell. There were no effects of particle size on tibial properties: dry defatted weight, calcium content, or breaking strength. Limestone increased albumen height, shell content of calcium and phosphorus, and the breaking strength of tibia (P < 0.05). It is concluded that limestone with a large particle size provided for superior productive performance, egg quality, and bone characteristics and is more suitable than oyster shell for practical applications. PMID- 25143595 TI - Response to dietary supplementation of L-glutamine and L-glutamate in broiler chickens reared at different stocking densities under hot, humid tropical conditions. AB - A study was conducted to determine whether supplementing AminoGut (a commercial dietary supplement containing a mixture of l-glutamine and l-glutamic acid) to broiler chickens stocked at 2 different densities affected performance, physiological stress responses, foot pad dermatitis incidence, and intestinal morphology and microflora. A randomized design in a factorial arrangement with 4 diets [basal diet, basal diet + 0.5% AminoGut from d 1 to 21, basal diet + 0.5% AminoGut from d 1 to 42, and basal diet + virginiamycin (0.02%) for d 1 to 42] and 2 stocking densities [0.100 m(2)/bird (23 birds/pen; LD) or 0.067 m(2)/bird (35 birds/pen; HD)]. Results showed that villi length and crypt depth were not changed by different dietary treatments. However, birds in the HD group had smaller villi (P = 0.03) compared with those of the LD group. Regardless of diet, HD consistently increased the serum concentrations of ceruloplasmin, alpha-1 acid glycoprotein, ovotransferin, and corticosterone (P = 0.0007), and elevated heterophil to lymphocyte ratio (0.0005). Neither AminoGut supplementation nor stocking density affected cecal microflora counts. In conclusion, under the conditions of this study, dietary supplementation of AminoGut, irrespective of stocking density, had no beneficial effect on growth performance, intestinal morphology, and physiological adaptive responses of broiler chickens raised under hot and humid tropical conditions. However, AminoGut supplementation from d 1 to 42 was beneficial in reducing mortality rate. Also, the increased serum concentrations of a wide range of acute phase proteins together with elevated corticosterone and heterophil to lymphocyte ratio suggested that high stocking density induced an acute phase response either indirectly as a result of increased incidence of inflammatory diseases such as foot pad dermatitis or possibly as a direct physiological response to the stress of high stocking density. PMID- 25143596 TI - Structural basis of an engineered dual-specific antibody: conformational diversity leads to a hypervariable loop metal-binding site. AB - To explore dual-specificity in a small protein interface, we previously generated a 'metal switch' anti-RNase A VHH antibody using a combinatorial histidine library approach. While most metal-binding sites in proteins are found within rigid secondary structure, the engineered VHH antibody (VHH(metal)), which contained three new histidine residues, possessed metal-binding residues within the flexible hypervariable loops. Here, crystal structure analysis of the free and bound states of VHH(metal) reveals the structural determinants leading to dual-function. Most notably, CDR1 is observed in two distinct conformations when adopting the metal or RNase A bound states. Furthermore, mutagenesis studies revealed that one of the engineered residues, not located in the metal-binding pocket, contributed indirectly to metal recognition, likely through influencing CDR1 conformation. Despite these changes, VHH(metal) possesses a relatively minor energetic penalty toward binding the original antigen, RNase A (~1 kcal/mol), where the engineered gain-of-function metal-binding residues are observed to possess a mix of favorable and unfavorable contributions towards RNase A recognition. Ultimately, the conformationally distinct metal-switch interface architecture reflects the robust, library-based strategy used to produce VHH(metal). These results also suggest that even small protein interfaces, such as VHH, may be structurally and energetically forgiving in adopting novel function, while maintaining original function. PMID- 25143597 TI - Is action-perception coupling improved with delay in patients with focal cerebellar lesions? PMID- 25143598 TI - Second order receptive field properties of simple and complex cells support a new standard model of thalamocortical circuitry in V1. PMID- 25143599 TI - Temporal and region-specific requirements of alphaCaMKII in spatial and contextual learning. AB - The alpha isoform of the calcium/calmodulin-dependent protein kinase II (alphaCaMKII) has been implicated extensively in molecular and cellular mechanisms underlying spatial and contextual learning in a wide variety of species. Germline deletion of Camk2a leads to severe deficits in spatial and contextual learning in mice. However, the temporal and region-specific requirements for alphaCaMKII have remained largely unexplored. Here, we generated conditional Camk2a mutants to examine the influence of spatially restricted and temporally controlled expression of alphaCaMKII. Forebrain-specific deletion of the Camk2a gene resulted in severe deficits in water maze and contextual fear learning, whereas mice with deletion restricted to the cerebellum learned normally. Furthermore, we found that temporally controlled deletion of the Camk2a gene in adult mice is as detrimental as germline deletion for learning and synaptic plasticity. Together, we confirm the requirement for alphaCaMKII in the forebrain, but not the cerebellum, in spatial and contextual learning. Moreover, we highlight the absolute requirement for intact alphaCaMKII expression at the time of learning. PMID- 25143600 TI - Associative encoding and retrieval are predicted by functional connectivity in distinct hippocampal area CA1 pathways. AB - Determining how the hippocampus supports the unique demands of memory encoding and retrieval is fundamental for understanding the biological basis of episodic memory. One possibility proposed by theoretical models is that the distinct computational demands of encoding and retrieval are accommodated by shifts in the functional interaction between the hippocampal CA1 subregion and its input structures. However, empirical tests of this hypothesis are lacking. To test this in humans, we used high-resolution fMRI to measure functional connectivity between hippocampal area CA1 and regions of the medial temporal lobe and midbrain during extended blocks of associative encoding and retrieval tasks. We found evidence for a double dissociation between the pathways supporting successful encoding and retrieval. Specifically, during the associative encoding task, but not the retrieval task, functional connectivity only between area CA1 and the ventral tegmental area predicted associative long-term memory. In contrast, connectivity between area CA1 and DG/CA3 was greater, on average, during the retrieval task compared with the encoding task, and, importantly, the strength of this connectivity significantly correlated with retrieval success. Together, these findings serve as an important first step toward understanding how the demands of fundamental memory processes may be met by changes in the relative strength of connectivity within hippocampal pathways. PMID- 25143601 TI - Opposing brain differences in 16p11.2 deletion and duplication carriers. AB - Deletions and duplications of the recurrent ~600 kb chromosomal BP4-BP5 region of 16p11.2 are associated with a broad variety of neurodevelopmental outcomes including autism spectrum disorder. A clue to the pathogenesis of the copy number variant (CNV)'s effect on the brain is that the deletion is associated with a head size increase, whereas the duplication is associated with a decrease. Here we analyzed brain structure in a clinically ascertained group of human deletion (N = 25) and duplication (N = 17) carriers from the Simons Variation in Individuals Project compared with age-matched controls (N = 29 and 33, respectively). Multiple brain measures showed increased size in deletion carriers and reduced size in duplication carriers. The effects spanned global measures of intracranial volume, brain size, compartmental measures of gray matter and white matter, subcortical structures, and the cerebellum. Quantitatively, the largest effect was on the thalamus, but the collective results suggest a pervasive rather than a selective effect on the brain. Detailed analysis of cortical gray matter revealed that cortical surface area displays a strong dose-dependent effect of CNV (deletion > control > duplication), whereas average cortical thickness is less affected. These results suggest that the CNV may exert its opposing influences through mechanisms that influence early stages of embryonic brain development. PMID- 25143602 TI - Chromophore supply rate-limits mammalian photoreceptor dark adaptation. AB - Efficient regeneration of visual pigment following its destruction by light is critical for the function of mammalian photoreceptors. Here, we show that misexpression of a subset of cone genes in the rd7 mouse hybrid rods enables them to access the normally cone-specific retina visual cycle. The rapid supply of chromophore by the retina visual cycle dramatically accelerated the mouse rod dark adaptation. At the same time, the competition between rods and cones for retina-derived chromophore slowed cone dark adaptation, indicating that the cone specificity of the retina visual cycle is key for rapid cone dark adaptation. Our findings demonstrate that mammalian photoreceptor dark adaptation is dominated by the supply of chromophore. Misexpression of cone genes in rods may represent a novel approach to treating visual disorders associated with mutations of visual cycle proteins or with reduced retinal pigment epithelium function due to aging. PMID- 25143603 TI - Correlations in V1 are reduced by stimulation outside the receptive field. AB - The trial-to-trial response variability of nearby cortical neurons is correlated. These correlations may strongly influence population coding performance. Numerous studies have shown that correlations can be dynamically modified by attention, adaptation, learning, and potent stimulus drive. However, the mechanisms that influence correlation strength remain poorly understood. Here we test whether correlations are influenced by presenting stimuli outside the classical receptive field (RF) of visual neurons, where they recruit a normalization signal termed surround suppression. We recorded simultaneously the activity of dozens of cells using microelectrode arrays implanted in the superficial layers of V1 in anesthetized, paralyzed macaque monkeys. We presented annular stimuli that encircled--but did not impinge upon--the RFs of the recorded cells. We found that these "extra-classical" stimuli reduced correlations in the absence of stimulation of the RF, closely resembling the decorrelating effects of stimulating the RFs directly. Our results suggest that normalization signals may be an important mechanism for modulating correlations. PMID- 25143604 TI - Astroglial connexin43 hemichannels tune basal excitatory synaptic transmission. AB - Fast exchange of extracellular signals between neurons and astrocytes is crucial for synaptic function. Over the last few decades, different pathways of astroglial release of neuroactive substances have been proposed to modulate neurotransmission. However, their involvement in physiological conditions is highly debated. Connexins, the gap junction forming proteins, are highly expressed in astrocytes and have recently been shown to scale synaptic transmission and plasticity. Interestingly, in addition to gap junction channels, the most abundant connexin (Cx) in astrocytes, Cx43, also forms hemichannels. While such channels are mostly active in pathological conditions, they have recently been shown to regulate cognitive function. However, whether astroglial Cx43 hemichannels are active in resting conditions and regulate basal synaptic transmission is unknown. Here we show that in basal conditions Cx43 forms functional hemichannels in astrocytes from mouse hippocampal slices. We furthermore demonstrate that the activity of astroglial Cx43 hemichannels in resting states regulates basal excitatory synaptic transmission of hippocampal CA1 pyramidal cells through ATP signaling. These data reveal Cx43 hemichannels as a novel astroglial release pathway at play in basal conditions, which tunes the moment-to-moment glutamatergic synaptic transmission. PMID- 25143605 TI - Responses of prefrontal multisensory neurons to mismatching faces and vocalizations. AB - Social communication relies on the integration of auditory and visual information, which are present in faces and vocalizations. Evidence suggests that the integration of information from multiple sources enhances perception compared with the processing of a unimodal stimulus. Our previous studies demonstrated that single neurons in the ventrolateral prefrontal cortex (VLPFC) of the rhesus monkey (Macaca mulatta) respond to and integrate conspecific vocalizations and their accompanying facial gestures. We were therefore interested in how VLPFC neurons respond differentially to matching (congruent) and mismatching (incongruent) faces and vocalizations. We recorded VLPFC neurons during the presentation of movies with congruent or incongruent species-specific facial gestures and vocalizations as well as their unimodal components. Recordings showed that while many VLPFC units are multisensory and respond to faces, vocalizations, or their combination, a subset of neurons showed a significant change in neuronal activity in response to incongruent versus congruent vocalization movies. Among these neurons, we typically observed incongruent suppression during the early stimulus period and incongruent enhancement during the late stimulus period. Incongruent-responsive VLPFC neurons were both bimodal and nonlinear multisensory, fostering their ability to respond to changes in either modality of a face-vocalization stimulus. These results demonstrate that ventral prefrontal neurons respond to changes in either modality of an audiovisual stimulus, which is important in identity processing and for the integration of multisensory communication information. PMID- 25143606 TI - Distinct roles of bulbar muscarinic and nicotinic receptors in olfactory discrimination learning. AB - The olfactory bulb (OB) and piriform cortex receive dense cholinergic projections from the basal forebrain. Cholinergic modulation within the piriform cortex has long been proposed to serve important functions in olfactory learning and memory. We here investigate how olfactory discrimination learning is regulated by cholinergic modulation of the OB inputs to the piriform cortex. We examined rats' performance on a two-alternative choice odor discrimination task following local, bilateral blockade of cholinergic nicotinic and/or muscarinic receptors in the OB. Results demonstrate that acquisition, but not recall, of novel discrimination problems is impaired following blockade of OB cholinergic receptors, although the relative contribution of muscarinic and nicotinic receptors depends on task difficulty. Blocking muscarinic receptors impairs learning for nearly all odor sets, whereas blocking nicotinic receptors only affects performance for perceptually similar odors. This pattern of behavioral effects is consistent with predictions from a model of cholinergic modulation in the OB and piriform cortex (de Almeida et al., 2013). Model simulations suggest that muscarinic and nicotinic receptors may serve complementary roles in regulating coherence and sparseness of the OB network output, which in turn differentially regulate the strength and overlap in cortical odor representations. Overall, our results suggest that muscarinic receptor blockade results in a bona fide learning impairment that may arise because cortical neurons are activated less often. Behavioral impairment following nicotinic receptor blockade may not be due to the inability of the cortex to learn, but rather arises because the cortex is unable to resolve highly overlapping input patterns. PMID- 25143607 TI - Network organization unfolds over time during periods of anxious anticipation. AB - Entering a state of anxious anticipation triggers widespread changes across large scale networks in the brain. The temporal aspects of this transition into an anxious state are poorly understood. To address this question, an instructed threat of shock paradigm was used while recording functional MRI in humans to measure how activation and functional connectivity change over time across the salience, executive, and task-negative networks and how they interact with key regions implicated in emotional processing; the amygdala and bed nucleus of the stria terminalis (BNST). Transitions into threat blocks were associated with transient responses in regions of the salience network and sustained responses in a putative BNST site, among others. Multivariate network measures of communication were computed, revealing changes to network organization during transient and sustained periods of threat, too. For example, the salience network exhibited a transient increase in network efficiency followed by a period of sustained decreased efficiency. The amygdala became more central to network function (as assessed via betweenness centrality) during threat across all participants, and the extent to which the BNST became more central during threat depended on self-reported anxiety. Together, our study unraveled a progression of responses and network-level changes due to sustained threat. In particular, our results reveal how network organization unfolds with time during periods of anxious anticipation. PMID- 25143608 TI - Neural cell adhesion molecule NrCAM regulates Semaphorin 3F-induced dendritic spine remodeling. AB - Neuron-glial related cell adhesion molecule (NrCAM) is a regulator of axon growth and repellent guidance, and has been implicated in autism spectrum disorders. Here a novel postsynaptic role for NrCAM in Semaphorin3F (Sema3F)-induced dendritic spine remodeling was identified in pyramidal neurons of the primary visual cortex (V1). NrCAM localized to dendritic spines of star pyramidal cells in postnatal V1, where it was coexpressed with Sema3F. NrCAM deletion in mice resulted in elevated spine densities on apical dendrites of star pyramidal cells at both postnatal and adult stages, and electron microscopy revealed increased numbers of asymmetric synapses in layer 4 of V1. Whole-cell recordings in cortical slices from NrCAM-null mice revealed increased frequency of mEPSCs in star pyramidal neurons. Recombinant Sema3F-Fc protein induced spine retraction on apical dendrites of wild-type, but not NrCAM-null cortical neurons in culture, while re-expression of NrCAM rescued the spine retraction response. NrCAM formed a complex in brain with Sema3F receptor subunits Neuropilin-2 (Npn-2) and PlexinA3 (PlexA3) through an Npn-2-binding sequence (TARNER) in the extracellular Ig1 domain. A trans heterozygous genetic interaction test demonstrated that Sema3F and NrCAM pathways interacted in vivo to regulate spine density in star pyramidal neurons. These findings reveal NrCAM as a novel postnatal regulator of dendritic spine density in cortical pyramidal neurons, and an integral component of the Sema3F receptor complex. The results implicate NrCAM as a contributor to excitatory/inhibitory balance in neocortical circuits. PMID- 25143609 TI - Intersubject variability of and genetic effects on the brain's functional connectivity during infancy. AB - Infancy is a period featuring a high level of intersubject variability but the brain basis for such variability and the potential genetic/environmental contributions remain largely unexplored. The assessment of the brain's functional connectivity during infancy by the resting state functional magnetic resonance imaging (rsfMRI) technique (Biswal et al., 1995) provides a unique means to probe the brain basis of intersubject variability during infancy. In this study, an unusually large typically developing human infant sample including 58 singletons, 132 dizygotic twins, and 98 monozygotic twins with rsfMRI scans during the first 2 years of life was recruited to delineate the spatial and temporal developmental patterns of both the intersubject variability of and genetic effects on the brain's functional connectivity. Through systematic voxelwise functional connectivity analyses, our results revealed that the intersubject variability at birth features lower variability in primary functional areas but higher values in association areas. Although the relative pattern remains largely consistent, the magnitude of intersubject variability undergoes an interesting U-shaped growth during the first 2 years of life. Overall, the intersubject variability patterns during infancy show both adult-like and infant-specific characteristics (Mueller et al., 2013). On the other hand, age-dependent genetic effects were observed showing significant but bidirectional relationships with intersubject variability. The temporal and spatial patterns of the intersubject variability of and genetic contributions to the brain's functional connectivity documented in this study shed light on the largely uncharted functional development of the brain during infancy. PMID- 25143610 TI - Transfer of learning relates to intrinsic connectivity between hippocampus, ventromedial prefrontal cortex, and large-scale networks. AB - An important aspect of adaptive learning is the ability to flexibly use past experiences to guide new decisions. When facing a new decision, some people automatically leverage previously learned associations, while others do not. This variability in transfer of learning across individuals has been demonstrated repeatedly and has important implications for understanding adaptive behavior, yet the source of these individual differences remains poorly understood. In particular, it is unknown why such variability in transfer emerges even among homogeneous groups of young healthy participants who do not vary on other learning-related measures. Here we hypothesized that individual differences in the transfer of learning could be related to relatively stable differences in intrinsic brain connectivity, which could constrain how individuals learn. To test this, we obtained a behavioral measure of memory-based transfer outside of the scanner and on a separate day acquired resting-state functional MRI images in 42 participants. We then analyzed connectivity across independent component analysis-derived brain networks during rest, and tested whether intrinsic connectivity in learning-related networks was associated with transfer. We found that individual differences in transfer were related to intrinsic connectivity between the hippocampus and the ventromedial prefrontal cortex, and between these regions and large-scale functional brain networks. Together, the findings demonstrate a novel role for intrinsic brain dynamics in flexible learning-guided behavior, both within a set of functionally specific regions known to be important for learning, as well as between these regions and the default and frontoparietal networks, which are thought to serve more general cognitive functions. PMID- 25143611 TI - Neuronal somata and extrasomal compartments play distinct roles during synapse formation between Lymnaea neurons. AB - Proper synapse formation is pivotal for all nervous system functions. However, the precise mechanisms remain elusive. Moreover, compared with the neuromuscular junction, steps regulating the synaptogenic program at central cholinergic synapses remain poorly defined. In this study, we identified different roles of neuronal compartments (somal vs extrasomal) in chemical and electrical synaptogenesis. Specifically, the electrically synapsed Lymnaea pedal dorsal A cluster neurons were used to study electrical synapses, whereas chemical synaptic partners, visceral dorsal 4 (presynaptic, cholinergic), and left pedal dorsal 1 (LPeD1; postsynaptic) were explored for chemical synapse formation. Neurons were cultured in a soma-soma or soma-axon configuration and synapses explored electrophysiologically. We provide the first direct evidence that electrical synapses develop in a soma-soma, but not soma-axon (removal of soma) configuration, indicating the requirement of gene transcription regulation in the somata of both synaptic partners. In addition, the soma-soma electrical coupling was contingent upon trophic factors present in Lymnaea brain-conditioned medium. Further, we demonstrate that chemical (cholinergic) synapses between soma-soma and soma-axon pairs were indistinguishable, with both exhibiting a high degree of contact site and target cell type specificity. We also provide direct evidence that presynaptic cell contact-mediated, clustering of postsynaptic cholinergic receptors at the synaptic site requires transmitter-receptor interaction, receptor internalization, and a protein kinase C-dependent lateral migration toward the contact site. This study provides novel insights into synaptogenesis between central neurons revealing both distinct and synergistic roles of cell cell signaling and extrinsic trophic factors in executing the synaptogenic program. PMID- 25143613 TI - NMDA receptors are upregulated and trafficked to the plasma membrane after sigma 1 receptor activation in the rat hippocampus. AB - Sigma-1 receptors (sigma-1Rs) are endoplasmic reticulum resident chaperone proteins implicated in many physiological and pathological processes in the CNS. A striking feature of sigma-1Rs is their ability to interact and modulate a large number of voltage- and ligand-gated ion channels at the plasma membrane. We have reported previously that agonists for sigma-1Rs potentiate NMDA receptor (NMDAR) currents, although the mechanism by which this occurs is still unclear. In this study, we show that in vivo administration of the selective sigma-1R agonists (+) SKF 10,047 [2S-(2alpha,6alpha,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2 propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride (N-allylnormetazocine) hydrochloride], PRE-084 (2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate hydrochloride), and (+)-pentazocine increases the expression of GluN2A and GluN2B subunits, as well as postsynaptic density protein 95 in the rat hippocampus. We also demonstrate that sigma-1R activation leads to an increased interaction between GluN2 subunits and sigma-1Rs and mediates trafficking of NMDARs to the cell surface. These results suggest that sigma-1R may play an important role in NMDAR-mediated functions, such as learning and memory. It also opens new avenues for additional studies into a multitude of pathological conditions in which NMDARs are involved, including schizophrenia, dementia, and stroke. PMID- 25143612 TI - Role of bed nucleus of the stria terminalis corticotrophin-releasing factor receptors in frustration stress-induced binge-like palatable food consumption in female rats with a history of food restriction. AB - We developed recently a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after 15 min exposure to the sight of the palatable food. This "frustration stress" manipulation also activates the hypothalamic-pituitary-adrenal stress axis. Here, we determined the role of the stress neurohormone corticotropin-releasing factor (CRF) in stress-induced binge eating in our model. We also assessed the role of CRF receptors in the bed nucleus of the stria terminalis (BNST), a brain region implicated in stress responses and stress-induced drug seeking, in stress-induced binge eating. We used four groups that were first exposed or not exposed to repeated intermittent cycles of regular chow food restriction during which they were also given intermittent access to high-caloric palatable food. On the test day, we either exposed or did not expose the rats to the sight of the palatable food for 15 min (frustration stress) before assessing food consumption for 2 h. We found that systemic injections of the CRF1 receptor antagonist R121919 (2,5 dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7 dipropylamino pyrazolo[1,5 a]pyrimidine) (10-20 mg/kg) and BNST (25-50 ng/side) or ventricular (1000 ng) injections of the nonselective CRF receptor antagonist D-Phe-CRF(12-41) decreased frustration stress-induced binge eating in rats with a history of food restriction. Frustration stress also increased Fos (a neuronal activity marker) expression in ventral and dorsal BNST. Results demonstrate a critical role of CRF receptors in BNST in stress-induced binge eating in our rat model. CRF1 receptor antagonists may represent a novel pharmacological treatment for bingeing-related eating disorders. PMID- 25143614 TI - Anterior insula activity reflects the effects of intentionality on the anticipation of aversive stimulation. AB - If someone causes you harm, your affective reaction to that person might be profoundly influenced by your inferences about the intentionality of their actions. In the present study, we aimed to understand how affective responses to a biologically salient aversive outcome administered by others are modulated by the extent to which a given individual is judged to have deliberately or inadvertently delivered the outcome. Using fMRI, we examined how neural responses to anticipation and receipt of an aversive stimulus are modulated by this fundamental social judgment. We found that affective evaluations about an individual whose actions led to either noxious or neutral consequences for the subject did indeed depend on the perceived intentions of that individual. At the neural level, activity in the anterior insula correlated with the interaction between perceived intentionality and anticipated outcome valence, suggesting that this region reflects the influence of mental state attribution on aversive expectations. PMID- 25143615 TI - Spatial irregularities of sensitivity along the organ of Corti of the cochlea. AB - Fine structures of spatial profiles were computed from existing records of cat and chinchilla auditory-nerve fibers on the basis of their characteristic frequencies and cochlear maps. The spatial fine structures of characteristic frequency thresholds and of "spontaneous" and driven firing rates were mutually correlated, implying the presence of sensitivity fluctuations due to spatial irregularities of presynaptic structures or processes of the inner hair cells and their input. These findings suggest that activity that appears spontaneous is not actually spontaneous and may indicate irregularities of tonotopic mapping in cochlear mechanics. PMID- 25143616 TI - Theta and high-frequency activity mark spontaneous recall of episodic memories. AB - Humans possess the remarkable ability to search their memory, allowing specific past episodes to be re-experienced spontaneously. Here, we administered a free recall test to 114 neurosurgical patients and used intracranial theta and high frequency activity (HFA) to identify the spatiotemporal pattern of neural activity underlying spontaneous episodic retrieval. We found that retrieval evolved in three electrophysiological stages composed of: (1) early theta oscillations in the right temporal cortex, (2) increased HFA in the left hemisphere including the medial temporal lobe (MTL), left inferior frontal gyrus, as well as the ventrolateral temporal cortex, and (3) motor/language activation during vocalization of the retrieved item. Of these responses, increased HFA in the left MTL predicted recall performance. These results suggest that spontaneous recall of verbal episodic memories involves a spatiotemporal pattern of spectral changes across the brain; however, high-frequency activity in the left MTL represents a final common pathway of episodic retrieval. PMID- 25143618 TI - Mechanisms of sharp wave initiation and ripple generation. AB - Replay of neuronal activity during hippocampal sharp wave-ripples (SWRs) is essential in memory formation. To understand the mechanisms underlying the initiation of irregularly occurring SWRs and the generation of periodic ripples, we selectively manipulated different components of the CA3 network in mouse hippocampal slices. We recorded EPSCs and IPSCs to examine the buildup of neuronal activity preceding SWRs and analyzed the distribution of time intervals between subsequent SWR events. Our results suggest that SWRs are initiated through a combined refractory and stochastic mechanism. SWRs initiate when firing in a set of spontaneously active pyramidal cells triggers a gradual, exponential buildup of activity in the recurrent CA3 network. We showed that this tonic excitatory envelope drives reciprocally connected parvalbumin-positive basket cells, which start ripple-frequency spiking that is phase-locked through reciprocal inhibition. The synchronized GABA(A) receptor-mediated currents give rise to a major component of the ripple-frequency oscillation in the local field potential and organize the phase-locked spiking of pyramidal cells. Optogenetic stimulation of parvalbumin-positive cells evoked full SWRs and EPSC sequences in pyramidal cells. Even with excitation blocked, tonic driving of parvalbumin positive cells evoked ripple oscillations. Conversely, optogenetic silencing of parvalbumin-positive cells interrupted the SWRs or inhibited their occurrence. Local drug applications and modeling experiments confirmed that the activity of parvalbumin-positive perisomatic inhibitory neurons is both necessary and sufficient for ripple-frequency current and rhythm generation. These interneurons are thus essential in organizing pyramidal cell activity not only during gamma oscillation, but, in a different configuration, during SWRs. PMID- 25143617 TI - Role of the dorsal medial habenula in the regulation of voluntary activity, motor function, hedonic state, and primary reinforcement. AB - The habenular complex in the epithalamus consists of distinct regions with diverse neuronal populations. Past studies have suggested a role for the habenula in voluntary exercise motivation and reinforcement of intracranial self stimulation but have not assigned these effects to specific habenula subnuclei. Here, we have developed a genetic model in which neurons of the dorsal medial habenula (dMHb) are developmentally eliminated, via tissue-specific deletion of the transcription factor Pou4f1 (Brn3a). Mice with dMHb lesions perform poorly in motivation-based locomotor behaviors, such as voluntary wheel running and the accelerating rotarod, but show only minor abnormalities in gait and balance and exhibit normal levels of basal locomotion. These mice also show deficits in sucrose preference, but not in the forced swim test, two measures of depression related phenotypes in rodents. We have also used Cre recombinase-mediated expression of channelrhodopsin-2 and halorhodopsin to activate dMHb neurons or silence their output in freely moving mice, respectively. Optical activation of the dMHb in vivo supports intracranial self-stimulation, showing that dMHb activity is intrinsically reinforcing, whereas optical silencing of dMHb outputs is aversive. Together, our findings demonstrate that the dMHb is involved in exercise motivation and the regulation of hedonic state, and is part of an intrinsic reinforcement circuit. PMID- 25143619 TI - Developmental profiles of the intrinsic properties and synaptic function of auditory neurons in preterm and term baboon neonates. AB - The human fetus starts to hear and undergoes major developmental changes in the auditory system during the third trimester of pregnancy. Although there are significant data regarding development of the auditory system in rodents, changes in intrinsic properties and synaptic function of auditory neurons in developing primate brain at hearing onset are poorly understood. We performed whole-cell patch-clamp recordings of principal neurons in the medial nucleus of trapezoid body (MNTB) in preterm and term baboon brainstem slices to study the structural and functional maturation of auditory synapses. Each MNTB principal neuron received an excitatory input from a single calyx of Held terminal, and this one to-one pattern of innervation was already formed in preterm baboons delivered at 67% of normal gestation. There was no difference in frequency or amplitude of spontaneous excitatory postsynaptic synaptic currents between preterm and term MNTB neurons. In contrast, the frequency of spontaneous GABA(A)/glycine receptor mediated inhibitory postsynaptic synaptic currents, which were prevalent in preterm MNTB neurons, was significantly reduced in term MNTB neurons. Preterm MNTB neurons had a higher input resistance than term neurons and fired in bursts, whereas term MNTB neurons fired a single action potential in response to suprathreshold current injection. The maturation of intrinsic properties and dominance of excitatory inputs in the primate MNTB allow it to take on its mature role as a fast and reliable relay synapse. PMID- 25143621 TI - Amyloid-beta-induced action potential desynchronization and degradation of hippocampal gamma oscillations is prevented by interference with peptide conformation change and aggregation. AB - The amyloid-beta hypothesis of Alzheimer's Disease (AD) focuses on accumulation of amyloid-beta peptide (Abeta) as the main culprit for the myriad physiological changes seen during development and progression of AD including desynchronization of neuronal action potentials, consequent development of aberrant brain rhythms relevant for cognition, and final emergence of cognitive deficits. The aim of this study was to elucidate the cellular and synaptic mechanisms underlying the Abeta-induced degradation of gamma oscillations in AD, to identify aggregation state(s) of Abeta that mediate the peptides neurotoxicity, and to test ways to prevent the neurotoxic Abeta effect. We show that Abeta(1-42) in physiological concentrations acutely degrades mouse hippocampal gamma oscillations in a concentration- and time-dependent manner. The underlying cause is an Abeta induced desynchronization of action potential generation in pyramidal cells and a shift of the excitatory/inhibitory equilibrium in the hippocampal network. Using purified preparations containing different aggregation states of Abeta, as well as a designed ligand and a BRICHOS chaperone domain, we provide evidence that the severity of Abeta neurotoxicity increases with increasing concentration of fibrillar over monomeric Abeta forms, and that Abeta-induced degradation of gamma oscillations and excitatory/inhibitory equilibrium is prevented by compounds that interfere with Abeta aggregation. Our study provides correlative evidence for a link between Abeta-induced effects on synaptic currents and AD-relevant neuronal network oscillations, identifies the responsible aggregation state of Abeta and proofs that strategies preventing peptide aggregation are able to prevent the deleterious action of Abeta on the excitatory/inhibitory equilibrium and on the gamma rhythm. PMID- 25143620 TI - Leptin acts via lateral hypothalamic area neurotensin neurons to inhibit orexin neurons by multiple GABA-independent mechanisms. AB - The adipocyte-derived hormone leptin modulates neural systems appropriately for the status of body energy stores. Leptin inhibits lateral hypothalamic area (LHA) orexin (OX; also known as hypocretin)-producing neurons, which control feeding, activity, and energy expenditure, among other parameters. Our previous results suggest that GABAergic LHA leptin receptor (LepRb)-containing and neurotensin (Nts)-containing (LepRb(Nts)) neurons lie in close apposition with OX neurons and control Ox mRNA expression. Here, we show that, similar to leptin, activation of LHA Nts neurons by the excitatory hM3Dq DREADD (designer receptor exclusively activated by designer drugs) hyperpolarizes membrane potential and suppresses action potential firing in OX neurons in mouse hypothalamic slices. Furthermore, ablation of LepRb from Nts neurons abrogated the leptin-mediated inhibition, demonstrating that LepRb(Nts) neurons mediate the inhibition of OX neurons by leptin. Leptin did not significantly enhance GABAA-mediated inhibitory synaptic transmission, and GABA receptor antagonists did not block leptin-mediated inhibition of OX neuron activity. Rather, leptin diminished the frequency of spontaneous EPSCs onto OX neurons. Furthermore, leptin indirectly activated an ATP-sensitive potassium (K(ATP)) channel in OX neurons, which was required for the hyperpolarization of OX neurons by leptin. Although Nts did not alter OX activity, galanin, which is coexpressed in LepRb(Nts) neurons, inhibited OX neurons, whereas the galanin receptor antagonist M40 (galanin-(1-12)-Pro3-(Ala Leu)2-Ala amide) prevented the leptin-induced hyperpolarization of OX cells. These findings demonstrate that leptin indirectly inhibits OX neurons by acting on LHA LepRb(Nts) neurons to mediate two distinct GABA-independent mechanisms of inhibition: the presynaptic inhibition of excitatory neurotransmission and the opening of K(ATP) channels. PMID- 25143622 TI - The major cholesterol metabolite cholestane-3beta,5alpha,6beta-triol functions as an endogenous neuroprotectant. AB - Overstimulation of NMDA-type glutamate receptors is believed to be responsible for neuronal death of the CNS in various disorders, including cerebral and spinal cord ischemia. However, the intrinsic and physiological mechanisms of modulation of these receptors are essentially unknown. Here we report that cholestane 3beta,5alpha,6beta-triol (triol), a major metabolite of cholesterol, is an endogenous neuroprotectant and protects against neuronal injury both in vitro and in vivo via negative modulation of NMDA receptors. Treatment of cultured neurons with triol protects against glutamate-induced neurotoxicity, and administration of triol significantly decreases neuronal injury after spinal cord ischemia in rabbits and transient focal cerebral ischemia in rats. An inducible elevation of triol is associated with ischemic preconditioning and subsequent neuroprotection in the spinal cord of rabbits. This neuroprotection is effectively abolished by preadministration of a specific inhibitor of triol synthesis. Physiological concentrations of triol attenuate [Ca(2+)]i induced by glutamate and decrease inward NMDA-mediated currents in cultured cortical neurons and HEK-293 cells transiently transfected with NR1/NR2B NMDA receptors. Saturable binding of [(3)H]triol to cerebellar granule neurons and displacement of [(3)H]MK-801 binding to NMDA receptors by triol suggest that direct blockade of NMDA receptors may underlie the neuroprotective properties. Our findings suggest that the naturally occurring oxysterol, the major cholesterol metabolite triol, functions as an endogenous neuroprotectant in vivo, which may provide novel insights into understanding and developing potential therapeutics for disorders in the CNS. PMID- 25143623 TI - Human brain responses to concomitant stimulation of Adelta and C nociceptors. AB - Intense radiant heat pulses concomitantly activate Adelta- and C-fiber skin nociceptors, and elicit a typical double sensation: an initial Adelta-related pricking pain is followed by a C-related prolonged burning sensation. It has been repeatedly reported that C-fiber laser-evoked potentials (C-LEPs) become detectable only when the concomitant activation of Adelta-fibers is avoided or reduced. Given that the saliency of the eliciting stimulus is a major determinant of LEPs, one explanation for these observations is that the saliency of the C input is smaller than that of the preceding Adelta-input. However, even if the saliency of the C-input is reduced because of the preceding Adelta-input, a C-LEP should still be visible even when preceded by an Adelta-LEP response. Here we tested this hypothesis by applying advanced signal processing techniques (peak alignment and time-frequency decomposition) to electroencephalographic data collected in two experiments conducted in 34 and 96 healthy participants. We show that, when using optimal stimulus parameters (delivering >80 stimuli within a small skin territory), C-LEPs can be reliably detected in most participants. Importantly, C-LEPs are observed even when preceded by Adelta-LEPs, both in average waveforms and single trials. By providing quantitative information about several response properties of C-LEPs (latency jitter, stimulus-response and perception-response functions, dependency on stimulus repetitions and stimulated area), these results define optimal parameters to record C-LEPs simply and reliably. These findings have important clinical implications for assessing small fiber function in neuropathies and neuropathic pain. PMID- 25143624 TI - Neonatal amygdala lesions lead to increased activity of brain CRF systems and hypothalamic-pituitary-adrenal axis of juvenile rhesus monkeys. AB - The current study examined the long-term effects of neonatal amygdala (Neo-A) lesions on brain corticotropin-releasing factor (CRF) systems and hypothalamic pituitary-adrenal (HPA) axis function of male and female prepubertal rhesus monkeys. At 12-months-old, CSF levels of CRF were measured and HPA axis activity was characterized by examining diurnal cortisol rhythm and response to pharmacological challenges. Compared with controls, Neo-A animals showed higher cortisol secretion throughout the day, and Neo-A females also showed higher CRF levels. Hypersecretion of basal cortisol, in conjunction with blunted pituitary adrenal responses to CRF challenge, suggest HPA axis hyperactivity caused by increased CRF hypothalamic drive leading to downregulation of pituitary CRF receptors in Neo-A animals. This interpretation is supported by the increased CRF CSF levels, suggesting that Neo-A damage resulted in central CRF systems overactivity. Neo-A animals also exhibited enhanced glucocorticoid negative feedback, as reflected by an exaggerated cortisol suppression following dexamethasone administration, indicating an additional effect on glucocorticoid receptor (GR) function. Together these data demonstrate that early amygdala damage alters the typical development of the primate HPA axis resulting in increased rather than decreased activity, presumably via alterations in central CRF and GR systems in neural structures that control its activity. Thus, in contrast to evidence that the amygdala stimulates both CRF and HPA axis systems in the adult, our data suggest an opposite, inhibitory role of the amygdala on the HPA axis during early development, which fits with emerging literature on "developmental switches" in amygdala function and connectivity with other brain areas. PMID- 25143625 TI - Threonine 149 phosphorylation enhances DeltaFosB transcriptional activity to control psychomotor responses to cocaine. AB - Stable changes in neuronal gene expression have been studied as mediators of addicted states. Of particular interest is the transcription factor DeltaFosB, a truncated and stable FosB gene product whose expression in nucleus accumbens (NAc), a key reward region, is induced by chronic exposure to virtually all drugs of abuse and regulates their psychomotor and rewarding effects. Phosphorylation at Ser(27) contributes to DeltaFosB's stability and accumulation following repeated exposure to drugs, and our recent work demonstrates that the protein kinase CaMKIIalpha phosphorylates DeltaFosB at Ser(27) and regulates its stability in vivo. Here, we identify two additional sites on DeltaFosB that are phosphorylated in vitro by CaMKIIalpha, Thr(149) and Thr(180), and demonstrate their regulation in vivo by chronic cocaine. We show that phosphomimetic mutation of Thr(149) (T149D) dramatically increases AP-1 transcriptional activity while alanine mutation does not affect transcriptional activity when compared with wild type (WT) DeltaFosB. Using in vivo viral-mediated gene transfer of DeltaFosB T149D or DeltaFosB-T149A in mouse NAc, we determined that overexpression of DeltaFosB-T149D in NAc leads to greater locomotor activity in response to an initial low dose of cocaine than does WT DeltaFosB, while overexpression of DeltaFosB-T149A does not produce the psychomotor sensitization to chronic low dose cocaine seen after overexpression of WT DeltaFosB and abrogates the sensitization seen in control animals at higher cocaine doses. We further demonstrate that mutation of Thr(149) does not affect the stability of DeltaFosB overexpressed in mouse NAc, suggesting that the behavioral effects of these mutations are driven by their altered transcriptional properties. PMID- 25143626 TI - The generalization of prior uncertainty during reaching. AB - Bayesian statistics defines how new information, given by a likelihood, should be combined with previously acquired information, given by a prior distribution. Many experiments have shown that humans make use of such priors in cognitive, perceptual, and motor tasks, but where do priors come from? As people never experience the same situation twice, they can only construct priors by generalizing from similar past experiences. Here we examine the generalization of priors over stochastic visuomotor perturbations in reaching experiments. In particular, we look into how the first two moments of the prior--the mean and variance (uncertainty)--generalize. We find that uncertainty appears to generalize differently from the mean of the prior, and an interesting asymmetry arises when the mean and the uncertainty are manipulated simultaneously. PMID- 25143629 TI - Sensory axonal dysfunction in cervical radiculopathy. AB - OBJECTIVE: The aim of this study was to evaluate changes in sensory axonal excitability in the distal nerve in patients with cervical radiculopathy. METHODS: The patients were classified by the findings of cervical MRI into two subgroups: 22 patients with C6/7 root compression and 25 patients with cervical cord and root compression above/at C6/7. Patients were investigated using conventional nerve conduction studies (NCS) and nerve excitability testing. Sensory nerve excitability testing was undertaken with stimulation at the wrist and recording from digit II (dermatome C6/7). The results were compared with healthy controls. Both preoperative and postoperative tests were performed if the patient underwent surgery. RESULTS: Sensory axonal excitability was significantly different in both cohorts compared with healthy controls, including prolonged strength-duration time constant, reduced S2 accommodation, increased threshold electrotonus hyperpolarisation (TEh (90-100 ms)), and increased superexcitability. The changes in these excitability indices are compatible with axonal membrane hyperpolarisation. In five patients who underwent surgery, the postoperative sensory excitability was tested after 1 week, and showed significant changes in TE (TEh (90-100 ms) and TEh slope, p<0.05) between presurgery and postsurgery. CONCLUSIONS: The present study demonstrated distal nerve axonal hyperpolarisation in patients with cervical radiculopathy. These findings suggest that the hyperpolarised pattern might be due to Na(+)-K(+) ATPase overactivation induced by proximal ischaemia, or could reflect the remyelinating process. Distal sensory axons were hyperpolarised even though there were no changes in NCS, suggesting that nerve excitability testing may be more sensitive to clinical symptoms than NCS in patients with cervical radiculopathy. PMID- 25143628 TI - Regulation of blood flow in the retinal trilaminar vascular network. AB - Light stimulation evokes neuronal activity in the retina, resulting in the dilation of retinal blood vessels and increased blood flow. This response, named functional hyperemia, brings oxygen and nutrients to active neurons. However, it remains unclear which vessels mediate functional hyperemia. We have characterized blood flow regulation in the rat retina in vivo by measuring changes in retinal vessel diameter and red blood cell (RBC) flux evoked by a flickering light stimulus. We found that, in first- and second-order arterioles, flicker evoked large (7.5 and 5.0%), rapid (0.73 and 0.70 s), and consistent dilations. Flicker evoked dilations in capillaries were smaller (2.0%) and tended to have a slower onset (0.97 s), whereas dilations in venules were smaller (1.0%) and slower (1.06 s) still. The proximity of pericyte somata did not predict capillary dilation amplitude. Expression of the contractile protein alpha-smooth muscle actin was high in arterioles and low in capillaries. Unexpectedly, we found that blood flow in the three vascular layers was differentially regulated. Flicker stimulation evoked far larger dilations and RBC flux increases in the intermediate layer capillaries than in the superficial and deep layer capillaries (2.6 vs 0.9 and 0.7% dilation; 25.7 vs 0.8 and 11.3% RBC flux increase). These results indicate that functional hyperemia in the retina is driven primarily by active dilation of arterioles. The dilation of intermediate layer capillaries is likely mediated by active mechanisms as well. The physiological consequences of differential regulation in the three vascular layers are discussed. PMID- 25143630 TI - SANDO syndrome in a cohort of 107 patients with CPEO and mitochondrial DNA deletions. AB - OBJECTIVE: The sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) syndrome is a subgroup of mitochondrial chronic progressive external ophthalmoplegia (CPEO)-plus disorders associated with multiple mitochondrial DNA (mtDNA) deletions. There is no systematic survey on SANDO in patients with CPEO with either single or multiple large-scale mtDNA deletions. METHODS: In this retrospective analysis, we characterised the frequency, the genetic and clinical phenotype of 107 index patients with mitochondrial CPEO (n=66 patients with single and n=41 patients with multiple mtDNA deletions) and assessed these for clinical evidence of a SANDO phenotype. Patients with multiple mtDNA deletions were additionally screened for mutations in the nuclear-encoded POLG, SLC25A4, PEO1 and RRM2B genes. The clinical, histological and genetic data of 11 patients with SANDO were further analysed. RESULTS: None of the 66 patients with single, large-scale mtDNA deletions fulfilled the clinical criteria of SANDO syndrome. In contrast, 9 of 41 patients (22%) with multiple mtDNA deletions and two additional family members fulfilled the clinical criteria for SANDO. Within this subgroup, multiple mtDNA deletions were associated with the following nuclear mutations: POLG (n=6), PEO1 (n=2), unidentified (n=2). The combination of sensory ataxic neuropathy with ophthalmoparesis (SANO) was observed in 70% of patients with multiple mtDNA deletions but only in 4% with single deletions. The combination of CPEO and sensory ataxic neuropathy (SANO, incomplete SANDO) was found in 43% of patients with multiple mtDNA deletions but not in patients with single deletions. CONCLUSION: The SANDO syndrome seems to indicate a cluster of symptoms within the wide range of multisystemic symptoms associated with mitochondrial CPEO. SANO seems to be the most frequent phenotype associated with multiple mtDNA deletions in our cohort but not or is rarely associated with single, large-scale mtDNA deletions. PMID- 25143627 TI - Activation of TRPML1 clears intraneuronal Abeta in preclinical models of HIV infection. AB - Antiretroviral therapy extends the lifespan of human immunodeficiency virus (HIV) infected patients, but many survivors develop premature impairments in cognition. These residual cognitive impairments may involve aberrant deposition of amyloid beta-peptides (Abeta). By unknown mechanisms, Abeta accumulates in the lysosomal and autophagic compartments of neurons in the HIV-infected brain. Here we identify the molecular events evoked by the HIV coat protein gp120 that facilitate the intraneuronal accumulation of Abeta. We created a triple transgenic gp120/APP/PS1 mouse that recapitulates intraneuronal deposition of Abeta in a manner reminiscent of the HIV-infected brain. In cultured neurons, we found that the HIV coat protein gp120 increased the transcriptional expression of BACE1 through repression of PPARgamma, and increased APP expression by promoting interaction of the translation-activating RBP heterogeneous nuclear ribonucleoprotein C with APP mRNA. APP and BACE1 were colocalized into stabilized membrane microdomains, where the beta-cleavage of APP and Abeta formation were enhanced. Abeta-peptides became localized to lysosomes that were engorged with sphingomyelin and calcium. Stimulating calcium efflux from lysosomes with a TRPM1 agonist promoted calcium efflux, luminal acidification, and cleared both sphingomyelin and Abeta from lysosomes. These findings suggest that therapeutics targeted to reduce lysosomal pH in neurodegenerative conditions may protect neurons by facilitating the clearance of accumulated sphingolipids and Abeta peptides. PMID- 25143631 TI - Neurological picture. Multiple intracranial arteritis and hypothyroidism secondary to Streptococcus anginosus infection. PMID- 25143632 TI - 20 years of leptin: what we know and what the future holds. AB - This special issue of Journal of Endocrinology celebrates the 20th anniversary of the discovery of leptin, a hormone produced by adipose tissue, which provides critical signals to the organism regarding the status of its energy stores. The discovery of leptin not only revolutionised our understanding of endocrine physiology but has also resulted in a registered medicinal product which is already improving the health of patients with serious metabolic diseases. In this issue, we have gathered together a group of essays by some of the world leaders in leptin research, including an overview by Dr Jeffrey Friedman who, in his seminal article in December 1994, described the adipocyte-derived hormone, the lack of which was responsible for the severe obesity in ob/ob mice and suggested that it should be named leptin. PMID- 25143633 TI - Oestrogen, ocular function and low-level vision: a review. AB - Over the past 10 years, a literature has emerged concerning the sex steroid hormone oestrogen and its role in human vision. Herein, we review evidence that oestrogen (oestradiol) levels may significantly affect ocular function and low level vision, particularly in older females. In doing so, we have examined a number of vision-related disorders including dry eye, cataract, increased intraocular pressure, glaucoma, age-related macular degeneration and Leber's hereditary optic neuropathy. In each case, we have found oestrogen, or lack thereof, to have a role. We have also included discussion of how oestrogen related pharmacological treatments for menopause and breast cancer can impact the pathology of the eye and a number of psychophysical aspects of vision. Finally, we have reviewed oestrogen's pharmacology and suggest potential mechanisms underlying its beneficial effects, with particular emphasis on anti-apoptotic and vascular effects. PMID- 25143634 TI - Convergence of Sample Eigenvalues, Eigenvectors, and Principal Component Scores for Ultra-High Dimensional Data. AB - The development of high-throughput biomedical technologies has led to increased interest in the analysis of high-dimensional data where the number of features is much larger than the sample size. In this paper, we investigate principal component analysis under the ultra-high dimensional regime, where both the number of features and the sample size increase as the ratio of the two quantities also increases. We bridge the existing results from the finite and the high-dimension low sample size regimes, embedding the two regimes in a more general framework. We also numerically demonstrate the universal application of the results from the finite regime. PMID- 25143635 TI - Social Norms and Global Environmental Challenges: The Complex Interaction of Behaviors, Values, and Policy. AB - Government policies are needed when people's behaviors fail to deliver the public good. Those policies will be most effective if they can stimulate long-term changes in beliefs and norms, creating and reinforcing the behaviors needed to solidify and extend the public good.It is often the short-term acceptability of potential policies, rather than their longer-term efficacy, that determines their scope and deployment. The policy process should consider both time scales. The academy, however, has provided insufficient insight on the coevolution of social norms and different policy instruments, thus compromising the capacity of decision makers to craft effective solutions to the society's most intractable environmental problems. Life scientists could make fundamental contributions to this agenda through targeted research on the emergence of social norms. PMID- 25143636 TI - Bone formation in rabbit's leg muscle after autologous transplantation of bone marrow-derived mesenchymal stem cells expressing human bone morphogenic protein 2. AB - BACKGROUND: To test whether autologous transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) expressing human bone morphogenic protein-2 (hBMP-2) can produce bone in rabbit leg muscles. MATERIALS AND METHODS: MSCs were isolated from BM of the iliac crest of rabbits and then infected with lentiviral vectors (LVs) bearing hBMP-2 and green fluorescent protein under the control of the cytomegalovirus (immediate early promoter). Differentiation of transduced MSCs to osteoblasts in vitro was evaluated with an alkaline phosphatase activity assay and immuohistochemistry against osteoblast specific markers. MSCs expressing hBMP-2 were placed in an absorbable gelatin sponge, which was then transplanted into the gastrocnemius of rabbits from which MSCs were isolated. Bone formation was examined by X-ray and histological analysis. RESULTS: LVs efficiently mediated hBMP-2 gene expression in rabbit BM-MSCs. Ectopic expression of hBMP in these MSCs induced osteoblastic differentiation in vitro. Bone was formed after the MSCs expressing hBMP-2 were transplanted into rabbit muscles. CONCLUSION: Ectopic expression of hBMP-2 in rabbit MSCs induces them to differentiate into osteoblasts in vitro and to form a bone in vivo. PMID- 25143637 TI - High sensitive C-reactive protein-Effective tool in determining postoperative recovery in lumbar disc disease. AB - BACKGROUND: It is common in medical practice to see patients having persistent pain and radiculopathy even after undergoing discectomy surgery. Inflammatory cytokines, such as interleukins are produced at the site of disc herniation and are now considered responsible for the pain perceived by the patient. This study has used high sensitive C-reactive protein (HSCRP) assay for predicting inflammation around the nerve roots on very same principle, which has used HSCRP for predicting coronary artery diseases in current clinical practice. Thus, purpose of this study is to test whether HSCRP can stand as an objective tool to predict postoperative recovery in patients undergoing lumbar discectomy. That is, to study association between preoperative HSCRP blood level and postoperative recovery with the help of modified Oswestry Back Disability Score. MATERIALS AND METHODS: A study group consisting of 50 cases of established lumbar disc disease and control group of 50 normal subjects, matched with the study group. Both the study and control groups were subjected to detailed evaluation with the help of modified Oswestry Low Back Pain Scale both pre and postoperatively at 3 months, 6 months and 1-year. The preoperative blood samples were analyzed to assess the HSCRP concentration. All the cases underwent surgery over a period of 1-year by the same surgeon. RESULTS: The level of HSCRP in the study group was between 0.050- and 0.710 mg/dL and in the control group, 0.005-0.020 mg/dL. There was highly significant positive correlation between preoperative HSCRP level and postoperative score at P < 0.005. Cases with HSCRP level in the range of 0.1820 +/- 0.079 mg/dL, showed better recovery (score improved > 10 points), while those with HSCRP level in the range of 0.470 +/- 0.163 mg/dL, showed poor recovery (score improved < 10 points). CONCLUSION: HSCRP will serve as a good supplementary prognostic marker for operative decision making in borderline and troublesome cases of lumbar disc disease. PMID- 25143638 TI - Evaluation of postoperative change in lung volume in adolescent idiopathic scoliosis: Measured by computed tomography. AB - BACKGROUND: Change in total lung volume after surgical correction in adolescent idiopathic scoliosis (AIS), measured by computed tomography (CT), has not been studied previously. The primary objective of this study was to measure the change in lung volume between pre and postoperative AIS using low-dose CT and secondary objective was to investigate its relationship to postoperative pulmonary complications. MATERIALS AND METHODS: 55 AIS patients underwent surgery for correction and fusion using a posterior only approach and pedicle screws. Pre and postoperative lung volumes were measured using a 3-dimensional (3D) whole spine CT (low dose protocol: Tube current, 60 mA; tube voltage 120 kV). Postoperative low dose CT was undertaken at 4 weeks after operation to evaluate the acute changes of postoperative lung volumes and pulmonary complications. The software that was used recognizes the "air density shade" of the lung and the volume of every section of the lung. The software then automatically calculates total lung volume by summation of all section volumes. The relationships between postoperative pulmonary complications and changes in lung volume on low dose CT as well as preoperative forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were calculated using logistic regression analysis. RESULTS: There was a decrease of 12% +/- 23.2% in total lung volume postoperatively on 3D low dose CT (P < 0.001). Thirteen patients had increased lung volume while 42 had decreased lung volume postoperatively. Pulmonary complications were treated without severe sequale. Lung volume increased by 19.65% +/- 19.84% in 13 patients and decreased by 21.85% +/- 13.32% in 42 patients (P = 0.647). Lung volume was increased in patients whose preoperative lung volume, FEV1 and FVC were lower than in patients whose values were higher (r = -0.273, -0.291 and - 0.348; P = 0.044, 0.045 and 0.015, respectively). Postoperative lung volume was also increased when intraoperative fluid administration was larger and operative time was longer (r = 0.354, 0.417 and P = 0.008, 0.002, respectively). There was a statistically significant negative correlation in the change of lung volume in female patients when compared with male patients (r = -0.294, P = 0.03). CONCLUSION: Patients with AIS who have preoperative reduced lung volumes or lung functions can achieve further increased lung volume after surgical correction. Pulmonary complications during perioperative period were mostly treated with proper management without severe sequale. Therefore, although surgery for AIS is considered to be a high risk procedure, we can recommend to correct spine deformity in patients with severe AIS in order to improve lung function and long term prognosis. PMID- 25143639 TI - Correlation between neurological recovery and magnetic resonance imaging in Pott's paraplegia. AB - BACKGROUND: Spinal cord/nerve root compression secondary to a tubercular epidural abscess leads to neurological deficit. Depending on the extent and duration of compression, the end result after treatment may vary from complete recovery to permanent deficit. ASIA has been used extensively to correlate between MRI and neurological status due to traumatic spine injuries. MRI has stood as an invaluable diagnostic tool out of the entire range of current imaging modalities. However, inspite of considerable literature on the applications of MRI in spinal tuberculosis, there have been few studies to assess the relationship between the MRI findings and the neurological deficit as assessed by clinical examination. AIMS: The objective of this study was to ascertain whether the findings of magnetic resonance imaging (MRI) correlate well with the actual neurological recovery status using the American Spinal Injury Association impairment scale (ASIA) in patients with spinal compression secondary to tuberculous spondylitis. MATERIALS AND METHODS: 60 patients (mean age 43.6 years) diagnosed as spinal tuberculosis by MRI/cytology/histopathology were examined and classified into ASIA impairment scale A-E based on the ASIA and again reclassified after 6 months of therapy to assess functional recovery. Similarly, they underwent MR imaging at the start and at the completion of 6 months of therapy to assess the structural recovery. The MRI features of recovery were correlated with the actual neurological recovery as ascertained by the ASIA. RESULTS: Before starting treatment 1 patient (2.08%) was in ASIA A, 2 (4.16%) were in ASIA B, 9 (18.75%) were in ASIA C, 36 (75%) were in ASIA D and 12 (20%) were in ASIA E. There was a significant difference in the epidural abscess thickness, thecal compression and cord compression between ambulatory (ASIA D and ASIA E) and non ambulatory patients (ASIA A, ASIA B and ASIA C). After 6 months of therapy 30 (90%) patients in ASIA D and 5 (55.5%) in ASIA C had complete neurological recovery. Both patients from ASIA B improved to ASIA D. Single patient who was in ASIA A before treatment remained non ambulatory (ASIA C) after treatment. Overall 33 (78.5%) patients showed complete recovery at final followup. Out of all the MRI features, only size of epidural abscess was found to be a poor prognostic factor for recovery of neurological deficit. CONCLUSIONS: There are several parameters on MRI which correlate with the severity of neurological impairment according to ASIA score and resolution of those features on treatment is also correlated well with neurological recovery. PMID- 25143640 TI - Transforaminal lumbar interbody fusion using unilateral pedicle screw fixation plus contralateral translaminar facet screw fixation in lumbar degenerative diseases. AB - BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) has been used in lumbar degenerative diseases. Some researchers have applied unilateral fixation in TLIF to reduce operational trauma without compromising the clinical outcome, but it is always suspected biomechanically unstable. The supplementary contralateral translaminar facet screw (cTLFS) seemed to be able to overcome the inherent drawbacks of unilateral pedicle screw (uPS) fixation theoretically. This study evaluates the safety, feasibility and efficacy of TLIF using uPS with cTLFS fixation in the treatment of lumbar degenerative diseases (LDD). MATERIALS AND METHODS: 50 patients (29 male) underwent the aforementioned surgical technique for their LDD between December 2009 and April 2012. The results were evaluated based on visual analogue scale (VAS) of the leg and back, Japanese Orthopedic Association (JOA) score and Oswestry Disability Index (ODI) were recorded. The radiographic examinations in form of X-ray, computed tomography (CT) or magnetic resonance imaging was done preoperatively and 1 week, 3 months, 6 months, 12 months and 24 months postoperatively. The student t-test was used for comparison between the preoperative values and postoperative counterparts. P < 0.05 was considered to be statistically significant. RESULTS: Among 50 patients, 22 received one level fusion and 28 two level's, with corresponding operation time and estimated blood loss being approximately 90 min, 150 ml and 120 min, 200 ml, respectively. No severe complications happened perioperatively. The mean VAS (back, leg) scores dropped from (7.6, 7.5) preoperatively to (2.1, 0.6) at 12 months' followup, ODI from 49.1 preoperatively to 5.6 and JOA score raised from 10.6 preoperatively to 28.5, all P < 0.001, suggesting of good clinical outcome. From the three-dimensional reconstructed CT, 62 out of 70 segments displayed solid fusion with fusion rate of 88.6% at 12 months postoperatively. CONCLUSIONS: TLIF using uPS fixation plus cTLFS fixation is a safe, feasible and effective technique in the treatment of one or two level lumbar degenerative diseases short termly. PMID- 25143641 TI - Midterm results of Oxford shoulder hemiarthroplasty. AB - BACKGROUND: Hemiarthroplasty of the shoulder is known to provide satisfactory long term results provided concentric reduction can be obtained in a high percentage of patients. Careful soft tissue balancing with appropriate adaptation of version of the component appears to allow good results permitting centering of the arthroplasty without replacement of a glenoid component. MATERIALS AND METHODS: 29 consecutive patients (30 shoulders) who underwent Oxford cementless shoulder hemiarthroplasty between 2004 and 2006 were analyzed. Mean age was 71 years (range 34-91 years, 95% of the confidence interval [CI] of standard deviation [SD] was 10.32-17.58). Mean duration of preoperative symptoms was 42.8 months (range 9-84 months, 95% CI of SD was 17.83-30.11). Patients' self reported Oxford shoulder score (OSS) was collected prospectively and was used as an assessment tool to measure final outcome. RESULTS: The mean initial OSS was 17.9 (range 7-43, 95% CI of the SD was 7.19-12.13). The score improved by an average of 16.9 points at a mean followup of 5.9 years (range 4.3-7.6 years) to reach mean final OSS of 34.8 (range 13-48, 95% CI of the SD was 9.31-15.73). The improvement of OSS was highly significant with a two tailed P < 0.0001 and 95% CI of this difference was 11.47-22.20. CONCLUSION: This study demonstrates shoulder hemiarthroplasty as reliable procedure for improvement of shoulder function as shown by the patients' self reported outcome score (OSS) in end stage glenohumeral arthritis with intact or reparable rotator cuff at midterm followup. Our results suggest successful outcome of the Oxford shoulder hemiarthroplasty (Corin, UK) away from its originating center and in hospitals where fewer shoulder replacements are performed. PMID- 25143642 TI - Outcome analysis of arthroscopic treatment of partial thickness rotator cuff tears. AB - BACKGROUND: Partial thickness rotator cuff tears occupy an important position in the spectrum of rotator cuff disease. The development of a more comprehensive classification has been sought to address both the tear location and extent, which may influence clinical results. The purpose of this study is to classify partial thickness rotator cuff tears according to the arthroscopic findings and to evaluate the clinical outcomes after arthroscopic repair of partial thickness tears. MATERIALS AND METHODS: One hundred and two patients had arthroscopic treatment of partial thickness rotator cuff tears. The inclusion criterion for the study was a partially torn supraspinatus tendon involving articular or bursal side, verified by direct arthroscopic visualization. Outcome analysis was exclusively applied to patients who underwent transtendon repair, using the shoulder index of American Shoulder and Elbow Society and the University of California Los Angeles (UCLA) rating system. RESULTS: Partial thickness rotator cuff tears were divided into five groups according to arthroscopic findings. There was significant improvement after surgery in all parameters of clinical evaluation in the tears that warranted repair. Arthroscopic repair in situ (transtendon technique) may be the preferred option in unstable partial thickness tear. CONCLUSION: The proposed classification system may assist decision making in the treatment of partial thickness rotator cuff tears. PMID- 25143643 TI - Platelet rich plasma versus laser therapy in lateral epicondylitis of elbow. AB - BACKGROUND: Platelet rich plasma (PRP) extract has shown to be a general stimulation for repair and currently used widely in various sports injury. A prospective observational study was done to assess the efficacy of autologous PRP injection in lateral epicondylitis of elbow, and compare the result with low level laser therapy. MATERIALS AND METHODS: The trial was conducted at a tertiary care center for a period of 2 years. Eighty-one patients with chronic lateral epicondylitis were divided into two groups. PRP group (n = 39) and laser therapy group (n = 42). The primary analysis included Nirschl pain score, local tenderness, pain on wrist extension, grip strength, elbow swelling were clinically assessed at different interval of followup (minimum followup: 52 weeks) and; clinical and functional outcome evaluated at final followup. The statistical analysis were done. RESULTS: The mean Nirschl pain score decreased significantly from baseline in PRP when compared with low level laser therapy (P <= 0.05). CONCLUSIONS: Treatment of patients with chronic lateral epicondylitis with PRP extract reduced pain and significantly increased function, exceeding the effect of low level laser therapy on long term followup. Low-level laser therapy is better in the short term period, but on long term followup injection PRP therapy is better than laser therapy in lateral epicondylitis. PMID- 25143645 TI - Results of pronator quadratus repair in distal radius fractures to prevent tendon ruptures. AB - BACKGROUND: Distal radius fractures are one of the the most common adult fractures encountered during the clinical practice of an orthopedic surgeon.12 Although several methods of treatment are suggested for these fractures, there are still controversies about the best treatment approach in the literature. Volar plating of distal radius fracture is a method of treatment which has become increasingly popular. One of the complications of this technique is flexor tendon rupture. The purpose of this study was to evaluate the protectiveness of complete repair of pronator quadratus muscle against flexor tendon rupture. MATERIALS AND METHODS: From September 2010 to September 2012, a consecutive series of 157 patients who were younger than 60 years with unstable distal radius fractures were included in the study. A standard volar approach to the distal radius was carried out. The radial and distal ends of pronator quadratus muscle were meticulously elevated from the radius and after volar plate fixation of the fracture, pronator quadratus muscle was restored to its normal insertion. We achieved full coverage of the plate with this muscle and followed the patients postoperatively. RESULTS: A total of 135 patients were studied. The mean age of patients was 34 +/- 10 years (range 20-60 years). One 55-year-old diabetic female patient with flexor tendon rupture was identified. The flexor pollicis longus tendon had ruptured 16 months after surgery. CONCLUSIONS: Pronator quadratus repair should be done in distal radius fracture to protect flexor tendons. PMID- 25143644 TI - Outcome of uncemented trapeziometacarpal prosthesis for treatment of thumb carpometacarpal joint arthritis. AB - BACKGROUND: Osteoarthritis of the trapeziometacarpal joint of thumb occurs frequently and can be very disabling. Numerous surgical techniques including trapeziectomy with or without tendon interposition arthrodesis and partial or total joint arthroplasty with cemented and noncemented prosthesis have been described for the treatment of trapeziometacarpal joint osteoarthritis. Initial problems of osteolysis and implant loosening have been substantially reduced with improvement in implant design. The aim of this study is to demonstrate that trapeziometacarpal osteoarthritis of the thumb can be effectively treated with uncemented total joint replacement prosthesis. MATERIALS AND METHODS: We retrospectively collected data for 16 trapeziometacarpal joint replacements in 14 patients. One patient was excluded as they required revision with trapeziectomy and ligament reconstruction following fracture of Trapezium. The trapeziometacarpal joint prosthesis was used in all cases and all operations were carried out by one surgeon. Clinical outcome was determined by a pre and postoperative patient rated wrist evaluation (PRWE) and Michigan Hand Questionnaire Score. Range of motion, grip, tip pinch and key pinch strength were measured and compared with the unoperated hand. Radiological assessment was carried out by plain radiographs for preoperative staging of arthritis and postoperative radiographs at latest followup for evaluation of osteolysis and implant loosening. Average followup period was 26 months. RESULTS: There was an improvement in hand function and pain level based on PRWE and Mischigan Hand outcome Questionnaire Score. One patient had intraoperative fracture of Trapezium and subsequent radiographs at 14 months followup showed loosening of the trapezial component due to nonunion of the fracture and complete disintegration of the trapezium. There were no cases of dislocation or implant loosening for the remaining 15 CMC joints at the latest followup. CONCLUSION: The use of uncemented prosthesis in treatment of Questionnaire Score. Range of motion joint osteoarthritis gives excellent short term results in improving hand function in terms of strength and stability and achieving pain relief. PMID- 25143646 TI - Outcome in primary cemented total knee arthroplasty with or without drain: A prospective comparative study. AB - BACKGROUND: Suction drain insertion is a common practice in orthopedic surgery, especially after joint arthroplasty to prevent the formation of a hematoma. Theoretically the use of a drain should diminish the volume of hematoma; however the literature has conflicting data. Some authors state that drainage evacuates fluid from a limited area only and can be a cause of infection due to retrograde migration of bacteria. It can also impair the early postoperative rehabilitation. The aim of this study was to evaluate the clinical outcome (especially postoperative pain) and intake of analgesics in patients who had undergone primary cemented total knee arthroplasty (TKA) with or without a postoperative drain. MATERIALS AND METHODS: A prospective comparative study of 108 consecutive patients (121 knees) was conducted. They were divided into two groups: A study group, with no drainage and a control group with drain inserted at the end of surgery. A total of 121 patients were recruited into two groups. A study group consisted of 59 knees, in which we did not use drainage after TKA and a control group with 62 knees, in which drain was inserted post surgery. Both groups were comparable in terms of preoperative characteristics. The indication for TKA was osteoarthritis (n = 105) and rheumatoid arthritis (n = 16). RESULTS: In patients without drainage we observed lower need for opioids, higher blood loss on the 1(st) postoperative day and a lower need for change of dressings. There were no statistically significant differences in terms of total blood loss, hidden blood loss, transfusion rate, range of motion, length of hospital stay or incidence of complications between the two groups. In 1 year observation there were no differences in clinical outcome between the two groups. CONCLUSIONS: The present study conclude that there is no rationale for the use of drain after primary TKA. There are benefits in terms of lower opioid intake, lower blood loss on the first postoperative day and lower need for dressing reinforcement during hospitalization. PMID- 25143647 TI - Functional outcome following a large head total hip arthroplasty: A retrospective analysis of mid term results. AB - BACKGROUND: One of the reasons that hip resurfacing and large head metal on metal (MOM) total hip arthroplasty (THA) became popular in Asia was the possible increased range of movement and thereby improved function of the hip joint. Due to concerns of MOM articulation an alternative bearing was sought. Hence, a shift from large head MOM to large head ceramic on ceramic (COC) was made. The aim of this study was to compare the functional outcome including range of motion (ROM) and dislocation rates following large head MOM and large head COC THA. MATERIALS AND METHODS: Retrospectively, 39 primary THA with large head MOM with a mean age of 56 years (range 36-72 years) and average followup of 54 months (range 38-70 months) were compared with 23 primary THA with large head COC bearing with a mean age of 48 years (range 36-68 years) and an average followup of 18 months (range 12-26 months). Functional outcome was assessed using the Modified Harris Hip Score. Dislocation rate and ROM were compared. RESULTS: Global ROM averaged 248 degrees with MOM group and 252 degrees with the COC group. One patient with metal bearing had dislocation at an average 3 year followup which required revision THA while there were no complications in the COC group. MHHS averaged 89 points in MOM and 94 in COC THR. CONCLUSION: This study has shown that large head ceramic on ceramic THA is a good alternative to large head metal on metal THA with comparable dislocation rates and range of movements and without complications of metallosis in Asian patients. PMID- 25143648 TI - Tibial lengthening for unilateral Crowe type-IV developmental dysplasia of the hip. AB - BACKGROUND: Developmental dysplasia of the hip (DDH) is associated with chronic pain and limping which especially has a negative impact on the patients' daily activities, body image, and self-esteem. Although total hip arthroplasty remains the first choice for treatment of DDH in adults, minimally invasive alternative approaches are being increasingly favored both by the surgeon and the patients with severe DDH. This study aimed to evaluate the outcome of these patients treated with a mono-lateral external fixator-based tibial lengthening procedure. MATERIALS AND METHODS: During the period of month between June 1999 and January 2006, 13 (mean ages 20.8 years) adult patients with unilateral Crowe type-IV DDH were treated by tibial lengthening using a mono-lateral external fixator over an intramedullary nail. Bone healing, infection, gait correction and improvement in body image were assessed during postoperative followup. Patients' overall health status at the end of followup was assessed using the short form-36 (SF-36) health survey. RESULTS: Patients were followed up for an average of 7.3 years. Successful bone healing was observed in all 13 patients and no further surgeries were indicated. A mean external fixation index of 12.4 days/cm was achieved. Bone formation fell in good to excellent categories with a mean consolidation index of 50.1 days/cm. Pin-tract infections were observed in two patients. The degree of limping was reduced from severe or moderate preoperatively to mild postoperatively. Neither equinus deformity nor painful degenerative osteoarthritis and hip dysfunction were observed in any of the patients studied. The SF-36 questionnaire survey showed that all patients were satisfied with their outcomes. CONCLUSIONS: Tibial lengthening may effectively correct gait and satisfactorily improve body image in young patients with unilateral Crowe type-IV DDH. Mono-lateral external fixator allows for accelerated postoperative rehabilitation and optimal preservation of ankle movements. Lengthening along with intramedullary nails may significantly reduce the external fixation time and the risk of fixator-related complications. PMID- 25143649 TI - Walking ability in patients with arthrogryposis multiplex congenita. AB - BACKGROUND: Arthrogryposis multiplex congenita (AMC) is a multiple joint condition which affects both lower and upper extremities and thus affects ambulation. Multiple surgeries are needed to correct limb deformity in order to promote walking. The objective of this study is to identify the most critical residual deformity that diminishes the ambulatory status. MATERIALS AND METHODS: 51 patients were included in this study, 14 patients were nonambulatory. The mean age at first surgery was 4.1 years (range 2-16 years). The mean length of followup was 44.0 months (range 22-168 months). Type of procedures and number of operations, residual deformity and walking ability were recorded. Residual deformity including hip flexion contracture more than 30 degrees , knee flexion contracture more than 30 degrees , scoliosis, hip dysplasia or dislocation, knee extension contracture or recurvatum, active motion of hips and knees and upper limb involvement were evaluated. Statistical analysis was done to evaluate factors that were statistically significant to affect walking ability in AMC patients. RESULTS: At the latest followup, 31 patients were community ambulators, 3 patients were household ambulators, 3 patients were nonfunctional ambulatory, and 14 patients were nonambulatory. There were an average of 4.3 surgeries per patient. Statistical analysis of all factors was done and the results were significant with a P < 0.037 in knee flexion contracture >30 degrees with odds ratio of 4.58. Hip flexion contracture >30 degrees was a trend toward significant with a P value of 0.058 and odds ratio of 4.53. Multivariate analysis showed that knee flexion contracture was significant with 4.58 (95% CI 1.01 20.6). CONCLUSION: AMC is a rare disease that causes disability, requiring multiple surgeries to correct deformities. Our study showed that residual knee flexion contracture was associated with nonambulatory status of patients with AMC. PMID- 25143650 TI - Late extensor pollicis longus rupture following plate fixation in Galeazzi fracture dislocation. AB - Late rupture of extensor pollicis longus (EPL) tendon after Galeazzi fracture dislocation fixation is an unknown entity though it is a well-established complication following distal radius fractures. We report the case of a 55-year old male who presented with late EPL tendon rupture 4 months following internal fixation of Galeazzi fracture dislocation with a Locking Compression Plate (LCP). He was managed with extensor indicis proprius (EIP) transfer to restore thumb extension. At 4 years followup, functional result of the transfer was good. We identify possible pitfalls with this particular patient and discuss how to avoid them in future. PMID- 25143651 TI - An atypical monomelic presentation of Mazabraud syndrome. AB - Mazabraud syndrome is a rare condition characterized by a combination of fibrous dysplasia and intramuscular myxomas. In Mazabraud syndrome, the distribution of fibrous dysplasia is mostly polyomelic and frequently located in the femur, with myxomas adjacent to the fibrous dysplasia lesion of bone (mostly in the quadriceps muscle). However, when presented as atypical clinical features, patients of Mazabraud syndrome is either misdiagnosed or difficult to diagnose. We report an atypical monomelic case of Mazabraud syndrome in the right upper arm and discuss the difficulties in making an accurate diagnosis. PMID- 25143652 TI - Bifurcated intraarticular long head of biceps tendon. AB - Though rare, many anomalous origins of long head of the biceps tendon (LHBT) have been reported in the literature. Anatomic variations commonly explained are a third humeral head, anomalous insertion, congenital absence and adherence to the rotator cuff. We report a rare case who underwent shoulder arthroscopy with impingement symptoms where in LHBT was found to be bifurcated with a part attached to superior labrum and the other part to the posterior capsule of joint. Furthermore, intraarticular portion of LHBT was adherent to the undersurface of the supraspinatus tendon. Awareness of such an anatomical aberration during the shoulder arthroscopy is of great importance as it can potentially avoid unnecessary confusion and surgery. PMID- 25143653 TI - Congenital pseudoarthrosis of the clavicle with bifurcation. AB - Congenital pseudoarthrosis of clavicle is a rare clinical entity. It usually presents as a swelling in the clavicular region at birth or soon after birth. Fitzwilliam's original description of 60 subtypes of congenital pseudoarthrosis of clavicle have addressed several anatomical variants, e.g. association with cervical rib and abnormally vertical and elevated upper ribs. However, congenital pseudoarthrosis of clavicle associated with bifurcation is an atypical anatomic variant. To the best of our knowledge, this variant has never been mentioned in the literature. In the present report, we have described this subtype of symptomatic congenital pseudoarthrosis of the clavicle with bifurcation and its possible management. PMID- 25143654 TI - Head size and dislocation rate in primary total hip arthroplasty. PMID- 25143655 TI - Author's reply. PMID- 25143656 TI - Long proximal femoral nail in ipsilateral fractures of proximal femur and shaft of femur. PMID- 25143657 TI - Author's reply. PMID- 25143659 TI - Sorting it Out: Pile Sorting as a Mixed Methodology for Exploring Barriers to Cancer Screening. AB - We discuss a mixed methodology for analyzing pile sorting data. We created a list of 14 barriers to colon cancer screening and recruited 18, 13, and 14 participants from three American Indian (AI) communities to perform pile sorting. Quantitative data were analyzed by cluster analysis and multidimensional scaling. Differences across sites were compared using permutation bootstrapping. Qualitative data collected during sorting were compiled by AI staff members who determined names for the clusters found in quantitative analysis. Results showed 5 clusters of barriers in each site although barriers in the clusters varied slightly across sites. Simulation demonstrated type I error rates around the nominal 0.05 level whereas power depended on the numbers of clusters, and between and within cluster variability. PMID- 25143658 TI - Physical Modeling of Aqueous Solvation. AB - We consider the free energies of solvating molecules in water. Computational modeling usually involves either detailed explicit-solvent simulations, or faster computations, which are based on implicit continuum approximations or additivity assumptions. These simpler approaches often miss microscopic physical details and non-additivities present in experimental data. We review explicit-solvent modeling that identifies the physical bases for the errors in the simpler approaches. One problem is that water molecules that are shared between two substituent groups often behave differently than waters around each substituent individually. One manifestation of non-additivities is that solvation free energies in water can depend not only on surface area or volume, but on other properties, such as the surface curvature. We also describe a new computational approach, called Semi-Explicit Assembly, that aims to repair these flaws and capture more of the physics of explicit water models, but with computational efficiencies approaching those of implicit-solvent models. PMID- 25143660 TI - Reductive Cyclizations of Nitroarenes to Hydroxamic Acids by Visible Light Photoredox Catalysis. AB - We have developed a photocatalytic reduction of nitroarenes as an efficient, chemoselective route to biologically important N-phenyl hydroxamic acid scaffolds. Optimal conditions call for 2.5 mol% of a ruthenium photocatalyst, visible light irradiation, and a dihydropyridine terminal reductant. Because of the mild nature of the visible light activation, functional groups that might be sensitive to other non-photochemical reduction methods are easily tolerated. PMID- 25143661 TI - Testing the Effects of the Addition of Videos to a Website Promoting Environmental Breast Cancer Risk Reduction Practices: Are Videos Worth It? AB - Searching for ways to reach wider audiences in more comprehensible ways, health promotion agencies might add videos to their current web offerings. While potentially costly and time consuming to create, the effect of these videos on websites has not received much attention. This study translated research about the potential breast cancer risk for young girls associated with the household chemical PFOA into two websites mothers with young daughters were randomly assigned to view (website with videos vs. website without videos). Results revealed participants in the video condition found the advocated risk protective behaviors easier to perform and stated they were more likely to perform them than those in the non-video condition. Approximately 15 days after exposure, those in the video condition performed on average one more protective behavior than those in the non-video condition. Results also suggest that agencies' efforts should focus on creating one quality video to place on a homepage, as video views declined the deeper people navigated into the site. Behaviors advocated should also be ones that can have lasting impacts with one-time actions, as effects wore away over time. Additional strategies are discussed for health promoters seeking to create videos to add to their current websites. PMID- 25143662 TI - Stable Estimation of a Covariance Matrix Guided by Nuclear Norm Penalties. AB - Estimation of a covariance matrix or its inverse plays a central role in many statistical methods. For these methods to work reliably, estimated matrices must not only be invertible but also well-conditioned. The current paper introduces a novel prior to ensure a well-conditioned maximum a posteriori (MAP) covariance estimate. The prior shrinks the sample covariance estimator towards a stable target and leads to a MAP estimator that is consistent and asymptotically efficient. Thus, the MAP estimator gracefully transitions towards the sample covariance matrix as the number of samples grows relative to the number of covariates. The utility of the MAP estimator is demonstrated in two standard applications - discriminant analysis and EM clustering - in this sampling regime. PMID- 25143663 TI - Longitudinal Data Analysis Using Bayesian-frequentist Hybrid Random Effects Model. AB - The mixed random effect model is commonly used in longitudinal data analysis within either frequentist or Bayesian framework. Here we consider a case, we have prior knowledge on partial-parameters, while no such information on rest. Thus, we use the hybrid approach on the random-effects model with partial-parameters. The parameters are estimated via Bayesian procedure, and the rest of parameters by the frequentist maximum likelihood estimation (MLE), simultaneously on the same model. In practices, we often know partial prior information such as, covariates of age, gender, and etc. These information can be used, and get accurate estimations in mixed random-effects model. A series of simulation studies were performed to compare the results with the commonly used random effects model with and without partial prior information. The results in hybrid estimation (HYB) and Maximum likelihood estimation (MLE) were very close each other. The estimated theta values in with partial prior information model (HYB) were more closer to true theta values, and shown less variances than without partial prior information in MLE. To compare with true theta values, the mean square of errors (MSE) are much less in HYB than in MLE. This advantage of HYB is very obvious in longitudinal data with small sample size. The methods of HYB and MLE are applied to a real longitudinal data for illustration. PMID- 25143664 TI - Developmental Change and Time-Specific Variation in Global and Specific Aspects of Self-Concept in Adolescence and Association with Depressive Symptoms. AB - Previous research has demonstrated that adolescents make differential self evaluations in multiple domains that include physical appearance, academic competence, and peer acceptance. We report growth curve analyses over a seven year period from age 9 to age 16 on the six domains of the Harter Self-Perception Profile for Children. In general, we find little change in self-concept, on average, but do find substantial individual differences in level, rate of change, and time-specific variation in these self- evaluations. The results suggest that sex differences and adoptive status were related to only certain aspects of the participants' self-concept. Depressive symptoms were found to have significant effects on individual differences in rate of change and on time-specific variation in general self-concept, as well as on some of the specific domains of self-concept. PMID- 25143666 TI - Specific Reading Comprehension Disability: Major Problem, Myth, or Misnomer? AB - The goal of the present study was to test three competing hypotheses about the nature of comprehension problems of students who are poor in reading comprehension. Participants in the study were first, second, and third graders, totaling 9 cohorts and over 425,000 participants in all. The pattern of results was consistent across all cohorts: Less than one percent of first- through third grade students who scored as poor in reading comprehension were adequate in both decoding and vocabulary. Although poor reading comprehension certainly qualifies as a major problem rather than a myth, the term specific reading comprehension disability is a misnomer: Individuals with problems in reading comprehension that are not attributable to poor word recognition have comprehension problems that are general to language comprehension rather than specific to reading. Implications for assessment and intervention are discussed. PMID- 25143665 TI - Recipients with in utero induction of tolerance upregulated MHC class I in the engrafted donor skin. AB - The alterations in MHC class I expression play a crucial step in immune evasion of cancer or virus-infected cells. This study aimed to examine whether tolerized grafts modified MHC class I expression. FVB/N mice were rendered tolerant of C57BL/6 alloantigens by in utero transplantation of C57BL/6 marrows. Postnatally, engrafted donor skins and leukocytes were examined for their MHC expression by quantitative real-time PCR and flow cytometry. Engrafted donor skins upregulated their MHC class I related gene transcripts after short-term (1~2 weeks) or long term (>1 month) engraftment. This biological phenomenon was simultaneously associated with upregulation of TAP1 gene transcripts, suggesting an important role of TAP1 in the regulation of MHC class I pathway. The surface MHC class I molecules of H-2K(b) in engrafted donor leukocytes consistently showed overexpression. Conclusively, the induction of allograft tolerance involved biological modifications of donor transplants. The overexpression of MHC class I within engrafted transplants of tolerant mice might be used as the tolerance biomarkers for identifying a state of graft tolerance. PMID- 25143667 TI - Roles of chronic low-grade inflammation in the development of ectopic fat deposition. AB - Pattern of fat distribution is a major determinant for metabolic homeostasis. As a depot of energy, the storage of triglycerides in adipose tissue contributes to the normal fat distribution. Decreased capacity of fat storage in adipose tissue may result in ectopic fat deposition in nonadipose tissues such as liver, pancreas, and kidney. As a critical biomarker of metabolic complications, chronic low-grade inflammation may have the ability to affect the process of lipid accumulation and further lead to the disorder of fat distribution. In this review, we have collected the evidence linking inflammation with ectopic fat deposition to get a better understanding of the underlying mechanism, which may provide us with novel therapeutic strategies for metabolic disorders. PMID- 25143669 TI - Diversity and toxicity of the diatom Pseudo-nitzschia Peragallo in the Gulf of Maine, Northwestern Atlantic Ocean. AB - Multiple species in the toxic marine diatom genus Pseudo-nitzschia have been identified in the Northwestern Atlantic region encompassing the Gulf of Maine (GOM), including the Bay of Fundy (BOF). To gain further knowledge of the taxonomic composition and toxicity of species in this region, Pseudo-nitzschia isolates (n=146) were isolated from samples collected during research cruises that provided broad spatial coverage across the GOM and the southern New England shelf, herein referred to as the GOM region, during 2007-2008. Isolates, and cells in field material collected at 38 stations, were identified using electron microscopy (EM). Eight species (P. americana, P. fraudulenta, P. subpacifica, P. heimii, P. pungens, P. seriata, P. delicatissima and P. turgidula), and a novel form, Pseudo-nitzschia sp. GOM, were identified. Species identity was confirmed by sequencing the large subunit of the ribosomal rDNA (28S) and the internal transcribed spacer 2 (ITS2) for six species (36 isolates). Phylogenetic analyses (including neighbor joining, maximum parsimony, and maximum likelihood estimates and ITS2 secondary structure analysis) and morphometric data supported the placement of P. sp. GOM in a novel clade that includes morphologically and genetically similar isolates from Australia and Spain and is genetically most similar to P. pseudodelicatissima and P. cuspidata. Seven species (46 isolates) were grown in nutrient-replete batch culture and aliquots consisting of cells and growth medium were screened by Biosense ASP ELISA to measure total domoic acid (DA) produced (intracellular + extracellular); P. americana and P. heimii were excluded from all toxin analyses as they did not persist in culture long enough for testing. All 46 isolates screened produced DA in culture and total DA varied among species (e.g., 0.04 to 320 ng ml-1 for P. pungens and P. sp. GOM isolates, respectively) and among isolates of the same species (e.g., 0.24 - 320 ng ml-1 for P. sp. GOM). The 15 most toxic isolates corresponded to P. seriata, P. sp. GOM and P. pungens, and fg DA cell-1 was determined for whole cultures (cells and medium) using ELISA and liquid chromatography (LC) with fluorescence detection (FLD); for seven isolates, toxin levels were also estimated using LC - with mass spectrometry and ultraviolet absorbance detection. Pseudo-nitzschia seriata was the most toxic species (up to 3,500 fg cell-1) and was observed in the GOM region during all cruises (i.e., during the months of April, May, June and October). Pseudo-nitzschia sp. GOM, observed only during September and October 2007, was less toxic (19 - 380 fg cell-1) than P. seriata but more toxic than P. pungens var. pungens (0. 4 fg cell-1). Quantitation of DA indicated that concentrations measured by LC and ELISA were positively and significantly correlated; the lower detection limit of the ELISA permitted quantification of toxicity in isolates that were found to be nontoxic with LC methods. The confirmation of at least seven toxic species and the broad spatial and temporal distribution of toxic Pseudo-nitzschia spp. have significant implications for the regional management of nearshore and offshore shellfisheries resources. PMID- 25143668 TI - Hyperthermia differently affects connexin43 expression and gap junction permeability in skeletal myoblasts and HeLa cells. AB - Stress kinases can be activated by hyperthermia and modify the expression level and properties of membranous and intercellular channels. We examined the role of c-Jun NH2-terminal kinase (JNK) in hyperthermia-induced changes of connexin43 (Cx43) expression and permeability of Cx43 gap junctions (GJs) in the rabbit skeletal myoblasts (SkMs) and Cx43-EGFP transfected HeLa cells. Hyperthermia (42 degrees C for 6 h) enhanced the activity of JNK and its target, the transcription factor c-Jun, in both SkMs and HeLa cells. In SkMs, hyperthermia caused a 3.2 fold increase in the total Cx43 protein level and enhanced the efficacy of GJ intercellular communication (GJIC). In striking contrast, hyperthermia reduced the total amount of Cx43 protein, the number of Cx43 channels in GJ plaques, the density of hemichannels in the cell membranes, and the efficiency of GJIC in HeLa cells. Both in SkMs and HeLa cells, these changes could be prevented by XG-102, a JNK inhibitor. In HeLa cells, the changes in Cx43 expression and GJIC under hyperthermic conditions were accompanied by JNK-dependent disorganization of actin cytoskeleton stress fibers while in SkMs, the actin cytoskeleton remained intact. These findings provide an attractive model to identify the regulatory players within signalosomes, which determine the cell-dependent outcomes of hyperthermia. PMID- 25143670 TI - Basal cell carcinoma-mimicking lesions in korean clinical settings. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common form of skin cancer and possesses various clinical features including translucency, ulceration, pigmentation, telangiectasia, and rolled borders. Accordingly, many cutaneous lesions can mimic BCCs and differential diagnosis is difficult. OBJECTIVE: To clarify the differences in clinical characteristics between BCCs and BCC mimicking lesions (BMLs), and to determine which clinical characteristics are helpful for an accurate clinical diagnosis of BCC. METHODS: We performed clinicopathologic analysis of cutaneous lesions that received a clinical diagnosis of BCC. All lesions included in this study showed more than one of the following characteristics of BCCs: translucency, ulceration, flecked pigmentation, black or blue hue, telangiectasia, and rolled borders. We compared six clinical characteristics between the BCC group and the BML group. RESULTS: Among 48 lesions in the BML group, there were 15 premalignant or malignant lesions and 33 benign lesions. Various dermatoses mimicking BCC that have not been reported in the dermatological literature were identified, including angiosarcoma, vulvar intraepithelial neoplasm, foreign body granuloma, intravascular papillary endothelial hyperplasia, sarcoidosis, and others. Compared to the BML group, the BCC group had a significantly higher frequency of translucency (76.3% vs. 52.1%, p<0.001), ulceration or erosion (44.2% vs. 27.1%, p=0.022), black or blue hue (40.0% vs. 22.9%, p=0.020), and rolled borders (49.5% vs. 14.6%, p<0.001). Cutaneous lesions with two or less clinical features of BCC were significantly more likely to be BMLs. CONCLUSION: The results of this study could be helpful for the differential diagnosis of BCCs and BCC-mimicking cutaneous lesions. PMID- 25143671 TI - Clinical availability of component-resolved diagnosis using microarray technology in atopic dermatitis. AB - BACKGROUND: Various allergens play a role in the elicitation or exacerbation of eczematous skin lesions in atopic dermatitis (AD), and much research effort has been focused on improving diagnostic tests to identify causative allergens. OBJECTIVE: The purpose of this study was to evaluate the diagnostic effectiveness of a newly introduced microarray-based specific immunoglobulin E detection assay, ImmunoCAP ISAC, for use in AD patients. METHODS: The serum samples of 25 AD patients were tested by using ISAC and a multiple allergen simultaneous test enzyme immunoassay (MAST-EIA). In addition, 10 of the 25 patients underwent skin prick testing (SPT). The positive reaction rates to allergens in each test and the agreements, sensitivities, and specificities of ISAC and MAST-EIA were evaluated versus the SPT results. RESULTS: FOR ISAC VERSUS SPT, THE OVERALL RESULTS WERE AS FOLLOWS: sensitivity, 90.0%; specificity, 98.2%; positive predictive value (PPV), 90.0%; and negative predictive value (NPV), 98.2%. The total agreement and kappa value for ISAC versus SPT were 96.9% and 0.882, respectively. For MAST-EIA versus SPT, the sensitivity was 80.0%, specificity 92.7%, PPV 66.7%, and NPV 96.2%. The total agreement and kappa value for MAST-EIA versus SPT were 90.8% and 0.672, respectively. The overall agreement between the ISAC and MAST-EIA results was 88%. CONCLUSION: The ISAC results in AD correlated well with the SPT results, and compared favorably to the MAST-EIA results. This study demonstrates the potential of ISAC as a convenient allergic diagnostic method in AD patients. PMID- 25143672 TI - The efficacy, longevity, and safety of combined radiofrequency treatment and hyaluronic Acid filler for skin rejuvenation. AB - BACKGROUND: Recent advances in hyaluronic acid (HA) fillers and radiofrequency (RF) devices have been made in the context of skin rejuvenation and cosmetic surgery. Moreover, combination regimens with both techniques are currently being developed. OBJECTIVE: The present study was designed to examine the clinical and histologic effects of a new needle that incorporates an RF device for HA injections. METHODS: A new intradermal needle RF device (INNOfill; Pacific Pharma, Korea) was assessed in the present study. In the animal arm, procollagen production was measured by using enzyme-linked immunosorbent assay, the filler volume was quantified by incorporating a dye with filler, and the filler distribution was assessed through the changes in tissue structure. In the human arm, the efficacy of the combination regimen was assessed by using the wrinkle severity rating scale (WSRS). RESULTS: In the animal study, RF treatment increased procollagen production in a time-dependent fashion. The total volume was significantly increased with the RF treatment when compared with the filler injections alone, and lasted for up to 7 weeks after treatment. Additionally, the filler distribution was reduced in animals treated with RF when compared with the untreated group. In the human study, the nasolabial folds of subjects treated with RF before filler injections exhibited a significantly greater change in the WSRS score from baseline when compared with the nasolabial folds treated with filler injections alone. CONCLUSION: A new device incorporating RF treatment before HA filler injection may represent a biocompatible and long-lasting advance in skin rejuvenation. PMID- 25143673 TI - Turkish PASE: Turkish Version of the Psoriatic Arthritis Screening and Evaluation Questionnaire. AB - BACKGROUND: Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis and causes irreversible joint damage, unless detected early and treated with systemic drugs. OBJECTIVE: There is no reliable tool for screening PsA among Turkish psoriasis patients. Therefore, we aimed to validate the psoriatic arthritis screening and evaluation (PASE) questionnaire in the Turkish. METHODS: A 15-item Turkish PASE questionnaire was administered to 122 consecutive psoriasis patients who visited our dermatology clinic for routine evaluations. Then, the patients were evaluated for PsA by a rheumatologist who was blinded to the results of the questionnaire. RESULTS: Among the 113 patients who participated in the study, 11.5% (13 of 113) had a diagnosis of PsA. The Turkish PASE total scores ranged from 15 to 67 (possible range, 15~75). The median total score was 49 (25th and 75th percentile, 36 and 50) for the PsA group and 35 (25th and 75th percentile, 27 and 42) for the non-PsA group. The median total score of the PsA group was significantly higher than that of the non-PsA group (p=0.33). The Turkish PASE total score of 44 distinguished PsA from non-PsA participants, with 62% sensitivity and 76% specificity. For further analysis of each question, we counted the responses according to symptoms (positive for "agree" and "strongly agree" and negative for "disagree" and "strongly disagree"), and the sensitivity ranged from 23% (third question of the functions subscale) to 77% (second question of the symptoms subscale, first and fifth questions of the functions subscale) and the specificity ranged from 51% (second question of the symptoms subscale) to 87% (fourth question of the functions subscale). No relation was found between the PASI scores and the presence (p=0.899) or absence (p=0.941) of PsA, as well as between the PASI and PASE scores of each patient (p=0.961). CONCLUSION: Thirteen of the 15 items demonstrated significant test retest reliability as assessed with the Spearman correlation coefficient (p<0.05). These results show that the Turkish version of the PASE questionnaire may be useful for identifying PsA patients for inclusion in trials; however, it is not a reliable tool for screening PSA patients in a dermatology clinic. PMID- 25143674 TI - Efficacy and Safety Results of a Drug-Free Cosmetic Fluid for Perioral Dermatitis: The Toleriane Fluide Efficacy in Perioral Dermatitis (TOLPOD) Study. AB - BACKGROUND: Perioral dermatitis (POD) is a common inflammatory skin disease without standard therapy. OBJECTIVE: We sought to evaluate the clinical value of a soothing fluid for the treatment of POD. METHODS: We included 51 patients with POD in this 8-week clinical trial. The Toleriane Fluide Efficacy in Perioral Dermatitis (TOLPOD) study had an open-label design and involved twice-daily application of Toleriane Fluide, a soothing cosmetic fluid. Clinical assessment of POD was performed with a predefined questionnaire including the POD severity index (PODSI). Control visits were made after 4 and 8 weeks of treatment. RESULTS: The results were compared with those of a historical control group treated with a vehicle cream. Patients treated with the soothing fluid showed a continuous and significant improvement of the PODSI over time. The improvement of PODSI observed with the soothing fluid was better, but not significantly better, than that observed in the historical controls. In addition, the subjective complaints of patients such as disease burden, itching, distension of the skin, and appearance improved during treatment. CONCLUSION: A soothing fluid could be a clinically useful treatment option for POD. PMID- 25143675 TI - Possible existence of melanocytes or melanoblasts in human sebaceous glands. AB - BACKGROUND: Melanocytes are present in both basal epidermis and hair follicles. Melanocyte stem cells have been found in hair follicle bulge. During embryogenesis, the outer cells of the bulge differentiate into the sebaceous gland (SG) and proliferate. OBJECTIVE: To identify and determine the distribution and morphological characteristics of melanocytes in human SGs. METHODS: A total of 171 biopsy specimens of face and scalp were studied. Of these specimens, 103 samples contained SGs. We conducted a retrospective review of slides stained with H&E, F-M, anti-S100, anti-c-kit, anti-HMB-45, anti-CD1a, anti-MITF, and anti tyrosinase. The presence and distribution of melanocytes in human SGs was also evaluated by electron microscopy. In addition, melanocytes were isolated from SGs for primary culture. RESULTS: S-100-positive cells were observed mainly at the periphery of SGs in 34 of 54 specimens. We did not find F-M-positive and HMB-45 positive cells in SGs. CD1a-positve cells were identified in two specimens. We also found c-kit-, MITF-, and tyrosinase-positive cells in SGs. Electron micrograph showed the presence of melanocytes in the suprabasal portion of SGs. These melanocytes showed fewer melanin-containing granules than the melanocytes of basal epidermis. However, the individually distributed melanosomes in suprabasal melanocytes were larger than those in epidermal melanocytes. Primary culture of melanocytes derived from SGs showed morphologically homogeneous, slender cell bodies with few dendrites. CONCLUSION: Our study confirms the presence of non-melanogenic melanocytes and Langerhans cells in human SGs. In addition, the characteristics of the melanocytes in SGs were found to be different from those of the epidermal melanocytes. PMID- 25143676 TI - The use of long pulsed neodymium-doped yttrium aluminum garnet for the treatment of paediatric venous malformations. AB - BACKGROUND: Venous malformation in the pediatric population can present with pain, bleeding, or a debilitating deformity that can be difficult to manage. Sclerotherapy, surgery, and more recently, long pulsed neodymium-doped yttrium aluminum garnet (Nd : YAG) laser have been used with variable success rates. OBJECTIVE: Our aims and objectives, were to identify the specific group of patients that would benefit from this treatment. METHODS: A prospective clinical trial was carried out with 59 consecutive patients. The treatment criteria included a large facial deformity and painful or bleeding lesions. One to three treatments were administered at 6~8-week intervals. RESULTS: A total of 59 patients were treated. The average follow-up was 24 months. All patients achieved good to excellent results in pain and bleeding control as well as in the reduction of the size of lesions in the lip and oral mucosa. The treatment however, is not effective in reducing the size of large, relatively high-flow lesions in the limbs. Complications from treatment include skin blistering (n=4), ulceration (n=4), and subsequent hypertrophic scarring (n=3). Three patients had partial recurrence after a 3-year follow-up. CONCLUSION: Complex venous malformations cannot be cured but can be symptomatically controlled with the long pulsed Nd : YAG laser treatment. The treatment satisfaction is high, and there is a small but definite risk of scarring from treatment. PMID- 25143677 TI - Scalp dermatoscopic findings in androgenetic alopecia and their relations with disease severity. AB - BACKGROUND: Clinicians are searching for new methods to diagnose and predict the course of androgenetic alopecia noninvasively. OBJECTIVE: Our aim is to evaluate trichoscopic findings and their relations with disease severity in androgenetic alopecia. METHODS: The videodermatoscopic findings of 143 female and 63 male patients with androgenetic alopecia were compared with each other, with those of healthy subjects (n=100), and with those of patients with other nonscarring alopecias (n=208). Mann-Whitney U-test, chi(2) analyses, and logistic regression analysis were used for statistical analysis. RESULTS: No statistically significant relation was found between trichoscopic findings and severity in male androgenetic alopecia (MAGA) on the basis of the modified Hamilton Norwood scale (among 7 degrees); however, multihair follicular unit and perifollicular pigmentation were related to low severity whereas white dots, honeycomb pattern pigmentation, and brown dots were related to high severity. On the other hand, according to the Ludwig classification, arborizing red lines were related to low severity and brown dots were related to high severity, whereas there was no difference in stages between the Ebling and Olsen classifications in female androgenetic alopecia (FAGA). In the characteristic trichoscopic findings in this study, perifollicular pigmentation was found as a normal feature of the scalp, whereas multihair follicular unit and honeycomb pigment pattern, which were previously considered as normal features, were observed to be related to androgenetic alopecia. CONCLUSION: No relation was found between MAGA severity and trichoscopic findings, as well as between FAGA severity according to different disease severity classifications and trichoscopic findings. PMID- 25143678 TI - Comparison of Melanoma Subtypes among Korean Patients by Morphologic Features and Ultraviolet Exposure. AB - BACKGROUND: Genetic alterations have been identified in melanomas according to different levels of sun exposure. Whereas the conventional morphology-based classification provides a clue for tumor growth and prognosis, the new classification by genetic alterations offers a basis for targeted therapy. OBJECTIVE: The purpose of this study is to demonstrate the biological behavior of melanoma subtypes and compare the two classifications in the Korean population. METHODS: A retrospective chart review was performed on patients found to have malignant melanoma in Severance Hospital from 2005 to 2012. Age, sex, location of the tumor, histologic subtype, tumor depth, ulceration, lymph node invasion, visceral organ metastasis, and overall survival were evaluated. RESULTS: Of the 206 cases, the most common type was acral melanoma (n=94, 45.6%), followed by nonchronic sun damage-induced melanoma (n=43, 20.9%), and mucosal melanoma (n=40, 19.4%). Twenty-one patients (10.2%) had the chronic sun-damaged type, whereas eight patients (3.9%) had tumors of unknown primary origin. Lentigo maligna melanoma was newly classified as the chronic sun-damaged type, and acral lentiginous melanoma as the acral type. More than half of the superficial spreading melanomas were newly grouped as nonchronic sun-damaged melanomas, whereas nodular melanoma was rather evenly distributed. CONCLUSION: The distribution of melanomas was largely similar in both the morphology-based and sun exposure-based classifications, and in both classifications, mucosal melanoma had the worst 5-year survival owing to its tumor thickness and advanced stage at the time of diagnosis. PMID- 25143679 TI - The efficacy of intense pulsed light for treating erythematotelangiectatic rosacea is related to severity and age. AB - BACKGROUND: Rosacea is a chronic cutaneous disease. Therapeutic modalities should be chosen based on the identified sub-types and clinical features in each patient. Vascular lasers, including intense pulsed light (IPL), are reportedly safe and effective in treating erythematotelangiectatic rosacea (ETR). OBJECTIVE: In this study, we assess the comparative efficacy of IPL related to several factors including clinical severity and the age of patients with ETR. METHODS: Patients with ETR were classified into two groups according to the National Rosacea Society Severity Guideline. Severity score and erythema index (EI) were measured using a clinical scorecard and mexameter. For additional evaluation of therapeutic efficacy, investigator and patient global assessments (IGA, PGA) were checked. Efficacy of IPL was analyzed according to severity score, EI, IGA, and PGA related to sex, age, lactic acid stinging test, and severity. RESULTS: Analyses of the efficacy of IPL according to severity score, EI, IGA, and PGA based on sex, age, lactic acid stinging test, and severity revealed significant differences with age and severity only. CONCLUSION: This study supports the efficacy of IPL treatment for patients with ETR. IPL may be more effective in patients with more severe ETR and in younger patients with ETR. PMID- 25143680 TI - Intravascular cytotoxic T-cell lymphoma in a young immunocompetent woman. AB - Intravascular lymphoma (IVL) is a rare disorder characterized by the presence of large neoplastic lymphoid cells restricted to the lumens of small vessels with a predilection for the skin and the central nervous system. While the vast majority of cases involving IVL are of B-cell lineage, the disease rarely affects the T cell, the histiocytes, and the natural killer cells. We report a case of intravascular T-cell lymphoma (IVTL) associated with Epstein-Barr virus (EBV). A 23-year-old healthy woman presented with tender indurated erythematous patches with overlying telangiectasia on her right breast, abdomen, both the upper and the lower extremities and the back for 3 months. The pathology revealed an infiltration of dermal and subcutaneous vessels by large and atypical lymphoid cells with immunohistochemical features of the T-cell lineage with a cytotoxic phenotype (CD3+, CD8+, granzyme B+, TIA-1+, CD4-, CD5-, CD20-, CD56-). Interestingly, the DNA extracted from the skin biopsies demonstrated evidence of a monoclonal immunoglobulin heavy chain gene rearrangement, but no T-cell receptor gene rearrangement was found. In situ hybridization study for EBV encoded RNA was positive. She was diagnosed with an EBV-associated IVTL. The patient's skin lesions were refractory to the combination of chemotherapy and autologous stem cell transplant, and she expired. The findings in the present case may highlight the unique clinicopathologic aspects of EBV-associated cytotoxic IVTL that occurred in a young, immunocompetent woman. PMID- 25143681 TI - Two Concurrent Facial Epidermal Nevi without Systemic Abnormalities: Nevus Sebaceus and Nevus Comedonicus. AB - Epidermal nevi (EN) are hamartomatous lesions derived from epidermal components originating from pluripotent cell mutations. They have been categorized according to their predominant component. The existence of >2 types of EN concurrently within a single area or within contiguous areas has been rarely reported. This report describes the case of simultaneous presence of a yellowish plaque on the left medial canthus and an aggregation of closed comedo-like papules on the right side of the cheek of a 15-year-old girl. PMID- 25143682 TI - Three cases of lichen nitidus associated with various cutaneous diseases. AB - Lichen nitidus (LN) is an uncommon, usually asymptomatic cutaneous eruption characterized by the presence of multiple, small, flesh-colored papules. The epidemiologic and pathophysiologic characteristics of LN have not yet been defined. Furthermore, LN has rarely been described in association with other cutaneous diseases. We herein report 3 cases of LN associated with various cutaneous diseases, including lichen striatus, oral lichen planus, and psoriasis vulgaris. PMID- 25143683 TI - Myxoid Cellular Neurothekeoma: A New Entity of S100-Negative, CD68-Positive Myxoid Neurothekeoma. AB - Neurothekeoma is a rare cutaneous neoplasm, occurring as a cutaneous papule or nodule on the face, shoulders, and upper extremities. Neurothekeoma has been subclassified as either the myxoid, cellular, or mixed type, depending on the amount of myxoid matrix and on immunohistochemical analysis. We observed a clinical case with conflicting histopathological and immunohistochemical findings. In this case, microscopic examination showed the typical presentation of myxoid neurothekeoma; however, immunohistochemical staining was negative for S100 protein and positive for CD68, which is the characteristic pattern of cellular neurothekeoma. We report a very rare form of myxoid cellular neurothekeoma of the face in a young woman. PMID- 25143684 TI - Green nail syndrome treated with the application of tobramycin eye drop. AB - Green nail syndrome (chromonychia) is a nail disorder characterized by onycholysis and green-black discoloration of the nail bed. This condition is often associated with chronic paronychia. Pseudomonas aeruginosa is the most commonly identified organism in cultures from the affected area. Despite the various treatment options available, removal of the nail is still necessary in many cases. A 35-year-old man presented with dark-greenish discoloration of the nail plate and onycholysis on the left thumbnail. He had been treated with oral antifungal and antibiotic agents for several months; however, the lesion showed no improvement. The diagnosis of green nail syndrome was established after a positive bacterial culture, and on the basis of the antibiotic sensitivity test result, tobramycin eye drop (Tobrex(r)) was then prescribed. Three weeks later, the nail discoloration almost vanished but the onycholysis remained. Herein, we recommend the application of tobramycin eye drop as an easy and safe treatment option for green nail syndrome. PMID- 25143685 TI - Tazarotene-induced gene 3 may affect inflammatory angiogenesis in psoriasis by downregulating placental growth factor expression. PMID- 25143686 TI - Eosinophilic pustular folliculitis: association with long-term immunosuppressant use in a solid organ transplant recipient. PMID- 25143687 TI - Decreased Serum Level of Interferon-gamma in Patients with Pityriasis Rosea. PMID- 25143688 TI - Benzoin Spray: Cause of Allergic Contact Dermatitis due to Its Rosin Content. PMID- 25143689 TI - Autohemotherapy in chronic urticaria: what could be the autoreactive factors and curative mechanisms? PMID- 25143690 TI - Use of emollients in atopic dermatitis: a questionnaire survey study. PMID- 25143691 TI - Imatinib mesylate-induced hyperpigmentation of the nose and palate. PMID- 25143692 TI - Cutaneous pili migrans. PMID- 25143693 TI - Clinical significance of serum vascular endothelial-cadherin levels in inflammatory skin diseases. PMID- 25143694 TI - A case of multiple eruptive dermatofibromas in a healthy adult. PMID- 25143695 TI - Wells syndrome: response to dapsone therapy. PMID- 25143696 TI - Bilateral Eyelid Contact Dermatitis and Toxic Conjunctivitis due to Acrylate Containing Glue. PMID- 25143697 TI - Lipomatosis of the nerves in the back. PMID- 25143698 TI - Four cases of dysplastic nevus syndrome. PMID- 25143699 TI - A case of mucinous nevus clinically mimicking nevus lipomatosus superficialis. PMID- 25143700 TI - Pacinian neuromas presenting as soft tumors on the volar aspect of the fingertips. PMID- 25143701 TI - An unusual presentation of a progressive zosteriform macular pigmented lesion. PMID- 25143702 TI - Giant congenital melanocytic nevus with proliferative nodules mimicking a congenital malignant melanoma. PMID- 25143705 TI - For Application to Human Spaceflight and ISS Experiments: VESGEN Mapping of Microvascular Network Remodeling during Intestinal Inflammation. AB - Challenges to long-duration space exploration and colonization in microgravity and cosmic radiation environments by humans include poorly understood risks for gastrointestinal function and cancer. Nonetheless, constant remodeling of the intestinal microvasculature is critical for tissue viability, healthy wound healing, and successful prevention or recovery from vascular-mediated inflammatory or ischemic diseases such as cancer. Currently no automated image analysis programs provide quantitative assessments of the complex structure of the mucosal vascular system that are necessary for tracking disease development and tissue recovery. Increasing abnormalities to the microvascular network geometry were therefore mapped with VESsel GENeration Analysis (VESGEN) software from 3D tissue reconstructions of developing intestinal inflammation in a dextran sulfate sodium (DSS) mouse model. By several VESGEN parameters and a novel vascular network linking analysis, inflammation strongly disrupted the regular, lattice-like geometry that defines the normal microvascular network, correlating positively with the increased recruitment of dendritic cells during mucosal defense responses. PMID- 25143706 TI - Test-retest variability of multifocal electroretinography in normal volunteers and short-term variability in hydroxychloroquine users. AB - PURPOSE: To determine measurement variability of N1P1 amplitudes and the R1/R2 ratio in normal subjects and hydroxychloroquine users without retinopathy. DESIGN: Retrospective, observational study. SUBJECTS: Normal subjects (n=21) and 44 patients taking hydroxychloroquine (n=44) without retinopathy. METHODS: Multifocal electroretinography (mfERG) was performed twice in one session in the 21 normal subjects and twice within 1 year in the hydroxychloroquine users, during which time no clinical change in macular status occurred. MAIN OUTCOME MEASURES: N1P1 amplitudes of rings R1-R5, the R1/R2 ratio, and coefficients of repeatability (COR) for these measurements. RESULTS: Values for N1P1 amplitudes in hydroxychloroquine users were reduced compared with normal subjects by the known effect of age, but R1/R2 was not affected by age. The COR for R1-R5 ranged from 43% to 52% for normal subjects and from 43% to 59% for hydroxychloroquine users; for R1/R2 the COR was 29% in normal subjects and 45% in hydroxychloroquine users. CONCLUSION: mfERG measurements show high test-retest variability, limiting the ability of a single mfERG test to influence a decision to stop hydroxychloroquine; corroborative evidence with a different ancillary test is recommended in a suspicious case. PMID- 25143707 TI - Pseudoexfoliation material on posterior chamber intraocular lenses. AB - The presence of pseudoexfoliation material on the surface of an intraocular lens (IOL) is a rare finding. We report a series of seven cases with different patterns of pseudoexfoliation material deposition on the posterior chamber IOLs, recognized 2-20 years after cataract surgery. Six patients had an IOL implanted in the capsular bag and one in the ciliary sulcus. Two patients had undergone posterior capsulotomy. Although the pathophysiological mechanisms and clinical significance of this finding remain unknown, the careful follow-up of pseudophakic patients with known or suspected pseudoexfoliation syndrome is essential to monitor the development or progression of glaucoma, since deposition of pseudoexfoliation material continues even after cataract surgery. PMID- 25143704 TI - Dry needling: a literature review with implications for clinical practice guidelines. AB - BACKGROUND: Wet needling uses hollow-bore needles to deliver corticosteroids, anesthetics, sclerosants, botulinum toxins, or other agents. In contrast, dry needling requires the insertion of thin monofilament needles, as used in the practice of acupuncture, without the use of injectate into muscles, ligaments, tendons, subcutaneous fascia, and scar tissue. Dry needles may also be inserted in the vicinity of peripheral nerves and/or neurovascular bundles in order to manage a variety of neuromusculoskeletal pain syndromes. Nevertheless, some position statements by several US State Boards of Physical Therapy have narrowly defined dry needling as an 'intramuscular' procedure involving the isolated treatment of 'myofascial trigger points' (MTrPs). OBJECTIVES: To operationalize an appropriate definition for dry needling based on the existing literature and to further investigate the optimal frequency, duration, and intensity of dry needling for both spinal and extremity neuromusculoskeletal conditions. MAJOR FINDINGS: According to recent findings in the literature, the needle tip touches, taps, or pricks tiny nerve endings or neural tissue (i.e. 'sensitive loci' or 'nociceptors') when it is inserted into a MTrP. To date, there is a paucity of high-quality evidence to underpin the use of direct dry needling into MTrPs for the purpose of short and long-term pain and disability reduction in patients with musculoskeletal pain syndromes. Furthermore, there is a lack of robust evidence validating the clinical diagnostic criteria for trigger point identification or diagnosis. High-quality studies have also demonstrated that manual examination for the identification and localization of a trigger point is neither valid nor reliable between-examiners. CONCLUSIONS: Several studies have demonstrated immediate or short-term improvements in pain and/or disability by targeting trigger points (TrPs) using in-and-out techniques such as 'pistoning' or 'sparrow pecking'; however, to date, no high-quality, long-term trials supporting in-and out needling techniques at exclusively muscular TrPs exist, and the practice should therefore be questioned. The insertion of dry needles into asymptomatic body areas proximal and/or distal to the primary source of pain is supported by the myofascial pain syndrome literature. Physical therapists should not ignore the findings of the Western or biomedical 'acupuncture' literature that have used the very same 'dry needles' to treat patients with a variety of neuromusculoskeletal conditions in numerous, large scale randomized controlled trials. Although the optimal frequency, duration, and intensity of dry needling has yet to be determined for many neuromusculoskeletal conditions, the vast majority of dry needling randomized controlled trials have manually stimulated the needles and left them in situ for between 10 and 30 minute durations. Position statements and clinical practice guidelines for dry needling should be based on the best available literature, not a single paradigm or school of thought; therefore, physical therapy associations and state boards of physical therapy should consider broadening the definition of dry needling to encompass the stimulation of neural, muscular, and connective tissues, not just 'TrPs'. PMID- 25143708 TI - Effect of intravitreal bevacizumab on diabetic macular edema with hard exudates. AB - BACKGROUND: We evaluated the efficacy of intravitreal bevacizumab on diabetic macular edema with subfoveal and perifoveal hard exudates. MATERIALS AND METHODS: Eleven eyes (11 patients) exhibiting diabetic macular edema with subfoveal and perifoveal hard exudates were included in this prospective, nonrandomized interventional pilot study. All patients were treated with monthly scheduled intravitreal bevacizumab injections for 6 months. Changes in the Early Treatment Diabetic Retinopathy Study best corrected visual acuity, amount of hard exudates on fundus photography, and macular edema detected by central subfield thickness on spectral domain optical coherence tomography after six serial injections, were assessed. The amount of hard exudates at each visit was evaluated as pixels in fundus photography, using an Adobe Photoshop program. RESULTS: Ten of 11 patients completed follow-up. The mean Early Treatment Diabetic Retinopathy Study best corrected visual acuity was 59.9+/-5.7 letters (Snellen equivalent, 20/63) at baseline evaluation. The best corrected visual acuity exhibited no significant difference at month 6 compared with at baseline (57.9+/-6.0 letters or 20/70 at month 6; P=0.085). At month 6, mean central subfield thickness decreased from 370.4+/-56.5 to 334.6+/-65.0 MUm (P=0.009). The mean amount of hard exudates increased from 4467.1+/-2736.1 to 6592.4+/-2498.3 pixels at month 6 (P=0.022). No serious adverse events occurred. CONCLUSION: Continuous intravitreal bevacizumab was found to have no benefit in visual acuity and amount of hard exudates, despite the improvement of macular edema at 6 months. PMID- 25143709 TI - Association of retinal vessel attenuation with visual function in eyes with retinitis pigmentosa. AB - PURPOSE: To investigate the association between visual changes and retinal vessel attenuation in patients with retinitis pigmentosa (RP). DESIGN: A retrospective, longitudinal, observational cohort study. METHODS: We analyzed 45 eyes from 45 subjects who were followed-up for >=3 years at our clinic. Using the computer based Interactive Vessel Analysis program, central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) were determined. Age- and sex matched controls from normal subjects were selected from our archived fundus photograph library. Visual acuity, visual field area (Goldmann perimetry, V4e white test light), mean deviation (Humphrey perimetry, central 10-2 program), and central macular thickness (optical coherence tomography) were analyzed for correlations with CRAE and CRVE. RESULTS: Both CRAE and CRVE were significantly decreased in RP eyes (94.9+/-13.5 MUm and 155.6+/-20.0 MUm, respectively) compared with control eyes (138.1+/-14.7 MUm and 215.0+/-20.4 MUm, respectively, both P<0.001). After 3 years of follow-up, visual field area was associated with both CRAE (r=0.584, P<0.01) and CRVE (r=0.500, P=0.008). A significant association was also observed between mean deviation and CRAE (r=0.298, P=0.047). In eyes with RP, a narrower vessel caliber at baseline was associated with a larger decline in visual acuity over the 3-year follow-up interval (CRAE: r= 0.344, P=0.021; CRVE: r=-0.314, P=0.035). CONCLUSION: Retinal vessel caliber is associated with some visual functions in patients with RP. PMID- 25143710 TI - Efficacy of the small molecule inhibitor of Lipid II BAS00127538 against Acinetobacter baumannii. AB - OBJECTIVE: To test the activity of a small molecule compound that targets Lipid II against Acinetobacter baumannii. METHODS: Susceptibility to small molecule Lipid II inhibitor BAS00127538 was assessed using carbapenem- and colistin resistant clinical isolates of A. baumannii. In addition, synergy between colisitin and this compound was assessed. RESULTS: Small molecule Lipid II inhibitor BAS00127538 potently acts against A. baumannii and acts synergistically with colistin. CONCLUSION: For the first time, a compound that targets Lipid II is described that acts against multi-drug resistant isolates of A. baumannii. The synergy with colistin warrants further lead development of BAS00127538. PMID- 25143711 TI - Optimization of nebulized delivery of linezolid, daptomycin, and vancomycin aerosol. AB - BACKGROUND: At this time, several antibiotics have been investigated as possibilities for aerosol administration, but local therapy has been found to be more efficient in several diseases. MATERIALS AND METHODS: The drugs linezolid (Zyvox), vancomycin (Voncon), and daptomycin (Cubicin) were tested with three jet nebulizers with seven different residual cups and different loadings. Moreover, three ultrasound nebulizers were again tested with these drugs, with different loadings and mouthpiece attachments. RESULTS: When drugs are combined with particular cup designs, they significantly lower the droplet size to 1.60 and 1.80 MUm, which represents the best combination of Zyvox and cup G and Cubicin and cup D, respectively. Cup design D is suggested as the most effective cup for lowering the droplet size (2.30 MUm) when considering a higher loading level (8 mL). CONCLUSION: Modification of current drugs from dry powder to solution is possible, and the residual cup design plays the most important role in droplet size production when the nebulization systems have the same properties. PMID- 25143712 TI - Meclofenamate elicits a nephropreventing effect in a rat model of ischemic acute kidney injury by suppressing indoxyl sulfate production and restoring renal organic anion transporters. AB - Indoxyl sulfate (IS), a putative low-molecular weight uremic toxin, is excreted in the urine under normal kidney function, but is retained in the circulation and tissues during renal dysfunction in acute kidney injury and chronic kidney disease. IS, which is one of the most potent inducers of oxidative stress in the kidney and cardiovascular system, is enzymatically produced in the liver from indole by cytochrome P450-mediated hydroxylation to indoxyl, followed by sulfotransferase-mediated sulfate conjugation. We used rat liver S9 fraction to identify inhibitors of IS production. After testing several compounds, including phytochemical polyphenols, we identified meclofenamate as a potent inhibitor of IS production with an apparent IC50 value of 1.34 MUM. Ischemia/reperfusion (I/R) of rat kidney caused a marked elevation in the serum IS concentration 48 hours after surgery. However, intravenous administration of meclofenamate (10 mg/kg) significantly suppressed this increase in the serum level of IS. Moreover, IS concentrations in both kidney and liver were dramatically elevated by renal I/R treatment, but this increase was blocked by meclofenamate. Serum creatinine and blood urea nitrogen were markedly elevated in rats after renal I/R treatment, but these increases were significantly restored by administration of meclofenamate. Renal expression of both basolateral membrane-localized organic anion transporters rOAT1 and rOAT3 was downregulated by I/R treatment. However, expression of rOAT1 and rOAT3 recovered after administration of meclofenamate, which is associated with the inhibition of I/R-evoked elevation of prostaglandin E2. Our results suggest that meclofenamate inhibits hepatic sulfotransferase mediated production of IS, thereby suppressing serum and renal accumulation of IS. Meclofenamate also prevents the prostaglandin E2-dependent downregulation of rOAT1 and rOAT3 expression. In conclusion, meclofenamate was found to elicit a nephropreventive effect in ischemic acute kidney injury. PMID- 25143713 TI - Clinical utility and patient perspectives on the use of extended half-life rFIXFc in the management of hemophilia B. AB - Hemophilia B is an X-linked genetic disease caused by mutation of the gene for coagulation protein factor IX (FIX), with an incidence of approximately once every 30,000 male births in all populations and ethnic groups. When severe, the disease leads to spontaneous life threatening bleeding episodes. When untreated, most patients die from bleeding complications before 25 years of age. Current therapy requires frequent intravenous infusions of therapeutic recombinant or plasma-derived protein concentrates containing FIX. Most patients administer the infusions at home every few days, and must limit their physical activities to avoid abnormal bleeding when the FIX activity levels are below normal. After completing the pivotal Phase III clinical trial, a new therapeutic FIX preparation that has been engineered for an extended half-life in circulation, received regulatory approval in March 2014 in Canada and the US. This new FIX represents a major therapeutic advance for patients with hemophilia B. The half life is prolonged due to fusion of the native FIX molecule with the normal constant region of immunoglobulin G. This fusion molecule then follows the normal immunoglobulin recirculation pathways through endothelial cells, resulting in prolonged times in circulation. In the clinical trials, over 150 patients successfully used eftrenonacog alfa regularly for more than 1 year to prevent spontaneous bleeding, to successfully treat any bleeding episodes, and to provide effective coagulation for major surgery. All infusions were well tolerated and effective, with no inhibitors detected and no safety concerns. This promising therapy should allow patients to use fewer infusions to maintain appropriate FIX activity levels in all clinical settings. PMID- 25143714 TI - Cardiovascular program to improve physical fitness in those over 60 years old - pilot study. AB - BACKGROUND: In Spain, more than 50% of 60-year-olds are obese. Obesity is a disease with serious cardiovascular risks. The mortality rate for cardiovascular disease in Spain is 31.1%. OBJECTIVES: To improve aerobic fitness, strength, flexibility and balance, and body composition (BC) in persons over 60 years old. MATERIALS AND METHODS: A clinical intervention study of 24 participants was carried out over a period of 3 months. Aerobic fitness was assessed using the Rockport 1-Mile Walk Test. Upper-body strength was evaluated with an ad hoc test. Flexibility and balance were evaluated using the Sit and Reach Test and the Stork Balance Stand Test, respectively. Anthropometric measurements were taken by bioelectrical impedance. RESULTS: After 3 months of training, aerobic fitness was improved, as demonstrated by improved test times (pretest 13.04 minutes, posttest 12.13 minutes; P<0.05). Body composition was also improved, but the results were not statistically significant (fat mass pretest 31.58%+/- 5.65%, posttest 30.65%+/- 6.31%; skeletal muscle mass pretest 43.99 +/- 9.53 kg, posttest 46.63 +/- 10.90 kg). CONCLUSION: Our data show that in subjects over 60 years old, aerobic fitness was improved due to program intervention. However, these results should be treated with caution, because of the limited sample size and the brief time period of this pilot study. A more rigorous study would include a sample of at least 100 participants. PMID- 25143715 TI - Nonalcoholic fatty liver disease (NAFLD) - a new factor that interplays between inflammation, malnutrition, and atherosclerosis in elderly hemodialysis patients. AB - BACKGROUND/AIM: In the past decade, in most regions of the world, an increasing number of adults aged 65 years and older were started on renal replacement therapy each year. In contrast to the general population for whom overnutrition or obesity is associated with increased cardiovascular risk, for patients who are maintained on hemodialysis (HD), malnutrition and malnutrition-inflammation complex syndrome are associated with poor outcome. In recent years, nonalcoholic fatty liver disease (NAFLD) has been considered to be the liver manifestation of metabolic syndrome, and the development of NAFLD is strongly associated with all components of metabolic syndrome (arterial hypertension, dyslipidemia, obesity, and diabetes mellitus type 2) in the general population. The primary end point of this study was to determine the patient's survival in relation to nutritional and inflammatory state and the presence or absence of NAFLD. The secondary end point of this analysis was the association among NAFLD and various clinical and laboratory data, with the nutritional and inflammatory state of our elderly HD patients. METHODS: Using a single-center, prospective, cohort study design, we followed the progress of 76 patients who were >= 65 years and treated with chronic HD for at least 6 months, at the Department of Nephrology, Dialysis and Transplantation. All patients were followed for a minimum of 18 months or until death. Survival was defined as the time from study initiation to death (or end of study, if still alive). RESULTS: The main findings of our study were a remarkable positive correlation between NAFLD and high-sensitivity C-reactive protein (hs CRP) (r=0.659; P<0.0001) and consequent negative correlation with the nutritional parameter, serum albumin (r=-0.321; P=0.004). Interestingly, we showed that in contrast to the general population, where NAFLD is associated with obesity, in the present study, there was no statistically significant association between NAFLD and overnutrition in elderly HD patients. Furthermore, the presence of NAFLD, low serum albumin levels, and high hs-CRP were strong predictors of poor outcome in our elderly HD patients. CONCLUSION: Our results indicated that NAFLD probably interplays between inflammation, malnutrition, and atherosclerosis in elderly HD patients. NAFLD could be a new factor that contributes to type 2 malnutrition in elderly HD patients, who may be amenable to adequate nutritional and HD support. PMID- 25143716 TI - Severe unexpected adverse effects after permanent eye makeup and their management by Q-switched Nd:YAG laser. AB - Permanent makeup is a cosmetic tattoo that is used to enhance one's appearance, and which has become more popular among middle-aged and elderly women. A couple of benefits seem to be associated with permanent tattoos in the elderly: saving time (wake up with makeup); poor eyesight (difficult to apply makeup); and saving money. On the other hand, cosmetic tattoos bear the same risks as other tattoo procedures. We report on fading and unintended hyperpigmentation after tattooing on eyebrows and eyelids, and discuss the scientific and anatomical background behind the possible cause. Dermatochalasis may be a possible risk factor for excessive unwanted discolorations. Q-switched neodymium-doped yttrium aluminum garnet laser is an appropriate and safe therapeutic tool that can manage such adverse effects. Consumer protection warrants better information and education of the risks of cosmetic tattoos - in particular, for elderly women. PMID- 25143717 TI - The efficacy of traditional Thai massage in decreasing spasticity in elderly stroke patients. AB - PURPOSE: To study the efficacy of traditional Thai massage (TTM) versus conventional physical therapy (PT) programs in treating muscle spasticity, functional ability, anxiety, depression, and quality of life (QoL) in Thai stroke patients. METHODS: This randomized controlled trial with a blinded assessor was carried out at the Department of Rehabilitation Medicine, Siriraj Hospital (Bangkok, Thailand). The study included 50 stroke (onset >= 3 months) outpatients experiencing spasticity at the elbow or knee muscles at a grade of >= 1+ on the modified Ashworth Scale who were >= 50 years old and able to communicate. The subjects were randomly allocated to the treatment group receiving TTM (24 subjects) or the control group receiving the PT program (26 subjects). Both groups received treatment (either TTM or PT) twice a week for 6 weeks. Spasticity grade, functional ability, anxiety, depression, and QoL were measured at Week 0 and Week 6. RESULTS: At Week 6, the percentage of patients whose modified Ashworth Scale score had decreased by at least one grade was not statistically significant between the two groups. Both TTM and PT groups experienced a significant increase in functional ability and QoL, but no difference was found between the groups. Anxiety and depression scores showed a decreasing trend in the TTM group. CONCLUSION: This preliminary report showed no evidence that TTM differed from the PT program in decreasing spasticity. However, both interventions may relieve spasticity, increase functional ability, and improve QoL after 6 weeks. Only TTM can decrease anxiety and depression scores. Further studies with adequate sample size are necessary. PMID- 25143718 TI - The control of blood pressure might be important in delaying progression of arterial aging in patients with type 2 diabetes mellitus. AB - OBJECTIVE: Arterial stiffness, as assessed by the brachial-ankle pulse wave velocity (baPWV), is associated with arterial aging and has been consistently linked to cardiovascular disease. The factors involved in reducing the progression of arterial stiffness in patients with type 2 diabetes mellitus (DM) have not yet been fully established. METHODS: Of 478 patients who underwent two baPWV measurements (at baseline and 1 year later) at the Department of Internal Medicine, St Vincent's Hospital, from November 2009 to June 2011, 341 subjects were enrolled in this study (male to female ratio =150:191; mean age, 62.1 +/- 7.7 years). The 341 subjects were over the age of 50 with type 2 DM, were diagnosed without peripheral artery disease, and 170 if the subjects (50%) had hypertension. RESULTS: baPWV at baseline increased in a linear manner along with age (beta=22.8, t=10.855; P<0.0001, R (2)=0.258). After 1 year follow-up, the change in baPWV (DeltabaPWV) was variable (median 32.7 cm/s [approximate range, 557 to ~745]). In multiple linear regression, the change in systolic blood pressure (beta=7.142, 95% confidence interval =4.557-9.727; P<0.0001, R (2)=0.305) was associated with DeltabaPWV during follow-up. The change in glycated hemoglobin (HbA1c) and a glycemic control of keeping HbA1c levels below 7.0% were not associated with DeltabaPWV. CONCLUSION: We found that the variation of blood pressure was associated with the progression of vascular aging of the large- to middle-sized arteries in patients with type 2 DM. Therefore, control of blood pressure might be important in reducing arterial aging or PWV in patients with type 2 DM. PMID- 25143719 TI - Cognitive effects of testosterone and finasteride administration in older hypogonadal men. AB - Serum concentrations of neuroactive androgens decline in older men and, in some studies, low testosterone is associated with decreased cognitive function and incidence of depression. Existing studies evaluating the effect of testosterone administration on cognition in older men have been largely inconclusive, with some studies reporting minor to moderate cognitive benefit, while others indicate no cognitive effect. Our objective was to assess the cognitive effects of treating older hypogonadal men for 1 year with a supraphysiological dose of testosterone, either alone or in combination with finasteride (a type II 5alpha reductase inhibitor), in order to determine whether testosterone produces cognitive benefit and whether suppressed dihydrotestosterone influences cognition. Sixty men aged >= 60 years with a serum testosterone concentration of <= 300 ng/dL or bioavailable testosterone <= 70 ng/dL and no evidence of cognitive impairment received testosterone-enanthate (125 mg/week) versus vehicle, paired with finasteride (5 mg/day) versus placebo using a 2*2 factorial design. Testosterone caused a small decrease in depressive symptoms as assessed by the Geriatric Depression Scale and a moderate increase in visuospatial memory as assessed by performance on a recall trial of the Rey-Osterrieth Complex Figure Test. Finasteride caused a small increase in performance on the Benton Judgment of Line Orientation test. In total, major improvements in cognition were not observed either with testosterone or finasteride. Further studies are warranted to determine if testosterone replacement may improve cognition in other domains. PMID- 25143720 TI - Comparison of the clinical features and outcomes in two age-groups of elderly patients with atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) disproportionately affects older adults. However, direct comparison of clinical features, medical therapy, and outcomes in AF patients aged 65-74 and >= 75 years is rare. The objective of the present study was to evaluate the differences in clinical characteristics and prognosis in these two age-groups of geriatric patients with AF. MATERIALS AND METHODS: A total of 1,336 individuals aged >= 65 years from a Chinese AF registry were assessed in the present study: 570 were in the 65- to 74-year group, and 766 were in the >= 75-year group. Multivariable Cox hazards regression was performed to analyze the major adverse cardiac events (MACEs) between groups. RESULTS: In our population, the older group were more likely to have coronary artery disease, hypertension, previous stroke, cognitive disorder, or chronic obstructive pulmonary disease, and the 65- to 74-year group were more likely to have valvular heart disease, left ventricular systolic dysfunction, or sleep apnea. The older patients had 1.2-fold higher mean CHADS2 (congestive heart failure, hypertension, age >= 75 years, diabetes, stroke) scores, but less probability of being prescribed drugs. Compared with those aged 65-74 years, the older group had a higher risk of death (hazard ratio 2.881, 95% confidence interval 1.981-4.189; P<0.001) or MACE (hazard ratio 2.202, 95% confidence interval 1.646-2.945; P<0.001) at the 1-year follow-up. In multivariable Cox analyses, secondary AF diagnosis, a history of chronic obstructive pulmonary disease, and left ventricular systolic dysfunction were independent predictors of MACE in the older group. CONCLUSION: Patients aged >= 75 years had a worse prognosis than those aged 65-74 years, and were associated with a higher risk of both death and MACE. PMID- 25143722 TI - Airway epithelial platelet-activating factor receptor expression is markedly upregulated in chronic obstructive pulmonary disease. AB - BACKGROUND: We recently published that platelet-activating factor receptor (PAFr) is upregulated on the epithelium of the proximal airways of current smokers and also in bronchial epithelial cells exposed to cigarette smoke extract. These treated cells also showed upregulation of Streptococcus pneumoniae adhesion. Bacterial wall phosphorylcholine specifically binds to PAFr expressed on airway epithelium, thus facilitating adherence and tissue invasion, which may be relevant to chronic obstructive pulmonary disease (COPD). Moreover, the use of inhaled corticosteroids (ICS) in COPD patients is associated with an increased risk of invasive respiratory pneumococcal infections. OBJECTIVE: In this study, we have investigated whether PAFr expression is especially upregulated in airway epithelium in COPD patients and whether this expression may be modulated by ICS therapy. METHODS: We cross-sectionally evaluated PAFr expression in bronchial biopsies from 15 COPD patients who were current smokers (COPD-smokers) and 12 COPD-ex-smokers, and we compared these to biopsies from 16 smokers with normal lung function. We assessed immunostaining with anti-PAFr monoclonal antibody. We also used material from a previous double-blinded randomized placebo-controlled 6 month ICS intervention study in COPD patients to explore the effect of ICS on PAFr expression. We employed computer-aided image analysis to quantify the percentage of epithelium stained for PAFr. RESULTS: Markedly enhanced expression of PAFr was found in both COPD-smokers (P<0.005) and COPD-ex-smokers (P<0.002) compared to smokers with normal lung function. There was little evidence that PAFr expression was affected by ICS therapy over 6 months. CONCLUSION: Epithelial PAFr expression is upregulated in smokers, especially in those with COPD, and is not obviously affected by ICS therapy. PMID- 25143723 TI - Role of surface modification in zinc oxide nanoparticles and its toxicity assessment toward human dermal fibroblast cells. AB - The wide-scale applications of zinc oxide (ZnO) nanoparticles (NPs) in photocatalysts, gas sensors, and cosmetics may cause toxicity to humans and environments. Therefore, the aim of the present study was to reduce the toxicity of ZnO NPs by coating them with a silica (SiO2) layer, which could be used in human applications, such as cosmetic preparations. The sol-gel method was used to synthesize core ZnO with SiO2-shelled NPs (SiO2/ZnO NPs) with varying degrees of coating. Diverse studies were performed to analyze the toxicity of NPs against cells in a dose- and time-dependent manner. To ensure the decreased toxicity of the produced SiO2/ZnO NPs, cytotoxicity in membrane damage and/or intracellular reactive oxygen species (ROS) were assessed by employing 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide, lactate dehydrogenase, 2',7' dichlorofluorescin, and lipid peroxide estimations. The cores of ZnO NPs exhibited cytotoxicity over time, regardless of shell thickness. Nevertheless, the thicker SiO2/ZnO NPs revealed reduced enzyme leakage, decreased peroxide production, and less oxidative stress than their bare ZnO NPs or thinner SiO2/ZnO NPs. Therefore, thicker SiO2/ZnO NPs moderated the toxicity of ZnO NPs by restricting free radical formation and the release of zinc ions, and decreasing surface contact with cells. PMID- 25143721 TI - Noninvasive ventilation in acute respiratory failure. AB - After the institution of positive-pressure ventilation, the use of noninvasive ventilation (NIV) through an interface substantially increased. The first technique was continuous positive airway pressure; but, after the introduction of pressure support ventilation at the end of the 20th century, this became the main modality. Both techniques, and some others that have been recently introduced and which integrate some technological innovations, have extensively demonstrated a faster improvement of acute respiratory failure in different patient populations, avoiding endotracheal intubation and facilitating the release of conventional invasive mechanical ventilation. In acute settings, NIV is currently the first line treatment for moderate-to-severe chronic obstructive pulmonary disease exacerbation as well as for acute cardiogenic pulmonary edema and should be considered in immunocompromised patients with acute respiratory insufficiency, in difficult weaning, and in the prevention of postextubation failure. Alternatively, it can also be used in the postoperative period and in cases of pneumonia and asthma or as a palliative treatment. NIV is currently used in a wide range of acute settings, such as critical care and emergency departments, hospital wards, palliative or pediatric units, and in pre-hospital care. It is also used as a home care therapy in patients with chronic pulmonary or sleep disorders. The appropriate selection of patients and the adaptation to the technique are the keys to success. This review essentially analyzes the evidence of benefits of NIV in different populations with acute respiratory failure and describes the main modalities, new devices, and some practical aspects of the use of this technique. PMID- 25143725 TI - Biophysical evaluation of cells on nanotubular surfaces: the effects of atomic ordering and chemistry. AB - After the implantation of a biomaterial in the body, the first interaction occurs between the cells in contact with the biomaterial surface. Therefore, evaluating the cell-substrate interface is crucial for designing a successful implant. In this study, the interaction of MC3T3 osteoblasts was studied on commercially pure and alloy (Ti6Al4V) Ti surfaces treated with amorphous and crystalline titanium dioxide nanotubes. The results indicated that the presence of nanotubes increased the density of osteoblast cells in comparison to bare surfaces (no nanotubes). More importantly, our finding shows that the chemistry of the substrate affects the cell density rather than the morphology of the cells. A novel approach based on the focused ion beam technique was used to investigate the biophysical cell substrate interaction. The analysis revealed that portions of the cells migrated inside the crystalline nanotubes. This observation was correlated with the super hydrophilic properties of the crystalline nanotubes. PMID- 25143727 TI - Extraction of human genomic DNA from whole blood using a magnetic microsphere method. AB - With the rapid development of molecular biology and the life sciences, magnetic extraction is a simple, automatic, and highly efficient method for separating biological molecules, performing immunoassays, and other applications. Human blood is an ideal source of human genomic DNA. Extracting genomic DNA by traditional methods is time-consuming, and phenol and chloroform are toxic reagents that endanger health. Therefore, it is necessary to find a more convenient and efficient method for obtaining human genomic DNA. In this study, we developed urea-formaldehyde resin magnetic microspheres and magnetic silica microspheres for extraction of human genomic DNA. First, a magnetic microsphere suspension was prepared and used to extract genomic DNA from fresh whole blood, frozen blood, dried blood, and trace blood. Second, DNA content and purity were measured by agarose electrophoresis and ultraviolet spectrophotometry. The human genomic DNA extracted from whole blood was then subjected to polymerase chain reaction analysis to further confirm its quality. The results of this study lay a good foundation for future research and development of a high-throughput and rapid extraction method for extracting genomic DNA from various types of blood samples. PMID- 25143724 TI - Nanotechnology-based drug delivery systems for treatment of oral cancer: a review. AB - Oral cancer (oral cavity and oropharynx) is a common and aggressive cancer that invades local tissue, can cause metastasis, and has a high mortality rate. Conventional treatment strategies, such as surgery and chemoradiotherapy, have improved over the past few decades; however, they remain far from optimal. Currently, cancer research is focused on improving cancer diagnosis and treatment methods (oral cavity and oropharynx) nanotechnology, which involves the design, characterization, production, and application of nanoscale drug delivery systems. In medicine, nanotechnologies, such as polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, gold nanoparticles, hydrogels, cyclodextrin complexes, and liquid crystals, are promising tools for diagnostic probes and therapeutic devices. The objective of this study is to present a systematic review of nanotechnology-based drug delivery systems for oral cancers. PMID- 25143726 TI - Therapeutics with SPION-labeled stem cells for the main diseases related to brain aging: a systematic review. AB - The increase in clinical trials assessing the efficacy of cell therapy for structural and functional regeneration of the nervous system in diseases related to the aging brain is well known. However, the results are inconclusive as to the best cell type to be used or the best methodology for the homing of these stem cells. This systematic review analyzed published data on SPION (superparamagnetic iron oxide nanoparticle)-labeled stem cells as a therapy for brain diseases, such as ischemic stroke, Parkinson's disease, amyotrophic lateral sclerosis, and dementia. This review highlights the therapeutic role of stem cells in reversing the aging process and the pathophysiology of brain aging, as well as emphasizing nanotechnology as an important tool to monitor stem cell migration in affected regions of the brain. PMID- 25143728 TI - Supercritical fluid-mediated liposomes containing cyclosporin A for the treatment of dry eye syndrome in a rabbit model: comparative study with the conventional cyclosporin A emulsion. AB - BACKGROUND: The objective of this study was to compare the efficacy of cyclosporin (CsA)-encapsulated liposomes with the commercially available CsA emulsion (Restasis) for the treatment of dry eye syndrome in rabbits. METHODS: Liposomes containing CsA were prepared by the supercritical fluid (SCF) method consisted of phosphatidylcholine from soybean (SCF-S100) and egg lecithins (SCF EPCS). An in vitro permeation study was carried out using artificial cellulose membrane in Franz diffusion cells. Dry eye syndrome was induced in male albino rabbits and further subdivided into untreated, Restasis-treated, EPCS, and S100 treated groups. Tear formation in the dry-eye-induced rabbits was evaluated using the Schirmer tear test. All formulations were also evaluated by ocular irritation tests using the Draize eye and winking methods with the determination of CsA concentration in rabbit tears. RESULTS: After the treatment, the Schirmer tear test value significantly improved in EPCS-treated (P=0.005) and S100-treated (P=0.018) groups compared to the Restasis-treated group. The AUC0-24 h for rabbit's tear film after the administration of SCF-S100 was 32.75+/-9.21 MUg.h/mg which was significantly higher than that of 24.59+/-8.69 MUg.h/mg reported with Restasis. Liposomal CsA formulations used in this study showed lower irritation in rabbit eyes compared with Restasis. CONCLUSION: These results demonstrate that the novel SCF-mediated liposomal CsA promises a significant improvement in overcoming the challenges associated with the treatment of dry eyes. PMID- 25143729 TI - Synthesis, characterization, and antimicrobial activity of an ampicillin conjugated magnetic nanoantibiotic for medical applications. AB - Because of their magnetic properties, magnetic nanoparticles (MNPs) have numerous diverse biomedical applications. In addition, because of their ability to penetrate bacteria and biofilms, nanoantimicrobial agents have become increasingly popular for the control of infectious diseases. Here, MNPs were prepared through an iron salt coprecipitation method in an alkaline medium, followed by a chitosan coating step (CS-coated MNPs); finally, the MNPs were loaded with ampicillin (amp) to form an amp-CS-MNP nanocomposite. Both the MNPs and amp-CS-MNPs were subsequently characterized and evaluated for their antibacterial activity. X-ray diffraction results showed that the MNPs and nanocomposites were composed of pure magnetite. Fourier transform infrared spectra and thermogravimetric data for the MNPs, CS-coated MNPs, and amp-CS-MNP nanocomposite were compared, which confirmed the CS coating on the MNPs and the amp-loaded nanocomposite. Magnetization curves showed that both the MNPs and the amp-CS-MNP nanocomposites were superparamagnetic, with saturation magnetizations at 80.1 and 26.6 emu g(-1), respectively. Amp was loaded at 8.3%. Drug release was also studied, and the total release equilibrium for amp from the amp-CS-MNPs was 100% over 400 minutes. In addition, the antimicrobial activity of the amp-CS MNP nanocomposite was determined using agar diffusion and growth inhibition assays against Gram-positive bacteria and Gram-negative bacteria, as well as Candida albicans. The minimum inhibitory concentration of the amp-CS-MNP nanocomposite was determined against bacteria including Mycobacterium tuberculosis. The synthesized nanocomposites exhibited antibacterial and antifungal properties, as well as antimycobacterial effects. Thus, this study introduces a novel beta-lactam antibacterial-based nanocomposite that can decrease fungus activity on demand for numerous medical applications. PMID- 25143730 TI - The influence of bile salt on the chemotherapeutic response of docetaxel-loaded thermosensitive nanomicelles. AB - The primary aim of this work was to investigate the potential of bile salt, sodium taurocholate (NaTC), in improving the bioavailability and anti-tumor efficacy of docetaxel (DCT) upon rectal administration. Poloxamer-based nanomicelles with thermosensitive and mucoadhesive properties were prepared using the cold method. The optimized nanomicellar formulation was evaluated in terms of physicochemical and viscoelastic parameters. Nanomicelles containing bile salt maintained sufficient gelation strength (234*10(2) mPa.s) and mucoadhesive force (17.3*10(2) dyne/cm(2)) to be retained in the upper part of the rectum. They significantly enhanced the DCT internalization across the rectal mucosa and showed a high plasma level during the first 4 hours of the study period, compared to nanomicelles with no bile salt. As a result, a slightly higher rectal bioavailability of ~33% was observed in nanomicelles containing bile salt, compared to ~28% from the latter system. The higher pharmacokinetic parameters for rectally administered DCT/P407/P188/Tween 80/NaTC (0.25%/11%/15%/10%/0.1% by weight, respectively) resulted in significant anti-tumor efficacy. However, the tumor regression rate for the NaTC group was not statistically different from that for nanomicelles without NaTC. Therefore, overall results suggest that thermosensitive nanomicelles could be a potential dosage form for improvement of the bioavailability and chemotherapeutic profile of DCT. PMID- 25143731 TI - EGFR-targeted plasmonic magnetic nanoparticles suppress lung tumor growth by abrogating G2/M cell-cycle arrest and inducing DNA damage. AB - BACKGROUND: We have previously demonstrated the epidermal growth factor receptor (EGFR)-targeted hybrid plasmonic magnetic nanoparticles (225-NP) produce a therapeutic effect in human lung cancer cell lines in vitro. In the present study, we investigated the molecular mechanism of 225-NP-mediated antitumor activity both in vitro and in vivo using the EGFR-mutant HCC827 cell line. METHODS: The growth inhibitory effect of 225-NP on lung tumor cells was determined by cell viability and cell-cycle analysis. Protein expression related to autophagy, apoptosis, and DNA-damage were determined by Western blotting and immunofluorescence. An in vivo efficacy study was conducted using a human lung tumor xenograft mouse model. RESULTS: The 225-NP treatment markedly reduced tumor cell viability at 72 hours compared with the cell viability in control treatment groups. Cell-cycle analysis showed the percentage of cells in the G2/M phase was reduced when treated with 225-NP, with a concomitant increase in the number of cells in Sub-G1 phase, indicative of cell death. Western blotting showed LC3B and PARP cleavage, indicating 225-NP-treatment activated both autophagy- and apoptosis-mediated cell death. The 225-NP strongly induced gammaH2AX and phosphorylated histone H3, markers indicative of DNA damage and mitosis, respectively. Additionally, significant gammaH2AX foci formation was observed in 225-NP-treated cells compared with control treatment groups, suggesting 225-NP induced cell death by triggering DNA damage. The 225-NP-mediated DNA damage involved abrogation of the G2/M checkpoint by inhibiting BRCA1, Chk1, and phospho Cdc2/CDK1 protein expression. In vivo therapy studies showed 225-NP treatment reduced EGFR phosphorylation, increased gammaH2AX foci, and induced tumor cell apoptosis, resulting in suppression of tumor growth. CONCLUSION: The 225-NP treatment induces DNA damage and abrogates G2/M phase of the cell cycle, leading to cellular apoptosis and suppression of lung tumor growth both in vitro and in vivo. Our findings provide a rationale for combining 225-NP with other DNA damaging agents for achieving enhanced anticancer activity. PMID- 25143732 TI - The therapeutic effects of MSc1 nanocomplex, synthesized by nanochelating technology, on experimental autoimmune encephalomyelitic C57/BL6 mice. AB - PURPOSE: Currently approved therapies for multiple sclerosis (MS) at best only slow down its progression. Therefore, it is necessary to utilize novel technologies in order to synthesize smart multifunctional structures. In the present study, for the first time we evaluated the therapeutic potential of MSc1 nanocomplex, which was designed based on novel nanochelating technology. MATERIALS AND METHODS: MSc1 cell-protection capacity, with and without iron bond, was evaluated against hydrogen peroxide (H2O2)-induced oxidative stress in cultured rat pheochromocytoma-12 cells. The ability of MSc1 to maintain iron bond at pH ranges of 1-7 was evaluated. Nanocomplex toxicity was examined by estimating the intraperitoneal median lethal dose (LD50). Experimental autoimmune encephalomyelitic mice were injected with MSc1 14 days after disease induction, when the clinical symptoms appeared. The clinical score, body weight, and disease induced mortality were monitored until day 54. In the end, after collecting blood samples for assessing hemoglobin and red blood cell count, the brains and livers of the mice were isolated for hematoxylin and eosin staining and analysis of iron content, respectively. RESULTS: The results showed that MSc1 prevented H2O2 induced cell death even after binding with iron, and it preserved its bond with iron constant at pH ranges 1-7. The nanocomplex intraperitoneal LD50 was 1,776.59 mg/kg. MSc1 prompted therapeutic behavior and improved the disabling features of experimental autoimmune encephalomyelitis, which was confirmed by decreased clinical scores versus increased body mass and 100% survival probability. It did not cause any adverse effects on hemoglobin or red blood cell count. Histopathological studies showed no neural loss or lymphocyte infiltration in MSc1-treated mice, while the hepatic iron content was also normal. CONCLUSION: These results demonstrate that MSc1 could be a promising beneficial novel agent and has the capacity to be evaluated in further studies. PMID- 25143733 TI - Design, characterization, and clinical evaluation of argan oil nanostructured lipid carriers to improve skin hydration. AB - Given its advantages in skin application (eg, hydration, antiaging, and protection), argan oil could be used in both dermatological and cosmetic formulations. Therefore, the preparation of nanostructured lipid carriers (NLCs) using argan oil as a liquid lipid is a promising technique, since the former constitute well-established systems for dermal delivery. The aim of this work was to develop a topical formulation of argan oil NLCs to improve skin hydration. Firstly an NLC dispersion was developed and characterized, and afterward an NLC based hydrogel was prepared. The in vivo evaluation of the suitability of the prepared formulation for the proposed application was assessed in volunteers, by measuring different skin-surface parameters for 1 month. An argan oil NLC-based hydrogel formulation was successfully prepared and characterized. Moreover, the entrapment of the NLCs in the hydrogel net did not affect their colloidal sizes. Additionally, it was observed that this formulation precipitated an increase in skin hydration of healthy volunteers. Therefore, we concluded that the preparation of NLC systems using argan oil as the liquid lipid is a promising strategy, since a synergistic effect on the skin hydration was obtained (ie, NLC occlusion plus argan oil hydration). PMID- 25143734 TI - Preparation, characterization, and optimization of primaquine-loaded solid lipid nanoparticles. AB - Primaquine (PQ) is one of the most widely used antimalarial drugs and is the only available drug that combats the relapsing form of malaria. PQ use in higher doses is limited by severe tissue toxicity including hematological- and gastrointestinal-related side effects. Nanoformulation of drugs in an appropriate drug carrier system has been extensively studied and shown to have the potential to improve bioavailability, thereby enhancing activity, reducing dose frequency, and subsequently reducing toxicity. The aim of this work was to design, synthesize, and characterize PQ-loaded solid lipid nanoparticles (SLNs) (PQ-SLNs) as a potential drug-delivery system. SLNs were prepared by a modified solvent emulsification evaporation method based on a water-in-oil-in-water (w/o/w) double emulsion. The mean particle size, zeta potential, drug loading, and encapsulation efficiency of the PQ-SLNs were 236 nm, +23 mV, 14%, and 75%, respectively. The zeta potential of the SLNs changed dramatically, from -6.54 mV to +23.0 mV, by binding positively charged chitosan as surface modifier. A spherical morphology of PQ-SLNs was seen by scanning electron microscope. In vitro, release profile depicted a steady drug release over 72 hours. Differential scanning calorimeter thermograms demonstrated presence of drug in drug-loaded nanoparticles along with disappearance of decomposition exotherms, suggesting increased physical stability of drug in prepared formulations. Negligible changes in characteristic peaks of drug in Fourier transform infrared spectra indicated absence of any interaction among the various components entrapped in the nanoparticle formulation. The nanoformulated PQ was 20% more effective as compared with conventional oral dose when tested in Plasmodium berghei-infected Swiss albino mice. This study demonstrated an efficient method of forming a nanomedicine delivery system for antimalarial drugs. PMID- 25143735 TI - Development of nanofluorapatite polymer-based composite for bioactive orthopedic implants and prostheses. AB - Fluorapatite with low solubility is a promising biomaterial due to its structure, which is similar to hydroxyapatite. In this study a bioactive composite of nanofluorapatite (n-FA) and polyamide 12 (PA12) was fabricated. The results revealed that the mechanical properties (such as compressive strength and elastic modulus), hydrophilicity, and antibacterial properties of n-FA/PA12 composite were obviously improved by adding n-FA into PA12 as compared with PA12. In addition, cell proliferation of MC3T3-E1 cells cultured on n-FA/PA12 composite was significantly higher than with PA12, and alkaline phosphatase activity of MC3T3-E1 cells on the n-FA/PA12 composite was expressed at obviously higher levels as compared with PA12. The results suggest that n-FA/PA12 composite could support cell proliferation and differentiation, showing good cytocompatibility. Histological evaluation indicates that n-FA/PA12 composite enhances the efficiency of new bone formation with the introduction of n-FA into PA12, and the quantity of the newly formed bone for n-FA/PA12 composite is significantly higher than with PA12. In conclusion, n-FA/PA12 composite exhibits good biocompatibility and osteogenesis, which might be used for various orthopedic prostheses and dental implants. PMID- 25143736 TI - Probing smoking craving with a multidimensional approach: validation of the 12 item French-language version of the Questionnaire on Smoking Urges. AB - BACKGROUND: The current study examined the psychometric properties of the 12-item French-language version of the Questionnaire on Smoking Urges (QSU-12), a widely used multidimensional measure of cigarette craving. METHODS: Daily smokers (n=230) completed the QSU-12, the Fagerstrom Test for Nicotine Dependence, and items about addiction-related symptoms. Additional participants (n=40) completed the QSU-12 and the Fagerstrom Test for Nicotine Dependence and were assessed for expired carbon monoxide. RESULTS: Consistent with studies validating the English version of the scale, confirmatory factor analyses supported a two-factor solution in the French version of the scale. Good scale and subscales reliabilities were observed, and convergent validity was evidenced through relationships with dependence and addiction-related symptoms. CONCLUSION: The French-language version of the QSU-12 is an adequate instrument to assess the multidimensional construct of craving in both research and clinical practice. PMID- 25143738 TI - A retrospective analysis focusing on a group of patients with dual diagnosis treated by both mental health and substance use services. AB - OBJECTIVE: To highlight which demographic, familial, premorbid, clinical, therapeutic, rehabilitative, and assistance factors were related to dual diagnosis, which, in psychiatry, means the co-occurrence of both mental disorder and substance use in the same patient. METHODS: Our sample (N=145) was chosen from all outpatients with a dual diagnosis treated from January 1, 2012 to July 31, 2012 by both the Mental Health Service and the Substance Use Service of Modena and Castelfranco Emilia, Italy. Patients who dropped out during the study period were excluded. Demographic data and variables related to familial and premorbid history, clinical course, rehabilitative programs, social support and nursing care, and outcome complications were collected. The patients' clinical and functioning conditions during the study period were evaluated. RESULTS: Our patients were mostly men suffering from a cluster B personality disorder. Substance use was significantly more likely to precede psychiatric disease (P<0.001), and 60% of the sample presented a positive familial history for psychiatric or addiction disease or premorbid traumatic factors. The onset age of substance use was related to the period of psychiatric treatment follow-up (P<0.001) and the time spent in rehabilitative facilities (P<0.05), which, in turn, was correlated with personality disorder diagnosis (P<0.05). Complications, which presented in 67% of patients, were related to the high number of psychiatric hospitalizations (P<0.05) and professionals involved in each patient's treatment (P<0.05). Males more frequently presented familial, health, and social complications, whereas females more frequently presented self threatening behavior (P<0.005). CONCLUSION: It was concluded that the course of dual diagnosis may be chronic, severe, and disabling, requiring many long-term therapeutic and rehabilitative programs to manage various disabilities. PMID- 25143737 TI - Post-traumatic epilepsy: current and emerging treatment options. AB - Traumatic brain injury (TBI) leads to many undesired problems and complications, including immediate and long-term seizures/epilepsy, changes in mood, behavioral, and personality problems, cognitive and motor deficits, movement disorders, and sleep problems. Clinicians involved in the treatment of patients with acute TBI need to be aware of a number of issues, including the incidence and prevalence of early seizures and post-traumatic epilepsy (PTE), comorbidities associated with seizures and anticonvulsant therapies, and factors that can contribute to their emergence. While strong scientific evidence for early seizure prevention in TBI is available for phenytoin (PHT), other antiepileptic medications, eg, levetiracetam (LEV), are also being utilized in clinical settings. The use of PHT has its drawbacks, including cognitive side effects and effects on function recovery. Rates of recovery after TBI are expected to plateau after a certain period of time. Nevertheless, some patients continue to improve while others deteriorate without any clear contributing factors. Thus, one must ask, 'Are there any actions that can be taken to decrease the chance of post-traumatic seizures and epilepsy while minimizing potential short- and long-term effects of anticonvulsants?' While the answer is 'probably,' more evidence is needed to replace PHT with LEV on a permanent basis. Some have proposed studies to address this issue, while others look toward different options, including other anticonvulsants (eg, perampanel or other AMPA antagonists), or less established treatments (eg, ketamine). In this review, we focus on a comparison of the use of PHT versus LEV in the acute TBI setting and summarize the clinical aspects of seizure prevention in humans with appropriate, but general, references to the animal literature. PMID- 25143739 TI - The role of erythropoietin stimulating agents in anemic patients with heart failure: solved and unresolved questions. AB - Anemia is a common finding in congestive heart failure (CHF) and is associated with an increased mortality and morbidity. Several conditions can cause depression of erythroid progenitor cells: reduction of iron absorption and reuptake, decreased bone marrow activity, reduced endogenous erythropoietin production, and chronic inflammatory state. Anemia's etiology in CHF is complex and partially understood; it involves several systems including impaired hemodynamic condition, reduced kidney and bone perfusion, increased inflammatory activity, and neurohormonal overdrive. The use of erythropoiesis stimulating agents (ESAs) such as erythropoietin and its derivatives is recently debated; the last interventional trial seems to demonstrate a neutral or negative effect in the active arm with darbepoetin treatment. The current data is opposite to many single blind studies and previous meta-analysis showing an improvement in quality of life, New York Heart Association class, and exercise tolerance using ESA therapy. These contrasting data raise several concerns regarding the target of hemoglobin levels needing intervention, the exact anemia classification and categorization, and the standardization of hematocrit cutoffs. Some cardiac and systemic conditions (ie, hypertension, atrial fibrillation, prothrombotic status) may predispose to adverse events, and ESA administration should be avoided. To prevent the negative effects, high-dosage and chronic administration should be avoided. Clarification of these items could probably identify patients that may benefit from additional iron or ESA treatment. In this review, we discuss the interventional trials made in anemic heart failure patients, the underlying mechanism of anemia in CHF, and the potential role of ESA in this setting. PMID- 25143740 TI - Heart rate variability measured early in patients with evolving acute coronary syndrome and 1-year outcomes of rehospitalization and mortality. AB - OBJECTIVE: This study sought to examine the prognostic value of heart rate variability (HRV) measurement initiated immediately after emergency department presentation for patients with acute coronary syndrome (ACS). BACKGROUND: Altered HRV has been associated with adverse outcomes in heart disease, but the value of HRV measured during the earliest phases of ACS related to risk of 1-year rehospitalization and death has not been established. METHODS: Twenty-four-hour Holter recordings of 279 patients with ACS were initiated within 45 minutes of emergency department arrival; recordings with >=18 hours of sinus rhythm were selected for HRV analysis (number [N] =193). Time domain, frequency domain, and nonlinear HRV were examined. Survival analysis was performed. RESULTS: During the 1-year follow-up, 94 patients were event-free, 82 were readmitted, and 17 died. HRV was altered in relation to outcomes. Predictors of rehospitalization included increased normalized high frequency power, decreased normalized low frequency power, and decreased low/high frequency ratio. Normalized high frequency >42 ms(2) predicted rehospitalization while controlling for clinical variables (hazard ratio [HR] =2.3; 95% confidence interval [CI] =1.4-3.8, P=0.001). Variables significantly associated with death included natural logs of total power and ultra low frequency power. A model with ultra low frequency power <8 ms(2) (HR =3.8; 95% CI =1.5-10.1; P=0.007) and troponin >0.3 ng/mL (HR =4.0; 95% CI =1.3-12.1; P=0.016) revealed that each contributed independently in predicting mortality. Nonlinear HRV variables were significant predictors of both outcomes. CONCLUSION: HRV measured close to the ACS onset may assist in risk stratification. HRV cut-points may provide additional, incremental prognostic information to established assessment guidelines, and may be worthy of additional study. PMID- 25143741 TI - Insulin degludec/insulin aspart combination for the treatment of type 1 and type 2 diabetes. AB - Glycemic control remains the major therapeutic objective to prevent or delay the onset and progression of complications related to diabetes mellitus. Insulin therapy represents a cornerstone in the treatment of diabetes and has been used widely for achieving glycemic goals. Nevertheless, a large portion of the population with diabetes does not meet the internationally agreed glycemic targets. Moreover, insulin treatment, especially if intensive, may be associated with emergency room visits and hospitalization due to hypoglycemic events. Therefore, fear of hypoglycemia or hypoglycemic events represents the main barriers to the attainment of glycemic targets. The burden associated with multiple daily injections also remains a significant obstacle to initiating and maintaining insulin therapy. The most attractive insulin treatment approach should meet the patients' preference, rather than demanding patients to change or adapt their lifestyle. Insulin degludec/insulin aspart (IDegAsp) is a new combination, formulated with ultra-long-acting insulin degludec and rapid-acting insulin aspart, with peculiar pharmacological features, clinical efficacy, safety, and tolerability. IDegAsp provides similar, noninferior glycemic control to a standard basal-bolus regimen in patients with type 1 diabetes mellitus, with additional benefits of significantly lower episodes of hypoglycemia (particularly nocturnal) and fewer daily insulin injections. Moreover, although treatment strategy and patients' viewpoint are different in type 1 and type 2 diabetes, trial results suggest that IDegAsp may be an appropriate and reasonable option for initiating insulin therapy in patients with type 2 diabetes inadequately controlled on maximal doses of conventional oral agents. This paper will discuss the role of IDegAsp combination as a novel treatment option in diabetic patients. PMID- 25143743 TI - Using peer observers to assess the quality of cancer multidisciplinary team meetings: a qualitative proof of concept study. AB - BACKGROUND: Multidisciplinary team (MDT) working is well established as the foundation for providing cancer services in the UK and elsewhere. A core activity is the weekly meeting (or case conference/tumor boards) where the treatment recommendations for individual patients are agreed. Evidence suggests that the quality of team working varies across cancer teams, and this may impact negatively on the decision-making process, and ultimately patient care. Feedback on performance by expert observers may improve performance, but can be resource intensive to implement. This proof of concept study sought to: develop a structured observational assessment tool for use by peers (managers or clinicians from the local workforce) and explore its usability; assess the feasibility of the principle of observational assessment by peers; and explore the views of MDT members and observers about the utility of feedback from observational assessment. METHODS: For tool development, the content was informed by national clinical consensus recommendations for best practice in cancer MDTs and developed in collaboration with an expert steering group. It consisted of ten subdomains of team working observable in MDT meetings that were rated on a 10-point scale (very poor to very good). For observational assessment, a total of 19 peer observers used the tool (assessing performance in 20 cancer teams from four hospitals). For evaluation, telephone interviews with 64 team members and all peer observers were analyzed thematically. RESULTS: The tool was easy to use and areas for refinement were identified. Peer observers were identified and most indicated that undertaking observation was feasible. MDT members generally reported that observational assessment and feedback was useful, with the potential to facilitate improvements in team working. CONCLUSION: This study suggests that observation and feedback by peers may provide a feasible and acceptable approach to enhance MDT performance. Further tool refinement and validation is required. PMID- 25143742 TI - Postconditioning in ST-elevation myocardial infarction: a systematic review, critical appraisal, and meta-analysis of randomized clinical trials. AB - OBJECTIVE: We aimed to summarize the evidence from randomized clinical trials studies examining the efficacy of ischemic postconditioning (IPost) in ST elevation myocardial infarction. DESIGN: The study was a systematic review and critical appraisal, with meta-analysis of randomized clinical trials. MATERIALS AND METHODS: We searched the literature. A total of 21 randomized clinical trials were identified. Both fixed effect and random effects models were used to synthesize the results of individual studies. Heterogeneity between studies was examined by subgroup and random effects meta-regression analyses, considering ptient-related and study-level variables. Publication bias, or "small-study effect", was evaluated. RESULTS: Substantial heterogeneity was present. The random effects model pooled estimate for the outcome infarct size assessed by cardiac magnetic resonance was estimated by the standardized mean difference (SMD) =-0.06, 95% confidence interval (CI): -0.34 to 0.21, ie, no effect of IPost. For the end point infarct size, estimated by biomarkers of myocardial necrosis, an overall pooled effect was SMD =-0.58, 95% CI: -0.96 to -0.19. This effect disappeared in powered and nonbiased studies (SMD =0.03, 95% CI: -0.48 to 0.55). Finally, for the outcome left ventricular ejection fraction, SMD =0.47 95% CI: 0.20 to 0.74. Unfortunately, selection bias (small-study effect) was present. For this outcome, the meta-regression showed that both presence of hypertension and the inclusion of nonbiased studies explained 28.3% of the heterogeneity among the studies. Simulation by the "trim and fill" method, which controlled for selection bias using random effects model, diluted the effect (SMD =0.17 95% CI: 0.13 to 0.48). No effects by IPost on ST-segment resolution or on the majority of adverse clinical events were observed during follow up, except the incidence of congestive heart failure was found. CONCLUSION: Evidence from this study suggests no cardioprotection from IPost, on surrogate and the majority of clinical end points. A possible beneficial effect on the incidence of congestive heart failure needs to be replicated by a large clinical trial. PMID- 25143744 TI - Potential implications of GRP58 expression and susceptibility of cervical cancer to cisplatin and thymoquinone-based therapy. AB - A new therapeutic approach of looking at the expression of glucose-regulated protein (GRP) 58 as an indication of cisplatin sensitivity may eradicate fruitless treatment and side effects in patients with cervical cancer. Thymoquinone, the bioactive compound in Nigella sativa, has been reported to have an antiproliferative effect on cervical cancer cells. This study compared the cytotoxic effects of cisplatin, a drug commonly used in the treatment of cervical cancer, and thymoquinone in cervical cancer (HeLa and SiHa) cell lines by 3-(4,5 Dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and measured GRP58 expression in the cells by quantitative real-time polymerase chain reaction and Western blotting. Cisplatin had higher antiproliferative activity towards the cervical cancer cell lines than thymoquinone in a dose-dependent and time dependent manner. However, cisplatin was more toxic to normal 3T3 and Vero cell lines than thymoquinone. The half maximal inhibitory concentration (IC50) of cisplatin in HeLa and SiHa cells at 72 hours was 13.3+/-2.52 MUM and 19.5+/-2.12 MUM, respectively. Meanwhile, the IC50 of thymoquinone in HeLa and SiHa cells was 29.57+/-5.81 MUM and 23.41+/-1.51 MUM, respectively (P<0.05). A significant correlation was found between the cytotoxicity of cisplatin and expression of GRP58, but this relationship was not significant for thymoquinone. Therefore, the response of cervical cancer cells to cisplatin can be predicted on the basis of GRP58 expression. PMID- 25143745 TI - Outcomes analysis of an alternative formulation of PEGylated liposomal doxorubicin in recurrent epithelial ovarian carcinoma during the drug shortage era. AB - BACKGROUND: In response to the critical shortage of Doxil((r)), the US Food and Drug Administration (FDA) allowed temporary importation of non-FDA-approved second-generation liposomal doxorubicin, Lipo-Dox((r)). Lipo-Dox utilizes a different liposomal particle than Doxil and demonstrates different pharmacokinetic properties. Its use has never been evaluated in a North American population. The objective of this study was to evaluate the efficacy and tolerability of Lipo-Dox at Magee-Womens Hospital, University of Pittsburgh Medical Center, for patients with recurrent epithelial ovarian cancer who were treated during the Doxil shortage. METHODS: Patients treated with Lipo-Dox from January 2012 to December 2012 were identified retrospectively. Disease response was defined radiographically by RECIST (Response Evaluation Criteria in Solid Tumors) or biochemically by CA-125 level if measurable disease was not present. Survival was defined from the start date of Lipo-Dox until the date of progression or death. Toxicity was assessed by the Gynecologic Oncology Group common toxicity criteria. RESULTS: Eighteen patients with recurrent epithelial ovarian cancer who received Lipo-Dox were identified. These patients had a median of three prior treatment regimens. The median number of Lipo-Dox cycles given was 3.5 (range 1-8). No patients had a complete or partial response. Two patients had stable disease over a mean follow-up of 144.5 days. Fourteen patients had progressive disease, with a median time to progression of 82 days. Progression was based on CA-125 in four patients and RECIST in the remainder. Nine patients died from the disease. CONCLUSION: Although this represents a small, pretreated population, there were no clinical responses to Lipo-Dox, raising the question as to whether it is an equivalent substitute for Doxil. Further evaluation is needed, but if confirmed, these findings raise concerns regarding the use of current stocks of Lipo-Dox, as well as the prudence of managing future drug shortages with pharmacologically similar, but clinically untested drugs. PMID- 25143746 TI - Initial LDH level can predict the survival benefit from bevacizumab in the first line setting in Chinese patients with metastatic colorectal cancer. AB - BACKGROUND: Markers to predict the efficacy of bevacizumab treatment have been not fully validated in most cancers, including metastatic colorectal cancer (mCRC). The aim of this study was to investigate the potential role of lactate dehydrogenase (LDH) in predicting the survival benefit from first-line bevacizumab treatment, in Chinese patients with mCRC. METHODS: All the patients were diagnosed with mCRC at the Sun Yat-sen University Cancer Center from 2003 to 2013. The study group and the control group were classified by receiving bevacizumab or not. The serum LDH value of all the patients had been detected before the first-line treatment. The primary end point was progression-free survival (PFS). RESULTS: The median PFS of the study and the control group (patients who received bevacizumab or not) was 11.3 and 9.1 months, respectively (P=0.004). In the control group, the median PFS of the high LDH level and the low LDH level groups was 6.9 and 10.2 months, respectively (P<0.001). However, in the study group, the corresponding median PFS was 9.9 and 11.9 months, respectively (P=0.145). In addition, for the low LDH level group, the median PFS was 11.9 and 10.2 months for patients who received bevacizumab or not, respectively (P=0.066); however, the median PFS of patients receiving bevacizumab or not was significantly different in the high LDH level group (9.9 and 6.9 months, respectively) (P=0.012). CONCLUSION: The addition of bevacizumab in the first line treatment setting could improve the PFS of mCRC patients notably. However, the benefit could only be potentially reflected on patients with high serum LDH level. PMID- 25143748 TI - Comparative analysis of the infectivity rate of both Borrelia burgdorferi and Anaplasma phagocytophilum in humans and dogs in a New Jersey community. AB - Ticks are important vectors of disease and transmit an extensive array of bacterial, viral and protozoan diseases to both humans and dogs within a community. Borrelia burgdorferi, the causative agent of Lyme disease, has been extensively studied within both the human and veterinary population. Anaplasma phagocytophilum, an intracellular rickettsial pathogen also transmitted by ixodid ticks, has emerged as an important zoonotic infection with significant veterinary and medical implications, and is responsible for both canine granulocytic anaplasmosis and human granulocytic anaplasmosis. Multiple surveys exist in the international literature referencing infectivity rates of both of these diseases separately in both the dog and human populations. This is the first study to simultaneously examine the infectivity rate of both anaplasmosis and Lyme disease in humans and dogs in a community endemic for tick-borne diseases. PMID- 25143747 TI - Dietary pattern and asthma: a systematic review and meta-analysis. AB - BACKGROUND: The literature on the relationship between diet and asthma has largely focused on individual nutrients, with conflicting results. People consume a combination of foods from various groups that form a dietary pattern. Studying the role of dietary patterns in asthma is an emerging area of research. The purpose of this study was to systematically review dietary patterns and asthma outcomes in adults and children, to review maternal diet and child asthma, and to conduct a meta-analysis on the association between asthma prevalence and dietary patterns in adults. METHODS: We searched Medline, Scopus, and ISI Web of Knowledge up to January 2014. Two researchers independently reviewed studies meeting the inclusion criteria using the American Dietetic Association quality criteria. A linear mixed model was used to derive the pooled effect size (95% confidence interval) for each of three dietary pattern categories (healthy, unhealthy, and neutral). RESULTS: Thirty-one studies were identified (16 cross sectional, one case-control, 13 cohort, and one randomized controlled trial), including 12 in adults, 13 in children, five in pregnant woman-child pairs, and one in both children and pregnant woman-child pairs. Six of the 12 adult studies reported significant associations between dietary patterns and asthma outcomes (eg, ever asthma and forced expiratory volume in one second). Seven of ten studies examining the Mediterranean diet showed protective effects on child asthma and/or wheeze. Four of the six studies in mother-child pairs showed that maternal dietary patterns during pregnancy were not associated with child asthma or wheeze. The meta-analysis including six adult studies, the primary outcome of which was the prevalence of current or ever asthma, showed no association with healthy, unhealthy, or neutral dietary patterns. CONCLUSION: The evidence suggests no association of dietary patterns with asthma prevalence in adults or of maternal diet with child asthma or wheeze. The Mediterranean diet in children may prevent asthma or wheeze, but randomized controlled trials are lacking. PMID- 25143749 TI - Economic burden associated with chronic constipation in Sweden: a retrospective cohort study. AB - BACKGROUND: Chronic constipation is a common condition, but few studies have assessed its cost and impact on resource use. The purpose of this cohort study was to assess the health care utilization and costs of chronic constipation in a Swedish population using health care claims data. METHODS: Data were compiled on health care costs, drug costs, and mortality for Vastra Gotaland, Sweden (2005 2009). These data were used to identify patients aged 18 years or older with chronic constipation, defined as: at least two health care contacts with a primary diagnosis of constipation within 12 months or at least one care contact with a primary diagnosis of constipation and two dispatches of laxatives 6 months before and 12 months after the index date. Patients with irritable bowel syndrome or taking opioids, both of which can cause constipation, were excluded. Costs, resource use, comorbidities, and laxative use were assessed during a 12-month follow-up period. RESULTS: In total, 4,043 patients with chronic constipation were identified. They had a mean (SD) age of 67+/-18 years. Mortality was 7% during the 12-month follow-up period and the most common comorbidity was hypertension (22%). In the 12-month follow-up period, patients with chronic constipation had a mean (SD) of 2.3+/-7.5 constipation-related health care contacts and a mean (SD) of 15.2+/-19.5 other health care contacts. Annual costs, adjusted for sex, age group, mortality, and comorbidities, were ?5,388, of which ?951 were for constipation-related care. CONCLUSION: Patients with chronic constipation constituted an elderly population with a high disease burden in Sweden between 2005 and 2009. Mean annual constipation-related health care costs, adjusted for potentially confounding factors, were ?951 per patient. PMID- 25143750 TI - A randomized, double-blind, placebo-controlled clinical trial evaluating Dermytol((r)) cream for the treatment of actinic keratoses. AB - PURPOSE: Actinic keratosis lesions (AKs) have the potential to develop into squamous cell carcinoma (SCC) and thus therapies to prevent SCC development from AKs are warranted. The aim of this study was to assess the effects of a 3 month application of a canola phenolic acid-based cream (CPA) on AK lesions. PATIENTS AND METHODS: This was a randomized, double-blind, placebo-controlled, 12 week clinical study conducted at a single-center in Santo Domingo, Dominican Republic. Forty-five subjects (30 CPA and 15 placebo), aged 45-85 years with 3-10 AKs within a 20 cm(2) treatment area (scalp, forehead, dorsal forearm, neck, or back of hand) were enrolled. The primary outcome was complete or partial lesion clearance and the secondary outcome was safety of CPA. RESULTS: Although complete AK lesion clearance was not seen in this study, a significant reduction in the mean change from baseline in the average lesion area was observed at weeks 3 (P=0.002), 6 (P<0.001), and 12 (P<0.001) in the CPA group, but only at weeks 6 and 12 in the placebo group (P=0.005 and P=0.002, respectively). Furthermore, the proportion of participants with a $10% decrease in average lesion area was significantly higher in the CPA group than the placebo group at weeks 3 (P=0.05) and 6 (P=0.02), and showed a trend at week 12 (P=0.06). A subset analysis of the change in average lesion area based upon the total lesion area at baseline revealed that CPA elicited a greater reduction than placebo (2*) in participants with a baseline total AK lesion area of 100-500 mm(2) than in participants with a total area <100 mm(2) (1.3*). CONCLUSION: The results of this study and previous in vitro studies suggest a potential role for CPA in the treatment of AK lesions and the prevention of SCC development. PMID- 25143752 TI - Population-based approaches to understanding disparities in cardiovascular disease risk in the United States. AB - This is a comprehensive narrative review of the literature on the current science and evidence of population-level differences in risk factors for heart disease among different racial and ethnic population in the US. It begins by discussing the importance of population-level risk assessment of heart disease in light of the growth rate of specific minority populations in the US. It describes the population-level dynamics for racial and ethnic minorities: a higher overall prevalence of risk factors for coronary artery disease that are unrecognized and therefore not treated, which increases their likelihood of experiencing adverse outcomes and, therefore, potentially higher morbidity and mortality. It discusses the rate of acute coronary syndrome (ACS) in minority communities. Minority patients with ACS are at greater risk of myocardial infarction, rehospitalization, and death from ACS. They also are less likely than nonminority patients to receive potentially beneficial treatments such as angiography or percutaneous coronary intervention. This paper looks at the data surrounding the increased rate of congestive heart failure in racial and ethnic minorities, where the risk is related to the prevalence of comorbidities with hypertension or diabetes mellitus, which, in combination with environmental factors, may largely explain congestive heart failure disparity. The conclusion is it is essential that health care providers understand these various communities, including nuances in disease presentation, risk factors, and treatment among different racial and ethnic groups. Awareness of these communities' attributes as well as differences in incidence, risk factor burdens, prognosis, and treatment are necessary to mitigate racial and ethnic disparities in heart disease. PMID- 25143753 TI - Spinal cord stimulation with implanted epidural paddle lead relieves chronic axial low back pain. AB - INTRODUCTION: Spinal cord stimulation (SCS) provides significant relief for lumbosacral radiculopathy refractory to both medical and surgical treatment, but historically only offers limited relief for axial low back pain (LBP). We aim to evaluate the response of chronic axial LBP treated with SCS using a surgically implanted epidural paddle lead. MATERIALS AND METHODS: This is a retrospective review of a consecutive series of patients with exclusive LBP or predominant LBP associated with lower extremity (LE) pain evaluated and treated with SCS using an implanted paddle lead within the dorsal thoracic epidural space. Baseline LBP, and if present LE pain, were recorded using the visual analogue scale (VAS) at an initial evaluation. At a follow-up visit (a minimum of 12 months later), LBP and LE pain after a spinal cord stimulator implantation were again recorded using the VAS. Patients were also asked to estimate total LBP pain relief achieved. RESULTS: Patients with either exclusive (n=7) or predominant (n=2) axial LBP were treated with SCS by implantation of a paddle lead at an average spine level of T9. The baseline VAS score for LBP was 7.2; after a follow-up of 20 months, the score decreased to 2.3 (P=0.003). The LE pain VAS score decreased from 7.5 to 0.0 (P=0.103). Patients also reported a subjective 66.4% decrease of their LBP at follow-up. There were no surgical complications. CONCLUSIONS: Axial LBP is refractory to many treatments, including SCS. SCS using a surgically implanted paddle electrode provides significant pain relief for chronic axial LPB, and is a safe treatment modality. PMID- 25143751 TI - A clinical perspective on the role of chronic inflammation in gastrointestinal cancer. AB - Chronic inflammation has been identified as an important risk factor for the development of malignancy, and knowledge about its molecular and cellular mechanisms is increasing. Several chronic inflammatory diseases of the gastrointestinal tract are important as risk factors for malignancy and have been studied in detail. In this review, we summarize important molecular mechanisms in chronic inflammation and highlight established and potential links between chronic inflammation and gastrointestinal cancer. In addition, we present the role of chronic inflammation in numerous tumors within the gastrointestinal tract as well as the relevant pathways or epidemiologic observations linking the pathogenesis of these tumors to inflammation. PMID- 25143754 TI - Chiang Mai University Health Worker Study aiming toward a better understanding of noncommunicable disease development in Thailand: methods and description of study population. AB - BACKGROUND: Urbanization is considered to be one of the key drivers of noncommunicable diseases (NCDs) in Thailand and other developing countries. These influences, in turn, may affect an individual's behavior and risk of developing NCDs. The Chiang Mai University (CMU) Health Worker Study aims to provide evidence for a better understanding of the development of NCDs and ultimately to apply the evidence toward better prevention, risk modification, and improvement of clinical care for patients with NCDs and NCD-related conditions. METHODS: A cross-sectional survey of health care workers from CMU Hospital was conducted between January 2013 and June 2013. Questionnaires, interviews, and physical and laboratory examinations were used to assess urban exposure, occupational shift work, risk factors for NCDs, self-reported NCDs, and other NCD-related health conditions. RESULTS: From 5,364 eligible workers, 3,204 participated (59.7%). About 11.1% of the participants had high blood pressure (systolic blood pressure >=140 mmHg or diastolic blood pressure >=90 mmHg) and almost 30% were considered to be obese (body mass index >=25 kg/m(2)). A total of 2.3% had a high fasting blood glucose level (>=126 mg/dL), and the most common abnormal lipid profile was high low-density lipoprotein (>=160 mg/dL), which was found in 19.2% of participants. DISCUSSION: The study of health workers offers three potential advantages. The first is that the study of migrants was possible. Socioenvironmental influence on NCD risk factors can be explored, as changes in environmental exposures can be documented. Second, it allows the investigators to control for access to care. Access to care is potentially a key confounder toward understanding the development of NCDs. Lastly, a study of health personnel allows easy access to laboratory investigations and potential for long-term follow-up. This enables ascertainment of a number of clinical outcomes and provides potential for future studies focusing on therapeutic and prognostic issues related to NCDs. PMID- 25143755 TI - Validating administrative data for the detection of adverse events in older hospitalized patients. AB - Older hospitalized patients are at risk of experiencing adverse events including, but not limited to, hospital-acquired pressure ulcers, fall-related injuries, and adverse drug events. A significant challenge in monitoring and managing adverse events is lack of readily accessible information on their occurrence. PURPOSE: The objective of this retrospective cross-sectional study was to validate diagnostic codes for pressure ulcers, fall-related injuries, and adverse drug events found in routinely collected administrative hospitalization data. METHODS: All patients 65 years of age or older discharged between April 1, 2009 and March 31, 2011 from a provincial academic health sciences center in Canada were eligible for inclusion in the validation study. For each of the three types of adverse events, a random sample of 50 patients whose records were positive and 50 patients whose records were not positive for an adverse event was sought for review in the validation study (n=300 records in total). A structured health record review was performed independently by two health care providers with experience in geriatrics, both of whom were unaware of the patient's status with respect to adverse event coding. A physician reviewed 40 records (20 reviewed by each health care provider) to establish interrater agreement. RESULTS: A total of 39 pressure ulcers, 56 fall-related injuries, and 69 adverse drug events were identified through health record review. Of these, 34 pressure ulcers, 54 fall related injuries, and 47 adverse drug events were also identified in administrative data. Overall, the diagnostic codes for adverse events had a sensitivity and specificity exceeding 0.67 (95% confidence interval [CI]: 0.56 0.99) and 0.89 (95% CI: 0.72-0.99), respectively. CONCLUSION: It is feasible and valid to identify pressure ulcers, fall-related injuries, and adverse drug events in older hospitalized patients using routinely collected administrative hospitalization data. The information is relatively inexpensive and easy to access with no impact on clinical staff. PMID- 25143756 TI - Role of uterine forces in intrauterine device embedment, perforation, and expulsion. AB - BACKGROUND: The purpose of this study was to examine factors that could help reduce primary perforation during insertion of a framed intrauterine device (IUD) and to determine factors that contribute in generating enough uterine muscle force to cause embedment and secondary perforation of an IUD. The objective was also to evaluate the main underlying mechanism of IUD expulsion. METHODS: We compared known IUD insertion forces for "framed" devices with known perforation forces in vitro (hysterectomy specimens) and known IUD removal forces and calculated a range of possible intrauterine forces using pressure and surface area. These were compared with known perforation forces. RESULTS: IUD insertion forces range from 1.5 N to 6.5 N. Removal forces range from 1 N to 5.8 N and fracture forces from 8.7 N to 30 N depending upon device. Measured perforation forces are from 20 N to 54 N, and calculations show the uterus is capable of generating up to 50 N of myometrial force depending on internal pressure and surface area. CONCLUSION: Primary perforation with conventional framed IUDs may occur if the insertion pressure exceeds the perforation resistance of the uterine fundus. This is more likely to occur if the front end of the inserter/IUD is narrow, the passage through the cervix is difficult, and the procedure is complex. IUD embedment and secondary perforation and IUD expulsion may be due to imbalance between the size of the IUD and that of the uterine cavity, causing production of asymmetrical uterine forces. The uterine muscle seems capable of generating enough force to cause an IUD to perforate the myometrium provided it is applied asymmetrically. A physical theory for IUD expulsion and secondary IUD perforation is given. PMID- 25143758 TI - A mixed methods study of student perceptions of using standardized patients for learning and evaluation. AB - BACKGROUND: Educators recognize the value of using standardized patients (SPs) when teaching and evaluating clinical skills in rehabilitation entry-to-practice education programs but have published little supporting evidence and have yet to evaluate programmatic SP use from a student perspective. This study explored occupational and physical therapy students' perceptions of SP use in their professional education. METHODS: Recruiting current and graduated students, we conducted a two-phase mixed-methods sequential-explanatory study integrating data from a quantitative survey (phase 1) and qualitative focus groups with representative students (phase 2). Quantitative data were used to direct the second phase and informed selection of a purposive sample to participate in four focus groups (N=12). RESULTS: The 24-item online survey obtained a 32% response rate (N=167). Mean ratings were high, but significant differences were found between the four subsections of Teaching, SP Experience, Feedback, and Evaluation (P=0.000). Secondary analyses revealed significant differences based on sex, program, and age. Qualitative analysis revealed that students found SP use especially helpful earlier in their program to bridge classroom teaching and clinical practice. Students in the occupational and physical therapy programs approached SP interactions differently in terms of the authenticity, personal investment, and value of SP feedback. Educator feedback was perceived as reflective of technical skill, and SP feedback reflective of therapeutic value, which students prioritized differently. Students identified a preferential continuum of options for learning and practicing skills, ranging from peers and instructors through SPs to actual patients. CONCLUSION: SPs were perceived as most useful early on in the professional education program, serving to bolster self-confidence and prepare students for clinical fieldwork. Discipline-specific differences impact the perception of SP use and value. Educators need to be aware of pragmatic and contextual issues when using SPs for examination purposes, including repeated exposure to the same actor. PMID- 25143757 TI - Modification of blood pressure in postmenopausal women: role of hormone replacement therapy. AB - The rate of hypertension increases after menopause. Whether estrogen and progesterone deficiency associated with menopause play a role in determining a worst blood pressure (BP) control is still controversial. Also, studies dealing with the administration of estrogens or hormone therapy (HT) have reported conflicting evidence. In general it seems that, despite some negative data on subgroups of later postmenopausal women obtained with oral estrogens, in particular conjugated equine estrogens (CEE), most of the data indicate neutral or beneficial effects of estrogen or HT administration on BP control of both normotensive and hypertensive women. Data obtained with ambulatory BP monitoring and with transdermal estrogens are more convincing and concordant in defining positive effect on BP control of both normotensive and hypertensive postmenopausal women. Overall progestin adjunct does not hamper the effect of estrogens. Among progestins, drospirenone, a spironolactone-derived molecule, appears to be the molecule with the best antihypertensive properties. PMID- 25143760 TI - Trends in Physical Dating Violence Victimization Among U.S. High School Students, 1999-2011. AB - Dating violence is a serious form of violence that places students at risk for injury, death, and negative mental health sequelae. The current analysis presents data on the prevalence of dating violence over a 12-year period among a nationally representative sample of high school-attending youth in the United States, stratified by race and gender. Data from the national Youth Risk Behavior Surveillance System (YRBSS) 1999-2011 revealed that physical dating violence victimization rates are similar for males and females; the 12-year prevalence rate of physical dating violence victimization was 9.4% for males and 9.2% for females. Black and Multiracial students were at increased risk for dating violence victimization in comparison to their White, Asian, and Hispanic counterparts. There were no changes in the reported rate of dating violence victimization over the 12-year period. PMID- 25143759 TI - Lung volume assessments in normal and surfactant depleted lungs: agreement between bedside techniques and CT imaging. AB - BACKGROUND: Bedside assessment of lung volume in clinical practice is crucial to adapt ventilation strategy. We compared bedside measures of lung volume by helium multiple-breath washout technique (EELVMBW,He) and effective lung volume based on capnodynamics (ELV) to those assessed from spiral chest CT scans (EELVCT) under different PEEP levels in control and surfactant-depleted lungs. METHODS: Lung volume was assessed in anaesthetized mechanically ventilated rabbits successively by measuring i) ELV by analyzing CO2 elimination traces during the application of periods of 5 consecutive alterations in inspiratory/expiratory ratio (1:2 to 1.5:1), ii) measuring EELVMBW,He by using helium as a tracer gas, and iii) EELVCT from CT scan images by computing the normalized lung density. All measurements were performed at PEEP of 0, 3 and 9 cmH2O in random order under control condition and following surfactant depletion by whole lung lavage. RESULTS: Variables obtained with all techniques followed sensitively the lung volume changes with PEEP. Excellent correlation and close agreement was observed between EELVMBW,He and EELVCT (r = 0.93, p < 0.0001). ELV overestimated EELVMBW,He and EELVCT in normal lungs, whereas this difference was not evidenced following surfactant depletion. These findings resulted in somewhat diminished but still significant correlations between ELV and EELVCT (r = 0.58, p < 0.001) or EELVMBW,He (0.76, p < 0.001) and moderate agreements. CONCLUSIONS: Lung volume assessed with bedside techniques allow the monitoring of the changes in the lung aeration with PEEP both in normal lungs and in a model of acute lung injury. Under stable pulmonary haemodynamic condition, ELV allows continuous lung volume monitoring, whereas EELVMBW,He offers a more accurate estimation, but intermittently. PMID- 25143762 TI - Slowly but Surely: Adverbs Support Verb Learning in 2-Year-Olds. AB - To acquire the meanings of verbs, toddlers make use of the surrounding linguistic information. For example, two-year-olds successfully acquire novel transitive verbs that appear in semantically rich frames containing content nouns ("The boy is gonna pilk a balloon"). But, they have difficulty with pronominal frames ("He is gonna pilk it") (Arunachalam & Waxman, 2010). We hypothesized that adverbs might facilitate toddlers' verb learning in these sparse pronominal frames, if their semantic content directed toddlers' attention to aspects of the event that are relevant to the verb's meaning (e.g., the manner of motion). As predicted, the semantic information from a specific manner-of-motion adverb (slowly) supported verb learning, but other adverbs lacking this semantic content (nicely, right now) did not. These results provide the first evidence that adverbs can facilitate verb learning in toddlers, and highlight the interaction of syntactic and semantic information in word learning. PMID- 25143761 TI - Predictors of response to methotrexate in juvenile idiopathic arthritis. AB - BACKGROUND: The response to methotrexate so far is unpredictable in patients with juvenile idiopathic arthritis. Thus such predictors have to be determined in a large patient cohort. METHODS: Demographic, clinical, articular and laboratory variables of patients newly treated with methotrexate were analysed by bivariate and logistic regression analysis to identify predictors of response to methotrexate. Minimal response was defined by the American College of Rheumatology pediatric (PedACR) 30 and strong response by the PedACR 70 criteria. RESULTS: The patient population consisted of 731 patients. At month 3, 77.4% and at month 12 83.1% of patients were responders according to the PedACR 30 criteria, while 43.1% and 65.9% of patients had a PedACR 70 response at month 3 and at month 12. Thus minimal response was frequently already reached at month 3 while strong response to MTX treatment took usually longer to achieve. In multivariate analysis the number of tender joints (p = 0.002), active joints (p < 0.001), concomitant use of NSAID (p = 0.027) and the parents evaluation of overall well-being (p < 0.001) were significant baseline parameters for minimal response at month 3, while at month 12 the determinants for reaching PedACR 70 were a disease duration < 1 year (p =0.001), a lower number of tender (p <0.001) but a higher number of active joints (p <0.001), a higher score of the parent's evaluation of child's pain (p =0.029), and the presence of morning stiffness (p =0.014). CONCLUSIONS: Baseline parameters for minimal response after 3 months of treatment and strong response after 12 months of treatment could be identified. Beside parameters defining activity and severity of disease, the disease duration and the concomitant use of NSAID were influencing factors. Overall the model of prediction could support physicians in making treatment decisions. PMID- 25143763 TI - Candidates for synergies: linear discriminants versus principal components. AB - Movement primitives or synergies have been extracted from human hand movements using several matrix factorization, dimensionality reduction, and classification methods. Principal component analysis (PCA) is widely used to obtain the first few significant eigenvectors of covariance that explain most of the variance of the data. Linear discriminant analysis (LDA) is also used as a supervised learning method to classify the hand postures corresponding to the objects grasped. Synergies obtained using PCA are principal component vectors aligned with dominant variances. On the other hand, synergies obtained using LDA are linear discriminant vectors that separate the groups of variances. In this paper, time varying kinematic synergies in the human hand grasping movements were extracted using these two diametrically opposite methods and were evaluated in reconstructing natural and American sign language (ASL) postural movements. We used an unsupervised LDA (ULDA) to extract linear discriminants. The results suggest that PCA outperformed LDA. The uniqueness, advantages, and disadvantages of each of these methods in representing high-dimensional hand movements in reduced dimensions were discussed. PMID- 25143764 TI - Prophylactic Appendectomy during Laparoscopic Surgery for Other Conditions. AB - Acute appendicitis remains the most common surgical emergency. Laparoscopy has gained increasing favor as a method of both investigating right iliac fossa pain and treating the finding of appendicitis. A question arises: what to do with an apparent healthy appendix discovered during laparoscopic surgery for other pathology. We present a case of unilateral hydroureteronephrosis complicated with rupture of the renal pelvis, due to gangrenous appendicitis with abscess of the right iliopsoas muscle and periappendicular inflammation in a 67-year-old woman, who underwent laparoscopic right annessiectomy for right ovarian cyst few years earlier, in which a healthy appendix was left inside. There is a lack of consensus in the literature about what to do with a normal appendix. The main argument for removing an apparently normal appendix is that endoluminal appendicitis may not be recognized during surgery, leading to concern that an abnormal appendix is left in place. Because of a lack of evidence from randomized trials, it remains unclear whether the benefits of routine elective coincidental appendectomy outweigh the costs and risks of morbidity associated with this prophylactic procedure. Nevertheless, it appears, from limited data, that women aged 35 years and under benefit most from elective coincidental appendectomy. PMID- 25143765 TI - Anatomic variation of subclavian artery visualized on ultrasound-guided supraclavicular brachial plexus block. AB - Use of ultrasonography for performance of nerve and plexus blocks has made the process simpler and safer. However, at times, variant anatomy of the visualized structures can lead to failure of blocks or complications such as intravascular injections. This is especially true in case of novice operators. We report a case of a variant branch of subclavian artery, possibly the dorsal scapular artery passing through the brachial plexus nerve bundles in the supraclavicular area. Since this variation in anatomy was visualized in the scout scan prior to the performance of the block, it was possible to avoid any accidental puncture. Hence, a thorough knowledge of the ultrasound anatomy is important in order to identify various aberrations and variations. It is also prudent to perform a preliminary scan, prior to performance of the block to localize the target area and avoid any inadvertent complications. PMID- 25143766 TI - Infantile spasm: a review article. AB - OBJECTIVE: Infantile spasm (IS) is a convulsive disease characterized by brief, symmetric axial muscle contraction (neck, trunk, and/or extremities). IS is a type of seizure that was first described by West in 1841, who witnessed the seizure in his own son. West's syndrome refers to the classic triad of spasms, characteristic EEG, and neurodevelopmental regression. Most cases involve flexors and extensors, but either of the types may be involved independently. IS, as its name implies, most often occurs during the first year of life with an incidence of approximately 1 per 2000-4000 live births. Most, but not all, patients with this disorder have severe EEG abnormalities; this pattern was originally referred to as hypsarrhythmia by Gibbs and Gibbs. Cases with known etiology or signs of brain damage are considered as symptomatic. The Overall prognosis of the disease is poor. Peak onset age of the epileptic syndrome is 3 to 7 months, which mainly occurs before 2 years of age in 93% of patients. Hypsarrhythmia is the EEG hallmark of IS, which comprised a chaotic, bilaterally asynchronous high-voltage polyspike, and slow wave discharges interspersed with multifocal spikes and slow waves. ETIOLOGICAL CLASSIFICATION IS AS FOLLOWS: 1) Symptomatic: with identifiable prenatal, perinatal, and postnatal causes with developmental delay at the presentation time; 2) Cryptogenic: unknown underlying cause, normal development at the onset of spasms, normal neurological exam and neuroimaging, and no abnormality in the metabolic evaluation; 3) Idiopathic: pure functional cerebral dysfunction with complete recovery, no residual dysfunction, normal neuroimaging and normal etiologic evaluation, and normal neurodevelopment. PMID- 25143767 TI - Familial hemiplegic migraine and spreading depression. AB - OBJECTIVE: Familial hemiplegic migraine (FHM) is an autosomal dominantly inherited subtype of migraine with aura, characterized by transient neurological signs and symptoms. Typical hemiplegic migraine attacks start in the first or second decade of life. Some patients with FHM suffer from daily recurrent attacks since childhood. Results from extensive studies of cellular and animal models have indicated that gene mutations in FHM increase neuronal excitability and reduce the threshold for spreading depression (SD). SD is a transient wave of profound neuronal and glial depolarization that slowly propagates throughout the brain tissue and is characterized by a high amplitude negative DC shift. After induction of SD, S218L mutant mice exhibited neurological signs highly reminiscent of clinical attacks in FHM type 1 patients carrying this mutation. FHM1 with ataxia is attributable to specific mutations that differ from mutations that cause pure FHM1 and have peculiar consequences on cerebellar Cav2.1 currents that lead to profound Purkinje cell dysfunction and neuronal loss with atrophy. SD in juvenile rats produced neuronal injury and death. Hormonal factors involved in FHM affect SD initiation and propagation. The data identify SD as a possible target of treatment of FHM. In addition, FHM is a useful model to explore the mechanisms of more common types of migraine. PMID- 25143768 TI - The ketogenic and atkins diets effect on intractable epilepsy: a comparison. AB - OBJECTIVE: Intractable epilepsy is a major difficulty in child neurology, because the numbers of drugs that are available for treatment are limited and new treatments such as diets must be tried. Now there are some diets available for treating patients with intractable epilepsy. The oldest diet is the classic ketogenic diet and one of the newest diets is the modified Atkins diet. Patients have a harder time accepting the classic ketogenic diet than the Atkins diet, which is easier to accept because the food tastes better. This study compares the efficacy of the ketogenic diet and the Atkins diet for intractable epilepsy in children. MATERIALS & METHODS: This study is a clinical trial survey with sample size of 40 children with refractory epilepsy who were patients at Mofid hospital in Tehran, Iran. Initially, from Jan 2005-Oct 2007, 20 children were treated with the Atkins diet, and then from Oct 2007-March 2010, the other group was treated with the classic ketogenic diet and the results were compared. RESULTS: In this study, response to treatment was greater than a 50% reduction in seizures and at the end of first, second, and third months for the ketogenic diet were 55%, 30%, and 70% and for the Atkins diet were 50%, 65%, and 70%, respectively. CONCLUSION: The results of this study show that there is no significant difference between the classic Ketogenic diet and the Atkins diet at the end of first, second, and third months and both had similar responses to the treatments. PMID- 25143769 TI - Iron deficiency and iron deficiency anemia in children with first attack of seizure and on healthy control group: a comparative study. AB - OBJECTIVE: Seizures are the most common pediatric neurologic problem. Research of the association between iron deficiency and seizures has shown conflicting results. This study evaluates iron status of children with a first seizure attack (febrile seizure (FS) or first unprovoked afebrile seizure (FUS) and healthy control group. MATERIALS & METHODS: In a cross sectional case control study, iron status of 6-60 month year old admitted children with first seizure to Shahid Sadoughi Hospital from August 2011-December 2012 were evaluated and compared with healthy control children that were referred to primary health care center of Azadshar, Yazd, Iran. RESULTS: 150 children were compared in three equal (FS, afebrile seizure, and control) groups. Hemoglobin levels in FUS (11.39 +/- 1.07 g/dl) and FS (11.46 +/- 1.18 g/dl) were lower than the control group (11.9 +/- 0.89 g/dl) group. Serum iron levels in FS (38.52 +/- 11.38 MUg/dL) and FUS (42.68 +/- 14.76 MUg/dL) were lower than the control group (54.32 +/- 13.46 MUg/dL). Serum ferritin level in FUS (46.21 +/- 27.63 ng/mL) and FS (48.91 +/- 22.96 ng/ mL) was lower than the control group (75.13 +/- 35.57 ng/mL). Iron deficiency (48% in FS, 44% in FUS and 28% in control group) and iron deficiency anemia (26% in FUS, 22% in FS, and 10% in healthy children) was more frequent in children with seizures. CONCLUSION: Iron status should be evaluated in children with a first attack of febrile or afebrile seizures. PMID- 25143770 TI - Melatonin's Effect in Febrile Seizures and Epilepsy. AB - OBJECTIVE: Recognition of risk factors for febrile seizures (FS) and epilepsy is essential. Studies regarding the role of melatonin in these convulsive disorders are limited. This study determines the relationship between serum melatonin levels and FS and epilepsy in children. MATERIALS & METHODS: A population of 111 children with simple FS, complex FS, and epilepsy (37 children per group, respectively) were included as case groups. In addition, 37 febrile children without seizures comprised the control group. Serum melatonin levels were measured and compared between all groups. RESULTS: The serum melatonin levels in the simple, complex FSs, and epilepsy groups were 2, 2.4, and 2 pg/ml, respectively. The serum melatonin level in the control group was 2.1pg/ml. Moreover, there were no significant differences observed while comparing the case groups. CONCLUSION: The present study reveals that there is no association between serum melatonin level and simple or complex FS and epilepsy. It appears that melatonin plays no significant role in these convulsive disorders. PMID- 25143771 TI - Febrile seizures: etiology, prevalence, and geographical variation. AB - OBJECTIVE: Febrile seizures (FSs) are the most common neurological disorder observed in the pediatric age group. The present study provides information about epidemiological and clinical characteristics as well as risk factors associated with FS among Iranian children. MATERIALS & METHODS: On the computerized literature valid databases, the FS prevalence and 95% confidence intervals were calculated using a random effects model. A metaregression analysis was introduced to explore heterogeneity between studies. Data manipulation and statistical analyses were performed using Stata10. RESULTS: The important viral or bacterial infection causes of FSs were; recent upper respiratory infection 42.3% (95% CI: 37.2%-47.4%), gastroenteritis21.5% (95% CI: 13.6%-29.4%), and otitis media nfections15.2% (95% CI: 9.8%- 20.7%) respectively. The pooled prevalence rate of FS among other childhood convulsions was 47.9% (95% CI: 38.8-59.9%). The meta regression analysis showed that the sample size does not significantly affect heterogeneity for the factor 'prevalence FS'. CONCLUSION: Almost half of all childhood convulsions among Iranian children are associated with Febrile seizure. PMID- 25143773 TI - IQ Score of Children with Persistent or Perennial Allergic Rhinitis: A Comparison with Healthy Children. AB - OBJECTIVE: Prevalence of allergies is different around the world. Allergic rhinitis is a common chronic disease in children. Intelligence quotient (IQ) is an indicator of efficacy and many factors including chronic diseases may affect it. This study compares the IQs of children diagnosed with persistent or perennial allergic rhinitis with healthy children. MATERIAL & METHODS: This was a comparative study that was conducted from June 2011-May 2013 in an academic referral clinic. In this study, 90 patients aged 6- to 14-yearsold who were diagnosed with persistent or perennial allergic rhinitis and were compared to 90 age and gender match healthy patients from their respective families. The Wechsler Intelligence Scale for Children was used to divide and calculate overall IQ, verbal IQ, and practical IQ. The t-test and chi square were used to analyze quantitative variables and qualitative variables, respectively. RESULTS: In this study, out of total 180 children, 90 (50%) in the case group and 90 children (50%), the control group participated for IQ comparison. One hundred (57%) were male and 80 (43%) were female. The overall IQ for allergic rhinitis patients and healthy patients was 109.2 and 107.5, respectively. This difference was not considered significant. Furthermore, there was no significant difference between the IQ scores of males and females. CONCLUSION: Although allergic rhinitis is a chronic disease and effects quality of life, there were no identifiable negative effects on IQ. PMID- 25143772 TI - Is "benign Childhood Epilepsy with Centrotemporal Spikes" Always Benign? AB - OBJECTIVE: To determine the prevalence of associated behavioral problems and prognosis with Benign Childhood Epilepsy with CentroTemporal Spikes (BCECTS). Descriptive, Cross Sectional study that was conducted from October 2009 to April 2013 in the Department of Pediatric Neurology, the Children's Hospital Taif, KSA. MATERIAL & METHODS: This study was conducted after approval from the Ethics Committee of the Children's Hospital Taif, Saudi Arabia. Thirty-two patients from the age of 3 to 10 years old were recruited from the pediatric neurology clinic over a period of 4 years. All the patients were selected based on history, EEGs, and neuropsychological and neurological examinations. EEGs were performed for all the patients while in awake and sleep states. Those who had centrotemporal discharges were included in the study. All the patients also underwent a brain MRI. Only two patients had mild cortical atrophy but developmentally they were normal. RESULTS: In our study, prevalence of BRE is 32/430 (7.44%). Among the 32 cases, 24 were male and eight were female. Six cases out of 32 indicated a family history of BRE. Twenty-eight cases had unilateral right sided centrotemporal discharges and four had bilateral discharges. CONCLUSION: It is possible that for BECTS, a high number of seizures might play an important role in the development of mild cognitive impairment and/or behavior disturbances. PMID- 25143774 TI - Comparison of Serum Zinc and Copper levels in Children and adolescents with Intractable and Controlled Epilepsy. AB - OBJECTIVE: Trace elements such as zinc and copper have physiological effects on neuronal excitability that may play a role in the etiology of intractable epilepsy. This topic has been rarely discussed in Iranian epileptic patients. This study with the analysis of serum zinc and copper levels of children and adolescents with intractable and controlled epilepsy may identifies the potential role of these two trace elements in the development of epilepsy and intractability to antiepileptic drug treatment. MATERIALS & METHODS: Seventy patients between the ages of 6 months to 15 years that referred to Children's Medical Center with the diagnosis of epilepsy, either controlled or intractable to treatment enrolled in the study. After informed parental consent the levels of serum zinc and copper were measured with atomic absorption spectrophotometer and analyzed with SPSS version 11. RESULTS: 35 patients were enrolled in each group of intractable (IE) and controlled epilepsy (CE). 71.45% of the IE and 25.72% of the CE group had zinc deficiency that was statistically significant. 48.58% of the IE and 45.72 of the CE group were copper deficient, which was not statistically significant. CONCLUSION: Our findings showed significant low serum zinc levels of patients with intractable epilepsy in comparison with controlled epilepsy group. We recommend that serum zinc level may play a role in the etiology of epilepsy and intractable epilepsy therefore its measurement and prescription may be regarded in the treatment of intractable epilepsy. PMID- 25143775 TI - GM2-Gangliosidosis (Sandhoff and Tay Sachs disease): Diagnosis and Neuroimaging Findings (An Iranian Pediatric Case Series). AB - OBJECTIVE: GM2-Gangliosidosis disease is a rare autosomal recessive genetic disorder that includes two disorders (Tay-Sachs and Sandhoff disease).These disorders cause a progressive deterioration of nerve cells and inherited deficiency in creating hexosaminidases A, B, and AB. MATERIALS & METHODS: Patients who were diagnosed withGM2-Gangliosidosis in the Neurology Department of Mofid Children's Hospital in Tehran, Iran from October 2009 to February 2014were included in our study. The disorder was confirmed by neurometabolic and enzyme level detection of hexosaminidases A, B, and AB in reference to Wagnester Laboratory in Germany. We assessed age, gender, past medical history, developmental status, clinical manifestations, and neuroimaging findings of 9 patients with Sandhoff disease and 9 with Tay Sachs disease. RESULTS: 83% of our patients were the offspring of consanguineous marriages. All of them had a developmental disorder as a chief complaint. 38%of patients had a history of developmental delay or regression and 22% had seizures. The patients with Sandhoff and Tay Sachs disease were followed for approximately 5 years and the follow-up showed all patients were bedridden or had expired due to refractory seizures, pneumonia aspiration, or swallowing disorders. Neuro-imaging findings included bilateral thalamic involvement, brain atrophy, and hypo myelination in near half of our patients (48%). CONCLUSION: According to the results of this study, we suggest that cherry-red spots, hyperacusis, refractory seizures, and relative parents in children with developmental delay and/or regression should be considered for assessment of GM2-Gangliosidosis disease. PMID- 25143776 TI - Ring-enhancing lesions in the brain: a diagnostic dilemma. AB - The most common radiological abnormality seen in young Indian patients with epilepsy is single small enhancing (ring/disc) computed tomographic (CT) lesions. The two most common differential diagnosis of this lesion in clinical practice include neurocysticercosis (NCC) and tuberculomas. They have similar clinical and neuroimaging features. Few researchers believe that in poor and developing countries (where both tuberculosis and NCC are common) that it is difficult to differentiate between tuberculomas and a single cysticercal granulomas. We report a case of a 6-year-old female patient who presented with complex partial seizures. The patient's neuroimaging showed a single ring-enhancing lesion in the brain that was not differentiated between NCC and Tuberculoma. Finally, Magnetic resonance spectroscopy (MRS) was suggestive of tuberculoma that was successfully treated with antituberculosis therapy. This report highlights diagnostic difficulties with conventional investigations in single ring enhancing lesions in the brain and role of MRS in a diagnosis.MRS is helpful in differentiating these two conditions. PMID- 25143777 TI - Does electroencephalography contribute to examining children with attention deficit hyperactivity disorder? PMID- 25143778 TI - The development of simple anthropometric measures to diagnose antiretroviral therapy-associated lipodystrophy in resource limited settings. AB - BACKGROUND: Lipohypertrophy does not appear to be an adverse ART reaction while lipoatrophy is clearly associated with the use of stavudine (d4T) and zidovudine (AZT). In low and middle income countries d4T has only recently been phased out and AZT is still widely being used. Several case definitions have been developed to diagnose lipodystrophy, but none of them are generalizable to sub-Saharan Africa where black women have less visceral adipose tissue and more subcutaneous adipose tissue than white women. We aimed to develop a simple, objective measure to define lipoatrophy and lipohypertrophy by comparing patient report to anthropometric and dual-energy X-ray absorptiometry (DXA) -derived variables. METHODS: DXA and anthropometric measures were obtained in a cross sectional sample of black HIV-infected South African men (n = 116) and women (n = 434) on ART. Self-reported information on fat gain or fat loss was collected using a standard questionnaire. Receiver operating characteristic (ROC) curves were used to describe the performance of anthropometric and DXA-derived variables using patient reported lipoatrophy and lipohypertrophy as the reference standard. RESULTS: Lipoatrophy and lipohypertrophy were more common in women (25% and 33% respectively) than in men (10% and 13% respectively). There were insufficient numbers of men with DXA scans for meaningful analysis. The best predictors of lipoatrophy in women were the anthropometric variables tricep (AUC = 0.725) and thigh skinfold (AUC =0.720) thicknesses; and the DXA-derived variables percentage lower limb fat (AUC = 0.705) and percentage lower limb fat/height (AUC = 0.713). The best predictors of lipohypertrophy in women were the anthropometric variable waist/hip ratio (AUC = 0.645) and the DXA-derived variable percentage trunk fat/percentage limb fat (AUC = 0.647). CONCLUSIONS: We were able to develop simple, anthropometric measures for defining lipoatrophy and lipohypertrophy, using a sample of black HIV-infected South African women with DXA scans. This is of particular relevance in resource limited settings, where health professionals need simple and inexpensive methods of diagnosing patients with lipoatrophy and lipohypertrophy. PMID- 25143779 TI - Metabolite profiling of wheat (Triticum aestivum L.) phloem exudate. AB - BACKGROUND: Biofortification of staple crops with essential micronutrients relies on the efficient, long distance transport of nutrients to the developing seed. The main route of this transport in common wheat (Triticum aestivum) is via the phloem, but due to the reactive nature of some essential micronutrients (specifically Fe and Zn), they need to form ligands with metabolites for transport within the phloem. Current methods available in collecting phloem exudate allows for small volumes (MUL or nL) to be collected which limits the breadth of metabolite analysis. We present a technical advance in the measurement of 79 metabolites in as little as 19.5 nL of phloem exudate. This was achieved by using mass spectrometry based, metabolomic techniques. RESULTS: Using gas chromatography-mass spectrometry (GC-MS), 79 metabolites were detected in wheat phloem. Of these, 53 were identified with respect to their chemistry and 26 were classified as unknowns. Using the ratio of ion area for each metabolite to the total ion area for all metabolites, 39 showed significant changes in metabolite profile with a change in wheat reproductive maturity, from 8-12 to 17-21 days after anthesis. Of these, 21 were shown to increase and 18 decreased as the plant matured. An amine group derivitisation method coupled with liquid chromatography MS (LC-MS) based metabolomics was able to quantify 26 metabolites and semi quantitative data was available for a further 3 metabolites. CONCLUSIONS: This study demonstrates that it is possible to determine metabolite profiles from extremely small volumes of phloem exudate and that this method can be used to determine variability within the metabolite profile of phloem that has occurred with changes in maturity. This is also believed to be the first report of the presence of the important metal complexing metabolite, nicotianamine in the phloem of wheat. PMID- 25143780 TI - Segmentation of intensity inhomogeneous brain MR images using active contours. AB - Segmentation of intensity inhomogeneous regions is a well-known problem in image analysis applications. This paper presents a region-based active contour method for image segmentation, which properly works in the context of intensity inhomogeneity problem. The proposed region-based active contour method embeds both region and gradient information unlike traditional methods. It contains mainly two terms, area and length, in which the area term practices a new region based signed pressure force (SPF) function, which utilizes mean values from a certain neighborhood using the local binary fitted (LBF) energy model. In turn, the length term uses gradient information. The novelty of our method is to locally compute new SPF function, which uses local mean values and is able to detect boundaries of the homogenous regions. Finally, a truncated Gaussian kernel is used to regularize the level set function, which not only regularizes it but also removes the need of computationally expensive reinitialization. The proposed method targets the segmentation problem of intensity inhomogeneous images and reduces the time complexity among locally computed active contour methods. The experimental results show that the proposed method yields better segmentation result as well as less time complexity compared with the state-of-the-art active contour methods. PMID- 25143781 TI - Image tracking for the high similarity drug tablets based on light intensity reflective energy and artificial neural network. AB - It is obvious that tablet image tracking exerts a notable influence on the efficiency and reliability of high-speed drug mass production, and, simultaneously, it also emerges as a big difficult problem and targeted focus during production monitoring in recent years, due to the high similarity shape and random position distribution of those objectives to be searched for. For the purpose of tracking tablets accurately in random distribution, through using surface fitting approach and transitional vector determination, the calibrated surface of light intensity reflective energy can be established, describing the shape topology and topography details of objective tablet. On this basis, the mathematical properties of these established surfaces have been proposed, and thereafter artificial neural network (ANN) has been employed for classifying those moving targeted tablets by recognizing their different surface properties; therefore, the instantaneous coordinate positions of those drug tablets on one image frame can then be determined. By repeating identical pattern recognition on the next image frame, the real-time movements of objective tablet templates were successfully tracked in sequence. This paper provides reliable references and new research ideas for the real-time objective tracking in the case of drug production practices. PMID- 25143783 TI - Prevalence of human papillomavirus infection and phylogenetic analysis of HPV-16 E6 variants among infected women from Northern Brazil. AB - BACKGROUND: The main cause of cervical cancer in the world is high risks human papillomavirus infection (mainly represented by HPV-16 and HPV-18), that are associated to the development of malign transformation of the epithelium. HPV prevalence exhibits a wide geographical variability and HPV-16 variants have been related to an increased risk of developing cervical intraepithelial lesion. The aim of this study was to describe DNA-HPV prevalence and HPV-16 variants among a women population from Northern Brazil. METHODS: One hundred and forty three women, during routine cervical cancer screening, at Juruti Project, fulfilled an epidemiological inquiry and were screened through a molecular HPV test. HPV-16 variants were determined by sequencing the HPV-16 E6 open reading frame. RESULTS: Forty two samples were considered HPV positive (29.4%). None of those had abnormal cytology results. HPV prevalence varied between different age groups (Z(U) = 14.62; p = <0.0001) and high-risk HPVs were more frequent among younger ages. The most prevalent type was HPV-16 (14%) and it variants were classified, predominantly, as European (87.5%). CONCLUSIONS: HPV prevalence in our population was higher than described by others and the most prevalent HPV types were high risk HPVs. The European HPV-16 variant was the most prevalent among HPV-16 positive samples. Our study reinforces the fact that women with normal cytology and a positive molecular test for high-risk HPVs should be submitted to continuous follow up, in order to verify persistence of infection, promoting an early diagnosis of cervical cancer and/or its precursors. PMID- 25143784 TI - Paroxysmal nocturnal hemoglobinuria presenting as cerebral venous sinus thrombosis: a case report. AB - Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare type of acquired hemolytic anemia that is frequently associated with thrombophilia. It may rarely present with cerebral venous sinus thrombosis, which manifests clinically with signs of raised intracranial pressure and requires lifelong anticoagulation therapy. One such rare presentation was seen in a 28 years old male who had history of recurrent episodes of passing red colored urine and this time presented with severe headache. He was diagnosed to have cerebral venous sinus thrombosis and on further workup was found to be suffering from PNH. PMID- 25143785 TI - Examining connections between screening for breast, cervical and prostate cancer and colorectal cancer screening. AB - AIM: To compare participation in breast, cervical and prostate cancer screening with colorectal cancer (CRC) screening. MATERIALS & METHODS: This random digit dialed survey includes participants (aged 50-75 years) from South Carolina (USA). Past participation information in fecal occult blood test, flexible sigmoidoscopy, colonoscopy, mammography, clinical breast examination, Pap test, prostate-specific antigen and digital rectal examination was obtained.Adjusted odds ratios are reported. RESULTS: Among European-American women, any cervical or breast cancer screening was associated with adherence to any CRC screening. Among African-American women, mammography was associated with adherence to any CRC screening. Digital rectal examination and prostate-specific antigen tests were associated with adherence to any CRC screening test among all men. CONCLUSION: Future research should explore approaches inclusive of cancer screening recommendations for multiple cancer types for reduction of cancer screening disparities. PMID- 25143787 TI - Eicosapentaenoic acid/arachidonic acid ratio and smoking status in elderly patients with type 2 diabetes mellitus. AB - BACKGROUND: A low ratio of eicosapentaenoic acid (EPA)/arachidonic acid (AA) is considered a risk factor for cardiovascular disease. Smoking is also a risk factor for cardiovascular disease even in an elderly population. This study investigated the relationship between EPA/AA ratio and smoking status among elderly patients with type 2 diabetes mellitus (T2DM). FINDINGS: A total of 188 elderly patients with T2DM (men/women, 114/74; mean age, 65.0 +/- 7.5 years) were studied in terms of their smoking status, diabetic conditions, and blood data, including EPA and AA. Current smokers showed a lower EPA/AA ratio than non smokers (current smokers: 0.29, n = 49; non-smokers: 0.39, n = 139, p < 0.01). This relationship remained significant after adjusting for multiple variables. CONCLUSIONS: Smoking may affect the EPA/AA ratio among elderly patients with T2DM, suggesting a possible mechanism of cardiovascular disease development and indicating the importance of smoking secession in such patients. PMID- 25143786 TI - CNX-013-B2, a unique pan tissue acting rexinoid, modulates several nuclear receptors and controls multiple risk factors of the metabolic syndrome without risk of hypertriglyceridemia, hepatomegaly and body weight gain in animal models. AB - BACKGROUND: In addition to their role in growth, cellular differentiation and homeostasis Retinoid X Receptors (RXR) regulate multiple physiological and metabolic pathways in various organs that have beneficial glucose and lipid (cholesterol) lowering, insulin sensitizing and anti-obesity effects. Rexinoids, compounds that specifically binds and activate RXR, are therefore considered as potential therapeutics for treating metabolic syndrome. Apparently many of the rexinoids developed in the past increased triglycerides, caused hepatomegaly and also suppressed the thyroid hormone axis. The aim of this study is to evaluate CNX-013-B2, a potent and highly selective rexinoid, for its potential to treat multiple risk factors of the metabolic syndrome. METHODS: CNX-013-B2 was selected in a screening system designed to identify compounds that selectively activated only a chosen sub-set of heterodimer partners of RXR of importance to treat insulin resistance. Male C57BL/6j mice (n = 10) on high fat diet (HFD) and 16 week old ob/ob mice (n = 8) were treated orally with CNX-013-B2 (10 mg/kg twice daily) or vehicle for 10 weeks and 4 weeks respectively. Measurement of plasma glucose, triglyceride, cholesterol including LDL-C, glycerol, free fatty acids, feed intake, body weight, oral glucose tolerance and non-shivering thermogenesis were performed at selected time points. After study termination such measurements as organ weight, triglyceride content, mRNA levels, protein phosphorylation along with histological analysis were performed. RESULTS: CNX-013-B2 selectively activates PPARs- alpha, beta/delta and gamma and modulates activity of LXR, THR and FXR. In ob/ob mice a significant reduction of 25% in fed glucose (p < 0.001 ), a 14% (p < 0.05) reduction in serum total cholesterol and 18% decrease (p < 0.01) in LDL-C and in DIO mice a reduction of 12% (p < 0.01 ) in fasting glucose, 20% in fed triglyceride (p < 0.01) and total cholesterol (p < 0.001) levels, coupled with enhanced insulin sensitivity, cold induced thermogenesis and 7% reduction in body weight were observed. CONCLUSION: CNX-013-B2 is an orally bio available selective rexinoid that can be used as a novel therapeutic agent for management of multiple risk factors of the metabolic syndrome without the risk of side effects reported to be associated with rexinoids. PMID- 25143788 TI - Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy. AB - BACKGROUND: Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (RAS) play a role in diabetic nephropathy (DN). Matrix metalloproteinase-2 (MMP-2) activation also contributes to DN. However, the pathological interaction among AGE-RAGE, RAS and MMP-2 in DN remains unknown. We examined here the involvement of AGE and RAS in MMP-2 activation in streptozotocin (STZ)-induced diabetic rats and in AGE-exposed rat renal proximal tubular cells (RPTCs). METHODS: Experimental diabetes was induced in 6-week-old male Sprague-Dawley (SD) rats by intravenous injection of STZ. Diabetic rats received ramipril (3 mg/kg body weight/day) or vehicle for 32 weeks. AGE-modified rat serum albumin (AGE-RSA) or RSA was intraperitoneally administrated to 6-week old male SD rats for 16 weeks. RPTCs were stimulated with 100 MUg/ml AGE-modified bovine serum albumin (AGE-BSA) or BSA in the presence or absence of 10(-7) M ramiprilat, an inhibitor of angiotensin-converting enzyme or 100 nM BAY11-7082, an IkappaB-alpha phosphorylation inhibitor. RESULTS: AGE and RAGE expression levels and MMP-2 activity in the tubules of diabetic rats was significantly increased in association with increased albuminuria, all of which were blocked by ramipril. AGE infusion induced tubular MMP-2 activation and RAGE gene expression in SD rats. Ramiprilat or BAY11-7082 inhibited the AGE-induced MMP-2 activation or reactive oxygen species generation in RPTCs. Angiotensin II increased MMP-2 gene expression in RPTCs, which was blocked by BAY11-7082. CONCLUSIONS: Our present study suggests the involvement of AGE-RAGE-induced, RAS-mediated MMP-2 activation in experimental DN. Blockade of AGE-RAGE axis by ramipril may protect against DN partly via suppression of MMP-2. PMID- 25143789 TI - Adherence: a review of education, research, practice and policy in Spain. AB - AIMS: To describe medication adherence education, practice, research and policy efforts carried out by pharmacists in Spain in the last decade. METHODS: A literature review using Medline and Embase was conducted covering the last ten years. Additional pharmaceutical bibliographic sources in Spain were consulted to retrieve articles of interest from the last decade. Articles were included if a pharmacist was involved and if medication adherence was measured or there was any direct or indirect pharmacist intervention in monitoring and/or improving adherence. Articles focusing on the development of tools for adherence assessment were collected. Pre- and post-graduate pharmacy training programs were also reviewed through the Spanish Ministry of Education and Science website. Information regarding policy issues was gathered from the Spanish and Autonomous Communities of Education and Health Ministries websites. RESULTS: Pharmacists receive no specific training focused on adherence. There is no specific government policies for pharmacists in Spain related to medication adherence regardless of their practice setting. A total of 24 research studies met our inclusion criteria. Of these, 10 involved pharmacist intervention in monitoring and/or improving adherence and 14 assessed only adherence. Ten studies involved hospital pharmacists working in collaboration with another healthcare professional. CONCLUSIONS: At present in Spain, the investigative role of the pharmacist is not well developed in the area of medication adherence. Adherence improvement services provided to patients by pharmacists are not implemented in a systematic way. However, recent efforts to implement new initiatives in this area may provide the basis for offering new cognitive services aimed at improving patient adherence in the near future. PMID- 25143790 TI - Survey of pharmacists and physicians on drug interactions between combined oral contraceptives and broad-spectrum antibiotics. AB - OBJECTIVE: To evaluate physician and pharmacist knowledge on potential drug interactions between combined oral contraceptives (COC) and broad-spectrum antibiotics and determine if any difference exists between responses. METHODS: Two hundred licensed retail pharmacists and 200 licensed family practice physicians in the states of Virginia, West Virginia, and Maryland were mailed an anonymous survey between August 2007 and November 2007. The survey consisted of 3 short questions asking practitioners about their current opinion on drug interactions with COCs and whether an alternative form of contraception is needed for patients taking COC and concomitant broad-spectrum antibiotics. The main outcome measure of the survey included: identifying how physicians and pharmacists handle prescribing or dispensing COCs along with broad-spectrum antibiotics. Gender, educational degree, and years in practice were also collected. RESULTS: A total of 182 participants returned the surveys (57% were physicians and 43% were pharmacists). When asked if broad-spectrum antibiotics have a clinically significant interaction with COCs, 82.7% of physicians and 88.5% of pharmacists answered, "yes". Of the respondents, 84.6% stated that the drug interaction warrants the patient to be advised to use back-up contraception. A total of 90.1% stated that they currently instruct patients to use back-up contraception when prescribing or dispensing antibiotics to a patient who is on COC, with no statistically significant difference existing between the responses of the pharmacists and the physicians. CONCLUSION: Physicians and pharmacists believe that broad-spectrum antibiotics decrease the effectiveness of COCs. These practitioners warn their patients of this interaction and advise the use of back up contraception. More education should be provided to practitioners regarding the data concerning COCs and broad spectrum antibiotics and lack of a proven interaction. PMID- 25143791 TI - Assessment of attitudes of University of Nigeria pharmacy students toward pharmaceutical care. AB - OBJECTIVE: The purpose of this study was to describe the attitude of University of Nigeria pharmacy students towards pharmaceutical care. METHOD: A survey of pharmacy students in their second to fifth year was conducted. A modified 13-item standard Pharmaceutical Care Attitudes Survey (PCAS) was used for the study. Reliability and factorial validity of the modified instrument were assessed. RESULTS: Modification of the instrument did not alter its validity. Students of the University of Nigeria had a positive attitude towards pharmaceutical care as attitude score of all the items were above the midpoint score of 2.5. The mean scale score of second and third year students were significantly lower than that of the fifth year's (Oneway ANOVA, p<0.001). Females had a higher positive attitude score compared to male students (Students t-test, p=0.005). There was no significant difference in the mean scale score among those that had work experience and those without work experience. Marital status did not influence attitude score. CONCLUSION: University of Nigeria pharmacy students had a positive attitude towards pharmaceutical care. However, it is necessary to provide sites were students could acquire practice experience and these sites should be designed to enable students observe the integration of pharmaceutical care activities into pharmacy practice. PMID- 25143792 TI - Effect of a pharmacist managed smoking cessation clinic on quit rates. AB - OBJECTIVE: The purpose of this study was to quantify quit rates, determine factors predicting success, and analyze patients' perceptions at 3 months after participation in the pharmacist-managed Smoking Cessation Group Clinic. METHODS: This was a prospective, single group study that was conducted in patients that had participated in the Smoking Cessation Group Clinic at the University of Iowa Hospitals and Clinics. Clinic participants received structured group counseling covering various topics associated with cessation. Varenicline, bupropion and nicotine replacement therapy were used as smoking cessation aids and selection was based on patient preference and absence of contraindications. The primary outcome of this trial was smoking status at 3 months. The patients were contacted by telephone at 3, and 6 months after the start of the clinic and asked about current smoking status. At 3 months, patients were asked to rate on a Likert scale of 1 to 5 (1=not helpful; 5=very helpful) their perceptions of individual aspects of the clinic and on a scale of 1 to 10 (1=not helpful; 10=very helpful) how they perceived their cessation aid. RESULTS: From February 2007 to January 2008, 21 patients enrolled in the intent-to-treat follow up study. Analysis of data was completed in August 2008. At 3 and 6 months, 47.6% and 52.4%, of patients reported being smoke-free, respectively. At 3 months, factors consistent with success included having more previous quit attempts and type of cessation aid used. These endpoints continued to be significant at 6 months, in addition to attending more clinic sessions, and type of insurance (favoring private insurance). Patients who quit smoking rated their cessation aid as more helpful than those who did not quit smoking (8.56; SD=0.88 verses 6.71; SD=2.81, respectively; p=0.14). The aspect of the clinic most helpful to patients was group interaction (4.53; SD=0.77). CONCLUSION: This study demonstrates that pharmacists can play a vital role with smoking cessation in a group setting. Group setting patient counseling can be an effective tool for pharmacists to reach more people within the same time frame as individual counseling. PMID- 25143793 TI - Consumer views of community pharmacy services in Bangalore city, India. AB - OBJECTIVE: The opinion about pharmacy services was studied using an instrument which measured satisfaction with pharmacy services. The main focus of the instrument was to assess patients' opinion and expectation of the present pharmacy services. METHOD: The instrument contained 20 items, which were grouped based on their similarity into eight dimensions, namely, General satisfaction, Interpersonal Skill, Evaluation, Gathering non-medical information, Trust, Helping Patients, Explanation, and Finance. Chance random sampling was done and the participants were the general public above the age of 18 years. The main outcome measure was to study participants' opinion regarding the current and desired pharmacy services. Descriptive statistics are presented for the satisfaction dimension score. The level of satisfaction with the different dimensions was compared across the different demographic characteristics. RESULT: The study results revealed significant difference in the General satisfaction and Interpersonal skill amongst the gender. Significant difference was seen in the Helping patients, Evaluation and Explanation skill among the various age groups. Education background showed significant difference in evaluation, Gathering-non medical information, Helping patients and Explanation skills of the pharmacist. There was an overall satisfaction dimension score of 56.83% in the current practice and 68.83% in the desired practice. CONCLUSION: Awareness about pharmacy service continuing education programme for practicing pharmacist will heighten the pharmacy profession in our country. PMID- 25143794 TI - Factors contributing to nonadherence to oral hypoglycemic medications among ambulatory type 2 diabetes patients in Southwestern Nigeria. AB - OBJECTIVE: The overall goal of the study was to evaluate the probable reasons for patients' nonadherence to prescribed oral hypoglycemic medications in an ambulatory care setting in Nigeria with a view to identifying points for necessary intervention to improve adherence and treatment outcomes. Also, the recommended non-drug management options for diabetes patients with emphasis on self monitoring of blood glucose were assessed. METHODS: A cross-sectional study was conducted at a 200-bed secondary health care facility in Southwestern Nigeria between 2(nd) April and 31(st) May 2008. Copies of pre-tested questionnaire were administered directly to 121 ambulatory patients with type 2 diabetes at the study site. Information on socio-demographic characteristic, probable barriers that affect adherence to prescribed oral hypoglycemic medications, non-drug treatment options for diabetes, and patients' self management efforts were obtained. Descriptive and chi-square statistics were used to evaluate the distribution of respondents' opinion. RESULTS: The response rate was almost 100%. The commonly cited intentional nonadherence practice included dose omission (70.2%). Almost 50% respondents were fed up with daily ingestion of drugs and 19.8% were inconvenienced with taking medications outside home and gave these as reasons for the dose omission. Forgetfulness (49.6%) and high cost of medication (35.5%) were mentioned as major non-intentional reasons for nonadherence. Aside oral medications, 82.6% and 95.0% of respondents respectively, reported moderate exercise and dietary restrictions as part of the prescribed treatment modalities. More than two third of respondents (81.8%) had never monitored blood glucose by themselves. Significant association exist between sex, occupation and patients' tendencies to forget doses of prescribed oral medications (p<0.05). CONCLUSION: Nonadherence behaviors among ambulatory patients with type 2 diabetes occur mostly, as omission and forgetfulness of doses of medication. Efforts are needed to increase the medication adherence and self management practices of these patients in Nigeria so they can realize the full benefits of prescribed therapies. PMID- 25143795 TI - The amount of liquid patients use to take tablets or capsules. AB - The correct use of pharmaceutical drugs supports therapy success and reduces the number of adverse side effects. One relevant aspect of use concerns the amount of liquid consumed when taking compact and shaped medicines. OBJECTIVE: The aim of this study was to investigate the volume of liquid used by patients when administering their medication. METHODS: Every patient who bought tablets or capsules from the study leader in a pharmacy in Jena (Germany), and wanted to take their medicine immediately, received a glass containing 150ml of water. The volume of water consumed by the patients was measured after they took their medication. RESULTS: 21 out of the 136 participants (15.4%) used only up to 60ml of liquid to take their tablets or capsules. Significant influences of demographic aspects, such as age or gender, on the volume of used liquid were not found. However, an increase in tablet or capsule size led to a significant increase in the volume of swallowed liquid. CONCLUSION: Patients need to be better informed about drinking a sufficient amount of liquid when taking tablets or capsules orally. Therefore, it is important that every package insert of compact and shaped medicines contains this information. In addition, medical and pharmaceutical experts should also provide this advice to their patients. PMID- 25143796 TI - A retrospective characterization of worsening renal function in patients with acute decompensated heart failure receiving nesiritide. AB - Nesiritide is approved by Food and Drug Administration (FDA) for the treatment of patients with acute decompensated heart failure (ADHF) due its ability to rapidly reduce cardiac filling pressures and improve dyspnea. Numerous studies have shown that renal dysfunction is associated with unfavorable outcomes in patients with heart failure. In addition, there have been reports suggesting that nesiritide may adversely affect renal function and mortality. OBJECTIVE: The purpose of this retrospective analysis was to assess the effect of dose and duration of nesiritide use and the dose and duration of diuretic therapy on worsening renal function and increased in-hospital mortality in this patient population. METHODS: Seventy-five patients who were hospitalized for ADHF and who were treated with nesiritide for at least 12 hours were reviewed retrospectively. RESULTS: The mean increase in SCr was 0.5 mg/dL (range 0 - 4.4 mg/dL). Thirty-six percent of patients (27/75) met the primary endpoint with an increase in SCr>0.5 mg/dL. Treatment dose and duration of nesiritide did not differ between those patients who had an increase in SCr>0.5 mg/dL and those who did not (p=0.44 and 0.61). Concomitant intravenous diuretics were used in 85% of patients with an increase in SCr >0.5 mg/dL compared to 90% of patients without an increase in SCr>0.5 mg/dL (p=0.57). The in-hospital mortality rate was also higher at 35% in those patients with an increase in creatinine >0.5 mg/dL compared to 11% in those without (p=0.01). CONCLUSION: Nesiritide was associated with an increase in SCr > 0.5 mg/dL in approximately one-third of patients. The increase occurred independently of dose, duration of nesiritide therapy, blood pressure changes, and concomitant intravenous diuretic use. However, the increase in SCr was associated with an increase in hospital stay and in hospital mortality consistent with previous reports in the literature. PMID- 25143797 TI - Effect of patient counseling on quality of life of hemodialysis patients in India. AB - End stage renal disease (ESRD) is a growing problem. The effect of patient counseling is to be defined on health-related quality of life. OBJECTIVE: The purpose of this study was to find out the impact of patient counseling in health related quality of life (QoL). METHODS: In this prospective interventional study, the Karnofsky Performance Status (KPS) for QoL questionnaire was used in test and control groups for data collection. The same data collection method was used during six months to study the effect of patient counseling. RESULTS: Health related quality of life in test group showed a consistent improvement of 2% in six months. Improvement of awareness by patient counseling was also improved. CONCLUSION: As part of medication therapy management (MTM), patient counseling focusing on dialysis compliance, diet and medications are an effective way to improve health-related QoL and awareness in ESRD. Such services should be made mandatory by law in India to improve outcomes in chronic illness. PMID- 25143798 TI - Payment for Environmental Services: Hypotheses and Evidence. AB - The use of payment for environmental services (PES) is not a new type of contract, but PES programs have become more in vogue because of the potential for sequestering carbon by paying to prevent deforestation and degradation of forestlands. We provide a framework utilizing transaction costs to hypothesize which services are more likely to be provided effectively. We then interpret the literature on PES programs to see the extent to which transaction costs vary as predicted across the type of service and to assess the performance of PES programs. As predicted, we find that transaction costs are the least for club goods like water and greatest for pure public goods like carbon reduction. Actual performance is difficult to measure and varies across the examples. More work and experimentation are needed to gain a better outlook on what elements support effective delivery of environmental services. PMID- 25143799 TI - Catching synaptic vesicles in action. AB - The synaptic vesicle (SV) cycle was initially discovered at the neuromuscular junction using electron microscopy (EM) analysis.(1) With the introduction of fluorescent probes that are able to monitor real-time cellular events in live cells, EM analysis was pushed to the side lines because it could not provide meaningful kinetic analyses of the various steps in the synaptic vesicle cycle. PMID- 25143801 TI - Semi-Automatic Neuron Segmentation in Electron Microscopy Images Via Sparse Labeling. AB - We introduce a novel method for utilizing user input to sparsely label membranes in electron microscopy images. Using gridlines as guides, the user marks where the guides cross the membrane to generate a sparsely labeled image. We use a best path algorithm to connect each of the sparse membrane labels. The resulting segmentation has a significantly better Rand error than automatic methods while requiring as little as 2% of the image to be labeled. PMID- 25143802 TI - Neuron Segmentation in Electron Microscopy Images Using Partial Differential Equations. AB - In connectomics, neuroscientists seek to identify the synaptic connections between neurons. Segmentation of cell membranes using supervised learning algorithms on electron microscopy images of brain tissue is often done to assist in this effort. Here we present a partial differential equation with a novel growth term to improve the results of a supervised learning algorithm. We also introduce a new method for representing the resulting image that allows for a more dynamic thresholding to further improve the result. Using these two processes we are able to close small to medium sized gaps in the cell membrane detection and improve the Rand error by as much as 9% over the initial supervised segmentation. PMID- 25143803 TI - Genetically engineered mouse models for drug development and preclinical trials. AB - Drug development and preclinical trials are challenging processes and more than 80% to 90% of drug candidates fail to gain approval from the United States Food and Drug Administration. Predictive and efficient tools are required to discover high quality targets and increase the probability of success in the process of new drug development. One such solution to the challenges faced in the development of new drugs and combination therapies is the use of low-cost and experimentally manageable in vivo animal models. Since the 1980's, scientists have been able to genetically modify the mouse genome by removing or replacing a specific gene, which has improved the identification and validation of target genes of interest. Now genetically engineered mouse models (GEMMs) are widely used and have proved to be a powerful tool in drug discovery processes. This review particularly covers recent fascinating technologies for drug discovery and preclinical trials, targeted transgenesis and RNAi mouse, including application and combination of inducible system. Improvements in technologies and the development of new GEMMs are expected to guide future applications of these models to drug discovery and preclinical trials. PMID- 25143804 TI - Neuroprotective Effect of Chebulagic Acid via Autophagy Induction in SH-SY5Y Cells. AB - Autophagy is a series of catabolic process mediating the bulk degradation of intracellular proteins and organelles through formation of a double-membrane vesicle, known as an autophagosome, and fusing with lysosome. Autophagy plays an important role of death-survival decisions in neuronal cells, which may influence to several neurodegenerative disorders including Parkinson's disease. Chebulagic acid, the major constituent of Terminalia chebula and Phyllanthus emblica, is a benzopyran tannin compound with various kinds of beneficial effects. This study was performed to investigate the autophagy enhancing effect of chebulagic acid on human neuroblastoma SH-SY5Y cell lines. We determined the effect of chebulagic acid on expression levels of autophago-some marker proteins such as, DOR/TP53INP2, Golgi-associated ATPase Enhancer of 16 kDa (GATE 16) and Light chain 3 II (LC3 II), as well as those of its upstream pathway proteins, AMP activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and Beclin 1. All of those proteins were modulated by chebulagic acid treatment in a way of enhancing the autophagy. Additionally in our study, chebulagic acid also showed a protective effect against 1-methyl-4-phenylpyridinium (MPP(+)) - induced cytotoxicity which mimics the pathological symptom of Parkinson's disease. This effect seems partially mediated by enhanced autophagy which increased the degradation of aggregated or misfolded proteins from cells. This study suggests that chebulagic acid is an attractive candidate as an autophagy-enhancing agent and therefore, it may provide a promising strategy to prevent or cure the diseases caused by accumulation of abnormal proteins including Parkinson's disease. PMID- 25143800 TI - Oxidative stress and metabolic pathologies: from an adipocentric point of view. AB - Oxidative stress plays a pathological role in the development of various diseases including diabetes, atherosclerosis, or cancer. Systemic oxidative stress results from an imbalance between oxidants derivatives production and antioxidants defenses. Reactive oxygen species (ROS) are generally considered to be detrimental for health. However, evidences have been provided that they can act as second messengers in adaptative responses to stress. Obesity represents a major risk factor for deleterious associated pathologies such as type 2 diabetes, liver, and coronary heart diseases. Many evidences regarding obesity-induced oxidative stress accumulated over the past few years based on established correlations of biomarkers or end-products of free-radical-mediated oxidative stress with body mass index. The hypothesis that oxidative stress plays a significant role in the development of metabolic disorders, especially insulin resistance state, is supported by several studies where treatments reducing ROS production reverse metabolic alterations, notably through improvement of insulin sensitivity, hyperlipidemia, or hepatic steatosis. In this review, we will develop the mechanistic links between oxidative stress generated by adipose tissue in the context of obesity and its impact on metabolic complications development. We will also attempt to discuss potential therapeutic approaches targeting obesity-associated oxidative stress in order to prevent associated metabolic complications. PMID- 25143805 TI - Silymarin Inhibits Cytokine-Stimulated Pancreatic Beta Cells by Blocking the ERK1/2 Pathway. AB - We show that silymarin, a polyphenolic flavonoid isolated from milk thistle (Silybum marianum), inhibits cytokine mixture (CM: TNF-alpha, IFN-gamma, and IL 1beta)-induced production of nitric oxide (NO) in the pancreatic beta cell line MIN6N8a. Immunostaining and Western blot analysis showed that silymarin inhibits iNOS gene expression. RT-PCR showed that silymarin inhibits iNOS gene expression in a dose-dependent manner. We also showed that silymarin inhibits extracellular signal-regulated protein kinase-1 and 2 (ERK1/2) phosphorylation. A MEK1 inhibitor abrogated CM-induced nitrite production, similar to silymarin. Treatment of MIN6N8a cells with silymarin also inhibited CM-stimulated activation of NF-kappaB, which is important for iNOS transcription. Collectively, we demonstrate that silymarin inhibits NO production in pancreatic beta cells, and silymarin may represent a useful anti-diabetic agent. PMID- 25143806 TI - Anti-Inflammatory Effect of Mangostenone F in Lipopolysaccharide-Stimulated RAW264.7 Macrophages by Suppressing NF-kappaB and MAPK Activation. AB - Mangostenone F (MF) is a natural xanthone isolated from Garcinia mangostana. However, little is known about the biological activities of MF. This study was designed to investigate the anti-inflammatory effect and underlying molecular mechanisms of MF in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. MF dose-dependently inhibited the production of NO, iNOS, and pro-inflammatory cytokines (TNF-alpha, IL-6, and IL-1beta) in LPS-stimulated RAW264.7 macrophages. Moreover, MF decreased the NF-kappaB luciferase activity and NF-kappaB DNA binding capacity in LPS-stimulated RAW264.7 macrophages. Furthermore, MF suppressed the NF-kappaB activation by inhibiting the degradation of IkappaBalpha and nuclear translocation of p65 subunit of NF-kappaB. In addition, MF attenuated the AP-1 luciferase activity and phosphorylation of ERK, JNK, and p38 MAP kinases. Taken together, these results suggest that the anti-inflammatory effect of MF is associated with the suppression of NO production and iNOS expression through the down-regulation of NF-kappaB activation and MAPK signaling pathway in LPS-stimulated RAW264.7 macrophages. PMID- 25143807 TI - Cytochalasin B modulates macrophage-mediated inflammatory responses. AB - The actin cytoskeleton plays an important role in macrophage-mediated inflammatory responses by modulating the activation of Src and subsequently inducing nuclear factor (NF)-kappaB translocation. In spite of its critical functions, few papers have examined how the actin cytoskeleton can be regulated by the activation of toll-like receptor (TLR). Therefore, in this study, we further characterized the biological value of the actin cytoskeleton in the functional activation of macrophages using an actin cytoskeleton disruptor, cytochalasin B (Cyto B), and explored the actin cytoskeleton's involvement in morphological changes, cellular attachment, and signaling events. Cyto B strongly suppressed the TLR4-mediated mRNA expression of inflammatory genes such as cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-alpha, and inducible nitric oxide (iNOS), without altering cell viability. This compound also strongly suppressed the morphological changes induced by lipopolysaccharide (LPS), a TLR4 ligand. Cyto B also remarkably suppressed NO production under non-adherent conditions but not in an adherent environment. Cyto B did not block the co localization between surface glycoprotein myeloid differentiation protein-2 (MD2), a LPS signaling glycoprotein, and the actin cytoskeleton under LPS conditions. Interestingly, Cyto B and PP2, a Src inhibitor, enhanced the phagocytic uptake of fluorescein isothiocyanate (FITC)-dextran. Finally, it was found that Cyto B blocked the phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at 1 min and the phosphorylation of heat shock protein 27 (HSP27) at 5 min. Therefore, our data suggest that the actin cytoskeleton may be one of the key components involved in the control of TLR4-mediated inflammatory responses in macrophages. PMID- 25143808 TI - Fucodiphlorethol G Purified from Ecklonia cava Suppresses Ultraviolet B Radiation Induced Oxidative Stress and Cellular Damage. AB - Fucodiphlorethol G (6'-[2,4-dihydroxy-6-(2,4,6-trihydroxyphenoxy)phenoxy]biphenyl 2,2',4,4',6-pentol) is a compound purified from Ecklonia cava, a brown alga that is widely distributed offshore of Jeju Island. This study investigated the protective effects of fucodiphlorethol G against oxidative damage-mediated apoptosis induced by ultraviolet B (UVB) irradiation. Fucodiphlorethol G attenuated the generation of 2, 2-diphenyl-1-picrylhydrazyl radicals and intracellular reactive oxygen species in response to UVB irradiation. Fucodiphlorethol G suppressed the inhibition of human keratinocyte growth by UVB irradiation. Additionally, the wavelength of light absorbed by fucodiphlorethol G was close to the UVB spectrum. Fucodiphlorethol G reduced UVB radiation-induced 8 isoprostane generation and DNA fragmentation in human keratinocytes. Moreover, fucodiphlorethol G reduced UVB radiation-induced loss of mitochondrial membrane potential, generation of apoptotic cells, and active caspase-9 expression. Taken together, fucodiphlorethol G protected human keratinocytes against UVB radiation induced cell damage and apoptosis by absorbing UVB radiation and scavenging reactive oxygen species. PMID- 25143809 TI - The Heterochromatin-1 Phosphorylation Contributes to TPA-Induced AP-1 Expression. AB - Activator protein-1 (AP-1) is an inducible transcription factor that contributes to the generation of chronic inflammation in response to oxidative and electrophilic stress. Previous studies have demonstrated that the PI3K/Akt1 pathway plays an important role in the transcriptional regulation of AP-1 expression. Although the histone post-translational modifications (PTMs) are assumed to affect the AP-1 transcriptional regulation by the PI3K/Akt pathway, the detailed mechanisms are completely unknown. In the present study, we show that heterochromatin 1 gamma (HP1gamma) plays a negative role in TPA-induced c Jun and c-Fos expression. We show that TPA-induced Akt1 directly phosphorylates HP1gamma, abrogates its suppressive function and increases the interaction between histone H3 and 14-3-3epsilon. Collectively, these our data illustrate that the activation of PI3K/Akt pathway may play a permissive role in the recruitment of histone readers or other coactivators on the chromatin, thereby affecting the degree of AP-1 transcription. PMID- 25143810 TI - Pachymic Acid Enhances Pentobarbital-Induced Sleeping Behaviors via GABAA-ergic Systems in Mice. AB - This study was investigated to know whether pachymic acid (PA), one of the predominant triterpenoids in Poria cocos (Hoelen) has the sedative-hypnotic effects, and underlying mechanisms are mediated via gamma-aminobutyric acid (GABA)-ergic systems. Oral administration of PA markedly suppressed locomotion activity in mice. This compound also prolonged sleeping time, and reduced sleep latency showing synergic effects with muscimol (0.2 mg/kg) in shortening sleep onset and enhancing sleep time induced by pentobarbital, both at the hypnotic (40 mg/kg) and sub-hypnotic (28 mg/kg) doses. Additionally, PA elevated intracellular chloride levels in hypothalamic primary cultured neuronal cells of rats. Moreover, Western blotting quantitative results showed that PA increased the amount of protein level expression of GAD65/67 over a broader range of doses. PA increased alpha- and beta-subunits protein levels, but decreased gamma-subunit protein levels in GABAA receptors. The present experiment provides evidence for the hypnotic effects as PA enhanced pentobarbital-induced sleeping behaviors via GABAA-ergic mechanisms in rodents. Taken together, it is proposed that PA may be useful for the treatment of sleep disturbed subjects with insomnia. PMID- 25143811 TI - Dermal Stability and In Vitro Skin Permeation of Collagen Pentapeptides (KTTKS and palmitoyl-KTTKS). AB - Collagen pentapeptide (Lys-Thr-Thr-Lys-Ser, KTTKS) and its palmitoylated derivative (pal-KTTKS) have received a great deal of attention as cosmeceutical ingredients for their anti-wrinkle effects. The objective of this study was to evaluate stability and permeability of KTTKS and pal-KTTKS in hairless mouse skin. In this study, a liquid chromatography-tandem mass spectrometric method was developed for the quantification of pal-KTTKS, and used for stability and permeability studies. Stability studies were performed using skin extracts and homogenates. Both KTTKS and pal-KTTKS were rapidly degraded, but pal-KTTKS was more stable than KTTKS. When protease inhibitors were added, the stability of both compounds (KTTKS and pal-KTTKS) improved significantly. In the skin permeation study, neither KTTKS nor pal-KTTKS was detected in the receptor solution, which indicates that neither compound could permeate through the full thickness hairless mouse skin in the experimental conditions of this study. While KTTKS was not detected in any of the skin layers (the stratum corneum, epidermis, and dermis), pal-KTTKS was observed in all skin layers: 4.2 +/- 0.7 MUg/cm(2) in the stratum corneum, 2.8 +/- 0.5 MUg/cm(2) in the epidermis, and 0.3 +/- 0.1 MUg/cm(2) in the dermis. In conclusion, this study indicated that pal-KTTKS had greater stability and permeability than that of un-modified KTTKS, and may be a useful anti-wrinkle and anti-aging cosmeceutical agent. PMID- 25143812 TI - Adipose-derived stem cells improve efficacy of melanocyte transplantation in animal skin. AB - Vitiligo is a pigmentary disorder induced by a loss of melanocytes. In addition to replacement of pure melanocytes, cocultures of melanocytes with keratinocytes have been used to improve the repigmentation outcome in vitiligo treatment. We previously identified by in vitro studies, that adipose-derived stem cells (ADSCs) could be a potential substitute for keratinocytes in cocultures with melanocytes. In this study, the efficacy of pigmentation including durability of grafted melanocytes and short-term safety was examined in the nude mouse and Sprague-Dawley rat after grafting of primary cultured human melanocytes, with or without different ratios of primary cultured human ADSCs. Simultaneous grafting of melanocytes and ADSCs, which were separately cultured and mixed on grafting at the ratios of 1:1, 1:2, or 1:3, showed better efficacy than that of pure melanocytes. Grafting of melanocytes cocultured with ADSCs resulted in a similar outcome as the grafting of cell mixtures. Skin pigmentation by melanocytes : ADSCs at the ratios of 1:1 and 1:2 was better than at 1:3. No significant difference was observed between the 1-week and 2-week durations in coculturing. Time-course microscopic examination showed that the grafted melanocytes remained a little longer than 6-week post-grafting. No inflammatory cell infiltration was observed in the grafted skin and no melanocytes were detectable in other organs. Collectively, grafting of melanocytes and ADSCs was equally safe and more effective than grafting of melanocytes alone. Despite the absence of significant differences in efficacy between the group of 1:1 and that of 1:2 ratio, 1:2 ratio for 1-week coculturing may be better for clinical use from the cost-benefit viewpoint. PMID- 25143813 TI - Anti-Inflammatory and PPAR Transactivational Effects of Oleanane-Type Triterpenoid Saponins from the Roots of Pulsatilla koreana. AB - In this study, 23 oleanane-type triterpenoid saponins were isolated from a methanol extract of the roots of Pulsatilla koreana. The NF-kappaB inhibitory activity of the isolated compounds was measured in TNFalpha-treated HepG2 cells using a luciferase reporter system. Compounds 19-23 inhibited TNFalpha-stimulated NF-kappaB activation in a dose-dependent manner, with IC50 values ranging from 0.75-8.30 MUM. Compounds 19 and 20 also inhibited the TNFalpha-induced expression of iNOS and ICAM-1 mRNA. Moreover, effect of the isolated compounds on PPARs transcriptional activity was assessed. Compounds 7-11 and 19-23 activated PPARs the transcriptional activity significantly in a dose-dependent manner, with EC50 values ranging from 0.9-10.8 MUM. These results suggest the presence of potent anti-inflammatory components in P. koreana, and will facilitate the development of novel anti-inflammatory agents. PMID- 25143814 TI - Antitumor and Apoptosis Induction Effects of Paeonol on Mice Bearing EMT6 Breast Carcinoma. AB - Paeonol is a major phenolic micromolecular component of Moutan cortex Radicis, a traditional Chinese Medicine. It has shown antitumor effects in previous studies; however, the underlying mechanisms remain unknown. This study investigated the mechanism by giving treatments of placebo, cyclophosphamide, paeonol of 150 and 300 mg/kg to 4 groups of mice bearing EMT6 breast cancer. Apoptosis in tumor cells were confirmed by morphology analysis, including hematoxylin, eosin staining and TUNEL staining. The results showed that the weight of EMT6 breast tumor was significantly reduced in the groups treated with both 150 and 300 mg/kg of paeonol. Immunohistochemical and Western blot results showed that the expression of Bcl-2 was down-regulated while the expression of Bax, caspase 8 and caspase 3 was up-regulated respectively. These results suggest that paeonol exhibits antitumor effects and the mechanism of the inhibition is via induction of apoptosis, regulation of Bcl-2 and Bax expression, and activation of caspase 8 and caspase 3. PMID- 25143815 TI - Selective Estrogen Receptor Modulation by Larrea nitida on MCF-7 Cell Proliferation and Immature Rat Uterus. AB - Larrea nitida is a plant that belongs to the Zygophyllaceae family and is widely used in South America to treat inflammatory diseases, tumors and menstrual pain. However, its pharmacological activity remains unclear. In this study we evaluated the property of selective estrogen receptor modulator (SERM) of Larrea nitida extracts (LNE) as a phytoestrogen that can mimic, modulate or disrupt the actions of endogenous estrogens, depending on the tissue and relative amount of other SERMs. To investigate the property of SERM of LNE, we performed MCF-7 cell proliferation assays, estrogen response element (ERE)-luciferase reporter gene assay, human estrogen receptor (hER) binding assays and in vivo uterotrophic assay. To gain insight into the active principles, we performed a bioassay-guided analysis of LNE employing solvents of various polarities and using classical column chromatography, which yielded 16 fractions (LNs). LNE showed high binding affinities for hERalpha and hERbeta with IC50 values of 1.20 *10(-7) g/ml and 1.00*10(-7) g/ml, respectively. LNE induced 17beta-estradiol (E2)-induced MCF-7 cell proliferation, however, it reduced the proliferation in the presence of E2. Furthermore, LNE had an atrophic effect in the uterus of immature rats through reducing the expression level of progesterone receptor (PR) proteins. LN08 and LN10 had more potent affinities for binding on hER alpha and beta than other fractions. Our results indicate that LNE had higher binding affinities for hERbeta than hERalpha, and showed SERM properties in MCF-7 breast cancer cells and the rat uterus. LNE may be useful for the treatment of estrogen-related conditions, such as female cancers and menopause. PMID- 25143816 TI - Microfluidic System Based High Throughput Drug Screening System for Curcumin/TRAIL Combinational Chemotherapy in Human Prostate Cancer PC3 Cells. AB - We have developed a fully automated high throughput drug screening (HTDS) system based on the microfluidic cell culture array to perform combinational chemotherapy. This system has 64 individually addressable cell culture chambers where the sequential combinatorial concentrations of two different drugs can be generated by two microfluidic diffusive mixers. Each diffusive mixer has two integrated micropumps connected to the media and the drug reservoirs respectively for generating the desired combination without the need for any extra equipment to perfuse the solution such as syringe pumps. The cell array is periodically exposed to the drug combination with the programmed LabVIEW system during a couple of days without extra handling after seeding the cells into the microfluidic device and also, this device does not require the continuous generation of solutions compared to the previous systems. Therefore, the total amount of drug being consumed per experiment is less than a few hundred micro liters in each reservoir. The utility of this system is demonstrated through investigating the viability of the prostate cancer PC3 cell line with the combinational treatments of curcumin and tumor necrosis factor-alpha related apoptosis inducing ligand (TRAIL). Our results suggest that the system can be used for screening and optimizing drug combination with a small amount of reagent for combinatorial chemotherapy against cancer cells. PMID- 25143817 TI - Dependence Potential of the Synthetic Cannabinoids JWH-073, JWH-081, and JWH-210: In Vivo and In Vitro Approaches. AB - Synthetic cannabinoids (CBs) such as the JWH series have caused social problems concerning their abuse liability. Because the JWH series produces euphoric and hallucinogenic effects, they have been distributed illegally under street names such as "Spice" and "Smoke". Many countries including Korea have started to schedule some of the JWH series compounds as controlled substances, but there are a number of JWH series chemicals that remain uncontrolled by law. In this study, three synthetic CBs with different binding affinities to the CB1 receptor (JWH 073, 081, and 210) and Delta(9)-tetrahydrocannabinol (Delta(9)-THC) were evaluated for their potential for psychological dependence. The conditioned place preference test (unbiased method) and self-administration test (fixed ratio of 1) using rodents were conducted. Ki values of the three synthetic cannabinoids were calculated as supplementary data using a receptor binding assay and overexpressed CB1 protein membranes to compare dependence potential with CB1 receptor binding affinity. All mice administered JWH-073, 081, or 210 showed significantly increased time spent at unpreferred space in a dose-dependence manner in the conditioned place preference test. In contrast, all tested substances except Delta(9)-THC showed aversion phenomenon at high doses in the conditioned place preference test. The order of affinity to the CB1 receptor in the receptor binding assay was JWH-210 > JWH-081 >> JWH-073, which was in agreement with the results from the conditioned place preference test. However, no change in self administration was observed. These findings suggest the possibility to predict dependence potential of synthetic CBs through a receptor binding assay at the screening level. PMID- 25143818 TI - Investigation and identification of etiologies involved in the development of acquired hydronephrosis in aged laboratory mice with the use of high-frequency ultrasound imaging. AB - Laboratory mice develop naturally occurring lesions that affect biomedical research. Hydronephrosis is a recognized pathologic abnormality of the mouse kidney. Acquired hydronephrosis can affect any mouse, as it is caused by any naturally occurring disease that impairs free urine flow. Many etiologies leading to this condition are of particular significance to aging mice. Non-invasive ultrasound imaging detects renal pelvic dilation, renal enlargement, and parenchymal loss for pre-mortem identification of this condition. High-frequency ultrasound transducers produce high-resolution images of small structures, ideal for detecting organ pathology in mice. Using a 40 MHz linear array transducer, we obtained high-resolution images of a diversity of pathologic lesions occurring within the abdomen of seven geriatric mice with acquired hydronephrosis that enabled a determination of the underlying etiology. Etiologies diagnosed from the imaging results include pyelonephritis, neoplasia, urolithiasis, mouse urologic syndrome, and spontaneous hydronephrosis, and were confirmed at necropsy. A retrospective review of abdominal scans from an additional 149 aging mice shows that the most common etiologies associated with acquired hydronephrosis are mouse urologic syndrome and abdominal neoplasia. This report highlights the utility of high-frequency ultrasound for surveying research mice for age-related pathology, and is the first comprehensive report of multiple cases of acquired hydronephrosis in mice. PMID- 25143820 TI - Dystrophin deregulation is associated with tumor progression in KIT/PDGFRA mutant gastrointestinal stromal tumors. AB - BACKGROUND: Intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene have been recently described in gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS) and leiomyosarcoma (LMS). We evaluated the copy numbers and gene expression levels of DMD in our series of GIST patients who were already studied with wide genome assays, to investigate more fully a correlation between dystrophin status and disease annotations. FINDINGS: Our study highlighted a recurrent intragenic deletion on chromosome X, involving the DMD gene that codes for human dystrophin in GIST patients. Of 29 KIT/PDGFRA mutant GIST samples, 9 (31%) showed deletions of the DMD gene, which were focal and intragenic in 8 cases, and involved loss of an entire chromosome in one case (GIST_188). DMD loss was seen in only 5 patients with metastasis, whereas 18 out of 20 patients with localized disease had wild-type DMD (P = 0.0004, Fisher exact test). None of the 6 KIT/PDGFRA WT GIST showed DMD alterations. CONCLUSIONS: Our study confirms the presence of DMD deletions only in KIT/PDGFRA mutant GIST and this event is almost associated with metastatic disease. These findings are, of course, quite preliminary but support development of potential therapeutic strategies that target and restore DMD function in the treatment of metastatic GIST. PMID- 25132958 TI - Short- and long-term habituation of auditory event-related potentials in the rat. AB - An auditory oddball paradigm in humans generates a long-duration cortical negative potential, often referred to as mismatch negativity. Similar negativity has been documented in monkeys and cats, but it is controversial whether mismatch negativity also exists in awake rodents. To this end, we recorded cortical and hippocampal evoked responses in rats during alert immobility under a typical passive oddball paradigm that yields mismatch negativity in humans. The standard stimulus was a 9 kHz tone and the deviant either 7 or 11 kHz tone in the first condition. We found no evidence of a sustained potential shift when comparing evoked responses to standard and deviant stimuli. Instead, we found repetition induced attenuation of the P60 component of the combined evoked response in the cortex, but not in the hippocampus. The attenuation extended over three days of recording and disappeared after 20 intervening days of rest. Reversal of the standard and deviant tones resulted is a robust enhancement of the N40 component not only in the cortex but also in the hippocampus. Responses to standard and deviant stimuli were affected similarly. Finally, we tested the effect of scopolamine in this paradigm. Scopolamine attenuated cortical N40 and P60 as well as hippocampal P60 components, but had no specific effect on the deviant response. We conclude that in an oddball paradigm the rat demonstrates repetition induced attenuation of mid-latency responses, which resembles attenuation of the N1-component of human auditory evoked potential, but no mismatch negativity. PMID- 25143819 TI - Routes and mechanisms of extracellular vesicle uptake. AB - Extracellular vesicles (EVs) are small vesicles released by donor cells that can be taken up by recipient cells. Despite their discovery decades ago, it has only recently become apparent that EVs play an important role in cell-to-cell communication. EVs can carry a range of nucleic acids and proteins which can have a significant impact on the phenotype of the recipient. For this phenotypic effect to occur, EVs need to fuse with target cell membranes, either directly with the plasma membrane or with the endosomal membrane after endocytic uptake. EVs are of therapeutic interest because they are deregulated in diseases such as cancer and they could be harnessed to deliver drugs to target cells. It is therefore important to understand the molecular mechanisms by which EVs are taken up into cells. This comprehensive review summarizes current knowledge of EV uptake mechanisms. Cells appear to take up EVs by a variety of endocytic pathways, including clathrin-dependent endocytosis, and clathrin-independent pathways such as caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft-mediated internalization. Indeed, it seems likely that a heterogeneous population of EVs may gain entry into a cell via more than one route. The uptake mechanism used by a given EV may depend on proteins and glycoproteins found on the surface of both the vesicle and the target cell. Further research is needed to understand the precise rules that underpin EV entry into cells. PMID- 25143823 TI - Evaluation of alfalfa inter-seeding effect on bahiagrass baleage fermentation and lactating Holstein performance. AB - BACKGROUND: Previous research indicates that bahiagrass may be successfully conserved as baleage, but nutritive value is typically low for lactating dairy cows. The purpose of this study was to determine the effect of adding modest amounts of alfalfa forage (22%), achieved by inter-seeding alfalfa into an existing bahiagrass pasture, on baleage nutritive value and lactation performance of Holstein cows. Forage treatments employed were monoculture bahiagrass baleage (MBB; negative control), bahiagrass-alfalfa mixture baleage (BAB) and conventional corn silage (CCS; positive control). Thirty six mid lactation Holstein cows [34.8 +/- 5.8 kg 3.5% fat-corrected milk and 112 +/- 19 d in milk (DIM)] were stratified according to milk yield and DIM and assigned randomly to 1 of 3 forage treatments. Cows were trained to Calan feeding gates and were offered a common CCS-based TMR in a 10-d covariance period followed by a 42-d treatment feeding period. RESULTS: The BAB contained more protein and less NDF than MBB (12.6 vs 10.3% CP and 71.8 vs 76.6% NDF). Diet DMI was similar for MBB and BAB (19.5 vs 21.6 kg/hd/d), but cows consumed more of the CCS diet (25.5 kg/hd/d) than either baleage-based diet. Cows offered BAB tended to produce more milk than cows offered MBB based TMR (28.4 vs 26.1 kg/hd/d), but both baleage diets generated less milk than CCS-based diets (33.1 kg/hd/d). Milk composition was similar across diets except for milk protein concentrations which were higher for CCS than either MBB or BAB diets; however, milk urea nitrogen (MUN) was lowest for cows fed CCS diets. Cow BW gain was higher for BAB than MBB implying that a portion of the higher energy contributed by the alfalfa was being used to replenish weight on these mid lactation cows. CONCLUSIONS: Data from this study indicate that alfalfa inter-seeded in bahiagrass sod that produces BAB with as little as 22% alfalfa may improve nutritive value compared to monoculture bahiagrass baleage and marginally improve lactation performance of Holstein cows. However, the CCS diet was vastly superior to either MBB or BAB-based diets for milk production. PMID- 25143822 TI - Annotated features of domestic cat - Felis catus genome. AB - BACKGROUND: Domestic cats enjoy an extensive veterinary medical surveillance which has described nearly 250 genetic diseases analogous to human disorders. Feline infectious agents offer powerful natural models of deadly human diseases, which include feline immunodeficiency virus, feline sarcoma virus and feline leukemia virus. A rich veterinary literature of feline disease pathogenesis and the demonstration of a highly conserved ancestral mammal genome organization make the cat genome annotation a highly informative resource that facilitates multifaceted research endeavors. FINDINGS: Here we report a preliminary annotation of the whole genome sequence of Cinnamon, a domestic cat living in Columbia (MO, USA), bisulfite sequencing of Boris, a male cat from St. Petersburg (Russia), and light 30* sequencing of Sylvester, a European wildcat progenitor of cat domestication. The annotation includes 21,865 protein-coding genes identified by a comparative approach, 217 loci of endogenous retrovirus-like elements, repetitive elements which comprise about 55.7% of the whole genome, 99,494 new SNVs, 8,355 new indels, 743,326 evolutionary constrained elements, and 3,182 microRNA homologues. The methylation sites study shows that 10.5% of cat genome cytosines are methylated. An assisted assembly of a European wildcat, Felis silvestris silvestris, was performed; variants between F. silvestris and F. catus genomes were derived and compared to F. catus. CONCLUSIONS: The presented genome annotation extends beyond earlier ones by closing gaps of sequence that were unavoidable with previous low-coverage shotgun genome sequencing. The assembly and its annotation offer an important resource for connecting the rich veterinary and natural history of cats to genome discovery. PMID- 25143824 TI - The nasal cavity microbiota of healthy adults. AB - BACKGROUND: The microbiota of the nares has been widely studied. However, relatively few studies have investigated the microbiota of the nasal cavity posterior to the nares. This distinct environment has the potential to contain a distinct microbiota and play an important role in health. RESULTS: We obtained 35,142 high-quality bacterial 16S rRNA-encoding gene sequence reads from the nasal cavity and oral cavity (the dorsum of the tongue and the buccal mucosa) of 12 healthy adult humans and deposited these data in the Sequence Read Archive (SRA) of the National Center for Biotechnology Information (NCBI) (Bioproject: PRJNA248297). In our initial analysis, we compared the bacterial communities of the nasal cavity and the oral cavity from ten of these subjects. The nasal cavity bacterial communities were dominated by Actinobacteria, Firmicutes, and Proteobacteria and were statistically distinct from those on the tongue and buccal mucosa. For example, the same Staphylococcaceae operational taxonomic unit (OTU) was present in all of the nasal cavity samples, comprising up to 55% of the community, but Staphylococcaceae was comparatively uncommon in the oral cavity. CONCLUSIONS: There are clear differences between nasal cavity microbiota and oral cavity microbiota in healthy adults. This study expands our knowledge of the nasal cavity microbiota and the relationship between the microbiota of the nasal and oral cavities. PMID- 25143825 TI - Case report: a 37-year-old male with telangiectasias, polycythemia vera, perinephric fluid collections, and intrapulmonary shunting. AB - BACKGROUND: The TEMPI syndrome was recently described in 2011, and is characterized by the constellation of five hallmarks: Telangiectasias, Erythrocytosis and elevated Erythropoietin, Monoclonal gammopathy, Perinephric fluids collections, and Intrapulmonary shunting. The underlying pathophysiology is unknown, though it has been postulated that the monoclonal gammopathy may play a causal role. CASE PRESENTATION: A 37-year-old non-smoking male presented to our institution with a fever and the sensation of fullness in the right flank. His exam was notable for telangiectasias, clubbing of the fingernails, plethora, and a palpable bulge in the right flank. Renal ultrasound demonstrated bilateral perinephric fluid collections. Laboratory evaluation revealed erythrocytosis with low serum erythropoietin, and testing for the JAK2V617F mutation was positive, confirming a diagnosis of polycythemia vera. Though his room air saturation was normal at rest, it decreased dramatically with exercise, felt to be secondary to microscopic intrapulmonary shunting. The patient's presentation is very similar to that of the TEMPI syndrome, a very rare syndrome of which there have been six published cases. In contrast to the TEMPI syndrome where the erythrocytosis is driven by highly elevated serum erythropoietin, our patient was found to have polycythemia vera. Also in contrast to the other patients with TEMPI syndrome, our patient did not have an identifiable monoclonal gammopathy. Our patient responded to treatment with hydroxyurea. His erythrocytosis, perinephric fluid collections, and telangiectasias resolved over the course of six months. The intrapulmonary shunting has continued to gradually improve with treatment, suggesting that this is an entirely reversible process. CONCLUSION: Our case is the first to describe the combination of polycythemia vera, telangiectasias, perinephric fluid collections, and intrapulmonary shunting. The presentation is highly similar to the previously described TEMPI syndrome, though calls into question the potential importance of the monoclonal gammopathy. Our patient demonstrated a response to treatment with hydroxyurea, while patients with the TEMPI syndrome have shown responses to plasma-cell directed therapies such as bortezomib. PMID- 25143826 TI - Improving Clinical Prediction of Bipolar Spectrum Disorders in Youth. AB - This report evaluates whether classification tree algorithms (CTA) may improve the identification of individuals at risk for bipolar spectrum disorders (BPSD). Analyses used the Longitudinal Assessment of Manic Symptoms (LAMS) cohort (629 youth, 148 with BPSD and 481 without BPSD). Parent ratings of mania symptoms, stressful life events, parenting stress, and parental history of mania were included as risk factors. Comparable overall accuracy was observed for CTA (75.4%) relative to logistic regression (77.6%). However, CTA showed increased sensitivity (0.28 vs. 0.18) at the expense of slightly decreased specificity and positive predictive power. The advantage of CTA algorithms for clinical decision making is demonstrated by the combinations of predictors most useful for altering the probability of BPSD. The 24% sample probability of BPSD was substantially decreased in youth with low screening and baseline parent ratings of mania, negative parental history of mania, and low levels of stressful life events (2%). High screening plus high baseline parent-rated mania nearly doubled the BPSD probability (46%). Future work will benefit from examining additional, powerful predictors, such as alternative data sources (e.g., clinician ratings, neurocognitive test data); these may increase the clinical utility of CTA models further. PMID- 25143827 TI - Comment on "Intravitreal Ampicillin Sodium for Antibiotic-Resistant Endophthalmitis: Streptococcus uberis First Human Intraocular Infection Report". PMID- 25143828 TI - Evaluation of pachymetric measurements with scheimpflug photography-based system and optical coherence tomography pachymetry at different stages of keratoconus. AB - The aim of this study was to compare the central and peripheral pachymetric measurements determined with Sirius system and Visante OCT and evaluate the agreement between them at different stages of keratoconus. Measurements were not significantly different in all patients and subgroups and showed high correlation for the corneal thicknesses of the entire cornea in different stages of keratoconus. PMID- 25143829 TI - Risk factors for glaucoma suspicion in healthy young asian and caucasian americans. AB - Purpose. To determine the prevalence of certain risk factors for glaucoma in a healthy, young population and to compare these risk factors between Asian Americans and Caucasians. Methods. 120 healthy graduate students (mean age 24.8 +/- 3.0 years) underwent a comprehensive ophthalmic examination. Regression analyses controlling for age, sex, and refraction, comparing glaucoma risk factors in Asians (n = 54) and Caucasians (n = 41), were performed. Outcome variables included family history, intraocular pressure (IOP), spherical equivalent, central corneal thickness (CCT), mean deviation (MD) and pattern standard deviation (PSD), and disc and retinal nerve fiber layer (RNFL) parameters. Results. 61% of subjects were female; the mean spherical equivalent was -3.81 +/- 3.2 D; and the mean axial length (AL) was 25.1 +/- 1.7 mm. Regression analysis showed race affected spherical equivalent (P < 0.001), AL (P = 0.0073), IOP (P < 0.001), and cup to disc area ratio (CDAR) (P = 0.012). Family history, CCT, MD, and PSD did not vary between Asians and Caucasians (P > 0.05). In this study, we found Asian Americans, compared to Caucasians, had 2.95 +/- 0.64 D greater myopia; greater IOP by 2.74 +/- 0.62 mmHg; and larger CDAR by 0.12 +/- 0.046. Conclusions. In our study population, young, healthy Asian Americans had greater myopia, IOP, and CDAR as compared to Caucasians, suggesting that racial variations can be important when diagnosing glaucoma. PMID- 25143831 TI - Comparing the effects of repetitive transcranial magnetic stimulation and electroconvulsive therapy in the treatment of depression: a systematic review and meta-analysis. AB - Electroconvulsive therapy (ECT) is the longest standing psychiatric treatment available and has unequivocal benefit in severe depression. However this treatment comes with a number of side effects such as memory impairment. On the other hand, Repetitive Transcranial Magnetic Stimulation (rTMS) is a relatively new form of treatment which has been shown to be efficacious in patients suffering from a number of psychopathologies, including severe depression, with few reported side effects. Due to its potential therapeutic efficacy and lack of side effects, rTMS has gained traction in the treatment of depression, with a number of authors keen to see it take over from ECT. However, it is not clear whether rTMS represents a therapeutic alternative to ECT. This meta-analysis will therefore compare the "gold standard" treatment for severe depression, with the relatively new but promising rTMS. A literature search will be performed with the intention to include all randomised clinical trials. The null hypothesis is that there is no difference in the antidepressant efficacy between the two types of treatment modalities. Statistical analysis of Hamilton Depression Rating Scale (HDRS) scores will be performed. PMID- 25143830 TI - Using the Medical Research Council framework for the development and evaluation of complex interventions in a theory-based infant feeding intervention to prevent childhood obesity: the baby milk intervention and trial. AB - INTRODUCTION: We describe our experience of using the Medical Research Council framework on complex interventions to guide the development and evaluation of an intervention to prevent obesity by modifying infant feeding behaviours. METHODS: We reviewed the epidemiological evidence on early life risk factors for obesity and interventions to prevent obesity in this age group. The review suggested prevention of excess weight gain in bottle-fed babies and appropriate weaning as intervention targets; hence we undertook systematic reviews to further our understanding of these behaviours. We chose theory and behaviour change techniques that demonstrated evidence of effectiveness in altering dietary behaviours. We subsequently developed intervention materials and evaluation tools and conducted qualitative studies with mothers (intervention recipients) and healthcare professionals (intervention deliverers) to refine them. We developed a questionnaire to assess maternal attitudes and feeding practices to understand the mechanism of any intervention effects. CONCLUSIONS: In addition to informing development of our specific intervention and evaluation materials, use of the Medical Research Council framework has helped to build a generalisable evidence base for early life nutritional interventions. However, the process is resource intensive and prolonged, and this should be taken into account by public health research funders. This trial is registered with ISRTCN: 20814693 Baby Milk Trial. PMID- 25143832 TI - Minimally invasive esophagectomy for esophageal cancer: the first experience from Pakistan. AB - BACKGROUND: Two common procedures for esophageal resection are Ivor Lewis esophagectomy and transhiatal esophagectomy. Both procedures have high morbidity rates of 20-46%. Minimally invasive esophagectomy has been introduced to decrease morbidity. We report initial experience of MIE to determine the morbidity and mortality associated with this procedure during learning phase. MATERIAL AND METHODS: Patients undergoing MIE at our institute from January 2011 to May 2013 were reviewed. Record was kept for any morbidity and mortality. Descriptive statistics were presented as frequencies and continuous variables were presented as median. Survival analysis was performed using Kaplan Meier curves. RESULTS: We performed 51 minimally invasive esophagectomies. Perioperative morbidity was in 16 (31.37%) patients. There were 3 (5.88%) anastomotic leaks. We encountered 1 respiratory complication. Reexploration was required in 3 (5.88%) patients. Median operative time was 375 minutes. Median hospital stay was 10 days. The most frequent long-term morbidity was anastomotic narrowing observed in 5 (9.88%) patients. There were no perioperative mortalities. Our mean overall survival was 37.66 months (95% confidence interval 33.75 to 41.56 months). Mean disease-free survival was 24.43 months (95% CI 21.26 to 27.60 months). CONCLUSION: Minimally invasive esophagectomy, when performed in the learning phase, has acceptable morbidity and mortality. PMID- 25143833 TI - A method to determine lysine acetylation stoichiometries. AB - Lysine acetylation is a common protein posttranslational modification that regulates a variety of biological processes. A major bottleneck to fully understanding the functional aspects of lysine acetylation is the difficulty in measuring the proportion of lysine residues that are acetylated. Here we describe a mass spectrometry method using a combination of isotope labeling and detection of a diagnostic fragment ion to determine the stoichiometry of protein lysine acetylation. Using this technique, we determined the modification occupancy for ~750 acetylated peptides from mammalian cell lysates. Furthermore, the acetylation on N-terminal tail of histone H4 was cross-validated by treating cells with sodium butyrate, a potent deacetylase inhibitor, and comparing changes in stoichiometry levels measured by our method with immunoblotting measurements. Of note we observe that acetylation stoichiometry is high in nuclear proteins, but very low in mitochondrial and cytosolic proteins. In summary, our method opens new opportunities to study in detail the relationship of lysine acetylation levels of proteins with their biological functions. PMID- 25143834 TI - Functional stretching exercise submitted for spastic diplegic children: a randomized control study. AB - Objective. Studying the effect of the functional stretching exercise in diplegic children. Design. Children were randomly assigned into two matched groups. Setting. Outpatient Clinic of the Faculty of Physical Therapy, Cairo University. Participants. Thirty ambulant spastic diplegic children, ranging in age from five to eight years, participated in this study. Interventions. The control group received physical therapy program with traditional passive stretching exercises. The study group received physical therapy program with functional stretching exercises. The treatment was performed for two hours per session, three times weekly for three successive months. Main Outcome Measure(s). H?M ratio, popliteal angle, and gait parameters were evaluated for both groups before and after treatment. Results. There was significant improvement in all the measuring variables for both groups in favor of study group. H?M ratio was reduced, popliteal angle was increased, and gait was improved. Conclusion(s). Functional stretching exercises were effectively used in rehabilitation of spastic diplegic children; it reduced H?M ratio, increased popliteal angle, and improved gait. PMID- 25143835 TI - The influence of the coexpression of CD4 and CD8 in cutaneous lesions on prognosis of mycosis fungoides: a preliminary study. AB - Background. Although techniques of immunophenotyping have been successful in characterizing the cells in the cutaneous infiltrates of mycosis fungoides little evidence suggests that variations in the phenotypic characterization correlate with prognosis. Objectives. In a preliminary prospective, single-centre, study we correlated the T-cell phenotype in cutaneous biopsies with the progression of the disease to determine whether the coexpression of CD4 and CD8 has an impact on prognosis. Methods. Skin biopsy specimens from 30 newly diagnosed patients were stained with immunoperoxidase techniques to determine their phenotypic characteristics. After a median followup of 42 months patients were divided into two groups with stable and progressive disease. Results. Eighteen patients had the conventional CD4+CD8- T-cell phenotype. Ten patients showed the coexpression of CD4 and CD8 and had a slightly lower rate of progressive disease. Conclusions. The coexpression of CD4 and CD8 in cutaneous lesions is not rare and is associated with a slightly lower rate of progressive disease. Since double positive CD4/CD8 phenotype is rarely reported in mycosis fungoides the presence on conventional immunophenotyping of both CD may be due to a "mixture" of neoplastic cells and inflammatory CD8+ tumor infiltrating lymphocytes. Immunohistochemical study combined with confocal microscopy could clarify this issue. PMID- 25143836 TI - Accidental left circumflex artery to right lung fistula in a suspected case of pulmonary hypertension. AB - A 56-year-old woman was referred to the cardiology department of the Shahid Modarres hospital. The patient had a history of pulmonary thromboembolism 20 years ago which had been managed by the inferior vena cava filter and since then the patient has been on warfarin. Her chief complaint was chronic dyspnea on exertion (NYHA class II) from several years ago. Right and left heart catheterization was performed for evaluation of pulmonary artery pressure. We found rich collateral formations between LCX as well as RCA and right pulmonary artery, primarily assumed as multiple fistulas. Among patients who have chronic thromboembolic pulmonary hypertension, systemic collateral supply to the pulmonary parenchyma has been previously reported to occur from both bronchial and/or nonbronchial systemic circulations. Our patient had neither signs of heart failure nor myocardial ischemia and, thus, was a candidate for conservative management. The adenosine pulmonary reactivity test was not performed because of low pulmonary pressure which had been estimated to be high. PMID- 25143837 TI - Acute Respiratory Distress Syndrome in Lemierre's Syndrome. AB - Lemierre's syndrome is an infectious disease defined by the presence of septic thrombophlebitis with associated embolic phenomenon, most commonly to the lungs. Here we present two cases from a single institution of acute respiratory distress syndrome (ARDS) developing as a result of Lemierre's syndrome in previously healthy young adult men. ARDS can occur as a consequence of pulmonary septic emboli and sepsis, both of which are well-described consequences of Lemierre's syndrome. We describe important diagnostic and management considerations in the care of patients with hypoxemic respiratory failure and Lemierre's syndrome. Essential components of management include prompt antibiotic therapy, lung protective ventilation strategies, and supportive care. PMID- 25143839 TI - Delayed bleeding and pelvic haematoma after low-energy osteoporotic pubic rami fracture in a warfarin patient: an unusual cause of abdominal pain. AB - Introduction. Acute abdominal pain may be the presenting symptom in a wide range of diseases in the elderly. Acute abdominal pain related to a delayed bleeding and pelvic haematoma after a low-energy pubic rami fracture is rare and can have important consequences; to the best of our knowledge, only one case has been previously described. Case Report. We present an unusual case of an 83-year-old woman taking warfarin for atrial fibrillation, admitted to the Emergency Department (ED) with acute abdominal pain and progressive anemia related to a delayed bleeding and pelvic haematoma 72 hours after a low-energy osteoporotic pubic rami fracture. Warfarin was withheld, anticoagulation was reversed by using fresh frozen plasma and vitamin K, and concentrated red blood cells were given. Haemoglobin level gradually returned to normal with a progressive resorption of the haematoma. Conclusion. Delayed bleeding and pelvic haematoma after osteoporotic pubic rami fracture should be considered in the differential diagnosis of acute abdominal pain in the elderly. This case indicates the need for hospital admission, careful haemodynamic monitoring, and early identification of bleeding in patients with "benign" osteoporotic pubic rami fracture, especially those receiving anticoagulants, to provide an adequate management and prevent severe complications. PMID- 25143840 TI - Treatment of coexisting chronic neutrophilic leukemia and light chain multiple myeloma with hydroxyurea, bortezomib, and dexamethasone. AB - A 63-year-old female was incidentally found to have leukocytosis and referred to the hematology service for evaluation. Complete blood count (CBC) revealed neutrophilia with band predominance and mild thrombocytopenia. Peripheral blood flow cytometry was unremarkable without any evidence of lymphoproliferative disorder or myeloblasts. Bone marrow aspiration and biopsy revealed a markedly hypercellular marrow with myeloid lineage predominance and approximately 10% plasma cells. The monoclonal gammopathy was determined as lambda light chain with a kappa/lambda ratio of 0.06. Cytogenetics revealed normal karyotype, JAK2 kinase was negative, and rearrangement of BCR-ABL1, PDGFRA, PDGFRB, and FGFR1 was negative. The patient was diagnosed with chronic neutrophilic leukemia (CNL) associated with light chain multiple myeloma, complicated by a subdural hemorrhage. She was treated with hydroxyurea and bortezomib/dexamethasone and had complete response with normalization of CBC and kappa/lambda ratio. To the best of our knowledge, we report the first case of chronic neutrophilic leukemia and multiple myeloma treated with bortezomib/dexamethasone. PMID- 25143838 TI - S-Shaped Canals: A Series of Cases Performed by Four Specialists around the World. AB - Recognition of anatomical variations is a real challenge for clinicians undertaking therapy regardless of the teeth that are to be treated. The extent of the curvature is one of the most important variables that could lead to instrument fracture. In clinical conditions, two curves can be present in the same root canal trajectory. This type of geometry is denoted as the "S" shape, and it is a challenging condition. This report describes a different clinical and educational scenario where four specialists around the world present different approaches for the treatment of root canals with double curvatures or S-shaped canals. Endodontic therapy is a very nuanced and challenging science and art. The clinical and teaching experience of the authors show different approaches that can be successfully employed to treat challenging teeth having roots with multiple curves. The necessity of precise knowledge of the root canal morphology and its variation is also underlined. PMID- 25143841 TI - Aggressive Subcutaneous Panniculitis-Like CD30+ Peripheral T-Cell Lymphoma with Diffuse EBER Expression. AB - T-cell lineage lymphoma with an intense membranous and paranuclear CD30 expression in the absence of ALK1 raises a differential diagnosis of peripheral T cell lymphoma (PTCL), NOS and anaplastic large cell lymphoma (ALCL), ALK negative. However, Epstein-Barr virus is consistently negative in ALCL and is not considered an implicating factor in its pathogenesis. We describe a case of T cell lymphoma showing anaplastic large cell morphology with scattered hallmark cells and a uniform CD30 and Epstein-Barr virus encoded early RNA (EBER) expression that primarily involved the subcutaneous tissue at presentation. On incisional biopsy, the neoplastic cells were positive for CD3, CD2, and CD30 while negative for LCA, CD20, PAX5, CD56, ALK1, and cytotoxic granules. Molecular analysis identified a positive T-cell receptor (beta and gamma) gene rearrangement by PCR. Proliferation index approached 100% and the patient had a rapidly progressive course; the subcutaneous lesions more than doubled in size within couple of weeks with new evidence for widespread systemic involvement. This case emphasizes a rare EBV association with a CD30 positive T-cell lymphoma where the morphologic and immunophenotypic findings are otherwise nondiscriminatory between PTCL, NOS and ALCL, ALK negative. PMID- 25143842 TI - Colectomy and acute renal failure: a case report with unusual presentation. AB - Surgery is the only curative modality but occasionally it can have some long term complication such as short bowel syndrome. We presented a case reporting a 63 year-old man who had subtotal colectomy with liver metastasectomy according to the colon adenocarcinoma, following the couple of months of surgery; he had acute kidney injury without any end-organ damage while he had a regular diet and nutrition. Following the regular treatment of renal failure, colorectal cancer recurrence was excluded and then he was discharged from the hospital with a normal serum creatinine level. The patient was admitted to the nephrology clinic again for acute renal failure within 3 weeks of last admission to the hospital. He also denied the insufficient oral water intake and nutrition, but laboratory examination revealed acute renal failure. We suspected for short bowel syndrome (SBS). Following the hydration, loperamide hydrochloride 10 mg/day was started and the patient was followed up with normal serum creatinine and uric acid levels. To the best of our knowledge, this is the first case report, in which a patient with short bowel syndrome presented with prerenal acute renal failure even though he had sufficient oral intake and nutrition and can be treated with hydration and loperamide hydrochloride. PMID- 25143843 TI - Valproate Treatment in an ALS Patient Carrying a c.194G>A Spastin Mutation and SMN2 Homozygous Deletion. AB - Here we report the case of an ALS patient found to carry both a novel heterozygous change (c.194G>A) within the spastin gene and a homozygous deletion of the SMN2 gene. The patient was started on valproic acid (VPA, 600 mg/die per os) considering the capacity of this drug of increasing survival motor neuron through an epigenetic mechanism. Patient clinical course and molecular effects of VPA on skin fibroblasts obtained from the proband are described. This c.194G>A spastin mutation might expand the previously known borders of type 4 spastic paraplegia (SPG4) and we suggest the intriguing possibility that the absence of SMN2 might have acted as a contributory risk factor for starting lower motor neuron damage. Exploring the relationship genocopy-phenocopy in selected ALS patients might represent an interesting strategy for understanding its clinical variability. PMID- 25143844 TI - A Beautician's Dystonia: Long-Lasting Effect of Botulinum Toxin. AB - Treatment options for dystonia are not curative but symptomatic; the treatment of choice for focal dystonias is repeated botulinum toxin injections. Here, we present the case of a 46-year-old beautician with focal dystonia in her left hand that affected her ability to work. Pharmacological treatment with clonazepam and gabapentin failed to resolve her symptoms and was discontinued due to side effects (sleepiness, gastrointestinal disorders). Intramuscular injection of botulinum toxin (incobotulinumtoxinA, Xeomin) into the extensor digitorum communis (35 U), flexor carpi radialis (35 U), and flexor digitorum superficialis (30 U) muscles resulted in complete resolution of symptoms at clinical assessments at 1, 3, 6, and 10 months after the injections, confirmed by the results of surface electromyography 10 months after treatment. The patient was able to work again 1 month after treatment. No reinjection has been necessary at the last evaluation (12 months after treatment). In conclusion, botulinum toxin is an effective treatment for focal dystonia that can have long-lasting effects and can improve patients' ability to work and quality of life. PMID- 25143845 TI - Successful pregnancy after treatment with ulipristal acetate for uterine fibroids. AB - This case report presents a clinical pregnancy after ulipristal acetate (UA) to decrease uterine fibroid size. A 37-year-old patient, gravida 1, abortus 1, with uterine fibroids was treated with 5 mg of UA daily for 13 weeks starting eight months after a multiple laparotomic myomectomy. Fibroid shrinkage and restoration of the morphology of endometrial cavity were evaluated in order to allow a subsequent pregnancy. A decrease of the uterine fibroids and a normal morphology of the endometrial cavity were noted by transvaginal ultrasound after treatment. An endometrial biopsy excluded histologic endometrial changes. Three months after the end of UA the patient reported amenorrhea for 5 weeks and a clinical pregnancy was confirmed with transvaginal ultrasound. She underwent a subsequent uneventful pregnancy. Thus, the spontaneous pregnancy after UA to reduce fibroid size may support the potential clinical utility of this selective progesterone receptor modulator in the management of women with pregnancy desire and uterine fibroids after a prior myomectomy. Patients who refuse a new surgical procedure and/or those who are going to undergo assisted reproductive techniques would benefit from UA. It effectively shrinks fibroids, avoids risks of a new surgical procedure, and allows an immediate attempt at conception after the end of treatment. PMID- 25143846 TI - Two Cases of Severe Preeclampsia Were Diagnosed with HELLP Postpartum after Caesarian Section. AB - HELLP occurs in 0.5%-0.9% of all pregnancies. About 30% of the cases happen within 48 hours after delivery. Women with postpartum HELLP syndrome have significantly higher incidences of complications. Because of the absence of classical signs of preeclampsia, it can confuse physicians and lead to delay in diagnosis. Therefore, it is associated with serious maternal morbidity. We present two cases of acute postpartum HELLP syndrome after caesarean section following severe preeclampsia. Our cases were successfully managed with the timely diagnosis and therapy. PMID- 25143847 TI - Partial and Total Descemet's Detachments in a Patient with Severe Terrien's Marginal Degeneration and Juvenile Idiopathic Arthritis. AB - A 16-year-old female with juvenile idiopathic arthritis presented with a one month history of decreasing vision and increasing corneal edema in her left eye. Slit-lamp examination, keratometric measurements, and OCT evaluation led to a diagnosis of Terrien's marginal degeneration in both eyes along with a complete detachment of Descemet's membrane in the left eye and partial detachment in the right eye. She was treated with an intracameral injection of air and then topical betamethasone and chloramphenicol which lead to the resolution of symptoms. We further examine the pathophysiology of this disease based on current literature. PMID- 25143848 TI - Ischemic retinopathy and neovascular proliferation secondary to severe head injury. AB - We report a case with severe head trauma and perforating globe injury in one eye and ischemic retinopathy and neovascular proliferation in the other eye. A 37 year-old male was brought to the emergency department after a motor vehicle accident with severe maxillofacial trauma. Ophthalmic examination revealed hematoma of the left eyelids as well as traumatic rupture and disorganization of the left globe. On the right eye, anterior segment and fundoscopic examination were normal. Primary globe repair was performed. At postoperative one-month visit, the right eye revealed no pathology of the optic disc and macula but severe neovascularization in the temporal peripheral retina. The patient was diagnosed as ischemic retinopathy and neovascular proliferation due to head trauma. PMID- 25143849 TI - An unusual case of clear cell chondrosarcoma with very late recurrence and lung metastases, 29 years after primary surgery. AB - Clear cell chondrosarcoma is a rare bone neoplasm with low-grade clinical course and the potential to metastasize to the skeleton and lungs. The aim of this report is to present a case that is extremely rare, but in accordance with the literature where the clear cell chondrosarcoma reportedly has a tendency for late metastases. In our patient the primary surgery was intralesional, since it was mistakenly interpreted as a benign tumour in the early 80s. The local recurrence and lung metastases occurred, however, 29 years after the initial treatment. The local recurrence was resected with wide margins, no additional surgery or oncological treatments were given, and two and half years postoperatively patient is doing well and there is no progression in the disease. In conclusion, it is important to have a long follow-up to the clear cell chondrosarcoma patients even for decades or lifelong, because the malignancy tends to metastasize or recur after an extended period. The course of metastasized disease may be unusually slow, so relatively aggressive treatment in metastasized and recurring cases is justified. PMID- 25143850 TI - Spinal hydatidosis relapse: a case report. AB - Human cystic echinococcosis (CE) is a zoonosis caused by the larval stage of the Echinococcus granulosus and the most common sites affected are the liver and lung in approximately 80-90% of cases. The hydatid bone represents the 0.5-2.5% of all cases and localization cord is present about 50% of the time. This benign and commonly asymptomatic disease may simulate an aggressive malignancy because of osseous destruction and aggressive extension. We report a case of a 42-year-old male patient, presented with an unusual spinal hydatidosis relapse, related to anthelmintic drug therapy withdrawal after 10-year treatment. The man had previous excision of chest and hepatic hydatid cysts (resp., 10 and 3 years ago) and after primary mediastinal and spinal involvement (3 years ago) he was lost to follow-up and discontinued drug therapy. The patient underwent surgery and the postoperative histopathology confirmed the diagnosis. The patient recovered with no complications. Despite significant progress in diagnostic imaging, pharmacological and surgical therapy, spinal CE remains associated with high morbidity. PMID- 25143851 TI - A rare tumor of nasal cavity: glomangiopericytoma. AB - Glomangiopericytoma is a rare vascular neoplasm characterized by a pattern of prominent perivascular growth. A 72-year-old woman was admitted to our clinic complaining of nasal obstruction, frequent epistaxis, and facial pain. A reddish tumor filling the left nasal cavity was observed on endoscopy and treated with endoscopic excision. Microscopically, closely packed cells interspersed with numerous thin-walled, branching staghorn vessels were seen. Glomangiopericytoma is categorized as a borderline low malignancy tumor by WHO classification. Long term follow-up with systemic examination is necessary due to high risk of recurrence. PMID- 25143852 TI - A case of conservatively managed invasive ceruminoma and a review of the literature. AB - Ceruminomas are rare tumours arising from the apocrine sweat glands of the ear canal. We present a case of a malignant ceruminoma, which was managed with local surgical excision only rather than the wider clearance more commonly undertaken with these invasive neoplasms. We present the clinical case, histological analysis, and clinical progression for this patient and review the literature on this uncommon pathology. PMID- 25143853 TI - Peritoneal inclusion cysts in female children: pathogenesis, treatment, and multimodality imaging review. AB - We report the multimodality imaging findings of peritoneal inclusion cysts in two adolescent females each with a prior history of abdominal surgery. The few reports of peritoneal inclusion cysts in the pediatric population have largely focused on the clinical and pathological features of this entity. We wish to emphasize the imaging findings of peritoneal inclusion cysts on multiple modalities, the advantage of MRI in confirming the diagnosis, and the need to keep considering this diagnosis in patients who present with a pelvic cystic mass, with a history of surgery, even if remote. Additionally, we review the pathology, pathophysiology, differential diagnosis, and treatment options of peritoneal inclusion cysts. PMID- 25143854 TI - Isolated asymptomatic short sternum in a healthy young girl. AB - Congenital sternal defects are rare deformities frequently associated with other anomalies of the chest wall and other organ systems. Although pectus excavatum, pectus carinatum, and cleft sternum can present as isolated deformity, in most cases they are associated with heart and inner organs anomalies and described as symptoms of syndromes like Marfan syndrome, Noonan syndrome, Poland anomaly, and Cantrell pentalogy. In contrast, the etiology of an isolated defect is not well understood. We observed a short sternum (dysmorphic manubrium, hypoplastic body, and complete absence of the xiphoid process) in a completely asymptomatic 13-year old woman. A comprehensive instrumental exams panel was performed to exclude associated anomalies of the heart and of the other organ systems. The patient was completely asymptomatic and she did not need any medical or surgical treatment. To our knowledge, this is the first case of isolated short sternum reported in literature. PMID- 25143855 TI - Management of intrathoracic benign schwannomas of the brachial plexus. AB - Primary tumours of the brachial plexus are rare entities. They usually present as extrathoracic masses located in the supraclavicular region. This report describes two cases of benign schwannomas arising from the brachial plexus with an intrathoracic growth. In the first case the tumour was completely intrathoracic and it was hardly removed through a standard posterolateral thoracotomy. In the second case the tumour presented as a cervicomediastinal lesion and it was resected through a one-stage combined supraclavicular incision followed by left video-assisted thoracoscopic surgery. A brachial plexus tumour should be suspected not only in patients with a supraclavicular or cervicomediastinal mass but also in those with intrathoracic apical lesions. A preoperative magnetic resonance imaging study of brachial plexus should be performed in such cases in order to plan the correct surgical approach. PMID- 25143856 TI - Fatty Acid composition of the muscle lipids of five fish species in isikli and karacaoren dam lake, Turkey. AB - Total fatty acid composition of muscle lipids in some fish species (Cyprinus carpio (Isikli Dam Lake), Tinca tinca (Isikli Dam Lake), Scardinius erythrophthalmus (Isikli Dam Lake), Cyprinus carpio (Karacaoren Dam Lake), and Carassius carassius (Karacaoren Dam Lake)) was determined by gas chromatography. Polyunsaturated fatty acids (PUFAs) of Cyprinus carpio (Isikli Dam Lake) were found higher than PUFA of other species. Palmitic acid was the highest saturated fatty acid (SFA) in Tinca tinca (24.64%). Oleic acid was the highest monounsaturated fatty acid (MUFAs) in Cyprinus carpio (Isikli Dam Lake) (19.25%). The most abundant polyunsaturated fatty acid in Scardinius erythrophthalmus was docosahexaenoic acid (DHA) (17.94%). Total omega3 fatty acid composition was higher than the total omega6 fatty acids of Cyprinus carpio in both dam lakes. omega3/omega6 rates in Cyprinus carpio (Isikli Dam Lake), Tinca tinca, Scardinius erythrophthalmus, Cyprinus carpio (Karacaoren), and Carassius carassius were 2.12, 1.19, 2.15, 2.87, and 2.82, respectively. PMID- 25143857 TI - Quantitative Analysis of Adulterations in Oat Flour by FT-NIR Spectroscopy, Incomplete Unbalanced Randomized Block Design, and Partial Least Squares. AB - This paper developed a rapid and nondestructive method for quantitative analysis of a cheaper adulterant (wheat flour) in oat flour by NIR spectroscopy and chemometrics. Reflectance FT-NIR spectra in the range of 4000 to 12000 cm(-1) of 300 oat flour objects adulterated with wheat flour were measured. The doping levels of wheat flour ranged from 5% to 50% (w/w). To ensure the generalization performance of the method, both the oat and the wheat flour samples were collected from different producing areas and an incomplete unbalanced randomized block (IURB) design was performed to include the significant variations that may be encountered in future samples. Partial least squares regression (PLSR) was used to develop calibration models for predicting the levels of wheat flour. Different preprocessing methods including smoothing, taking second-order derivative (D2), and standard normal variate (SNV) transformation were investigated to improve the model accuracy of PLS. The root mean squared error of Monte Carlo cross-validation (RMSEMCCV) and root mean squared error of prediction (RMSEP) were 1.921 and 1.975 (%, w/w) by D2-PLS, respectively. The results indicate that NIR and chemometrics can provide a rapid method for quantitative analysis of wheat flour in oat flour. PMID- 25143859 TI - Recent advances in diagnosis and treatment of gliomas using chlorotoxin-based bioconjugates. AB - Malignant gliomas, especially glioblastoma multiforme, are the most widely distributed and deadliest brain tumors because of their resistance to surgical and medical treatment. Research of glioma-specific bioconjugates for diagnosis and therapy developed rapidly during the past several years. Many studies have demonstrated that chlorotoxin (CTX) and Buthus martensii Karsch chlorotoxin (BmK CT) specifically inhibited glioma cells growth and metastasis, and accelerated tumor apoptosis. The bioconjugates of CTX or BmK CT with other molecules have played an increasing role in diagnostic imaging and treatment of gliomas. To date, CTX-based bioconjugates have achieved great success in phase I/II clinical trials about safety profiles. Here, we will provide a review on the important role of ion channels in the underlying mechanisms of gliomas invasive growth and how CTX suppresses gliomas proliferation and migration. We will summarize the recent advances in the applications of CTX bioconjugates for gliomas diagnosis and treatment. In addition, we will review recent studies on BmK CT bioconjugates and compare their efficacies with CTX derivatives. Finally, we will address advantages and challenges in the use of CTX or BmK CT bioconjugates as specific agents for theranostic applications in gliomas. PMID- 25143861 TI - The value of (68)Ga-DOTATATE PET/CT in diagnosis and management of neuroendocrine tumors compared to current FDA approved imaging modalities: a review of literature. AB - Neuroendocrine tumors (NETs) are rare group of neoplasms arising from nervous and endocrine systems. Somatostatin analogue imaging is a functional imaging modality of choice for evaluating the NETs. Recent availability of positron emitting radioisotope labeled somatostatin analogues to image neuroendocrine cancers, has raised the interests to use this new imaging modality in management of patients with NETs. (68)Ga-DOTATATE PET/CT has demonstrated superiority in lesion detection compared to Octreoscan, MIBG scintigraphy and MRI. In this article, we reviewed the published studies evaluating the role of (68)Ga-DOTATATE PET in diagnosis and management of patients with neuroendocrine tumors and comparing it to current FDA approved imaging modalities including Octreoscan, MIBG scintigraphy, (18)F FDG PET/CT, CT and MRI. PMID- 25143858 TI - Ionotropic GABA Receptors and Distal Retinal ON and OFF Responses. AB - In the vertebrate retina, visual signals are segregated into parallel ON and OFF pathways, which provide information for light increments and decrements. The segregation is first evident at the level of the ON and OFF bipolar cells in distal retina. The activity of large populations of ON and OFF bipolar cells is reflected in the b- and d-waves of the diffuse electroretinogram (ERG). The role of gamma-aminobutyric acid (GABA), acting through ionotropic GABA receptors in shaping the ON and OFF responses in distal retina, is a matter of debate. This review summarized current knowledge about the types of the GABAergic neurons and ionotropic GABA receptors in the retina as well as the effects of GABA and specific GABAA and GABAC receptor antagonists on the activity of the ON and OFF bipolar cells in both nonmammalian and mammalian retina. Special emphasis is put on the effects on b- and d-waves of the ERG as a useful tool for assessment of the overall function of distal retinal ON and OFF channels. The role of GABAergic system in establishing the ON-OFF asymmetry concerning the time course and absolute and relative sensitivity of the ERG responses under different conditions of light adaptation in amphibian retina is also discussed. PMID- 25143862 TI - Development of a peptide by phage display for SPECT imaging of resistance susceptible breast cancer. AB - Personalized medicine is at the forefront of cancer diagnosis and therapy. Molecularly targeted therapies such as trastuzumab and tamoxifen have enhanced prognosis of patients with cancers expressing ERBB2 and the estrogen receptor, respectively. One obstacle to targeted therapy is the development of resistance. A targeted peptide that could distinguish resistance-susceptible cancer would aid in treatment. BT-474 human breast cancer cells can be resistant to both tamoxifen and trastuzumab, and may serve as a model for malignancies in which targeted therapy may not work. Bacteriophage (phage) display is a combinatorial technology that has been used to isolate peptides that target a specific cancer subtype. It was hypothesized that in vivo phage display could be used to select a peptide for SPECT imaging of BT-474 human breast cancer xenografts. A phage library displaying random 15 amino acid peptides was subjected to four rounds of selection, after which 14 clones were analyzed for BT-474 binding and specificity. One phage clone, 51, demonstrated superior binding and specificity, and the displayed peptide was synthesized for in vitro characterization. Peptide 51 bound specifically to BT-474 cells with an EC50 = 2.33 uM and was synthesized as a DOTA-conjugated peptide and radiolabeled with (111)In for in vitro and in vivo analysis. The radiolabeled peptide exhibited an IC50 = 16.1 nM to BT-474 cells and its biodistribution and SPECT imaging in BT-474 xenografted mice was analyzed. Although tumor uptake was moderate at 0.11% ID/g, SPECT imaging revealed a distinct tumor vasculature binding pattern. It was discovered that peptide 51 had an identical 5 amino acid N-terminal sequence to a peptide, V1, which bound to Nrp1, a tumor vasculature protein. Peptide 51 and V1 were examined for binding to target cells, and 51 bound both target and endothelial cells, while V1 only bound endothelial cells. Truncated versions of 51 did not bind BT 474 cells, demonstrating that the targeting ability of 51 was independent of the homologous V1 sequence. These results demonstrate that in vivo phage display can effectively identify a peptide that specifically targets a breast cancer cell line that is susceptible to targeted therapy resistance. PMID- 25143860 TI - The role of molecular imaging in diagnosis of deep vein thrombosis. AB - Venous thromboembolism (VTE) mostly presenting as deep venous thrombosis (DVT) and pulmonary embolism (PE) affects up to 600,000 individuals in United States each year. Clinical symptoms of VTE are nonspecific and sometimes misleading. Additionally, side effects of available treatment plans for DVT are significant. Therefore, medical imaging plays a crucial role in proper diagnosis and avoidance from over/under diagnosis, which exposes the patient to risk. In addition to conventional structural imaging modalities, such as ultrasonography and computed tomography, molecular imaging with different tracers have been studied for diagnosis of DVT. In this review we will discuss currently available and newly evolving targets and tracers for detection of DVT using molecular imaging methods. PMID- 25143863 TI - Feasibility of simultaneous PET/MR in diet-induced atherosclerotic minipig: a pilot study for translational imaging. AB - Novel hybrid 18-fluoro-deoxy-D-glucose ((18)F-FDG) based positron emission tomography (PET) and magnetic resonance imaging (MRI) has shown promise for characterization of atherosclerotic plaques clinically. The purpose of this study was to evaluate the method in a pre-clinical model of diet-induced atherosclerosis, based on the Gottingen minipig. Using (18)F-FDG PET/MRI the goal was to develop and create a new imaging method in an in vivo animal model for translational studies of atherosclerosis. We used a strategy of multisequence MRI for optimal anatomical imaging of the abdominal aortas of the pigs (n=4): T1 weighted turbo spin-echo (T1-TSE), T2-weighted turbo spin-echo (T2-TSE) and proton density imaging with and without fat saturation. (18)F-FDG PET emission data were collected from a single bed position of the abdominal aorta in 3D mode for either 10 (n=4) or 10 and 20 minutes (n=2) to measure glycolysis as given by standardized uptake values (SUV). Ex vivo en face evaluation of aortas from an atherosclerotic animal illustrated plaque distribution macroscopically, compared to a lean control animal. Although T2-TSE weighted imaging was most consistent, no one MRI sequence was preferable and superior to another for visualization and identification of the abdominal aorta. We found poor correlation between SUVs obtained from 10 and 20 minutes of reconstructed PET emission data. This can most likely be ascribed to intestinal movement. In conclusion multisequence MRI is recommended for optimal imaging of the abdominal aorta using MRI. Furthermore we found that 10 minutes of PET emission data seems adequate. This is the first study to demonstrate that the method of (18)F-FDG PET/MRI is feasible in minipig models of atherosclerosis, and therefore relevant in larger prospective studies. Perspectives of the method include correlation to e.g. aortic immunohistochemistry findings and a range of genomic and proteomic analyses. PMID- 25143864 TI - A pilot study in epilepsy patients using simultaneous PET/MR. AB - Integrated PET/MR with simultaneous acquisition may improve the identification of pathologic findings in patients. This pilot study evaluated metabolic activity differences between epilepsy patients and healthy controls and directly correlated FDG uptake with MR regional abnormality. Epilepsy patients (n=11) and controls (n=6) were imaged on a whole-body simultaneous PET/MR scanner. After FDG injection, simultaneous images were acquired for 60 minutes. Statistical analyses on SUV values (over 117 brain regions, including left and right, for 96 cortical and 21 subcortical regions) derived from three normalization methods, by individual subject's mean cortical, white matter or global brain, were compared between groups. The asymmetry was compared. T2, T1 and PET co-registered images were also used for lesion detection and correlation of PET and MR regional abnormality. Left and right postcentral gyri were found to be consistently hypermetabolic regions, while right temporal pole and planum polare were consistently hypometabolic regions by all three normalization methods. Using the asymmetry index (AI > 10% or SUV ratios > 1.2), more metabolic asymmetry regions were detected in patients than in controls, with 96.2% agreement. The presence of hippocampal abnormalities or cortical tubers detected via T2 FLAIR in patients correlated well with the hypometabolism detected via FDG-PET. Our results showed specific patterns of metabolic abnormality and asymmetry over 117 brain regions in epilepsy patients, as compared to controls, suggest that simultaneous PET/MR imaging provides a useful tool to help understand etiopathogenesis and localize seizure foci. PMID- 25143865 TI - Clinical impact of FDG-PET/CT on colorectal cancer staging and treatment strategy. AB - FDG-PET/CT is rarely used for initial staging of patients with colorectal cancer (CRC). Surgical resection of primary tumor and isolated metastases may result in long-term survival or presumed cure, whereas disseminated disease contraindicates operation. We analyzed a retrospective material to elucidate the potential value of FDG-PET/CT for staging of CRC. Data were retrieved from 67 consecutive patients (24-84 years) with histopathologically proven CRC who had undergone FDG PET/CT in addition to conventional imaging for initial staging. Treatment plans before and after FDG-PET/CT were compared and patients divided as follows: (A) Patients with a change in therapy following FDG-PET/CT and (B) Patients without a change following FDG-PET/CT. Sixty-two patients had colon and five had rectal cancer. Of these, 20 (30%; CI 20.2-41.7) belonged to group A, whereas 47 (70%; CI 58.3-79.8) fell in group B. In conclusion, FDG-PET/CT changed treatment plan in 30% of cases. In 1/3 of these there was either a change from intended curative to palliative therapy or vice versa, while in the remaining 2/3 the pattern was more mixed. Thus, even in a retrospective routine material there were substantial changes in management strategy following FDG-PET/CT for staging in CRC. PMID- 25143866 TI - Initial in vivo PET imaging of 5-HT1A receptors with 3-[(18)F]mefway. AB - 4-trans-[(18)F]Mefway is a PET radiotracer with high affinity for 5-HT1A receptors. Our preliminary work indicated the positional isomer, 3-[(18)F]mefway, would be suitable for PET imaging of 5-HT1A receptors. We now compare the in vivo behaviour of 3-mefway with 4-mefway to evaluate 3-[(18)F]mefway as a potential 5 HT1A PET radiotracer. Two male rhesus macaques were given bolus injections of both 3- and 4-trans-[(18)F]mefway in separate experiments. 90 minute dynamic PET scans were acquired. TACs were extracted in the mesial temporal lobe (MTL) and caudal anterior cingulate gyrus (cACg). The cerebellum (CB) was used as a reference region. In vivo behavior of the radiotracers in the CB was compared based upon the ratio of normalized PET uptake for 3- and 4-trans-[(18)F]mefway. Specific binding was compared by examining MTL/CB and cACg/CB ratios. The subject averaged ratio of 3-[(18)F]mefway to 4-trans-[(18)F]mefway in the cerebellum was 0.96 for 60-90 minutes. MTL/CB reached plateaus of ~2.7 and ~6 by 40 minutes and 90 minutes for 3- and 4-trans-[(18)F]mefway, respectively. cACg/CB reached plateaus of ~2.5 and ~6 by 40 minutes and 70 minutes for 3- and 4-trans [(18)F]mefway, respectively. The short pseudoequilibration times and sufficient uptake of 3-[(18)F]mefway may be useful in studies requiring short scan times. Furthermore, the similar nondisplaceable clearance in the CB to 4-trans [(18)F]mefway suggests the lower BPND of 3-[(18)F]mefway is due to a lower affinity. The lower affinity of 3-[(18)F]mefway may make it useful for measuring changes in endogenous 5-HT levels, however, this remains to be ascertained. PMID- 25143867 TI - MicroRNA-570-3p regulates HuR and cytokine expression in airway epithelial cells. AB - Asthma is a chronic lung disease that affects people of all ages and is characterized by high morbidity. The mechanisms of asthma pathogenesis are unclear, and there is a need for development of diagnostic biomarkers and greater understanding of regulation of inflammatory responses in the lung. Post transcriptional regulation of cytokines, chemokines, and growth factors by the action of microRNAs and RNA-binding proteins on stability or translation of mature transcripts is emerging as a central means of regulating the inflammatory response. In this study, we demonstrate that miR-570-3p expression is increased with TNFalpha stimuli in normal human bronchial epithelial cells (2.6 +/- 0.6, p = 0.01) and the human airway epithelial cell line A549 (4.6 +/- 1.4, p = 0.0068), and evaluate the functional effects of its overexpression on predicted mRNA target genes in transfected A549 cells. MiR-570-3p upregulated numerous cytokines and chemokines (CCL4, CCL5, TNFalpha, and IL-6) and also enhanced their induction by TNFalpha. For other cytokines (CCL2 and IL-8), the microRNA exhibited an inhibitory effect to repress their upregulation by TNFalpha. These effects were mediated by a complex pattern of both direct and indirect regulation of downstream targets by miR-570-3p. We also show that the RNA-binding protein HuR is a direct target of miR-570-3p, which has implications for expression of numerous other inflammatory mediators that HuR is known regulate post transcriptionally. Finally, expression of endogenous miR-570-3p was examined in both serum and exhaled breath condensate (EBC) from asthmatic and healthy patients, and was found to be significantly lower in EBC of asthmatics and inversely correlated to their lung function. These studies implicate miR-570-3p as a potential regulator of asthmatic inflammation with potential as both a diagnostic and therapeutic target in asthma. PMID- 25143868 TI - Dominant B-cell epitopes from cancer/stem cell antigen SOX2 recognized by serum samples from cancer patients. AB - Human sex determining region Y-box 2 (SOX2) is an important transcriptional factor involved in the pluripotency and stemness of human embryonic stem cells. SOX2 plays important roles in maintaining cancer stem cell activities of melanoma and cancers of the brain, prostate, breast, and lung. SOX2 is also a lineage survival oncogene for squamous cell carcinoma of the lung and esophagus. Spontaneous cellular and humoral immune responses against SOX2 present in cancer patients classify it as a tumor-associated antigen (TAA) shared by lung cancer, glioblastoma, and prostate cancer among others. In this study, B-cell epitopes were predicted using computer-assisted algorithms. Synthetic peptides based on the prediction were screened for recognition by serum samples from cancer patients using ELISA. Two dominant B-cell epitopes, SOX2:52-87 and SOX2:98-124 were identified. Prostate cancer, glioblastoma and lung cancer serum samples that recognized the above SOX2 epitopes also recognized the full-length protein based on Western blot. These B-cell epitopes may be used in assessing humoral immune responses against SOX2 in cancer immunotherapy and stem cell-related transplantation. PMID- 25143869 TI - Molecular analysis of interleukin-25 exons 1 and 2 and its serum levels in Iranian patients with multiple sclerosis. AB - Overexpression of Interleukin-17 (IL-17) family has been shown in a variety of autoimmune diseases. IL-25 (IL-17E), as a member of this family of cytokines, induces the overexpression of IL-13 and impedes Th17/IL-17 responses. In the present study potential single nucleotide polymorphisms (SNP) of IL-25, its serum level in Multiple Sclerosis (MS) patients have been surveyed. Blood samples were obtained from 100 Relapsing-Remitting MS cases, and 100 healthy controls. Serum levels of IL-25 were measured by ELISA. IL-25 exons 1 and 2 were sequenced. IL-25 serum levels investigation showed significant association in cases compared to controls. Molecular analysis of IL-25exons 1 and 2 depicted significant differences in polymorphisms of exon 2 between two groups of study. However, no significant differences were found in polymorphisms for IL-25 exon. These results demonstrate that serum levels of IL-25 are reduced in MS patients compared to controls. This is the first study in Iran that shows polymorphisms in IL-25 among MS patients. Considering the role of IL-25 in suppression of the effects of IL 17A and active phase of Experimental Autoimmune Encephalomyelitis (EAE) in vivo, this cytokine seems to have therapeutic potentials for autoimmune diseases like MS. PMID- 25143870 TI - G protein signaling modulator-3: a leukocyte regulator of inflammation in health and disease. AB - G protein signaling modulator-3 (GPSM3), also known as G18 or AGS4, is a member of a family of proteins containing one or more copies of a small regulatory motif known as the GoLoco (or GPR) motif. GPSM3 interacts directly with Galpha and Gbeta subunits of heterotrimeric G proteins to regulate downstream intracellular signals initiated by G protein coupled receptors (GPCRs) that are activated via binding to their cognate ligands. GPSM3 has a selective tissue distribution and is highly expressed in immune system cells; genome-wide association studies (GWAS) have recently revealed that single nucleotide polymorphisms (SNPs) in GPSM3 are associated with chronic inflammatory diseases. This review highlights the current knowledge of GPSM3 function in normal and pathologic immune-mediated conditions. PMID- 25143871 TI - Phenotypic Identification of Spinal Cord-Infiltrating CD4+ T Lymphocytes in a Murine Model of Neuropathic Pain. AB - BACKGROUND: Neuropathic pain is one of the most devastating kinds of chronic pain. Neuroinflammation has been shown to contribute to the development of neuropathic pain. We have previously demonstrated that lumbar spinal cord infiltrating CD4+ T lymphocytes contribute to the maintenance of mechanical hypersensitivity in spinal nerve L5 transection (L5Tx), a murine model of neuropathic pain. Here, we further examined the phenotype of the CD4+ T lymphocytes involved in the maintenance of neuropathic pain-like behavior via intracellular flow cytometric analysis and explored potential interactions between infiltrating CD4+ T lymphocytes and spinal cord glial cells. RESULTS: We consistently observed significantly higher numbers of T-Bet+, IFN-gamma+, TNF alpha+, and GM-CSF+, but not GATA3+ or IL-4+, lumbar spinal cord-infiltrating CD4+ T lymphocytes in the L5Tx group compared to the sham group at day 7 post L5Tx. This suggests that the infiltrating CD4+ T lymphocytes expressed a pro inflammatory type 1 phenotype (Th1). Despite the observation of CD4+ CD40 ligand (CD154)+ T lymphocytes in the lumbar spinal cord post-L5Tx, CD154 knockout (KO) mice did not display significant changes in L5Tx-induced mechanical hypersensitivity, indicating that T lymphocyte-microglial interaction through the CD154-CD40 pathway is not necessary for L5Tx-induced hypersensitivity. In addition, spinal cord astrocytic activation, represented by glial fibillary acidic protein (GFAP) expression, was significantly lower in CD4 KO mice compared to wild type (WT) mice at day 14 post-L5Tx, suggesting the involvement of astrocytes in the pronociceptive effects mediated by infiltrating CD4+ T lymphocytes. CONCLUSIONS: In all, these data indicate that the maintenance of L5Tx-induced neuropathic pain is mostly mediated by Th1 cells in a CD154 independent manner via a mechanism that could involve multiple Th1 cytokines and astrocytic activation. PMID- 25143872 TI - Emerging Tools for Computer-Aided Diagnosis and Prognostication. PMID- 25143873 TI - Girls Just Wanna Have Fun: a process evaluation of a female youth-driven physical activity-based life skills program. AB - INTRODUCTION: Integrating a positive youth development framework into physical activity programming has become popular as it is believed that this integration can create the development of both physical and psychosocial skills. However, there has been a lack of intervention fidelity research within the field of positive youth development. CASE DESCRIPTION: The Girls Just Wanna Have Fun program was designed in response to increased calls for physical activity programs for female youth and is a theoretically-grounded physical activity-based life skills program that aims to empower female youth. The purpose of this paper was to provide a detailed description of the program and a process evaluation of the first year of program implementation. From interviews with youth and leaders, as well as documentation from the leaders' weekly online log of each implemented session, themes emerged regarding the successes. DISCUSSION AND EVALUATION: Findings from this study indicated that program goals were attained and it appears that the program was implemented, for the most part, as designed. The themes related to successes included using activities to facilitate relational time, providing intentional opportunities for leadership, having communicative program leaders who supported one another, and engaging youth in different types of physical activity. The themes related to challenges included difficulties with facility and transportation, some activities being too much like schoolwork, and social distractions and cliques. Included in the paper is a discussion of practical implications and recommendations for community programmers, as well as future directions for the program. CONCLUSIONS: Overall, this process evaluation represents an important step in responding to calls for increased evaluation in community-based programs and aids in understanding the process in which positive youth development programs can be effectively implemented. PMID- 25143874 TI - Prevalence of hospital malnutrition among cardiac patients: results from six nutrition screening tools. AB - Malnutrition is highly prevalent among hospitalized patients, ranging from 30% to 50% depending on the patient population and the criteria used for diagnosis. Identifying early those who are malnourished and at risk of malnutrition and intervening at an early stage will improve patients overall prognosis and will reduce the costs to the state. Even though cardiac patients are at risk of malnutrition, data on the prevalence of malnutrition among cardiology inpatients is limited. The aim of the study was to assess malnutrition status of the newly admitted patients in a specialist cardiology institution in Sri Lanka by internationally recommended nutrition screening and assessment tools. During study period, 322 (61.22%) males and 204 (38.78%) females were recruited. Malnutrition status assessed by each screening tool had a wide variation. According to Mini Nutritional Assessment tool 69.6% were having possible malnutrition. Malnutrition Screening Tool 47.9% to be at risk of malnutrition. Subjective Global Assessments categorized only 4.2% as malnourished on the other hand Malnutrition Universal Screening Tool categorized 20.4% and 19.6% subjects as at medium risk and high risk of malnutrition respectively. Nutritional Risk Screening detected 6.3%, 25.1% and 24.9% patients to be mildly, moderately and severely malnourished respectively. Short Nutrition Assessment Questionnaire categorized 5.0% and 17.7% patients to be moderately malnourished and severely malnourished correspondingly. In conclusion, Although malnutrition was prevalent among this population, a wide variation in the nutritional status when assessed by widely used internationally recognized tools was observed. PMID- 25143875 TI - Evaluation of five different suture materials in the skin of the earthworm (Lumbricus terrestris). AB - The purpose of this study was to determine which suture material is the most appropriate for dermal closure of terrestrial annelids. This paper describes the tissue reactions of the earthworm, Lumbricus terrestris, to five different types of suture materials in order to determine which suture material is the most appropriate for dermal closure. Silk, monofilament nylon, polydiaxonone, polyglactin 910, and chromic gut were studied. There was mild to moderate tissue reaction to all five suture materials. In all of the biopsies wound-healing reaction consisted of aggregates of blastemal cells which appeared in various stages of dedifferentiation from the body wall. Inflammatory cells infiltrated the wound sites, reminiscent of the typical foreign body reaction in vertebrates. The results indicate polyglactin 910 would be the best suture material with regards to tissue security and reaction scores. Chromic gut occupies the next position but there were problems with suture security over time. This appears to be the first suture material performance study on a terrestrial invertebrate. The earthworm, Lumbricus terrestris, was chosen for its wide availability, size, and the extensive species knowledge base. The earthworm may prove to be a good surgical/suture model for economically important invertebrates such as mollusks, tunicates, and insect larval stages. PMID- 25143876 TI - Joint National Committee 8 report: How it differ from JNC 7. PMID- 25143877 TI - Biosimilar drugs: Current status. AB - Biologic products are being developed over the past three decades. The expiry of patent protection for many biological medicines has led to the development of biosimilars in UK or follow on biologics in USA. This article reviews the literature on biosimilar drugs that covers the therapeutic status and regulatory guidelines. Appraisal of published articles from peer reviewed journals for English language publications, search from PubMed, and guidelines from European Medicines Agency, US Food Drug Administration (FDA) and India were used to identify data for review. Literature suggest that biosimilars are similar biological products, i.e., comparable but not identical to the reference product, are not generic version of innovator product and do not ensure therapeutic equivalence. Biosimilars present more challenges than conventional generics and marketing approval is also more complicated. To improve access, US Congress passed the Biologics Price Competition and Innovation act 2009 and US FDA allowed "abbreviated pathway" for their approval. U.S law has defined new standards and terms and EMA scientific guidelines have also set detailed approval standards. India being one of the most preferred manufacturing destinations of biosimilars, there is a need for stringent safety and regulatory guidelines. The New India Guidelines "Draft Guidelines on Similar Biologics were announced in June 2012, by Department of Biotechnology at Boston bio and available online. PMID- 25143878 TI - Effect of pranayama on rate pressure product in mild hypertensives. AB - CONTEXT: The modern living life-style is known to produce various physical and psychological stresses resulting in increased blood pressure (BP) and heart rate (HR). This can lead to increased myocardial oxygen demand (MVO2). MVO2 correlated best with rate pressure product (RPP). RPP is a product of HR and systolic BP. OBJECTIVE: The present study was conducted to evaluate the effect of relaxation in the form of pranayama on RPP in mild hypertensives. MATERIALS AND METHODS: Mild hypertensive patients were divided into two groups. Group A received antihypertensive drugs for 6 weeks and Group B received antihypertensive drugs along with pranayama training for 6 weeks. RESULTS: BP decreased significantly in Group B (148 +/- 8.09-127 +/- 12.10 mm of Hg) where pranayama was added. The decrease was significant as compared to Group A. HR decreased significantly in both the groups as compared to baseline, however the decrease was similar in both groups. RPP decreased significantly in both groups as compared to baseline, however the decrease was significantly more (P < 0.01) when pranayama was added to antihypertensive drugs (96.73 +/- 20.53) when compared to antihypertensive drugs alone (114.66 +/- 26.30). CONCLUSION: The pranayama produces relaxed state and in this state parasympathetic activity overrides sympathetic activity. Hence, addition of pranayama can be a useful addition to antihypertensive drugs for better control of hypertension in mild hypertensives. PMID- 25143879 TI - Does short-term exposure to elevated levels of natural gamma radiation in Ramsar cause oxidative stress? AB - BACKGROUND: Ramsar, a city in northern Iran, has areas with some of the highest recorded levels of natural radiation among inhabited areas measured on the earth. AIMS: To determine whether short-term exposure to extremely high levels of natural radiation induce oxidative stress. MATERIALS AND METHODS: In this study, 53 Wistar rats were randomly divided into five groups of 10-12 animals. Animals in the 1(st) group were kept for 7 days in an outdoor area with normal background radiation while the 2(nd) , 3(rd) , 4(th) and 5(th) groups were kept in four different outdoor areas with naturally elevated levels of gamma radiation in Ramsar. A calibrated RDS-110 survey meter, mounted on a tripod approximately 1 m above the ground, was used to measure exposure rate at each location. On days 7 and 9 blood sampling was performed to assess the serum levels of catalase (CAT) and malondialdehyde (MDA). On day 8, all animals were exposed to a lethal dose of 8 Gy gamma radiations emitted by a Theratron Phoenix (Theratronics, Canada) Cobalt-60 (55 cGy/min) at Radiotherapy Department of Razi Hospital in Rasht, Iran. RESULTS: Findings obtained in this study indicate that high levels of natural radiation cannot induce oxidative stress. CAT and MDA levels in almost all groups were not significantly different (P = 0.69 and P = 0.05, respectively). After exposure to the lethal dose, CAT and MDA levels in all groups were not significantly different (P = 0.054 and P = 0.163, respectively). CONCLUSIONS: These findings indicate that short-term exposure to extremely high levels of natural radiation (up to 196 times higher than the normal background) does not induce oxidative stress. PMID- 25143880 TI - Public knowledge, use and attitude toward multivitamin supplementation: A cross sectional study among general public. AB - BACKGROUND AND OBJECTIVE: The use of supplements has increased substantially in the past few decades. The present study is an effort to explore pattern of use, knowledge and attitude toward consumption of multivitamin supplements among the general public. MATERIALS AND METHODS: A descriptive cross-sectional study on 120 adult participants from the general public was conducted. The participants were interviewed and information was collected in a predesigned structured questionnaire. The data was analyzed and expressed as counts and percentages. RESULTS: Of the 120 study participants, 66 were males and 54 were females. Results revealed that 68.33% (82) of the participants were users of multivitamin supplements. Out of the users, 69.5% (57) participants consumed on the advice of doctors, 18.2% (15) were self-prescribers while 12.1% (10) relied on advice of family or friends. Among the users, 70.96% considered such supplements to be helpful. Reasons quoted for self-medication use of multivitamins were multiple such as maintenance of general health (55%), to allay weakness or fatigue (20%), to improve appetite (15%) etc. Majority of the participants were unaware regarding the correct indications for multivitamin supplementation. Regarding knowledge about the natural sources of these vitamins, as many as 76% showed ignorance. CONCLUSION: Finding from this study suggests that multivitamin use is highly prevalent and the majority of the participants were ignorant of any possible harm or drug interactions. In light of this, there is a need to adopt certain educational interventions to minimize self-directed supplement use and increase awareness regarding their correct usage. PMID- 25143881 TI - Female sterilization failure: Review over a decade and its clinicopathological correlation. AB - OBJECTIVES: The primary objective of the following study is to determine the demographic patterns of women presenting as sterilization-failure and secondary is to evaluate possible etiological factors for failure and lay standard guidelines to reduce failure rate. MATERIALS AND METHODS: The present study is retrospective study conducted in Department of Obstetrics and Gynecology, Government Medical College and Hospital-based on the case records maintained in our institution over a decade (April 2002-March 2012). RESULTS: Over a decade, 140 cases of sterilization-failure with longest interval of 20 years have been documented out of 80 (57.14%) cases were of minilaparotomy (minilap), 53 (37.86%) laparoscopic tubal ligation and 5 (3.57%) were lower segment cesarean section. In 84 cases (60%) sterilization were performed in Primary Health Centre (PHC). Only 58 (41.43%) patients reported failure in 1(st) trimester (<12 weeks). 14 cases (10%) were of ectopic pregnancy. There were 25 cases (17.86%) of spontaneous recanalization. In 27 cases (19.29%) failure was due to improper surgical procedure and rest 54 (38.57%) have conceived due to tuboperitoneal fistula. CONCLUSION: Female sterilization even though considered as permanent method of contraception, recanalization is possible even 20 years after procedure. Maximum cases of failure were with minilap and those were performed at PHC. The most common cause of failure was tuboperitoneal fistula. Ectopic pregnancies were seen in 10% of cases. Proper counseling of patient is must. There is a need to stick to standards of sterilization procedure to prevent future failure. PMID- 25143882 TI - Study of family factors in association with behavior problems amongst children of 6-18 years age group. AB - BACKGROUND: The 'behaviour problems' are having major impact on child's bodily and social development. The family provides emotional support to an individual as well as plays a major role in the formation of one's personality. The quality and nature of the parental nurturance that the child receives will profoundly influence his future development. The knowledge of these family factors associated with behaviour problems may be helpful to identify at risk children. AIMS AND OBJECTIVE: To study the family factors associated with behaviour problems amongst children of 6-18 Yrs age group. SETTING: an adopted urban slum area of Govt. Medical College, Miraj Dist-Sangli. DESIGN: Cross sectional study. MATERIALS AND METHODS: the sample size was calculated based upon 40% prevalence obtained in pilot study. Total 600 Children in the age group of 6-18 years residing in the urban slum area and their parents were interviewed with the help of predesigned, pretested proforma. ANALYSIS: chi-square test and risk estimate with Odd's ratio. RESULTS: Our study result reveals significant association between prevalence of behaviour problems with absence of either or both real parents and alcoholism in the parent or care taker. CONCLUSION: The behaviour problems have good prognosis if they are recognized earlier. Family has great role in prevention of behaviour problems in children, so parental counseling may be helpful. PMID- 25143883 TI - Modified case based learning: Our experience with a new module for pharmacology undergraduate teaching. AB - OBJECTIVE: The undergraduate teaching in pharmacology has always been a challenging task for medical teachers. Traditional lecture format is monotonous and a passive way of learning. There is a need to shift the educational focus from content centered to case based. In an effort to create interest and further improve the student learning, we have introduced simulated bedside teaching sessions as case based learning (CBL) module (modified CBL-[mCBL]) for 2(nd) professional MBBS students. MATERIALS AND METHODS: A case scenario of a clinical disease condition was prepared in consultation with a clinician. During the session, the case was presented along with discussion on the disease process, its management and rational drug use. Students were encouraged to participate actively. After the session, students were requested to fill the feedback questionnaire anonymously (both open-ended questions and responses on Likert scale). RESULTS: According to the students, factors such as clinical orientation, interactivity and re-enforcement of important points helped them to learn better. Majority of the students (76.09%) found the sessions to be better than theory lectures and tutorials. The fact that the interactive component of departmental feedback (taken at the institutional level) has improved during the last 2 years could be attributed to the introduction of these sessions. CONCLUSION: mCBL (in the presence of departmental faculty and concerned clinician) is a good method of integrating pharmacology with clinical subjects. To make such sessions more reliable, the next planned step is to assess the knowledge gained by the students during such sessions in the future. PMID- 25143884 TI - Dexmedetomidine versus esmolol to attenuate the hemodynamic response to laryngoscopy and tracheal intubation: A randomized double-blind clinical study. AB - CONTEXT: Sympathoadrenal response to laryngoscopy and tracheal intubation manifests as transient, but distinct tachycardia and hypertension. AIMS: The objective of this study is to compare the clinical effects of dexmedetomidine with esmolol and control in attenuating the presser response during laryngoscopy. SETTINGS AND DESIGN: A randomized, prospective, double-blind, controlled study. SUBJECTS AND METHODS: We studied consented, 90 adult, American Society of Anesthesiologists physical status I and II patients of either sex, scheduled for non-cardiac surgery requiring intubation. The patients were randomly divided into three groups (n = 30). Group C received placebo, Group E received 2.0 mg/kg of esmolol and Group D received 1.0 MUg/kg of dexmedetomidine, intravenously over 10 min and 3 min before induction of general anesthesia. All patients were uniformly pre-medicated, induced and intubated using thiopentone and succinylcholine as per standard protocol. Heart rate (HR), systemic arterial pressures were recorded at baseline, after study drug infusion, after induction, immediately and 3, 5, 7, 10 min after intubation. STATISTICAL ANALYSIS: Analysis of variance and t-test as appropriate. RESULTS: The mean arterial pressure was significantly increased in patients receiving placebo (P < 0.0001) and esmolol (P < 0.0001) after laryngoscopy and intubation compared with baseline value and Group D (P = 0.6294). The rise in HR (P = 0.08481) and rate pressure product (P = 0.0666) at the time of intubation were minimal and was statistically significant up to 15 min in Group D. CONCLUSIONS: Both the drugs attenuated the pressure response. Of the two drugs administered, dexmedetomidine 1.0 MUg/kg provides a consistent, reliable and effective attenuation of pressure responses when compared to esmolol 2.0 mg/kg. PMID- 25143885 TI - To compare the efficacy and safety of fixed dose combination of thiocolchicoside and aceclofenac versus chlorzoxazone, aceclofenac and paracetamol in patients with acute lower backache associated with muscle spasm. AB - BACKGROUND: The fixed dose combinations (FDCs) of muscle relaxants, non-steroidal anti-inflammatory drugs and paracetamol are commonly prescribed in the treatment of acute lower backache. AIM: The present study was undertaken with the aim of comparing the efficacy and safety of FDCs of thiocolchicoside and aceclofenac versus chlorzoxazone, aceclofenac and paracetamol in patients with acute lower backache associated with muscle spasm. MATERIALS AND METHODS: A total of 100 patients between ages range from 18 and 55 years having low back pain of <=7 days duration were randomly divided into two groups. Group A was prescribed thiocolchicoside (4 mg) + aceclofenac (100 mg) while Group B was prescribed chlorzoxazone (500 mg) + aceclofenac (100 mg) + paracetamol (325 mg) orally twice daily for 7 days. Severity of pain at rest and on movement was recorded using visual analogue scale. Muscle spasm was evaluated by hand-to-floor distance and Lasegue's maneuver. Readings were noted on day 1 (baseline), day 3 and day 7. RESULTS: There was statistically significant reduction in severity of pain and muscle spasm on day 3 and day 7 in both groups. There was no statistically significant difference in pain relief and muscle spasm among the treatment groups but clinically showed better improvement in the Group A. The adverse drug reactions occurring during study showed a statistically significant better safety profile in the Group A than Group B. CONCLUSION: These findings confirm that FDC of thiocolchicoside and aceclofenac is a preferred option for patients with lower backache pain associated with muscle spasm. PMID- 25143886 TI - Neurolaena lobata L. promotes wound healing in Sprague Dawley rats. AB - BACKGROUND: The leaves of the Neurolaena lobata (Asteraceae) plant are used to control diabetes and heal wounds and infections. AIM: The ethanolic extract of N. lobata leaf was evaluated for its ability to heal inflicted wounds in rats using the excision wound model. MATERIALS AND METHODS: Animals were divided into three groups of six each. Test group animals were treated topically with an ethanolic extract of N. lobata (1:1 with petroleum jelly, 100 mg/kg/day). Standard and control group animals were treated with mupirocin and petroleum jelly, respectively. Treatment was given for 13 days and the wound area was measured on alternate days. Parameters of healing assessed were the rate of wound contraction, period of epithelialization and hydroxyproline content. Antimicrobial activity of the extract was observed against Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli. RESULTS: Phytochemical analysis of the extract showed the presence of saponins, tannins, alkaloids and flavanoids. Extract-treated animals exhibited 87% reduction in the wound area over 13 days when compared with the control (78%) and standard (83%) groups (P < 0.05). A significant decrease in the epithelialization period was noticed with the extract-treated test group animals compared with the controls and the standard group animals (P < 0.008). The hydroxyproline content of the extract treated animals was higher (230.5 +/- 42.1) when evaluated against the control and (79.0 +/- 32.2) and the standard (115.0 +/- 44.5) groups (P < 0.05). CONCLUSION: Increase in the rate of wound contraction and hydroxyproline content with decrease in epithelialization time in extract-treated animals support further evaluation of N. lobata as a pharmacotherapy for wound healing. PMID- 25143887 TI - Frequency distribution of virulence factors in uropathogenic Escherichia coli isolated from Kermanshah in 2011-2012. AB - BACKGROUND: Uropathogenic Escherichia coli (UPEC) can cause urinary tract infection (UTI). To prevent urine flow lavage, UPEC has acquired several virulence factors called adhesins. These adhesins are expressed and controlled by different genes. AIM: This study was aimed to determine some of the most important genes that control virulence factors of UPEC (pyelonephritis associated pili [pap], S fimbrial adhesion [sfa] and A fimbrial adhesion [afa] genes), which code for adhesins and phenotypic factors. MATERIALS AND METHODS: In total, 205 UPEC isolates from in- and out-patients with UTI were obtained. Polymerase chain reaction was used for gene amplification. One drop of bacterial suspension, one of red blood cells and one of peripheral blood smear were mixed for hemagglutination (HA). Formation of a clump was considered to be positive. Bacteria were grown on blood agar to determine hemolysis. Surface hydrophobicity was determined using the SAT test. RESULT: Frequencies of pap, afa and sfa were 42 (20.5%), 17 (8.3%) and 44 (21.5%), respectively. Frequencies of HA, hemolysis and hydrophobicity were 138 (67.3%), 56 (27.3%) and 39 (19%), respectively. Among HA-positive bacteria, 103 (74.6%) were mannose resistant. Our results highlight higher frequency of HA than that of other virulence factors, indicating a crucial role of this virulence factor in UPEC. DISCUSSION: We concluded that major differences exist in the prevalence of virulence factors among different UPEC isolated from different countries. The association observed between pathogenicity and virulence factors may promote UPEC survival and growth within the urinary tract. Detecting these genes as the primary controllers of UPEC virulence factors may aid in better management of related infections. PMID- 25143888 TI - Low serum iron as a possible risk factor for neuroleptic malignant syndrome. AB - Neuroleptic malignant syndrome (NMS) is a rare, but fatal condition characterized by rigidity, fever, dysautonomia and altered consciousness along with elevated serum creatinine phosphokinase levels and leukocytosis. Treatment of NMS includes symptomatic and specific treatment with drugs like bromocriptine may be given. Risk factors for NMS include dehydration, parenteral antipsychotics and high potency antipsychotics. One of the important, but lesser known risk factors for NMS is low serum iron. Pronounced reduction in serum iron suggests that acute phase reactants do have a role in NMS. The present case report focuses on the importance of low serum iron as a risk factor for NMS. PMID- 25143889 TI - Recurrent ascites with severe hypoproteinemia in 4-year-old child: A diagnostic dilemma - An atypical presentation of hypothyroidism. AB - Hypothyroidism is frequently encountered condition to a pediatrician. Passive effusions into serous cavities, sometimes to considerable amount are frequently noted. However, the significant ascites caused by this is rare in a child and in no instance, it is too excessive. So diagnosis is frequently delayed and patient frequently receive unnecessary procedures such as liver, even gastrointestinal biopsies. Analysis of ascitic fluid shows exudative nature with high protein. The case we present here is a 4-year-old female child with recurrent ascites, developmental delay and hypoproteinemia. High index of suspicion can lead to diagnosis. Over all prognosis is excellent after stating replacement therapy with L-thyroxine. PMID- 25143890 TI - Sacro-coccygeal teratoma in adult: Two rare case reports and review of literature. AB - The sacrococcygeal area is the most common site of extragonadal teratomas in infants, but is a challenge to make clinical as well as radiological diagnosis in adults. We herein describe two cases of sacrococcygeal teratoma (SCT) in adult. The clinical, radiological and histopathological characteristics of both the cases with their outcome are described with review of the literature. The standard care for SCTs is complete surgical resection of the tumor. The presence of malignant transformation is associated with a less favorable outcome. PMID- 25143891 TI - Persistent mullerian duct syndrome: A case report and review of the literature. AB - Persistent mullerian duct syndrome (PMDS) is usually an accidental finding either during orchipexy or during routine inguinal hernia repair in male patients presenting with maldescended or crytorchid testes. It is caused by a defect in the mullerian inhibiting substance system. Intraoperatively, mullerian remnants consisting of an infantile uterus and fallopian tubes are usually found. Familiarity with PMDS is necessary to diagnose the condition. We report a case of PMDS in a 14-year-old male presenting with bilateral undescended testes. PMID- 25143892 TI - Leiomyosarcoma of the vagina: A rare entity with comprehensive review of the literature. AB - Primary malignant lesions of the vagina are uncommon, and vaginal sarcomas are even rarer. We describe a rare case of stage I, high-grade leiomyosarcoma of the vagina treated with combined modality treatment. A 39-year-old female presented with vaginal mass and underwent resection. Histopathological examination revealed atypical leiomyoma of the vagina with definite risk of recurrence. Eleven months later, she presented with a recurrent vaginal mass and underwent exploratory laparotomy with total abdominal hysterectomy and bilateral salpingo-oophorectomy plus resection of recurrent tumor and partial vaginectomy. The detailed histopathological examination was suggestive of leiomyosarcoma of the vagina. The patient received adjuvant radiotherapy and chemotherapy. The patient is alive and disease-free 29 months postsurgery. Experience with vaginal leiomyosarcomas is limited. The optimal treatment methods have not yet been established because of the rarity of the tumor. We add another case of leiomyosarcoma of the vagina to the limited existing literature. PMID- 25143893 TI - Neuro-cysticercosis presenting with single delusion: A rare psychiatric manifestation. AB - We report a case of multiple parenchymal neurocysticercosis in an elderly lady without raised intracranial tension which caused diagnostic confusion. The initial manifestation was only psychological as delusional disorder without any neurological symptoms or focal neurological deficit. Plain computed tomography scan showed mild bilateral periventricular and subcortical hypodensities. The development of hemiplegia during the course of psychiatric treatment prompted us to go for magnetic resonance imaging brain which clinched the diagnosis. PMID- 25143894 TI - Recurrent solitary fibrous tumor in distal lower extremity: An extremely rare entity. AB - Solitary fibrous tumor (SFT) represents a spectrum of mesenchymal tumors, encompassing tumors previously termed hemangiopericytoma, as having intermediate biological potential. Though they can occur at any site, lower distal extremity is a rare site and recurrence in it is extremely rare. Behavior of SFT is unpredictable. Histomorphology and clinical follow-up have poor correlation. The most important single indicator of clinical outcome is complete excision of the tumor at the time of primary presentation. Tumors with positive margins require close follow-up for several years owing to the potential for late local recurrence. PMID- 25143895 TI - Osteoporosis treatment in India: Call for action. PMID- 25143897 TI - Classification of hyperglycemia in pregnancy. PMID- 25143898 TI - The Asia-Pacific Regional Audit-Epidemiology, Costs, and Burden of Osteoporosis in India 2013: A report of International Osteoporosis Foundation. PMID- 25143899 TI - Medanta insulin protocols in patients undergoing cardiac surgery. AB - Hyperglycemia is common in patients undergoing cardiac surgery and is associated with poor outcomes. This is a review of the perioperative insulin protocol being used at Medanta, the Medicity, which has a large volume cardiac surgery setup. Preoperatively, patients are usually continued on their preoperative outpatient medications. Intravenous insulin infusion is intiated postoperatively and titrated using a column method with a choice of 7 scales. Insulin dose is calculated as a factor of blood glucose and patient's estimated insulin sensitivity. A comparison of this protocol is presented with other commonly used protocols. Since arterial blood gas analysis is done every 4 hours for first two days after cardiac surgery, automatic data collection from blood gas analyzer to a central database enables collection of glucose data and generating glucometrics. Data auditing has helped in improving performance through protocol modification. PMID- 25143901 TI - Undiagnosed diabetes mellitus in tuberculosis: A Lagos report. AB - BACKGROUND: Tuberculosis (TB) and diabetes mellitus (DM) are two diseases that are individually relatively common and of immense public health significance globally. There is a growing awareness on a global scale on the possible relationship between TB and DM. Nigeria is a country with a high burden of TB and an increasing incidence of DM. We set out to determine the frequency of occurrence of undiagnosed DM in TB patients. MATERIALS AND METHODS: This was an observational study that was carried out in TB patients recruited from 56 DOT centers in Lagos, Nigeria. The main objective of the study was to determine the disease burden of DM in patients with TB by comparing the frequency of occurrence of DM in TB to the occurrence of DM in people without TB. Screening was carried out by staff-nurses and community health workers-of these DOT facilities who all had capacity building on the detection of DM at the start of the project. RESULTS: Of 4000 TB patients, a total of 480 (12.3%) had DM. Of the pool of DM patients, newly diagnosed cases of DM were 310 (8%) in number and previously known persons with DM were 170 (4.3%). The newly diagnosed cases of DM made up 64% of the cases of DM. In the study population without TB, a total of 112 (5.6%) had DM. The number of newly diagnosed cases of DM were 40 in number and these made up 2% of this study group. The number of persons who were already known to have DM was 72 and these made up 3.6% of the study population. New cases of DM made up 44% of the total number of cases of DM detected in persons without TB. CONCLUSION: The detection rates of DM in patients with TB are higher than in persons without TB. Given the fact that DM may negatively impact TB treatment, we suggest that routine screening be carried out for TB in persons with DM. PMID- 25143900 TI - Diabetes mellitus and suicide. AB - Relationship of diabetes mellitus (DM) with metal health disorders such as depression has been explored extensively in the published literatures. However, association of diabetes mellitus with suicidal tendencies has been evaluated less extensively. The present narrative review aimed to assess the literature relating to diabetes mellitus and suicide. As a part of the review, Pubmed and Google Scholar databases were searched for English language peer reviewed published studies with keywords relating to diabetes and suicide. Additional references were identified using cross-references. The available literature suggests that suicidal ideas and attempts are more frequent in patients with diabetes mellitus than healthy or medically ill controls. Although, a few studies report evidence to the contrary. Suicide accounts for a large proportion of deaths in patients with diabetes mellitus type I (T1DM), and their mortality rate is higher than that of age matched control population. Psychological morbidity, including depression, precedes suicidal ideas and attempts; though many other factors can be hypothesized to impact and modulate this association. A common method of suicide attempt in patients with diabetes includes uses of high doses of insulin and its congeners or medications to treat the disease. Regular screening and prompt treatment of depression and suicidality is suggested for patients with DM. PMID- 25143902 TI - Switching from basal or basal-bolus insulin to biphasic insulin aspart 30: Results from the Indian cohort of the A1 chieve study. AB - AIM: To determine the safety and efficacy of biphasic insulin aspart 30 (BIAsp 30) therapy in the Indian patients with type 2 diabetes previously on basal or basal-bolus insulin therapies. MATERIALS AND METHODS: Patients switching from insulin glargine, neutral protamine Hagedorn (NPH) insulin, or basal-bolus insulin to BIAsp 30 in the Indian cohort of the A1 chieve study were included. Safety and efficacy of treatment was evaluated over 24 weeks. RESULTS: A total of 422 patients (pre-study basal-bolus insulin, 49; NPH insulin, 157; insulin glargine, 216) switched to BIAsp 30. Pre-study insulin doses were 0.61 +/- 0.26 U/kg, 0.34 +/- 0.2 U/kg and 0.40 +/- 0.21 U/kg and the mean week 24 BIAsp 30 doses were 0.50 +/- 0.21 U/kg, 0.35 +/- 0.15 U/kg and 0.42 +/- 0.16 U/kg in the prior basal-bolus insulin, NPH insulin and insulin glargine groups, respectively. No serious adverse drug reactions, major or nocturnal hypoglycemia were reported. The proportion of patients experiencing overall hypoglycemia was significantly lower from baseline (5.6%) to week 24 (1.0%) in the pre-study insulin-glargine group and appeared to be lower in pre-study NPH insulin and basal-bolus insulin groups. Glycemic control improved significantly from baseline week 24 in the pre study NPH insulin and insulin-glargine groups (P < 0.001), while it appeared to improve in the pre-study basal-bolus group. Quality of life was positively impacted after 24 weeks in all 3 groups. CONCLUSION: The switch from basal or basal-bolus insulin to BIAsp 30 was safe, well tolerated and improved the glycemic control in this Indian cohort. PMID- 25143903 TI - Prevalence of iodine deficiency among pregnant and lactating women: Experience in Kolkata. AB - OBJECTIVE: The cross-sectional study was carried out to assess the iodine status of pregnant and lactating mothers, using median urinary iodine excretion (UIE) as the measure of outcome, to document the prevalence of iodine deficiency. MATERIALS AND METHODS: The present study assessed the UIE in the morning urine samples from 237 pregnant women, 73 lactating mothers and 59 healthy non-pregnant female controls. RESULTS: Out of 237 pregnant women, 88 (37%) exhibited insufficient iodine nutrition (UIE < 150 MUg/l), out of 73 lactating mothers, 24 (33%) exhibited insufficient iodine nutrition (UIE < 100 MUg/l) and only 3% female control subjects exhibited insufficient iodine nutrition (UIE < 100MUg/l). Additionally, a number (32.3%) of babies born of iodine deficient mothers had respiratory distress at birth. CONCLUSION: It appears that the present salt iodination program is adequate for the general population but insufficient for the pregnant and lactating mothers. They need to be targeted with iodine supplements throughout pregnancy and lactation. Increased incidence of respiratory distress in the new born of iodine deficient mothers merits further study. PMID- 25143904 TI - Efficacy of insulin lispro in improving glycemic control in gestational diabetes. AB - AIM: To assess the safety and efficacy of insulin lispro in improving glycemic control in patients with gestational diabetes. MATERIALS AND METHODS: A retrospective observational study was conducted at a single center on 201 gestational women with diabetes. Subjects who received insulin lispro performed blood glucose self-monitoring and recorded the readings in the fasting state and 1 h after each meal. At each contact (in person or telephonic contact), the insulin dose was adjusted based on the readings measured. A total of 53 subjects also recorded glucose levels post-partum. Pregnancy and post-delivery glucose level and insulin requirements of these 53 patients were compared. RESULTS: Analysis of glucose levels both fasting and post-prandial glucose levels revealed that after using insulin lispro, the number of episodes of post-prandial hyperglycemia (1 h plasma glucose >120 mg/dL) was minimal and so was the incidence of hypoglycemia. Hypoglycemia was defined as a blood sugar value of. There was neither any congenital abnormality except for a poorly formed pinna in the right ear of one baby nor any post-partum complications of note. CONCLUSION: Insulin lispro is an effective and safe treatment option in gestational diabetes. PMID- 25143906 TI - LDL-cholesterol: Friedewald calculated versus direct measurement-study from a large Indian laboratory database. AB - BACKGROUND: Validity of Friedewald formula (FF) in patients with serum triglycerides (TGs) <400 mg/dl is unclear. MATERIALS AND METHODS: We compared low density lipoprotein (LDL)-cholesterol calculated by FF to directly measured LDL in a laboratory database of 14,620 lipid profile samples from south India. RESULTS: LDL by FF correlated with directly measured LDL with correlation coefficient of 0.89 with the best correlation seen in TG levels 100-150. Higher level of TG (>200) underestimates the LDL calculated by FF particularly at LDL values <70 mg/dl. On the other hand, LDL is overestimated by FF in more than 70% of cases at LDL levels >130 mg/dl. CONCLUSION: We suggest repeating the LDL by direct assay techniques particularly in patients with TG >200 and when LDL <70 or >130. This helps in correctly stratifying the coronary artery diseases' (CADs') risk and goals of treatment. PMID- 25143905 TI - Metabolic syndrome: Performance of five different diagnostic criterias. AB - BACKGROUND: The aim of this study is to describe the metabolic syndrome (MS) and to evaluate five diagnostic criteria of the MS with respect to their sensitivity and specificity in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: It is a cross-sectional case control study of T2DM patients and their first degree relatives (FDRs) recruited using convenience sampling and data collected through questionnaire administered technique. Variables of interest included anthropometric indices, blood pressure, serum lipid profile, fasting blood sugar (FBS), proteinuria, and microalbuminuria. The Chi-square test was used for comparison of proportions. A P value of less than 0.05 was taken as statistically significant. Kappa statistic was used to test the degree of agreement between the diagnostic criteria. RESULTS: The World Health Organization (WHO), International Diabetes Federation (IDF), revised National Cholesterol Education Program (NCEP-R), NCEP Adult Treatment Panel (ATP)-III, and American Association of Clinical Endocrinologists (AACE) criteria reported a prevalence of 87.1, 64.5, 61.3, 55.6, and 22.6%, respectively in persons with T2DM. Using the WHO criteria as a reference or gold standard, the sensitivity of the IDF, NCEP-R, NCEP ATP-III, and AACE criteria among persons with T2DM were 71.3, 67.6, 61.1, and 25.9% respectively. Using the WHO criteria as a reference or gold standard, the specificity of the IDF, NCEP-R, NCEP ATP-III, and AACE criteria among persons with T2DM were 81.3, 81.3, 81.3, and 100%, respectively. Using the WHO criteria as a reference or gold standard, the level of agreement of the IDF, NCEP-R, NCEP ATP-III, and AACE criteria with the WHO criteria among persons with T2DM (as estimated by the kappa statistics) were 0.30, 0.26, 0.21, and 0.08 respectively. CONCLUSION: THE LEVEL OF AGREEMENT APPEARS TO BE GENERALLY POOR, THOUGH THE IDF CRITERIA SHOWED A FAIR LEVEL OF AGREEMENT WITH THE WHO CRITERIA: Therefore the IDF criteria is recommended for screening of the MS in persons with T2DM because of its ease of application and its level of agreement with the WHO criteria being the best compared to the other three criteria. PMID- 25143907 TI - Serum monocyte chemoattractant protein-1 is a biomarker in patients with diabetes and periodontitis. AB - INTRODUCTION: The role of serum Monocyte Chemoattractant Protein-1 (MCP-1) as a biomarker of periodontitis is well documented; however, its role in diabetic patients with periodontitis is unknown. AIM: This study was conducted to determine the presence and concentration of serum MCP-1 in diabetic patients with and without periodontitis and correlate it glycemic status with periodontitis. MATERIALS AND METHODS: Adult diabetic patients were enrolled and grouped into group I, II, and III based on their glycemic status and serum MCP-1 estimated by ELISA. Linear regression and correlation tests were performed using R statistical software, Medcalc software to observe correlation between the serum MCP-1 and glycated hemoglobin level among different groups. RESULTS: Serum samples obtained from 37 patients tested positive for MCP-1. Mean serum MCP-1 concentration was highest (482.3 pg/ml) in group III, lowest (149.3 pg/ml) in group I, and intermediate 398.8 pg/ml in group II. Correlation and regression analysis was done between HbA1c and serum MCP-1. A significant positive correlation (P < 0.001) was observed. Serum MCP-1 increased by 37.278 pg/ml for every 1% rise in HbA1c, and the levels were raised in group II and group III than in group I irrespective of their glycemic status. With an HbA1c range of 6.5-6.9% (group II), the serum MCP-1 values cluster around 380-410 pg/ml. Elevated levels of serum MCP-1 (>500 pg/ml) in three subjects corresponded to HbA1c values more than 12.2% (group III). CONCLUSION: To our knowledge, this is the first study to document serum MCP-1 levels in diabetic patients with periodontitis. Glycemic status influences serum MCP-1, and lack of glycemic control contributes to increased serum MCP-1 levels. Serum MCP-1 may thus serve as a biomarker of inflammation and disease progression in diabetes with periodontitis. PMID- 25143908 TI - Vitamin D deficiency is associated with increased mortality in critically ill patients especially in those requiring ventilatory support. AB - INTRODUCTION: Vitamin D (VitD) classically recognized for its role in the musculoskeletal system, has been implicated in myriad of conditions such as diabetes, immune dysfunction, cancers, heart disease, metabolic syndrome, etc. We studied the role of VitD in acute care setting and its correlation with mortality. MATERIALS AND METHODS: A total of 85 consecutive consenting patients admitted in medical intensive care unit of tertiary care hospital who fulfilled the inclusion criteria were included. All patients were evaluated clinically, and blood samples were collected for hemogram, biochemical investigations including serum calcium, phosphorus, alkaline phosphatase, magnesium, along with 25(OH) VitD, 1,25(OH) VitD and intact parathormone levels. Simplified acute physiology score (SAPS II) was calculated for all patients. RESULTS: VitD was deficient (<30 ng/ml) in 27 patients (32%). The overall mortality was more in VitD deficient group as compared to VitD sufficient group (74 vs. 41%; P < 0.05). The actual mortality in VitD deficient group was higher than the mortality predicted by SAPS II score (50 vs. 74%; P < 0.0507). VitD deficiency was also associated with more mortality among those requiring ventilator support (95% vs. 40%; P < 0.05) as well as with higher blood glucose (124.5 +/- 29.7 vs. 94.8 +/- 19.8: P < 0.01) levels. CONCLUSION: VitD deficiency was associated with increased mortality, poor ventilator outcomes, and increased blood glucose in critically ill patients. PMID- 25143909 TI - RET mutations in a large indian family with medullary thyroid carcinoma. AB - BACKGROUND: Medullary thyroid carcinoma (MTC) is a tumor arising from the para follicular (C) cells of the thyroid gland and can occur either sporadically or as part of an inherited syndrome. A proportion of these cases carry an autosomal dominant mutation in the RET (REarranged during Transfection) proto-oncogene. Screening for these mutations in the affected patients and the carriers "at risk" which includes the first-degree relatives is of utmost importance for early detection and prompt treatment including prophylactic thyroidectomy in cases that harbor these mutations. RESULTS: This report presents details of screening and subsequent follow-up of a large Indian family, where the index case was found to carry p. Cys634Ser mutation involving exon 11 of the RET gene. These data are of value considering the paucity of information within the region in context of screening large families affected by these mutations. PMID- 25143910 TI - Differential response of idiopathic sporadic tumoral calcinosis to bisphosphonates. AB - CONTEXT: Tumoral calcinosis is a disorder of phosphate metabolism characterized by ectopic calcification around major joints. Surgery is the current treatment of choice, but a suboptimal choice in recurrent and multicentric lesions. AIMS: To evaluate the efficacy of bisphosphonates for the management of tumoral calcinosis on optimized medical treatment. SETTINGS AND DESIGN: The study was done in the endocrine department of a tertiary care hospital in South India. We prospectively studied two patients with recurrent tumoral calcinosis who had failed therapy with phosphate lowering measures. MATERIALS AND METHODS: After informed consent, we treated both patients with standard age adjusted doses of bisphosphonates for 18 months. The response was assessed by X ray and whole body 99mTc-methylene diphosphonate bone scan at the beginning of therapy and at the end of 1 year. We also estimated serum phosphate levels and urinary phosphate to document serial changes. RESULTS: Two patients (aged 19 and 5 years) with recurrent idiopathic hyperphosphatemic tumoral calcinosis, following surgery were studied. Both patients had failed therapy with conventional medical management - low phosphate diet and phosphate binders. They had restriction of joint mobility. Both were given standard doses of oral alendronate and parenteral pamidronate respectively for more than a year, along with phosphate lowering measures. At the end of 1 year, one of the patients had more than 95% and 90% reduction in the size of the lesions in right and left shoulder joints respectively with total improvement in range of motion. In contrast, the other patient (5-year-old) had shown no improvement, despite continuing to maintain normophosphatemia following treatment. CONCLUSIONS: Bisphosphonate therapy in tumoral calcinosis is associated with lesion resolution and may be used as a viable alternative to surgery, especially in cases with multicentric recurrence or treatment failure to other drugs. PMID- 25143911 TI - Low maternal iodine intake and early pregnancy hypothyroxinemia: Possible repercussions for children. AB - OBJECTIVE: Recent studies have shown that early pregnancy hypothyroxinemia (lower free thyroxin [FT4] and normal thyroid stimulating hormone [TSH] concentration) has deleterious effects on neuro-intellectual development of children. This study was designed to know its incidence in local pregnant women. MATERIALS AND METHODS: Urinary iodine (UI) and serum thyroid related hormone (FT4, free triiodothyronine [FT3], and TSH) were determined in 254 pregnant women during the first trimester. UI and thyroid related hormones were determined by colorimetric (Sandell-Kolthoff) and radioimmunoassay method respectively. RESULTS: Most of the pregnant women (n = 202; 79.5%) were iodine deficient (ID; UI <100 MUg/L) and only 52 (20.5%) women were taking sufficient iodine (IS; UI >= 100 MUg/L). Mean levels of FT4, FT3, and TSH were 13.0 +/- 2.8 pmol/L, 3.8 +/- 1.1 pmol/L and 1.2 +/- 1.1 mIU/L, respectively. Maternal FT4 levels were significantly correlated with UI (r = 0.36; P < 0.001). Mean FT4 level in IS women was significantly (P < 0.05) higher than ID women. However, mean FT3 and TSH levels were not significantly different in both groups. FT4 reference range in IS pregnant women was 10.2-19.4 pmol/L. Hypothyroxinemia (FT4 <10.2 pmol/L and TSH <2.5 mIU/L) was diagnosed in 30 (11.8%) pregnant women. Its incidence was almost entirely confined to ID pregnant women with an odd ratio of 8.5 (95% confidence interval: 1.1-64.3). CONCLUSION: About 12% pregnant women residing in urban areas of Pakistan are hypothyroxinemic because of low iodine intake. PMID- 25143912 TI - Comparison of Tc-99m pertechnetate images with dual-phase Tc 99m MIBI and SPECT images in primary hyperparathyroidism. AB - BACKGROUND: The purpose of this study was to evaluate the value of Tc-99m pertechnetate planar, dual-phase MIBI and MIBI-SPECT images in the determination and localization of parathyroid lesions. MATERIALS AND METHODS: In this study, 38 patients who underwent operation for primary hyperparathyroidism were included. Tc-99m pertechnetate planar-pinhole imaging of the neck and then MIBI planar and SPECT images in supine position was performed. Late SPECT images were acquired 120 minutes after the injection. Early and late MIBI images were quantitatively evaluated. RESULTS: Of the 38 patients, 30 of them had adenoma, 2 patients had hyperplasia and 6 of them were normal on planar images. Thirty-four of 38 patients were positive on SPECT images. SPECT images of the patients with positive results were matched with pathology results. CONCLUSION: As a result, Tc 99m pertechnetate planar-pinhole, Tc-99m MIBI planar and SPECT images are useful for localization of parathyroid lesions especially in multinodular thyroid gland. However, US or CT images are necessary for more accurate localization and Tc-99m pertechnetate images are useful for interpreting and comparing with the early and late MIBI images. PMID- 25143913 TI - Vitamin D levels and microvascular complications in type 2 diabetes. AB - BACKGROUND: Vitamin D has important actions on glucose metabolism. These include improved insulin exocytosis, direct stimulation of insulin receptor, improved uptake of glucose by peripheral tissues, improving insulin resistance. It has got various pleiotropic effects like suppression of cell mediated immunity, regulation of cell proliferation, stimulation of neurotropic factors such as nerve growth factor, Glial cell line-derived neurotrophic factor, neurotropin, suppression of RAAS, reduction of albuminuria, immunomodulatory effects, and anti inflammatory effects. Thus, vitamin D is implicated in many ways in the pathogenesis of retinopathy, neuropathy and nephropathy. OBJECTIVES: To study the correlation of vitamin D levels with microvascular complications in type 2 diabetes. MATERIALS AND METHODS: Cross-sectional case-control study of 18 patients (18-70 years), who met the American Diabetes Association 2011 criteria for type 2 diabetes, was conducted. Age and sex matched healthy controls were taken. Subjects were evaluated for the presence of microvascular complications by clinical evaluation, urine examination, fundus examination, nerve conduction studies, and various biochemical tests. 25-OH cholecalciferol levels were done for each. Cut off level for vitamin D deficiency was 20 ng/ml. RESULTS: Mean vitamin D was lower in type 2 diabetics than healthy subjects (19.046 vs. 27.186 ng/ml). Prevalence of vitamin D deficiency and insufficiency was found to significantly higher in diabetics when compared to healthy subjects (P = 0.0001). Vitamin D deficiency was found to be significantly associated with neuropathy (chi(2) = 5.39, df = 1, P = 0.020), retinopathy, (chi(2) = 6.6, df = 1, P = 0.010) and nephropathy (chi(2) = 10. 52, df = 1, P = 0.001). Lower levels of vitamin D were found to be associated with increasing prevalence of combinations of microvascular complications namely neuropathy with retinopathy (P = 0.036), neuropathy with nephropathy (P = 0.029), retinopathy with nephropathy (P = 0.022) and neuropathy with retinopathy with nephropathy (P = 0.0001). PMID- 25143914 TI - A retrospective study of surgically excised phaeochromocytomas in Newfoundland, Canada. AB - OBJECTIVE: A retrospective study detailing the circumstances surrounding diagnosis and treatment of pheochromocytomas with the associated genetic disorders. MATERIALS AND METHODS: All patients with surgically excised pheochromocytomas in the Health Sciences Center, St. John's, Newfoundland, Canada between January 2001 and December 2010 were retrospectively analyzed to determine associated familial syndromes, age, tumor size, symptomatology, and percentage of paragangliomas and bilateral pheochromocytomas. Pathology specimen reports, adrenalectomy lists and Meditech (electronic medical record) diagnostic codes provided a comprehensive database for this study. RESULTS: Twenty-four patients were studied; familial disorder patients comprised 42% (10/24). Average age at diagnosis was 57 among the sporadic and 34 in familial disorder groups (P = 0.006). Average tumor size was 4.5 cm in the sporadic group and 3 cm in the familial disorder group (P = 0.19). All atypical cases including bilateral or extra-adrenal tumors and malignancy occurred in familial disorder patients. CONCLUSIONS: The proportion of familial disorder patients (42%) was higher in this study than would be expected, likely a result of the relatively high incidence of hereditary autosomal dominant disorders within Newfoundland. Among familial disorder patients, the average younger age at diagnosis and the smaller tumor size suggest syndromic pheochromocytomas may develop earlier, however they are more likely to be diagnosed sooner due to biochemical surveillance testing in known genetic disorder patients. We also demonstrate a relatively high incidence of surgically resected pheochromocytomas of 4.679/million/year in Newfoundland. PMID- 25143915 TI - Effects of the anti-receptor activator of nuclear factor kappa B ligand denusomab on beta thalassemia major-induced osteoporosis. AB - INTRODUCTION: Osteoporosis represents the second most common cause of endocrinopathy in patients with beta thalassemia major (BTM). Some drugs proved effective to reduce vertebral and non-vertebral fracture risk. Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor kappa B ligand (RANKL), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. The efficacy and safety of denosumab in BTM induced osteoporosis has not been tested. OBJECTIVE: To evaluate the efficacy and safety of anti-RANKL on the biochemical and radiological parameters of bone mineralization in patients with BTM-induced osteoporosis. DESIGN: The study population was selected using the random sampling method from the patient's database of our thalassemia clinic. Transfusion-dependent BTM patients above 18 years with no history of treatment with bisphosphonates were randomly selected. Bone mineral density (BMD) of the lumbar spine (LS) and right femoral neck (FN) were measured by dual energy X-ray absorption (DEXA) scan using a calibrated method. Independent factors likely to be associated with low bone mass were determined and included in the analysis to ascertain possible associations. PATIENTS AND METHODS: We studied 30 patients with BTM-induced osteoporosis as per World Health Organization criteria (T Score of less than - 1.0 being defined as osteopenic and a T Score of less than - 2.5 being referred as osteoporotic). 19 males and 11 females aged between 18 and 32 years, with full pubertal development (Tanner's stage 5) at the time of the study. Their mean serum ferritin concentration was 3557 ng +/- 1488 ng/ml. Every patient underwent DEXA scan as a baseline and after 12 months of denosumab therapy. Biochemical evaluation including serum concentrations of creatinine, Na, K, calcium, phosphorus, parathormone, bone specific alkaline phosphatase and type 1 collagen carboxy telopetide (ICCT) using enzyme-linked immunosorbent assay (Nordic Bioscience Diagnostics A/S) was done at baseline, after a month and then every 3 months for 12 months after starting denosumab. 60 mg of denosumab was administered subcutaneously twice yearly for a year. The mean BMD T Scores at baseline were 2.7 at the LS and -2.1 at the FN. RESULTS: Denosumab therapy for a year was associated with a significant increase in BMD of 9.2% (95% confidence interval [CI], 8.2-10.1) at the LS and 6.0% (95% CI, 5.2-6.7) at the FN. Denosumab treatment decreased serum ICCT levels by 56% at 1 month and normalized them in all patients at 1 year. Significant correlations were found between BMD T Score before and 1 year after denosumab in LS (r = 0.752, P < 0.001) and FN (r = 0.758 P < 0.001), respectively. The most common side effects were pain in the back and extremities (12%) and nausea (10%). Asymptomatic hypocalcaemia occurred in two patients. CONCLUSION: Denosumab therapy for a year significantly increased BMD density at LS and FN of patients with BTM and was associated with a rapid and sustained reduction in ICCT levels. Further studies are required to confirm long term effects of this therapy. PMID- 25143916 TI - A study of bladder dysfunction in women with type 2 diabetes mellitus. AB - INTRODUCTION: Diabetes mellitus has been associated with an earlier onset and increased severity of urologic diseases that often result in debilitating urologic complications. Diabetic bladder dysfunction refers to a group of bladder symptoms occurring in patients with diabetes mellitus ranging from bladder over activity to impaired bladder contractility. AIM: Bladder dysfunction is an under evaluated issue in women with diabetes. Aim of our study was to investigate prevalence of bladder dysfunction and its relation with other chronic complications of diabetes in women with type 2 diabetes. MATERIALS AND METHODS: In a hospital-based cross sectional study, a cohort of women with type 2 diabetes mellitus who had lower urinary tract symptoms (LUTS) were enrolled. We used the American Urological Association Symptom Index (AUA-SI) to assess the severity of LUTS and the Indevus Urgency Severity Scale (IUSS) to assess presence of overactive bladder (OAB). Age-BMI- matched controls that did not have diabetes but had lower urinary tract symptoms were also studied and compared with women with type 2 diabetes. Urodynamic evaluation was done in willing patients. RESULTS: LUTS attributable to bladder dysfunction were reported in 67% of women with type 2 diabetes after exclusion of other causes. Out of them, 36% had moderate to severe LUTS (total AUA-SI score >7). Prevalence of OAB was 53%. Urodynamic evaluation revealed presence of stress urinary incontinence in 48% patients and changes of detrusor over activity and detrusor under activity in 23% and 11% patients, respectively. Among the chronic complications of diabetes, peripheral neuropathy, nephropathy, and presence of metabolic syndrome were significantly associated with moderate to severe LUTS and OAB. CONCLUSION: Bladder dysfunction is a highly prevalent complication in women with diabetes. Chronic complications of diabetes especially neuropathy, nephropathy, and presence of metabolic syndrome are important predictors of bladder dysfunction. PMID- 25143917 TI - Hormonal profile in children with isolated hypospadias associates better with comprehensive score of local anatomical factors as compared to meatal location or degree of chordee. AB - BACKGROUND: To evaluate if hormonal profile of children with isolated hypospadias (IH) associates better with comprehensive local anatomical factor score (LAFS) than with clinically adjudged urethral meatus location or severity of chordee/k.j. MATERIAL AND METHODS: Ninety-nine children with IH were enrolled, as per inclusion criteria. Meatal location was recorded at first clinical examination in OPD; while LAFS was computed per-operatively using indigenously devised scale, except for neonates. Hypospadiacs were first classified into three standard meatal based groups and subsequently into LAFS based two groups (<=19, >19). For all participants, pre HCG and post HCG (96 hour post- injection) estimation of serum gonadotropins, DHEA-S, estrogen (E), progesterone (P), testosterone (T) and Dihydrotestosterone (DHT) was done. Statistical tests were applied to assess significance of hormonal levels with respect to meatal location, chordee and LAFS. RESULTS: Only FSH levels differed significantly among meatal based groups; while among LAFS groups, multiple hormonal differences were noted; with poor LAFS associated significantly with higher FSH, LH and lower E, T/DHT. Children with severe degree of chordee had poorer T output and a significantly lower LAFS as compared to those with moderate/mild chordee. CONCLUSION: Serotoli cell dysfunction, indirectly indicated by high FSH was found among midpenile hypospadiacs and those with poorer LAFS. Since groups based on LAFS revealed multiple intergroup hormonal differences than what was seen for meatal/chordee based groups; LAFS should be considered a better guide for prognostication and for deciding about hormonal supplementation. Lower androgenic output was particularly noted in children with severe chordee. PMID- 25143918 TI - Preliminary study: Evaluation of melatonin secretion in children and adolescents with type 1 diabetes mellitus. AB - OBJECTIVE: Melatonin is an indolamine hormone, synthesized from tryptophan in the pineal gland primarily. Melatonin exerts both antioxidative and immunoregulatory roles but little is known about melatonin secretion in patients with type 1 diabetes mellitus (T1DM). The aim of this study was to measure serum melatonin levels in patients with T1DM and investigates their relationship with type 1 diabetes mellitus. MATERIALS AND METHODS: Forty children and adolescents with T1DM (18 boys and 22 girls) and 30 healthy control subjects (17 boys and 13 girls) participated in the study. All patients followed in Pediatric Endocrinology and Metabolism Unit of Gaziantep University Faculty of Medicine and also control subjects had no hypertension, obesity, hyperlipidemia, anemia, and infection. Blood samples were collected during routine analysis, after overnight fasting. Serum melatonin levels were analyzed with ELISA. RESULTS: There were no statistically significant differences related with age, sex, BMI distribution between diabetic group and control group. Mean diabetic duration was 2.89 +/- 2.69 years. The variables were in the equation. Mean melatonin level in diabetic group was 6.75 +/- 3.52 pg/ml and mean melatonin level in control group was 11.51 +/- 4.74 pg/ml. Melatonin levels were significantly lower in diabetic group compared to controls (P < 0.01). CONCLUSIONS: Melatonin was associated with type 1 diabetes mellitus significantly. Because of the varied roles of melatonin in human metabolic rhythms, these results suggest a role of melatonin in maintaining normal rhythmicity. Melatonin may play role in preventing process of inflammation and oxidative stress. PMID- 25143919 TI - Association between adolescence obesity and metabolic syndrome: Evidence from Isfahan Healthy Heart Program. AB - BACKGROUND: Metabolic syndrome (MetS) is more prevalent among Iranian adolescences. This study aimed to find the relationship between obesity and MetS among different education grades of Iranian adolescence. MATERIALS AND METHODS: Overall, 1039 junior high school and 953 high school students were selected using multistage random sampling. Fasting blood sugar, total cholesterol, triglyceride (TG), and high-density lipoprotein cholesterol (HDL) were measured. Trained individuals measured waist circumference and blood pressure. MetS was defined according to the De Ferranti definition. RESULTS: The prevalence of overweight and obesity was 12.6% and 6.2% in junior and 11.5% and 4.3% in high school students, respectively. Obese subjects in both grades have higher waist circumference, systolic and diastolic blood pressure, and triglyceride than comparable groups. Multiple logistic regression models showed that overweight and obesity were strongly associated with MetS components analyzed. Compared to normal-weight children, overweight and obese in junior high school students were 1.47 and 2.23 times more likely to be having high TG, respectively, whereas overweight and obese in high school-students were also more likely to have elevated TG [ORs 1.94 (1.28-2.94), 4.96 (2.39-10.3) respectively]. CONCLUSION: Obese children have the highest prevalence of MetS. Prevalence of MetS-related components has reached high level among Iranian adolescences that were overweight or obese. PMID- 25143922 TI - Completion report: Effect of Comprehensive Yogic Breathing program on type 2 diabetes: A randomized control trial. AB - BACKGROUND: Yoga has been shown to be beneficial in diabetes in many studies, though randomized control trials are few. The aim of this randomized control trial was to see the effect of Sudarshan Kriya and related practices (comprehensive yogic breathing program) on quality of life, glycemic control, and cardiac autonomic functions in diabetes. Diabetes mellitus is a risk factor for sudden cardiac death. Cardiac autonomic neuropathy has been implicated in the causation of sudden cardiac death. Therefore, a maneuver to prevent progression of cardiac autonomic neuropathy holds significance. MATERIALS AND METHODS: A total of 120 patients of diabetes on oral medication and diet and exercise advice were randomized into two groups: (1) Continued to receive standard treatment for diabetes. (2) Patients administered comprehensive yogic breathing program and monitored to regularly practice yoga in addition to standard treatment of diabetes. At 6 months, quality of life and postprandial plasma glucose significantly improved in the group practicing yoga compared to baseline, but there was no significant improvement in the fasting plasma glucose and glycated hemoglobin. RESULTS: On per protocol analysis, sympathetic cardiac autonomic functions significantly improved from baseline in the group practicing comprehensive yogic breathing. CONCLUSION: This randomized control trial points towards the beneficial effect of yogic breathing program in preventing progression of cardiac neuropathy. This has important implications as cardiac autonomic neuropathy has been considered as one of the factors for sudden cardiac deaths. PMID- 25143920 TI - Immunoregulatory T cells, LFA-3 and HLA-DR in autoimmune thyroid diseases. AB - AIM: The aim of the present study was to examine the changes in the expression of T-cell activation markers, namely CD4+ CD25+ and CD8+ in patients with AITD, namely Graves' disease and Hashimoto's thyroiditis as well as colloid nodular goitre. HLA-DR, LFA-3, and peripheral total lymphocytic count are also measured. MATERIALS AND METHODS: We compared the expression of CD4, CD25, and CD8 surface markers in peripheral blood lymphocyte in Graves' disease and Hashimoto's thyroiditis as autoimmune thyroid diseases, as well as colloid goitre in comparison with healthy controls. Also, LFA-3 and HLA-DR were measured in the same groups using three-color flow cytometry. Total lymphocytic count in peripheral blood, thyroid function tests, antithyroid antibodies were also included in the laboratory investigations. The total number of participants was 65. All were recruited from endocrine clinics in a tertiary care hospital in the southern region of Saudi Arabia. All participants underwent history taking, clinical examination, laboratory workup, and radiological investigations. Neck ultrasound, technecium pertechnetate(psipsi) thyroid uptake, and fine-needle aspiration and cytology (FNAC) of the thyroid were done when indicated. The study was approved by the Hospital Research Isthics Committee and informed consents were obtained from all participants before enrollment in the study. RESULTS: In comparison with thecontrol group, activation markers CD4, CD25, and CD8 were lower in the autoimmune thyroid diseases. Lymphocyte function antigen-3 (CD58) and total lymphocytic count were higher in the AIT diseases whereas HLA-DR was lower than that in the control group. The CD4/CD8 ratio was lower in the AITD compared with the healthy euthyroid subjects. No difference was found between patients with colloid nodular goitre and the healthy control in any of the study variables except for LFA-3 which was significantly higher in the colloid goitre group. CONCLUSION: Our findings indicate downregulation of CD4+ CD25+ Treg as well as CD8+ T cells in autoimmune thyroid diseases. Downregulation of suppressor T lymphocytes helps initiation, progression, and maintenance of the autoimmune thyroid diseases. Lower HLA-DR and higher CD58 in AITDs indicate their role in the expression of the autoantigen and its escape from the immune surveillance. High levels of LFA-3 in colloid goitre indicate that the autoimmune process needs interacting factors, and not only the high level of LFA-3. PMID- 25143923 TI - Normative data for stretched penile length in term neonates born in Tamil Nadu. AB - AIM: To establish normative data for stretched penile length (SPL) in term male neonates born in Tamil Nadu. MATERIALS AND METHODS: All live term male neonates delivered in a hospital during a given period were included. SPL was measured from the pubic ramus to the tip of the glans. Two consecutive measurements were taken and average was recorded. RESULTS: The mean SPL observed in our study was 2.83 +/- 0.49 cm. CONCLUSION: This study helps establish normative values for SPL in neonates of Tamil Nadu origin. PMID- 25143924 TI - Comment on the editorial "Health Economics in India: The case of diabetes mellitus". PMID- 25143925 TI - Response to "Health economics in India: The case of diabetes mellitus". PMID- 25143926 TI - Response to review article "Type 1 diabetes and osteoporosis: Review of literature". PMID- 25143927 TI - Thyroid acropachy: Frequently overlooked finding. PMID- 25143928 TI - Interventional endocrinology: A futuristic Perspective. PMID- 25143929 TI - Prevalence of hypodontia in a sample of Sudanese orthodontic patients. AB - OBJECTIVE: The aims of this study were to determine the prevalence of hypodontia in the permanent dentition in a sample of Sudanese patients who sought orthodontic treatment and to compare the results with the reported findings of other populations. MATERIALS AND METHODS: Orthodontic files including orthopantomographs of 1069 patients (760 females and 309 males - more than 8 years old) were examined and inspected for evidence of hypodontia. RESULTS: The prevalence of hypodontia of the present sample was 5.1%. Hypodontia was found considerably more frequently in the mandible than in the maxilla. The distribution of missing teeth was noticed in the left side more than in the right side. The most frequently missing teeth were the maxillary lateral incisors, followed by the mandibular second premolars, maxillary second premolars and mandibular left lateral incisor. The majority of patients had two or three teeth missing, but rarely more than 5 teeth missing. CONCLUSIONS: The prevalence of hypodontia of this study was within the range of that reported in the literature. The incidence of hypodontia in the anterior segment requires great need for orthodontic and prosthodontic treatment. With early detection of hypodontia, alternative treatment modalities can be planned and performed with a multidisciplinary team approach restoring the esthetic and function. PMID- 25143930 TI - Proposed regression equations for prediction of the size of unerupted permanent canines and premolars in Yemeni sample. AB - OBJECTIVE: The aim was to formulate a prediction regression equation for Yemeni and to compare it with Moyer's method for the prediction of the size of the un erupted permanent canines and premolars. SUBJECTS AND METHODS: Measurements of mesio-distal width of four permanent mandibular incisors, as well as canines and premolars in both arches were obtained from a sample of 400 school children aged 12-14 years old (13.80 +/- 0.42 standard deviation) using electronic digital calliper. The data were subjected to statistical and linear regression analysis and then compared with Moyer's prediction tables. RESULTS: The result showed that the mean mesio-distal tooth widths of the canines and premolars in the maxillary arch were significantly larger in boys than girls (P < 0.001), while, in the mandibular arch, only lateral incisors and canines were also significantly larger in boys than in girls (P < 0.001). Regression equations for the maxillary arch (boys, Y = 13.55 + 0.29X; girls, Y = 14.04 + 0.25X) and the mandibular arch (boys, Y = 9.97 + 0.40X; girls, Y = 9.56 + 0.41X) were formulated and used to develop new probability tables following the Moyer's method. Significant differences (P < 0.05) were found between the present study predicted widths and the Moyer's tables in almost all percentile levels, including the recommended 50% and 75% levels. CONCLUSIONS: The Moyer's probability tables significantly overestimate the mesio-distal widths of the un-erupted permanent canine and premolars of Yemeni in almost all percentile levels, including the commonly used 50% and 75% levels. Therefore, it was suggested with caution that the proposed prediction regression equations and tables developed in the present study could be considered as an alternative and more precise method for mixed dentition space analysis in Yemeni. PMID- 25143931 TI - Evaluation of relationship between cranial base angle and maxillofacial morphology in Indian population: A cephalometric study. AB - OBJECTIVE: To investigate the role played by the cranial base flexure in influencing the sagittal and vertical position of the jaws in Indian population. MATERIALS AND METHODS: Lateral cephalograms of 108 subjects were divided into three categories (Group A: NSAr > 125 degrees , Group B: NSAr-120 degrees -125 degrees , Group C: NSAr < 120 degrees ) according to value of NSAr. Measurement of eight angular (SNA, SNB, NPg-FH, ANB, NAPg, SN-GoGn, Y-Axis, ArGo-SN) and seven linear (N-S, S-Ar, Ar-N, Ar-Pt A, Ar-Gn, Wits appraisal, N- Pt A) variables were taken. RESULTS: Pearson correlation coefficient test was used to individually correlate angular and linear variables with NSAr for the whole sample as well as in individual group. Unpaired t-test was used to analyze the difference in the means of all the variables between the three groups. Significance was determined only when the confidence level was P < 0.05. Several parameters (SNB, NAPg, ANB, Y-Axis, GoGn-SN) showed significant positive correlation while others showed negative correlation (SNA, NPg-FH, N-S) with NSAr. CONCLUSIONS: This study show cranial base angle has a determinant role in influencing the mandibular position and it also affects both the mandibular plane angle and y-axis. Flattening of the cranial base angle caused a clockwise rotation of the mandible. The jaw relation tends to change from class III to class II, with progressive flattening of the cranial base and vice-versa. PMID- 25143932 TI - A normative study to evaluate inclination and angulation of teeth in North Indian population and comparision of expression of torque in preadjusted appliances. AB - AIM: The aim of this study was to evaluate angulation and inclination of teeth from the study models of individuals with normal occlusion and evaluation of actual expression of torque expressed by three different bracket systems. MATERIALS AND METHODS: In this study, the inclination and angulation were measured on 30 study models of North Indian individuals. A self-developed instrument (torque angle gauge) was used for the measurement. Fifteen study models were duplicated for the evaluation of torque expression in the bracket of three different manufacturers with different shape and size of bases. RESULTS: The results give the mean, minimum and maximum, standard deviation of the normative data individually for each tooth. A significant correlation was noted in the angulation of maxillary canine and first premolar, and between premolars; and between mandibular central incisor with lateral incisor and canine, and between premolars. CONCLUSIONS: There was a highly significant correlation of teeth angulation and inclination in the maxillary and mandibular arch. Though the error in expression of torque was not significant, but it showed a large range, indicating the need to vary the position of brackets in different bracket systems for achieving optimum torque. PMID- 25143933 TI - Shear bond strength comparison of moisture-insensitive primer and self-etching primer. AB - CONTEXT: The detrimental effect of moisture on orthodontic bonding has long been known. Hydrophilic bonding materials have been introduced suggesting the possibility of obtaining successful orthodontic bonding to a moisture contaminated enamel surface. AIMS: This study has been performed with an aim to compare the in vitro shear bond strength (SBS) and debonding characteristic of moisture-insensitive primer (MIP) (Transbond MIP) (3M Unitek, South Peck Road, Monrovia, California, USA) and self-etching primer (SEP) (Transbond Plus SEP) (3M Unitek, South Peck Road, Monrovia, California, USA) in combination with a color changing adhesive system (Transbond Plus Color Change) (3M Unitek, South Peck Road, Monrovia, California, USA) under both dry and contaminated condition. SETTINGS AND DESIGN: Randomized controlled clinical study. SUBJECTS AND METHODS: One hundred and twenty freshly extracted teeth for the purpose of orthodontic treatment were collected. Teeth were randomly assigned into four groups, each consisting of 30 specimen and stainless steel brackets were bonded using each primer-adhesive combination under different enamel conditions, that is, dry and enamel contaminated with natural saliva. SBS and adhesive remnant index were calculated for each group. RESULTS: Analysis of variance of SBS for both MIP and SEP under dry and contaminated condition showed no statistical significance (P = 0.5). Chi-square test showed significant difference in debonding characteristics among the test groups (P < 0.001). All the groups showed typical debonding characteristics of separation either at the bracket-adhesive interface or within the adhesive itself. CONCLUSIONS: Moisture contamination did not affect the SBS and adhesive remaining on tooth for both MIP and SEP. PMID- 25143935 TI - Hot melt extruded amorphous solid dispersion of posaconazole with improved bioavailability: investigating drug-polymer miscibility with advanced characterisation. AB - Invasive antifungal infections are reasons for morbidity and mortality in immunogenic patients worldwide. Posaconazole is a most promising antifungal agent against all types of invasive infections with high % of cure rate. The marketed suspension formulation has low bioavailability and is needed to be taken with food. In this paper, PCZ hot melt extruded amorphous solid dispersion (SD) with immediate release and improved bioavailability was prepared using Soluplus (Sol) as primary carrier for solubilization. Surfactants such as PEG 400, Lutrol F27, Lutrol F68, and TPGS are also used in combination with Soluplus to improve the physicochemical performance of the formulation when it comes in contact with GI (gastrointestinal) fluid. Drug-polymer miscibility of SD was investigated using advanced techniques. In the in vivo study, the AUC(0-72) and C(max) of PCZ/Soluplus were 11.5 and 11.74 time higher than those of pure PCZ. The formulation of the extrudate SD had an AUC(0-72) and C(max) higher than those with the commercial capsule (Noxafil). Molecular dynamic (MD) simulation studies were carried out using in silico molecular modelling to understand the drug polymer intermolecular behaviour. The results of this research ensure enhanced dissolution and bioavailability of the solid dispersion of PCZ prepared by HME compared with the PCZ suspension. PMID- 25143934 TI - A review of bioactive release from nerve conduits as a neurotherapeutic strategy for neuronal growth in peripheral nerve injury. AB - Peripheral nerve regeneration strategies employ the use of polymeric engineered nerve conduits encompassed with components of a delivery system. This allows for the controlled and sustained release of neurotrophic growth factors for the enhancement of the innate regenerative capacity of the injured nerves. This review article focuses on the delivery of neurotrophic factors (NTFs) and the importance of the parameters that control release kinetics in the delivery of optimal quantities of NTFs for improved therapeutic effect and prevention of dose dumping. Studies utilizing various controlled-release strategies, in attempt to obtain ideal release kinetics, have been reviewed in this paper. Release strategies discussed include affinity-based models, crosslinking techniques, and layer-by-layer technologies. Currently available synthetic hollow nerve conduits, an alternative to the nerve autografts, have proven to be successful in the bridging and regeneration of primarily the short transected nerve gaps in several patient cases. However, current research emphasizes on the development of more advanced nerve conduits able to simulate the effectiveness of the autograft which includes, in particular, the ability to deliver growth factors. PMID- 25143936 TI - Physicochemical characteristics of bone substitutes used in oral surgery in comparison to autogenous bone. AB - Bone substitutes used in oral surgery include allografts, xenografts, and synthetic materials that are frequently used to compensate bone loss or to reinforce repaired bone, but little is currently known about their physicochemical characteristics. The aim of this study was to evaluate a number of physical and chemical properties in a variety of granulated mineral-based biomaterials used in dentistry and to compare them with those of autogenous bone. Autogenous bone and eight commercial biomaterials of human, bovine, and synthetic origins were studied by high-resolution X-ray diffraction, atomic absorption spectrometry, and laser diffraction to determine their chemical composition, calcium release concentration, crystallinity, and granulation size. The highest calcium release concentration was 24. 94 mg/g for Puros and the lowest one was 2.83 mg/g for Ingenios beta-TCP compared to 20.15 mg/g for natural bone. The range of particles sizes, in terms of median size D50, varied between 1.32 MUm for BioOss and 902.41 MUm for OsteoSponge, compared to 282.1 MUm for natural bone. All samples displayed a similar hexagonal shape as bone, except Ingenios beta-TCP, Macrobone, and OsteoSponge, which showed rhomboid and triclinic shapes, respectively. Commercial bone substitutes significantly differ in terms of calcium concentration, particle size, and crystallinity, which may affect their in vivo performance. PMID- 25143937 TI - Does pulsed magnetic field therapy influence nerve regeneration in the median nerve model of the rat? AB - The aim of this study was to evaluate the impact of pulsed magnetic field therapy on peripheral nerve regeneration after median nerve injury and primary coaptation in the rat. Both median nerves were surgically exposed and denervated in 24 female Wistar rats. A microsurgical coaptation was performed on the right side, whereas on the left side a spontaneous healing was prevented. The study group underwent a daily pulsed magnetic field therapy; the other group served as a control group. The grasping force was recorded 2 weeks after the surgical intervention for a period of 12 weeks. The right median nerve was excised and histologically examined. The histomorphometric data and the functional assessments were analyzed by t-test statistics and one-way ANOVA. One-way ANOVA indicated a statistically significant influence of group affiliation and grasping force (P = 0.0078). Grasping strength was higher on a significant level in the experimental group compared to the control group permanently from the 9th week to the end of the study. T-test statistics revealed a significantly higher weight of the flexor digitorum sublimis muscle (P = 0.0385) in the experimental group. The histological evaluation did not reveal any statistically significant differences concerning the histomorphometric parameters. Our results suggest that the pulsed magnetic field therapy has a positive influence on the functional aspects of neural regeneration. More studies are needed to precisely evaluate and optimize the intensity and duration of the application. PMID- 25143938 TI - Test anxiety levels of board exam going students in Tamil Nadu, India. AB - The latest report by the National Crime Records Bureau has positioned Tamil Nadu as the Indian state with highest suicide rate. At least in part, this is happening due to exam pressure among adolescents, emphasizing the imperative need to understand the pattern of anxiety and various factors contributing to it among students. The present study was conducted to analyze the level of state anxiety among board exam attending school students in Tamil Nadu, India. A group of 100 students containing 50 boys and 50 girls from 10th and 12th grades participated in the study and their state anxiety before board exams was measured by Westside Test Anxiety Scale. We found that all board exam going students had increased level of anxiety, which was particularly higher among boys and 12th standard board exam going students. Analysis of various demographic variables showed that students from nuclear families presented higher anxiety levels compared to their desired competitive group. Overall, our results showing the prevalence of state anxiety among board exam going students in Tamil Nadu, India, support the recent attempt taken by Tamil Nadu government to improve student's academic performance in a healthier manner by appointing psychologists in all government schools. PMID- 25143939 TI - Assessment of free radical scavenging potential and oxidative DNA damage preventive activity of Trachyspermum ammi L. (carom) and Foeniculum vulgare Mill. (fennel) seed extracts. AB - Oxidation of biomolecules such as carbohydrates, proteins, lipids, and nucleic acids results in generation of free radicals in an organism which is the major cause of onset of various degenerative diseases. Antioxidants scavenge these free radicals, thereby protecting the cell from damage. The present study was designed to examine the free radical scavenging potential and oxidative DNA damage preventive activity of traditionally used spices Trachyspermum ammi L. (carom) and Foeniculum vulgare Mill. (fennel). The aqueous, methanolic, and acetonic extracts of T. ammi and F. vulgare seeds were prepared using soxhlet extraction assembly and subjected to qualitative and quantitative estimation of phytochemical constituents. Free radical scavenging potential was investigated using standard methods, namely, DPPH radical scavenging assay and ferric reducing antioxidant power assay along with the protection against oxidative DNA damage. The results stated that acetonic seed extracts (AAcSE and FAcSE) of both the spices possessed comparatively high amount of total phenolics whereas methanolic seed extracts (AMSE and FMSE) were found to have highest amount of total flavonoids. At 1 mg/mL concentration, highest DPPH radical scavenging activity was shown by FMSE (96.2%), AAcSE was recorded with highest FRAP value (2270.27 +/ 0.005 MUmol/L), and all the seed extracts have been shown to mitigate the damage induced by Fenton reaction on calf thymus DNA. Therefore, the study suggests that T. ammi and F. vulgare seed extracts could contribute as a highly significant bioresource of antioxidants to be used in our day-to-day life and in food and pharmaceutical industry. PMID- 25143941 TI - Gene delivery potential of biofunctional carbonate apatite nanoparticles in lungs. AB - Existing nonviral gene delivery systems to lungs are inefficient and associated with dose limiting toxicity in mammalian cells. Therefore, carbonate apatite (CO3Ap) nanoparticles were examined as an alternative strategy for effective gene delivery to the lungs. This study aimed to (1) assess the gene delivery efficiency of CO3Ap in vitro and in mouse lungs, (2) evaluate the cytotoxicity effect of CO3Ap/pDNA in vitro, and (3) characterize the CO3Ap/pDNA complex formulations. A significantly high level of reporter gene expression was detected from the lung cell line transfected with CO3Ap/pDNA complex prepared in both serum and serum-free medium. Cytotoxicity analysis revealed that the percentage of the viable cells treated with CO3Ap to be almost similar to the untreated cells. Characterization analyses showed that the CO3Ap/pDNA complexes are in a nanometer range with aggregated spherical structures and tended to be more negatively charged. In the lung of mice, highest level of transgene expression was observed when CO3Ap (8 MUL) was complexed with 40 MUg of pDNA at day 1 after administration. Although massive reduction of gene expression was seen beyond day 1 post administration, the level of expression remained significant throughout the study period. PMID- 25143940 TI - The role of oxidative stress and inflammation in cardiovascular aging. AB - Age is an independent risk factor of cardiovascular disease, even in the absence of other traditional factors. Emerging evidence in experimental animal and human models has emphasized a central role for two main mechanisms of age-related cardiovascular disease: oxidative stress and inflammation. Excess reactive oxygen species (ROS) and superoxide generated by oxidative stress and low-grade inflammation accompanying aging recapitulate age-related cardiovascular dysfunction, that is, left ventricular hypertrophy, fibrosis, and diastolic dysfunction in the heart as well as endothelial dysfunction, reduced vascular elasticity, and increased vascular stiffness. We describe the signaling involved in these two main mechanisms that include the factors NF-kappaB, JunD, p66(Shc), and Nrf2. Potential therapeutic strategies to improve the cardiovascular function with aging are discussed, with a focus on calorie restriction, SIRT1, and resveratrol. PMID- 25143942 TI - Upregulation of transglutaminase and epsilon (gamma-glutamyl)-lysine in the Fisher-Lewis rat model of chronic allograft nephropathy. AB - BACKGROUND: Tissue transglutaminase (TG2), a cross-linking enzyme, modulates deposition of extracellular matrix protein in renal fibrosis. This study aimed to examine TG2 and its cross-link product epsilon(gamma-glutamyl)-lysine in the Fisher-Lewis rat renal transplantation (RTx) model of chronic allograft nephropathy (CAN). MATERIALS AND METHODS: Left renal grafts from male Fisher and Lewis were transplanted into Lewis rats, generating allografts and isografts, respectively. Blood pressure, renal function, and proteinuria were monitored for up to 52 weeks. At termination, CAN was assessed in the renal tissue by light and electron microscopy, TG2 and epsilon(gamma-glutamyl)-lysine by immunofluorescence, and the urinary epsilon(gamma-glutamyl)-lysine by high performance liquid chromatography. RESULTS: Compared to the isograft, the allografts were hypertensive, proteinuric, and uraemic and developed CAN. Extracellular TG2 (glomerulus: 64.55 +/- 17.61 versus 2.11 +/- 0.17, P < 0.001; interstitium: 13.72 +/- 1.62 versus 3.19 +/- 0.44, P < 0.001), epsilon(gamma glutamyl)-lysine (glomerulus: 21.74 +/- 2.71 versus 1.98 +/- 0.37, P < 0.01; interstitium: 37.96 +/- 17.06 versus 0.42 +/- 0.11, P < 0.05), TG2 enzyme activity (1.09 +/- 0.13 versus 0.41 +/- 0.03 nmol/h/mg protein, P < 0.05), TG2 mRNA (20-fold rise), and urinary epsilon(gamma-glutamyl)-lysine (534.2 +/- 198.4 nmol/24 h versus 57.2 +/- 4.1 nmol/24 h, P < 0.05) levels were significantly elevated in the allografts and showed a positive linear correlation with tubulointerstitial fibrosis. CONCLUSION: CAN was associated with upregulation of renal TG2 pathway, which has a potential for pharmacological intervention. The elevated urinary epsilon(gamma-glutamyl)-lysine, measured for the first time in RTx, is a potential biomarker of CAN. PMID- 25143943 TI - Venomous and poisonous Australian animals of veterinary importance: a rich source of novel therapeutics. AB - Envenomation and poisoning by terrestrial animals (both vertebrate and invertebrate) are a significant economic problem and health risk for domestic animals in Australia. Australian snakes are some of the most venomous animals in the world and bees, wasps, ants, paralysis ticks, and cane toads are also present as part of the venomous and poisonous fauna. The diagnosis and treatment of envenomation or poisoning in animals is a challenge and can be a traumatic and expensive process for owners. Despite the potency of Australian venoms, there is potential for novel veterinary therapeutics to be modeled on venom toxins, as has been the case with human pharmaceuticals. A comprehensive overview of envenomation and poisoning signs in livestock and companion animals is provided and related to the potential for venom toxins to act as therapeutics. PMID- 25143944 TI - Mannose-binding lectin codon 54 gene polymorphism and vulvovaginal candidiasis: a systematic review and meta-analysis. AB - Mannose-binding lectin (MBL) plays a key role in the human innate immune response. It has been shown that polymorphisms in the MBL2 gene, particularly at codon 54 (variant allele B; wild-type allele designated as A), impact upon host susceptibility to Candida infection. This systematic review and meta-analysis were performed to assess the association between MBL2 codon 54 genotype and vulvovaginal candidiasis (VVC) or recurrent VVC (RVVC). Studies were searched in MEDLINE, SCOPUS, and ISI Web of Science until April 2013. Five studies including 704 women (386 cases and 318 controls) were part of the meta-analysis, and pooled ORs were calculated using the random effects model. For subjects with RVVC, ORs of AB versus AA and of BB versus AA were 4.84 (95% CI 2.10-11.15; P for heterogeneity = 0.013; I(2) = 68.6%) and 12.68 (95% CI 3.74-42.92; P for heterogeneity = 0.932, I(2) = 0.0%), respectively. For subjects with VVC, OR of AB versus AA was 2.57 (95% CI 1.29-5.12; P for heterogeneity = 0.897; I (2) = 0.0%). This analysis indicates that heterozygosity for the MBL2 allele B increases significantly the risk for both diseases, suggesting that MBL may influence the women's innate immunity in response to Candida. PMID- 25143945 TI - Identifying hierarchical and overlapping protein complexes based on essential protein-protein interactions and "seed-expanding" method. AB - Many evidences have demonstrated that protein complexes are overlapping and hierarchically organized in PPI networks. Meanwhile, the large size of PPI network wants complex detection methods have low time complexity. Up to now, few methods can identify overlapping and hierarchical protein complexes in a PPI network quickly. In this paper, a novel method, called MCSE, is proposed based on lambda-module and "seed-expanding." First, it chooses seeds as essential PPIs or edges with high edge clustering values. Then, it identifies protein complexes by expanding each seed to a lambda-module. MCSE is suitable for large PPI networks because of its low time complexity. MCSE can identify overlapping protein complexes naturally because a protein can be visited by different seeds. MCSE uses the parameter lambda_th to control the range of seed expanding and can detect a hierarchical organization of protein complexes by tuning the value of lambda_th. Experimental results of S. cerevisiae show that this hierarchical organization is similar to that of known complexes in MIPS database. The experimental results also show that MCSE outperforms other previous competing algorithms, such as CPM, CMC, Core-Attachment, Dpclus, HC-PIN, MCL, and NFC, in terms of the functional enrichment and matching with known protein complexes. PMID- 25143946 TI - Analysis of differential miRNA expression in primary tumor and stroma of colorectal cancer patients. AB - Microarray technology was used to profile miRNA expression in primary tumor and stromal tissue from paraffin embedded material of 51 patients with colorectal cancer. 26 miRNAs resulted differentially expressed with at least 2-fold change in tumor tissue with respect to stroma (16 more expressed in the tumor and 10 more expressed in the stroma). 10/26 were confirmed as differentially expressed at qRTPCR: miR-200c-3p, miR-141-3p, miR-200b-3p, miR-200a-3p, miR-1246, miR-92a 3p, miR-194-5p, miR-192-5p, miR-3651-5p, and miR-574-3p. No significant association was found between miRNA expressions and stage at diagnosis, site of primary tumor, first site of metastasis, progression-free, or overall survival. PMID- 25143947 TI - The impact of strenuous group physical activity on mood states, personal views, body composition, and markers of myocardial damage in overweight/obese adults: the "Step-by-step Italy's coast to coast" trek. AB - It is clinically relevant to understand whether it is safe to recommend to trained overweight/obese people long-distance treks and whether these experiences could have a negative psychological impact or become even dangerous exposing the trekkers to the risk of clinically silent myocardial damage. To answer these questions we have performed a quantitative/qualitative study comparing the changes in mood profiles, personal views, body composition, and plasma troponin levels of 40 overweight/obese subjects with those of 36 healthy normal weight subjects after the participation in a trek of 388 km from the Adriatic to the Tyrrhenian seas trek: the "Step by step...Italy's coast to coast". The results of this study demonstrate that long-distance treks are a safe activity for trained overweight/obese people which should be recommended because they improve mood, health status, and the relationship of participants with themselves and with the regular practice of exercise with effects similar to those obtained by healthy normal weight subjects. PMID- 25143949 TI - Pharmacogenomics in personalized medicine and drug metabolism. PMID- 25143948 TI - Continental monophyly and molecular divergence of Peninsular Malaysia's Macaca fascicularis fascicularis. AB - The phylogenetic relationships of long-tailed macaque (Macaca fascicularis fascicularis) populations distributed in Peninsular Malaysia in relation to other regions remain unknown. The aim of this study was to reveal the phylogeography and population genetics of Peninsular Malaysia's M. f. fascicularis based on the D-loop region of mitochondrial DNA. Sixty-five haplotypes were detected in all populations, with only Vietnam and Cambodia sharing four haplotypes. The minimum spanning network projected a distant relationship between Peninsular Malaysian and insular populations. Genetic differentiation (F(ST), Nst) results suggested that the gene flow among Peninsular Malaysian and the other populations is very low. Phylogenetic tree reconstructions indicated a monophyletic clade of Malaysia's population with continental populations (NJ = 97%, MP = 76%, and Bayesian = 1.00 posterior probabilities). The results demonstrate that Peninsular Malaysia's M. f. fascicularis belonged to Indochinese populations as opposed to the previously claimed Sundaic populations. M. f. fascicularis groups are estimated to have colonized Peninsular Malaysia ~0.47 million years ago (MYA) directly from Indochina through seaways, by means of natural sea rafting, or through terrestrial radiation during continental shelf emersion. Here, the Isthmus of Kra played a central part as biogeographical barriers that then separated it from the remaining continental populations. PMID- 25143950 TI - Netrins and their roles in placental angiogenesis. AB - Netrins, a family of laminin-related proteins, were originally identified as axonal guidance molecules. Subsequently, netrins were found to modulate various biological processes including morphogenesis, tumorogenesis, adhesion, and, recently, angiogenesis. In human placenta, the most vascularized organ, the presence of netrins has also been reported. Recent studies demonstrated the involvement of netrins in the regulation of placental angiogenesis. In this review we focused on the role of netrins in human placental angiogenesis. Among all netrins examined, netrin-4 and netrin-1 have been found to be either pro- or antiangiogenic factors. These opposite effects appear to be related to the endothelial cell phenotype studied and seem also to depend on the receptor type to which netrin binds, that is, the canonical receptor member of the DCC family, the members of the UNC5 family, or the noncanonical receptor members of the integrin family or DSCAM. PMID- 25143952 TI - Modeling biology spanning different scales: an open challenge. AB - It is coming nowadays more clear that in order to obtain a unified description of the different mechanisms governing the behavior and causality relations among the various parts of a living system, the development of comprehensive computational and mathematical models at different space and time scales is required. This is one of the most formidable challenges of modern biology characterized by the availability of huge amount of high throughput measurements. In this paper we draw attention to the importance of multiscale modeling in the framework of studies of biological systems in general and of the immune system in particular. PMID- 25143951 TI - A molecular view of autophagy in Lepidoptera. AB - Metamorphosis represents a critical phase in the development of holometabolous insects, during which the larval body is completely reorganized: in fact, most of the larval organs undergo remodeling or completely degenerate before the final structure of the adult insect is rebuilt. In the past, increasing evidence emerged concerning the intervention of autophagy and apoptosis in the cell death processes that occur in larval organs of Lepidoptera during metamorphosis, but a molecular characterization of these pathways was undertaken only in recent years. In addition to developmentally programmed autophagy, there is growing interest in starvation-induced autophagy. Therefore we are now entering a new era of research on autophagy that foreshadows clarification of the role and regulatory mechanisms underlying this self-digesting process in Lepidoptera. Given that some of the most important lepidopteran species of high economic importance, such as the silkworm, Bombyx mori, belong to this insect order, we expect that this information on autophagy will be fully exploited not only in basic research but also for practical applications. PMID- 25143953 TI - Punctuated evolution of influenza virus neuraminidase (A/H1N1) under opposing migration and vaccination pressures. AB - Influenza virus contains two highly variable envelope glycoproteins, hemagglutinin (HA) and neuraminidase (NA). The structure and properties of HA, which is responsible for binding the virus to the cell that is being infected, change significantly when the virus is transmitted from avian or swine species to humans. Here we focus first on the simpler problem of the much smaller human individual evolutionary amino acid mutational changes in NA, which cleaves sialic acid groups and is required for influenza virus replication. Our thermodynamic panorama shows that very small amino acid changes can be monitored very accurately across many historic (1945-2011) Uniprot and NCBI strains using hydropathicity scales to quantify the roughness of water film packages. Quantitative sequential analysis is most effective with the fractal differential hydropathicity scale based on protein self-organized criticality (SOC). Our analysis shows that large-scale vaccination programs have been responsible for a very large convergent reduction in common influenza severity in the last century. Hydropathic analysis is capable of interpreting and even predicting trends of functional changes in mutation prolific viruses directly from amino acid sequences alone. An engineered strain of NA1 is described which could well be significantly less virulent than current circulating strains. PMID- 25143956 TI - Advanced heat map and clustering analysis using heatmap3. AB - Heat maps and clustering are used frequently in expression analysis studies for data visualization and quality control. Simple clustering and heat maps can be produced from the "heatmap" function in R. However, the "heatmap" function lacks certain functionalities and customizability, preventing it from generating advanced heat maps and dendrograms. To tackle the limitations of the "heatmap" function, we have developed an R package "heatmap3" which significantly improves the original "heatmap" function by adding several more powerful and convenient features. The "heatmap3" package allows users to produce highly customizable state of the art heat maps and dendrograms. The "heatmap3" package is developed based on the "heatmap" function in R, and it is completely compatible with it. The new features of "heatmap3" include highly customizable legends and side annotation, a wider range of color selections, new labeling features which allow users to define multiple layers of phenotype variables, and automatically conducted association tests based on the phenotypes provided. Additional features such as different agglomeration methods for estimating distance between two samples are also added for clustering. PMID- 25143955 TI - Targeted therapy for HM1.24 (CD317) on multiple myeloma cells. AB - Multiple myeloma (MM) still remains an incurable disease, at least because of the existence of cell-adhesion mediated drug-resistant MM cells and/or continuous recruitment of presumed MM cancer stem cell-like cells (CSCs). As a new alternative treatment modality, immunological approaches using monoclonal antibodies (mAbs) and/or cytotoxic T lymphocytes (CTLs) are now attracting much attention as a novel strategy attacking MM cells. We have identified that HM1.24 [also known as bone marrow stromal cell antigen 2 (BST2) or CD317] is overexpressed on not only mature MM cells but also MM CSCs. We then have developed a humanized mAb to HM1.24 and defucosylated version of the mAb to adapt to clinical practice. Moreover, we have successfully induced HM1.24-specific CTLs against MM cells. The combination of these innovative therapeutic modalities may likely exert an anti-MM activity by evading the drug resistance mechanism and eliminating presumed CSCs in MM. PMID- 25143954 TI - Cell microenvironment engineering and monitoring for tissue engineering and regenerative medicine: the recent advances. AB - In tissue engineering and regenerative medicine, the conditions in the immediate vicinity of the cells have a direct effect on cells' behaviour and subsequently on clinical outcomes. Physical, chemical, and biological control of cell microenvironment are of crucial importance for the ability to direct and control cell behaviour in 3-dimensional tissue engineering scaffolds spatially and temporally. In this review, we will focus on the different aspects of cell microenvironment such as surface micro-, nanotopography, extracellular matrix composition and distribution, controlled release of soluble factors, and mechanical stress/strain conditions and how these aspects and their interactions can be used to achieve a higher degree of control over cellular activities. The effect of these parameters on the cellular behaviour within tissue engineering context is discussed and how these parameters are used to develop engineered tissues is elaborated. Also, recent techniques developed for the monitoring of the cell microenvironment in vitro and in vivo are reviewed, together with recent tissue engineering applications where the control of cell microenvironment has been exploited. Cell microenvironment engineering and monitoring are crucial parts of tissue engineering efforts and systems which utilize different components of the cell microenvironment simultaneously can provide more functional engineered tissues in the near future. PMID- 25143958 TI - Use of autoantibodies to detect the onset of breast cancer. AB - The widespread use of screening mammography has resulted in increased detection of early-stage breast disease, particularly for in situ carcinoma and early-stage breast cancer. However, the majority of women with abnormalities noted on screening mammograms are not diagnosed with cancer because of several factors, including radiologist assessment, patient age, breast density, malpractice concerns, and quality control procedures. Although magnetic resonance imaging is a highly sensitive detection tool that has become standard for women at very high risk of developing breast cancer, it lacks sufficient specificity and costeffectiveness for use as a general screening tool. Therefore, there is an important need to improve screening and diagnosis of early-invasive and noninvasive tumors, that is, in situ carcinoma. The great potential for molecular tools to improve breast cancer outcomes based on early diagnosis has driven the search for diagnostic biomarkers. Identification of tumor-specific markers capable of eliciting an immune response in the early stages of tumor development seems to provide an effective approach for early diagnosis. The aim of this review is to describe several autoantibodies identified during breast cancer diagnosis. We will focus on these molecules highlighted in the past two years and discuss the potential future use of autoantibodies as biomarkers of early-stage breast cancer. PMID- 25143957 TI - HLA-G as a tolerogenic molecule in transplantation and pregnancy. AB - HLA-G is a nonclassical HLA class I molecule. In allogeneic situations such as pregnancy or allograft transplantation, the expression of HLA-G has been related to a better acceptance of the fetus or the allograft. Thus, it seems that HLA-G is crucially involved in mechanisms shaping an allogeneic immune response into tolerance. In this contribution we focus on (i) how HLA-G is involved in transplantation and human reproduction, (ii) how HLA-G is regulated by genetic and microenvironmental factors, and (iii) how HLA-G can offer novel perspectives with respect to therapy. PMID- 25143959 TI - Wnt signaling in castration-resistant prostate cancer: implications for therapy. AB - Increasing evidence has indicated that Wnt signaling plays complex roles in castration resistant prostate cancer (CRPC). Although not all data were consistent, beta-catenin nuclear localization and its co-localization with androgen receptor (AR) were more frequently observed in CRPC compared to hormone naive prostate cancer. This direct interaction between AR and beta-catenin seemed to elicit a specific expression of a set of target genes in low androgen conditions in CRPC. Paracrine Wnt signaling also was shown to aid resistance to chemotherapy and androgen deprivation therapy. Results from the next generation sequencing studies (i.e. RNA-seq and whole exosome sequcing) of CRPC specimens have identified the Wnt pathway as one of the top signaling pathways with significant genomic alterations in CRPC, whereas, Wnt pathway alterations were virtually absent in hormone naive primary prostate cancer. Furthermore, Wnt signaling has been suggested to play an important role in cancer stem cell functions in prostate cancer recurrence and resistance to androgen deprivation therapy. Therefore, in this review we have summarized existing knowledge regarding potential roles of Wnt signaling in CRPC and underline Wnt signaling as a potential therapeutic target for CRPC. Further understanding of Wnt signaling in castration resistance may eventually contribute new insights into possible treatment options for this incurable disease. PMID- 25143962 TI - A note on the solutions of some nonlinear equations arising in third-grade fluid flows: an exact approach. AB - In this communication, we utilize some basic symmetry reductions to transform the governing nonlinear partial differential equations arising in the study of third grade fluid flows into ordinary differential equations. We obtain some simple closed-form steady-state solutions of these reduced equations. Our solutions are valid for the whole domain [0,infinity) and also satisfy the physical boundary conditions. We also present the numerical solutions for some of the underlying equations. The graphs corresponding to the essential physical parameters of the flow are presented and discussed. PMID- 25143961 TI - Can vascular endothelial growth factor and microvessel density be used as prognostic biomarkers for colorectal cancer? A systematic review and meta analysis. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) and microvessel density (MVD) are associated with greater incidence of metastases and decreased survival. Whether they can be used as prognostic indicators of colorectal cancer (CRC) is still controversial. METHODS: The authors performed a meta-analysis using the results of a literature search of databases of PubMed and EMBASE, and the references of articles included in the analysis. Meta-analysis was performed using random effects model and hazard ratios (HRs) and 95% confidence intervals (CIs) as effect measures. RESULTS: Twenty studies contributed to the analysis of VEGF, of which 16 were used for overall survival (OS) and 9 for disease-free survival (DFS). High VEGF levels has a relationship with unfavorable survival (OS: HR = 1.98, 95% CI: 1.30-3.02; DFS: HR = 2.10, 95% CI: 1.26-3.49) and a 4.22 fold increase in the rate of distant metastases. Analysis was performed on 18 studies for MVD; the results showed that patients with high MVD expression in tumors appeared to have poorer overall survival (HR = 1.39, 95% CI: 1.22-1.58) and were at a greater risk of having unfavorable clinical characteristics related to prognosis. Corresponding results were obtained from quantitative and/or qualitative analysis of clinicopathological. CONCLUSIONS: The meta-analysis demonstrates that VEGF and MVD can be used as prognostic biomarkers for CRC patients. PMID- 25143964 TI - On some nonclassical algebraic properties of interval-valued fuzzy soft sets. AB - Interval-valued fuzzy soft sets realize a hybrid soft computing model in a general framework. Both Molodtsov's soft sets and interval-valued fuzzy sets can be seen as special cases of interval-valued fuzzy soft sets. In this study, we first compare four different types of interval-valued fuzzy soft subsets and reveal the relations among them. Then we concentrate on investigating some nonclassical algebraic properties of interval-valued fuzzy soft sets under the soft product operations. We show that some fundamental algebraic properties including the commutative and associative laws do not hold in the conventional sense, but hold in weaker forms characterized in terms of the relation = L . We obtain a number of algebraic inequalities of interval-valued fuzzy soft sets characterized by interval-valued fuzzy soft inclusions. We also establish the weak idempotent law and the weak absorptive law of interval-valued fuzzy soft sets using interval-valued fuzzy soft J-equal relations. It is revealed that the soft product operations ? and ? of interval-valued fuzzy soft sets do not always have similar algebraic properties. Moreover, we find that only distributive inequalities described by the interval-valued fuzzy soft L-inclusions hold for interval-valued fuzzy soft sets. PMID- 25143963 TI - The genetic structure of wild Orobanche cumana Wallr. (Orobanchaceae) populations in eastern Bulgaria reflects introgressions from weedy populations. AB - Orobanche cumana is a holoparasitic plant naturally distributed from central Asia to south-eastern Europe, where it parasitizes wild Asteraceae species. It is also an important parasitic weed of sunflower crops. The objective of this research was to investigate genetic diversity, population structure, and virulence on sunflower of O. cumana populations parasitizing wild plants in eastern Bulgaria. Fresh tissue of eight O. cumana populations and mature seeds of four of them were collected in situ on wild hosts. Genetic diversity and population structure were studied with SSR markers and compared to weedy populations. Two main gene pools were identified in Bulgarian populations, with most of the populations having intermediate characteristics. Cross-inoculation experiments revealed that O. cumana populations collected on wild species possessed similar ability to parasitize sunflower to those collected on sunflower. The results were explained on the basis of an effective genetic exchange between populations parasitizing sunflower crops and those parasitizing wild species. The occurrence of bidirectional gene flow may have an impact on wild populations, as new physiological races continuously emerge in weedy populations. Also, genetic variability of wild populations may favour the ability of weedy populations to overcome sunflower resistance mechanisms. PMID- 25143960 TI - Sickle cell disease: new opportunities and challenges in Africa. AB - Sickle cell disease (SCD) is one of the most common genetic causes of illness and death in the world. This is a review of SCD in Africa, which bears the highest burden of disease. The first section provides an introduction to the molecular basis of SCD and the pathophysiological mechanism of selected clinical events. The second section discusses the epidemiology of the disease (prevalence, morbidity, and mortality), at global level and within Africa. The third section discusses the laboratory diagnosis and management of SCD, emphasizing strategies that been have proven to be effective in areas with limited resources. Throughout the review, specific activities that require evidence to guide healthcare in Africa, as well as strategic areas for further research, will be highlighted. PMID- 25143965 TI - Recent progress on nonlinear Schrodinger systems with quadratic interactions. AB - The study of nonlinear Schrodinger systems with quadratic interactions has attracted much attention in the recent years. In this paper, we summarize time decay estimates of small solutions to the systems under the mass resonance condition in 2-dimensional space. We show the existence of wave operators and modified wave operators of the systems under some mass conditions in n dimensional space, where n >= 2. The existence of scattering operators and finite time blow-up of the solutions for the systems in higher space dimensions is also shown. PMID- 25143966 TI - 2-Pentanone production from hexanoic acid by Penicillium roqueforti from blue cheese: is this the pathway used in humans? AB - Production of 2-pentanone, a methylketone, is increased in fasting ketotic humans. Its origin is unknown. We hypothesised that it is formed via beta oxidation of hexanoic acid by the peroxisomal pathway proposed for methylketone producing fungi and yeasts. We used Penicillium roqueforti cultured on fat (margarine) to investigate 2-pentanone production. Headspace gas of incubates of the mould with a range of substrates was analysed using solid-phase microextraction with gas chromatography-mass spectrometry. Consistent with the proposed pathway, 2-pentanone was formed from hexanoic acid, hexanoyl-CoA, hexanoylcarnitine, and ethyl-3-oxohexanoic acid but not from ethylhexanoic, 2 ethylhexanoic, octanoic, or myristic acids, octanoylcarnitine, or pentane. However, the products from deuterated (D) hexanoic-D11 acid and hexanoic-2, 2-D2 acid were 9D- and 2D-2-pentanone, respectively, and not 8D- and 1D-2-pentanone as predicted. When incubated under (18)O2/(14)N2, there was only a very small enrichment of [(16)O2]- with [(18)O2]-containing 2-pentanone. These are new observations. They could be explained if hydrogen ions removed from hexanoyl-CoA by acyl-CoA oxidase at the commencement of beta -oxidation were cycled through hydrogen peroxide and reentered the pathway through hydration of hexenoyl-CoA. This would protect other proteins from oxidative damage. Formation of 2-pentanone through a beta -oxidation cycle similar to Penicillium roqueforti would be consistent with observations in humans. PMID- 25143967 TI - Synthesis of CdIn2S4 microsphere and its photocatalytic activity for azo dye degradation. AB - CdIn2S4 was prepared by ultrasonic spray pyrolysis. The prepared CdIn2S4 was characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FSEM), transmission electron microscopy (TEM), UV-visible diffuse reflectance spectroscopy (UV-Vis DRS), and N2-sorption techniques. Aqueous photocatalytic activity was evaluated by the decomposition of methyl orange under visible light irradiation. The results indicate that the prepared CdIn2S4 has spherical morphology with mesoporous structure which can efficiently degrade methyl orange in water. The sample prepared at 500 degrees C exhibits the optimized photocatalytic activity. PMID- 25143968 TI - Analyzing big data with the hybrid interval regression methods. AB - Big data is a new trend at present, forcing the significant impacts on information technologies. In big data applications, one of the most concerned issues is dealing with large-scale data sets that often require computation resources provided by public cloud services. How to analyze big data efficiently becomes a big challenge. In this paper, we collaborate interval regression with the smooth support vector machine (SSVM) to analyze big data. Recently, the smooth support vector machine (SSVM) was proposed as an alternative of the standard SVM that has been proved more efficient than the traditional SVM in processing large-scale data. In addition the soft margin method is proposed to modify the excursion of separation margin and to be effective in the gray zone that the distribution of data becomes hard to be described and the separation margin between classes. PMID- 25143969 TI - Parallel batch scheduling of deteriorating jobs with release dates and rejection. AB - We consider the unbounded parallel batch scheduling with deterioration, release dates, and rejection. Each job is either accepted and processed on a single batching machine, or rejected by paying penalties. The processing time of a job is a simple linear increasing function of its starting time. The objective is to minimize the sum of the makespan of the accepted jobs and the total penalty of the rejected jobs. First, we show that the problem is NP-hard in the ordinary sense. Then, we present two pseudopolynomial time algorithms and a fully polynomial-time approximation scheme to solve this problem. Furthermore, we provide an optimal O(n log n) time algorithm for the case where jobs have identical release dates. PMID- 25143970 TI - Novel image encryption scheme based on Chebyshev polynomial and Duffing map. AB - We present a novel image encryption algorithm using Chebyshev polynomial based on permutation and substitution and Duffing map based on substitution. Comprehensive security analysis has been performed on the designed scheme using key space analysis, visual testing, histogram analysis, information entropy calculation, correlation coefficient analysis, differential analysis, key sensitivity test, and speed test. The study demonstrates that the proposed image encryption algorithm shows advantages of more than 10(113) key space and desirable level of security based on the good statistical results and theoretical arguments. PMID- 25143971 TI - Software authority transition through multiple distributors. AB - The rapid growth in the use of smartphones and tablets has changed the software distribution ecosystem. The trend today is to purchase software through application stores rather than from traditional offline markets. Smartphone and tablet users can install applications easily by purchasing from the online store deployed in their device. Several systems, such as Android or PC-based OS units, allow users to install software from multiple sources. Such openness, however, can promote serious threats, including malware and illegal usage. In order to prevent such threats, several stores use online authentication techniques. These methods can, however, also present a problem whereby even licensed users cannot use their purchased application. In this paper, we discuss these issues and provide an authentication method that will make purchased applications available to the registered user at all times. PMID- 25143972 TI - Development of vision based multiview gait recognition system with MMUGait database. AB - This paper describes the acquisition setup and development of a new gait database, MMUGait. This database consists of 82 subjects walking under normal condition and 19 subjects walking with 11 covariate factors, which were captured under two views. This paper also proposes a multiview model-based gait recognition system with joint detection approach that performs well under different walking trajectories and covariate factors, which include self-occluded or external occluded silhouettes. In the proposed system, the process begins by enhancing the human silhouette to remove the artifacts. Next, the width and height of the body are obtained. Subsequently, the joint angular trajectories are determined once the body joints are automatically detected. Lastly, crotch height and step-size of the walking subject are determined. The extracted features are smoothened by Gaussian filter to eliminate the effect of outliers. The extracted features are normalized with linear scaling, which is followed by feature selection prior to the classification process. The classification experiments carried out on MMUGait database were benchmarked against the SOTON Small DB from University of Southampton. Results showed correct classification rate above 90% for all the databases. The proposed approach is found to outperform other approaches on SOTON Small DB in most cases. PMID- 25143973 TI - On the limit cycles of a class of planar singular perturbed differential equations. AB - Relaxation oscillations of two-dimensional planar singular perturbed systems with a layer equation exhibiting canard cycles are studied. The canard cycles under consideration contain two turning points and two jump points. We suppose that there exist three parameters permitting generic breaking at both the turning points and the connecting fast orbit. The conditions of one (resp., two, three) relaxation oscillation near the canard cycles are given by studying a map from the space of phase parameters to the space of breaking parameters. PMID- 25143974 TI - Improved stability criteria of static recurrent neural networks with a time varying delay. AB - This paper investigates the stability of static recurrent neural networks (SRNNs) with a time-varying delay. Based on the complete delay-decomposing approach and quadratic separation framework, a novel Lyapunov-Krasovskii functional is constructed. By employing a reciprocally convex technique to consider the relationship between the time-varying delay and its varying interval, some improved delay-dependent stability conditions are presented in terms of linear matrix inequalities (LMIs). Finally, a numerical example is provided to show the merits and the effectiveness of the proposed methods. PMID- 25143975 TI - SVM-based spectrum mobility prediction scheme in mobile cognitive radio networks. AB - Spectrum mobility as an essential issue has not been fully investigated in mobile cognitive radio networks (CRNs). In this paper, a novel support vector machine based spectrum mobility prediction (SVM-SMP) scheme is presented considering time varying and space-varying characteristics simultaneously in mobile CRNs. The mobility of cognitive users (CUs) and the working activities of primary users (PUs) are analyzed in theory. And a joint feature vector extraction (JFVE) method is proposed based on the theoretical analysis. Then spectrum mobility prediction is executed through the classification of SVM with a fast convergence speed. Numerical results validate that SVM-SMP gains better short-time prediction accuracy rate and miss prediction rate performance than the two algorithms just depending on the location and speed information. Additionally, a rational parameter design can remedy the prediction performance degradation caused by high speed SUs with strong randomness movements. PMID- 25143976 TI - New trends in robotics for agriculture: integration and assessment of a real fleet of robots. AB - Computer-based sensors and actuators such as global positioning systems, machine vision, and laser-based sensors have progressively been incorporated into mobile robots with the aim of configuring autonomous systems capable of shifting operator activities in agricultural tasks. However, the incorporation of many electronic systems into a robot impairs its reliability and increases its cost. Hardware minimization, as well as software minimization and ease of integration, is essential to obtain feasible robotic systems. A step forward in the application of automatic equipment in agriculture is the use of fleets of robots, in which a number of specialized robots collaborate to accomplish one or several agricultural tasks. This paper strives to develop a system architecture for both individual robots and robots working in fleets to improve reliability, decrease complexity and costs, and permit the integration of software from different developers. Several solutions are studied, from a fully distributed to a whole integrated architecture in which a central computer runs all processes. This work also studies diverse topologies for controlling fleets of robots and advances other prospective topologies. The architecture presented in this paper is being successfully applied in the RHEA fleet, which comprises three ground mobile units based on a commercial tractor chassis. PMID- 25143977 TI - A DAG scheduling scheme on heterogeneous computing systems using tuple-based chemical reaction optimization. AB - A complex computing problem can be solved efficiently on a system with multiple computing nodes by dividing its implementation code into several parallel processing modules or tasks that can be formulated as directed acyclic graph (DAG) problems. The DAG jobs may be mapped to and scheduled on the computing nodes to minimize the total execution time. Searching an optimal DAG scheduling solution is considered to be NP-complete. This paper proposed a tuple molecular structure-based chemical reaction optimization (TMSCRO) method for DAG scheduling on heterogeneous computing systems, based on a very recently proposed metaheuristic method, chemical reaction optimization (CRO). Comparing with other CRO-based algorithms for DAG scheduling, the design of tuple reaction molecular structure and four elementary reaction operators of TMSCRO is more reasonable. TMSCRO also applies the concept of constrained critical paths (CCPs), constrained critical-path directed acyclic graph (CCPDAG) and super molecule for accelerating convergence. In this paper, we have also conducted simulation experiments to verify the effectiveness and efficiency of TMSCRO upon a large set of randomly generated graphs and the graphs for real world problems. PMID- 25143978 TI - A socially aware routing based on local contact information in delay-tolerant networks. AB - In delay-tolerant networks, network topology changes dynamically and there is no guarantee of continuous connectivity between any two nodes. These features make DTN routing one of important research issues, and the application of social network metrics has led to the design of recent DTN routing schemes. In this paper, we propose an efficient routing scheme by using a node's local contact history and social network metrics. Each node first chooses a proper relay node based on the closeness to the destination node. A locally computed betweenness centrality is additionally utilized to enhance the routing efficiency. Through intensive simulation, we finally demonstrate that our algorithm performs efficiently compared to the existing epidemic or friendship routing scheme. PMID- 25143979 TI - Followee recommendation in microblog using matrix factorization model with structural regularization. AB - Microblog that provides us a new communication and information sharing platform has been growing exponentially since it emerged just a few years ago. To microblog users, recommending followees who can serve as high quality information sources is a competitive service. To address this problem, in this paper we propose a matrix factorization model with structural regularization to improve the accuracy of followee recommendation in microblog. More specifically, we adapt the matrix factorization model in traditional item recommender systems to followee recommendation in microblog and use structural regularization to exploit structure information of social network to constrain matrix factorization model. The experimental analysis on a real-world dataset shows that our proposed model is promising. PMID- 25143980 TI - Fixed points of contractive mappings in b-metric-like spaces. AB - We discuss topological structure of b-metric-like spaces and demonstrate a fundamental lemma for the convergence of sequences. As an application we prove certain fixed point results in the setup of such spaces for different types of contractive mappings. Finally, some periodic point results in b-metric-like spaces are obtained. Two examples are presented in order to verify the effectiveness and applicability of our main results. PMID- 25143981 TI - Extension of weighted sum of gray gas data to mathematical simulation of radiative heat transfer in a boiler with gas-soot media. AB - In this study an expression for soot absorption coefficient is introduced to extend the weighted-sum-of-gray gases data to the furnace medium containing gas soot mixture in a utility boiler 150 MWe. Heat transfer and temperature distribution of walls and within the furnace space are predicted by zone method technique. Analyses have been done considering both cases of presence and absence of soot particles at 100% load. To validate the proposed soot absorption coefficient, the expression is coupled with the Taylor and Foster's data as well as Truelove's data for CO2-H2O mixture and the total emissivities are calculated and compared with the Truelove's parameters for 3-term and 4-term gray gases plus two soot absorption coefficients. In addition, some experiments were conducted at 100% and 75% loads to measure furnace exit gas temperature as well as the rate of steam production. The predicted results show good agreement with the measured data at the power plant site. PMID- 25143982 TI - A time delay predator-prey system with three-stage-structure. AB - A predator-prey system was studied that has a discrete delay, stage-structure, and Beddington-DeAngelis functional response, where predator species has three stages, immature, mature, and old age stages. By using of Mawhin's continuous theorem of coincidence degree theory, a sufficient condition is obtained for the existence of a positive periodic solution. PMID- 25143983 TI - Temporal and spatial evolution characteristics of disturbance wave in a hypersonic boundary layer due to single-frequency entropy disturbance. AB - By using a high-order accurate finite difference scheme, direct numerical simulation of hypersonic flow over an 8 degrees half-wedge-angle blunt wedge under freestream single-frequency entropy disturbance is conducted; the generation and the temporal and spatial nonlinear evolution of boundary layer disturbance waves are investigated. Results show that, under the freestream single-frequency entropy disturbance, the entropy state of boundary layer is changed sharply and the disturbance waves within a certain frequency range are induced in the boundary layer. Furthermore, the amplitudes of disturbance waves in the period phase are larger than that in the response phase and ablation phase and the frequency range in the boundary layer in the period phase is narrower than that in these two phases. In addition, the mode competition, dominant mode transformation, and disturbance energy transfer exist among different modes both in temporal and in spatial evolution. The mode competition changes the characteristics of nonlinear evolution of the unstable waves in the boundary layer. The development of the most unstable mode along streamwise relies more on the motivation of disturbance waves in the upstream than that of other modes on this motivation. PMID- 25143985 TI - Use of electrocautery for coagulation and wound complications in Caesarean sections. AB - OBJECTIVE: To evaluate the safety of electrocautery for coagulation during Caesarean sections. STUDY DESIGN: A randomized, controlled, clinical pilot study was performed at a university maternity hospital. After admission for delivery and decision to perform a C-section, volunteers were randomized to either the intervention group (use of electrocautery for coagulation) or nonintervention group. The women were examined at the time of postpartum discharge (day 3), at days 7 to 10, and again at days 30 to 40 for signs of infection, hematoma, seroma, or dehiscence. Data were analyzed using an intention-to-treat analysis, and risk ratios were calculated. RESULTS: No significant differences were found between the two groups. Only 2.8% of patients in the intervention group developed surgical wound complications during hospitalization. However, 7 to 10 days following discharge, these rates reached 23.0% and 15.4% in the intervention and nonintervention groups, respectively (RR = 1.50, 95% CI = 0.84-2.60). CONCLUSION: Further studies should confirm whether the use of electrocautery for coagulation does not increase the risk of surgical wound complications in patients undergoing Caesarean sections. PMID- 25143984 TI - Heat shock protein 70 gene polymorphisms and cancer risk: a meta-analysis. AB - The polymorphisms in the three main heat shock protein 70 (HSP70-1, HSP70-2, and HSP70-hom) genes were identified to be associated with cancer risk. However, the results are inconsistent. We perform a meta-analysis to evaluate the association between the three HSP70 polymorphisms and cancer risk. Relevant studies were identified using PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases up to March 29, 2014. The cancer risk associated with the HSP70 polymorphisms was estimated for each study by odds ratios (OR) together with its 95% confidence interval (CI), respectively. Twenty case-control studies from eighteen publications were included; a significant association was observed for HSP70-2 polymorphism (dominant model: OR = 1.53, 95% CI: 1.11-2.09; recessive model: OR = 1.91, 95% CI: 1.06-3.45; AG versus AA: OR = 1.38, 95% CI: 1.03-1.84; GG versus AA: OR = 2.34, 95% CI: 1.21-4.54), while there was no significant association for HSP70-1 and HSP70-hom polymorphisms. Besides, in stratification analyses by ethnicity, cancer type, and source of control, significant association was detected for HSP70-2 polymorphism, while for HSP70 hom polymorphism, we found a significant association in hospital-based population under homozygote comparison model. This meta-analysis suggests that the HSP70-2 polymorphism rather than HSP70-hom and HSP70-1 polymorphisms was associated with the risk of cancer. PMID- 25143986 TI - Secure and fair cluster head selection protocol for enhancing security in mobile ad hoc networks. AB - Mobile ad hoc networks (MANETs) are wireless networks consisting of number of autonomous mobile devices temporarily interconnected into a network by wireless media. MANETs become one of the most prevalent areas of research in the recent years. Resource limitations, energy efficiency, scalability, and security are the great challenging issues in MANETs. Due to its deployment nature, MANETs are more vulnerable to malicious attack. The secure routing protocols perform very basic security related functions which are not sufficient to protect the network. In this paper, a secure and fair cluster head selection protocol (SFCP) is proposed which integrates security factors into the clustering approach for achieving attacker identification and classification. Byzantine agreement based cooperative technique is used for attacker identification and classification to make the network more attack resistant. SFCP used to solve this issue by making the nodes that are totally surrounded by malicious neighbors adjust dynamically their belief and disbelief thresholds. The proposed protocol selects the secure and energy efficient cluster head which acts as a local detector without imposing overhead to the clustering performance. SFCP is simulated in network simulator 2 and compared with two protocols including AODV and CBRP. PMID- 25143987 TI - Mining 3D patterns from gene expression temporal data: a new tricluster evaluation measure. AB - Microarrays have revolutionized biotechnological research. The analysis of new data generated represents a computational challenge due to the characteristics of these data. Clustering techniques are applied to create groups of genes that exhibit a similar behavior. Biclustering emerges as a valuable tool for microarray data analysis since it relaxes the constraints for grouping, allowing genes to be evaluated only under a subset of the conditions. However, if a third dimension appears in the data, triclustering is the appropriate tool for the analysis. This occurs in longitudinal experiments in which the genes are evaluated under conditions at several time points. All clustering, biclustering, and triclustering techniques guide their search for solutions by a measure that evaluates the quality of clusters. We present an evaluation measure for triclusters called Mean Square Residue 3D. This measure is based on the classic biclustering measure Mean Square Residue. Mean Square Residue 3D has been applied to both synthetic and real data and it has proved to be capable of extracting groups of genes with homogeneous patterns in subsets of conditions and times, and these groups have shown a high correlation level and they are also related to their functional annotations extracted from the Gene Ontology project. PMID- 25143988 TI - RSSI-based smooth localization for indoor environment. AB - Radio frequency (RF) technique, for its better penetrability over traditional techniques such as infrared or ultrasound, is widely used for indoor localization and tracking. In this paper, three novel measurements, point decision accuracy, path matching error and wrong jumping ratio, are firstly defined to express the localization efficiency. Then, a novel RSSI-based smooth localization (RSL) algorithm is designed, implemented, and evaluated on the WiFi networks. The tree based mechanism determines the current position and track of the entity by assigning the weights and accumulative weights for all collected RSSI information of reference points so as to make the localization smooth. The evaluation results indicate that the proposed algorithm brings better localization smoothness of reducing 10% path matching error and 30% wrong jumping ratio over the RADAR system. PMID- 25143989 TI - Personalized privacy-preserving frequent itemset mining using randomized response. AB - Frequent itemset mining is the important first step of association rule mining, which discovers interesting patterns from the massive data. There are increasing concerns about the privacy problem in the frequent itemset mining. Some works have been proposed to handle this kind of problem. In this paper, we introduce a personalized privacy problem, in which different attributes may need different privacy levels protection. To solve this problem, we give a personalized privacy preserving method by using the randomized response technique. By providing different privacy levels for different attributes, this method can get a higher accuracy on frequent itemset mining than the traditional method providing the same privacy level. Finally, our experimental results show that our method can have better results on the frequent itemset mining while preserving personalized privacy. PMID- 25143990 TI - A novel chaotic map and an improved chaos-based image encryption scheme. AB - In this paper, we present a novel approach to create the new chaotic map and propose an improved image encryption scheme based on it. Compared with traditional classic one-dimensional chaotic maps like Logistic Map and Tent Map, this newly created chaotic map demonstrates many better chaotic properties for encryption, implied by a much larger maximal Lyapunov exponent. Furthermore, the new chaotic map and Arnold's Cat Map based image encryption method is designed and proved to be of solid robustness. The simulation results and security analysis indicate that such method not only can meet the requirement of imagine encryption, but also can result in a preferable effectiveness and security, which is usable for general applications. PMID- 25143991 TI - Insecticidal activity and chemical composition of the Morinda lucida essential oil against pulse beetle Callosobruchus maculatus. AB - Insecticidal activity of essential oil extracted from Morinda lucida was tested on pulse beetle Callosobruchus maculatus, which is a pest that causes serious damage to several pulses. The insecticidal activity was compared with two pesticides, Phostoxin and Primo-ban-20. 120 mixed sex adult C. maculatus were introduced, along with 30 g of cowpeas. Four concentrations (0.40, 0.20, 0.10, and 0.05 MUg/mL) of the M. lucida essential oil, Phostoxin, and Primo-ban-20 were tested. Essential oil chemical composition was analyzed by GC-MS. M. lucida essential oil showed a high toxicological effect, producing 100% mortality after 72 hours at a dose of 0.20 MUg/mL. M. lucida essential oil had a potent insecticidal activity (LC90 = 0.629 MUg/mL) compared to both pesticides, Phostoxin (LC90 = 0.652 MUg/mL) and Primo-ban-20 (LC90 = 0.726 MUg/mL), at 24 h. The main compounds of the essential oil were the oxygenated monoterpenoids, 1,8 cineole (43.4%), and alpha-terpinyl acetate (14.5%), and the monoterpene hydrocarbons, mostly sabinene (8.2%) and beta-pinene (4.0%). Results clearly indicate that M. lucida essential oil can be used as an effective alternative for pulse beetle C. maculatus control, and it could be tested against other pulse beetles affecting Asia and Africa and throughout the world, thereby reducing use of synthetic pesticides. PMID- 25143992 TI - Phytoestrogen alpha-zearalanol improves memory impairment and hippocampal neurogenesis in ovariectomized mice. AB - Estrogen is known to provide robust protection of memory in postmenopausal women, but the fact that estrogen may increase the incidence of uterine and breast tumors has undoubtedly limited the clinical use of estrogen. In the present study, the effect of alpha-zearalanol (alpha-ZAL), a plant-derived phytoestrogen with low side-effect on uterine and breast, on memory has been evaluated in ovariectomized (OVX) mice when using 17beta-estradiol (17beta-E2) as an estrogen positive control. Our findings demonstrated that OVX resulted in impaired spatial learning and memory and reduced numbers of newborn neurons in the dentate gyrus of the hippocampus, while 17beta-E2 or alpha-ZAL treatment significantly improved memory performance and restored hippocampal neurogenesis. We also found the reduction of brain derived neurotrophic factor (BDNF) and TrkB expression in OVX mice, which were ameliorated by 17beta-E2 or alpha-ZAL supplementation. These results indicated that alpha-ZAL may improve memory impairments induced by OVX and modulate the expression of BDNF-TrkB benefit to neurogenesis which may be involved in the memory protection from alpha-ZAL, in a manner similar to that of 17beta-E2. The present findings suggested that alpha-ZAL may be a plausible substitute of 17beta-E2 in improving memory in postmenopausal women. PMID- 25143993 TI - Iron(III) complexes of tripodal tetradentate 4N ligands as functional models for catechol dioxygenases: the electronic vs. steric effect on extradiol cleavage. AB - A few mononuclear iron(iii) complexes of the type [Fe(L)Cl2]Cl , where L is a tetradentate tripodal 4N ligand such as N,N-dimethyl-N',N'-bis(pyrid-2 ylmethyl)ethane-1,2-diamine (), N,N-diethyl-N',N'-bis(pyrid-2-ylmethyl)ethane-1,2 diamine (), N,N-dimethyl-N',N'-bis-(6-methylpyrid-2-ylmethyl)ethane-1,2-diamine (), N,N-dimethyl-N'-(pyrid-2-ylmethyl)-N'-(1-methyl-1H-imidazol-2-ylmethyl)ethane 1,2-diamine (), N,N-dimethyl-N',N'-bis(1-methyl-1H-imidazol-2-ylmethyl)ethane-1,2 diamine () and N,N-dimethyl-N',N'-bis(quinolin-2-ylmethyl)ethane-1,2-diamine (), have been isolated and characterized by CHN analysis, UV-Visible spectroscopy and electrochemical methods. The complex cation [Fe(H)Cl3](+) possesses a distorted octahedral geometry in which iron is coordinated by the monoprotonated 4N ligand in a tridentate fashion and the remaining three sites of the octahedron are occupied by chloride ions. The DFT optimized octahedral geometries of , and contain iron(iii) with a high-spin (S = 5/2) ground state. The catecholate adducts [Fe(L)(DBC)](+), where H2DBC is 3,5-di-tert-butylcatechol, of all the complexes have been generated in situ in acetonitrile solution and their spectral and redox properties and dioxygenase activities have been studied. The DFT optimized geometries of the catecholate adducts [Fe()(DBC)](+), [Fe()(DBC)](+) and [Fe()(DBC)](+) have also been generated to illustrate the ability of the complexes to cleave H2DBC in the presence of molecular oxygen to afford varying amounts of intra- (I) and extradiol (E) cleavage products. The extradiol to intradiol product selectivity (E/I, 0.1-2.0) depends upon the asymmetry in bidentate coordination of catecholate, as determined by the stereoelectronic properties of the ligand donor functionalities. While the higher E/I value obtained for [Fe()(DBC)](+) is on account of the steric hindrance of the quinolyl moiety to coordination the lower value observed for [Fe()(DBC)](+) and [Fe()(DBC)](+) is on account of the electron-releasing effect of the N methylimidazolyl moiety. Based on the data obtained it is proposed that the detachment of the -NMe2 group from the coordination sphere in the semiquinone intermediate is followed for dioxygen binding and activation to yield the extradiol cleavage product. PMID- 25143994 TI - Response letter. PMID- 25143995 TI - Guest editorial: Advances in control of multi-functional powered upper-limb prostheses. PMID- 25143998 TI - India: E-cigarettes banned in Punjab. PMID- 25143997 TI - Germany: Helping the tobacco industry to expand in South-East Asia. PMID- 25143996 TI - Sri Lanka: Bribery allegations and delayed health warnings. PMID- 25143999 TI - My approach to evaluating chest pain in the ER. PMID- 25144000 TI - Obituary. Franz Bernhard Reigel (2.4.1948-13.3.2014). PMID- 25144001 TI - Caring for a diverse workforce. PMID- 25144002 TI - A changing health and safety culture. PMID- 25144003 TI - Understanding urinary tract infections. PMID- 25144004 TI - Choosing the right direction. PMID- 25144111 TI - Modular assembly of purine-like bisphosphonates as inhibitors of HIV-1 reverse transcriptase. AB - Bisphosphonates can mimic the pyrophosphate leaving group of the nucleotidyl transfer reaction and effectively inhibit RNA/DNA polymerases. In a search of HIV 1 reverse transcriptase (RT) inhibitors, a new chemotype of nonhydrolyzable purine diphosphate mimic was synthesized. A modular synthetic protocol was developed, utilizing 2-amino-6-(methylthio)-4-(trimethylsilyl)nicotinonitrile as the key synthon in the preparation of highly substituted 2-aminonicotinonitriles. These building blocks were subsequently elaborated to the pyrido[2,3-d]pyrimidine bisphosphonates (PYPY-BPs). Biochemical screening identified analogs of PYPY-BPs that inhibit HIV-1 RT-catalyzed DNA synthesis. PMID- 25144112 TI - Detection and surveillance of viral hemorrhagic septicemia virus using real-time RT-PCR. I. Initial comparison of four protocols. AB - Eight laboratories worked collectively to evaluate 4 real-time RT-PCR (rRT-PCR) protocols targeting viral hemorrhagic septicemia virus (VHSV) being considered for deployment to a USA laboratory testing network. The protocols utilized previously published primers and probe sets developed for detection and surveillance of VHSV. All participating laboratories received and followed a standard operating protocol for extraction and for each of the rRT-PCR assays. Performance measures specifically evaluated included limit of detection (defined as the smallest amount of analyte in which 95% of the samples are classified as positive), analytical specificity, assay efficiency across genotype representatives, within- and between-plate variation within a laboratory, and variation between laboratories using the same platform, between platforms, and between software versions. This evaluation clearly demonstrated that the TaqMan(r)-based assay developed by Jonstrup et al. (2013; J Fish Dis 36:9-23) produced the most consistent analytical performance characteristics for detecting all genotypes of VHSV across the 8 participating laboratories. PMID- 25144113 TI - Detection and surveillance of viral hemorrhagic septicemia virus using real-time RT-PCR. II. Diagnostic evaluation of two protocols. AB - Two real-time reverse transcription polymerase chain reaction (rRT-PCR) assays under consideration for deployment to multiple testing laboratories across the USA were evaluated for diagnostic sensitivity and specificity on tissue homogenates obtained from natural and experimental viral hemorrhagic septicemia (VHS)-infected fish. Estimates for diagnostic specificity using virus isolation as the reference method were similar between laboratories regardless of the assay. Diagnostic sensitivity estimates of 0.96 (95% CI: 0.95, 0.97) for Jonstrup et al. (2013)'s assay (J Fish Dis 36:9-23) exceeded the diagnostic sensitivity of 0.85 (95% CI: 0.83, 0.87) for Phelps et al. (2012)'s assay (J Aquat Anim Health 24:238-243). The Jonstrup rRT-PCR assay is robust as demonstrated by high sensitivity and specificity estimates across laboratories and can be used as a valuable tool for targeted surveillance and for testing of suspect VHSV samples. PMID- 25144114 TI - White spot syndrome virus (WSSV) genome stability maintained over six passages through three different penaeid shrimp species. AB - White spot syndrome virus (WSSV) replicates rapidly, can be extremely pathogenic and is a common cause of mass mortality in cultured shrimp. Variable number tandem repeat (VNTR) sequences present in the open reading frame (ORF)94, ORF125 and ORF75 regions of the WSSV genome have been used widely as genetic markers in epidemiological studies. However, reports that VNTRs might evolve rapidly following even a single transmission through penaeid shrimp or other crustacean hosts have created confusion as to how VNTR data is interpreted. To examine VNTR stability again, 2 WSSV strains (PmTN4RU and LvAP11RU) with differing ORF94 tandem repeat numbers and slight differences in apparent virulence were passaged sequentially 6 times through black tiger shrimp Penaeus monodon, Indian white shrimp Feneropenaeus indicus or Pacific white leg shrimp Litopenaeus vannamei. PCR analyses to genotype the ORF94, ORF125 and ORF75 VNTRs did not identify any differences from either of the 2 parental WSSV strains after multiple passages through any of the shrimp species. These data were confirmed by sequence analysis and indicate that the stability of the genome regions containing these VNTRs is quite high at least for the WSSV strains, hosts and number of passages examined and that the VNTR sequences thus represent useful genetic markers for studying WSSV epidemiology. PMID- 25144115 TI - Type III secretion system genes of Edwardsiella tarda associated with intracellular replication and virulence in zebrafish. AB - The Type III secretion system (T3SS) is essential for intracellular replication of Edwardsiella tarda in phagocytes of fish and mammals. Two possible effector candidate genes (eseE and eseG) and 7 hypothetical genes (esaB, escC, orf13, orf19, orf26, orf29, and orf30) located in the T3SS gene cluster were inactivated by an allelic exchange method, and we found that E. tarda strains carrying insertion mutations in escC, orf13, orf19, orf29, and orf30 were unable to replicate within J774 macrophages and HEp-2 epithelial cells. Furthermore, the virulence of these mutants to zebrafish was severely attenuated as well. These data suggest that the escC, orf13, orf19, orf29, and orf30 genes are required for intracellular replication and virulence of E. tarda. PMID- 25144117 TI - Batrachochytrium dendrobatidis infection dynamics vary seasonally in upstate New York, USA. AB - The amphibian disease chytridiomycosis, caused by the fungus Batrachochytrium dendrobatidis (Bd), is a major cause of worldwide amphibian declines and extinctions. Although several studies indicate that Bd prevalence and infection intensity vary seasonally, temporal variation of Bd at high-latitude sites, such as the northeastern USA, is still poorly characterized. We screened amphibians for Bd monthly at 2 study sites in New York State from April to October 2011 and used quantitative polymerase chain reaction (qPCR) to detect and quantify temporal variability in Bd infection prevalence and intensity. We found pronounced seasonal variation in both Bd infection prevalence and intensity at the community level, and our data indicate that this pattern is due to a few species (Lithobates catesbeianus, L. clamitans, and Notophthalmus viridescens) that drive temporal variability in disease dynamics. Amphibian body mass and sex were significant predictors of infection intensity but not infection prevalence. Understanding the temporal dynamics of Bd host-pathogen interactions provides important insight into regional, seasonal, and host-specific determinants of disease outbreaks. Further, our study elucidates the most relevant and informative timing for Bd surveys in temperate amphibian assemblages. Seasonal variation of infection dynamics suggests that Bd surveys from different sampling time points are not comparable, and summer surveys to evaluate chytridiomycosis may significantly underestimate Bd prevalence and intensity, leading to false conclusions about the severity of chytridiomycosis-induced amphibian mortality and population decline. PMID- 25144116 TI - Persistence of Tetracapsuloides bryosalmonae (Myxozoa) in chronically infected brown trout Salmo trutta. AB - Proliferative kidney disease (PKD) is a widespread disease of farmed and wild salmonid populations in Europe and North America, caused by the myxozoan parasite Tetracapsuloides bryosalmonae. Limited studies have been performed on the epidemiological role in spread of the disease played by fish that survive infection with T. bryosalmonae. The aim of the present study was to evaluate the persistence of T. bryosalmonae developmental stages in chronically infected brown trout Salmo trutta up to 2 yr after initial exposure to laboratory-infected colonies of the parasite's alternate host, the bryozoan Fredericella sultana. Kidney, liver, spleen, intestine, brain, gills and blood were sampled 24, 52, 78 and 104 wk post-exposure (wpe) and tested for T. bryosalmonae by PCR and immunohistochemistry (IHC). Cohabitation trials with specific pathogen free (SPF) F. sultana colonies were conducted to test the viability of T. bryosalmonae. PCR detected T. bryosalmonae DNA in all tissue samples collected at the 4 time points. Developmental stages of T. bryosalmonae were demonstrated by IHC in most samples at the 4 time points. Cohabitation of SPF F. sultana with chronically infected brown trout resulted in successful transmission of T. bryosalmonae to the bryozoan. This study verified the persistence of T. bryosalmonae in chronically infected brown trout and their ability to infect the bryozoan F. sultana up to 104 wpe. PMID- 25144118 TI - Relating fibropapilloma tumor severity to blood parameters in green turtles Chelonia mydas. AB - Fibropapillomatosis is a neoplastic disease that is commonly found in the green turtles Chelonia mydas in tropical and subtropical regions of the world. In the current project, juvenile green turtles were captured with large-mesh tangle nets in the Indian River Lagoon and on nearshore reefs of Indian River County, Florida, USA, in 1998 and 1999. The purpose of the study was to determine the relationship between the severity of the disease and the general health of green turtles as indicated by blood parameters. All turtles were measured and examined, and the overall severity of the disease was rated by the size, number, and location of external fibropapilloma tumors. Hematocrit, total protein, and hemoglobin concentration were measured and compared with tumor scores (tumor severity appraisal). As the tumor score increased, the blood parameters of turtles decreased; for instance, the percentage of decrease in hematocrit for mildly afflicted, moderately afflicted, and severely afflicted groups were 2.6, 18.3, and 45.5%, respectively. Severely afflicted turtles suffered from anemia, while individuals with mild affliction did not. PMID- 25144119 TI - Gorgonian disease outbreak in the Gulf of Naples: pathology reveals cyanobacterial infection linked to elevated sea temperatures. AB - In recent years, mass mortality events of benthic invertebrates in the Mediterranean Sea have been documented to coincide with the increased seawater temperatures associated with global climate change. Following a disease outbreak in gorgonians during the summer seasons of 2008 and 2009 in the Gulf of Naples (Tyrrhenian Sea), we conducted gross and microscopic analyses of healthy and diseased specimens of Eunicella cavolinii and E. singularis using both light and electron microscopy (SEM). Macroscopically, diseased colonies exhibited evident tissue thinning, and dead colonies showed a complete loss of polyps and coenenchyme, exposing their skeletons to settlement by fouling organisms. Histopathology revealed chronic inflammatory lesions at the polyp and axial level, characterized by amoebocyte infiltration of tissue accompanied by new apposition of melanin/gorgonin sheets. We interpreted this response as a defense against different kinds of pathogens-identified as mainly a heterogeneous consortium of filamentous cyanobacteria-and which gradually led to enlargement and hardening of the coral axis, which resembled a wood-like structure at the final stage of the disease. These processes elicited the formation of multiple inflammatory nodules and capsules, some of which were macroscopically visible. A parallel 16S rRNA and ITS analysis of the diseased tissue identified Synechococcus, Arthrospira and other uncultured cyanobacteria grouped within the Oscillatoriales. These results suggest that a cyanobacterial consortium is involved in the pathogenesis of the inflammatory disease leading to the mortality of Gorgoniaceae in the area. Finally, there were anomalously high temperatures (up to 25 degrees C) between 10 and 20 m depth during the sampling period, particularly in June 2009. This supports the hypothesis that the coral skeleton may serve as a reservoir for the pathogens in cooler seasons, with warmer conditions leading to pathogen reactivation and recurring mortality events. PMID- 25144120 TI - Detection of acute hepatopancreatic necrosis disease (AHPND) in Mexico. AB - Acute hepatopancreatic necrosis disease (AHPND), which has also been referred to as early mortality syndrome (EMS), initially emerged as a destructive disease of cultured shrimp species in Asia in 2009. The pathogen associated with the disease, Vibrio parahaemolyticus, subsequently spread to the Western Hemisphere and emerged in Mexico in early 2013. The spread to the Western Hemisphere is a major concern to shrimp producers in the region. To date, the only peer-reviewed published method for determining whether mortalities are due to AHPND is through histological examination. A novel PCR detection method was employed to assess samples from Mexico in order to confirm the presence of the pathogen in this country. This manuscript details the detection methods used to confirm the presence of AHPND in Mexico. Both immersion and per os challenge studies were used to expose the Penaeus vannamei to the bacteria in order to induce the disease. Histological analysis confirmed AHPND status following the challenge studies. Also provided are the details of the molecular test by PCR that was used for screening candidate V. parahaemolyticus isolates. A rapid PCR assay for detection of AHPND may help with early detection and help prevent the spread of AHPND to other countries. PMID- 25144121 TI - Aplasia of the septum transversum has no effect on plasma biochemistry following an acute hypoxic event in Atlantic salmon. AB - Aplasia of the septum transversum (AST) is a malformation that results in alterations in ventricle morphology. The condition has been linked to increased mortality during periods of increased cardiac demand in Atlantic salmon Salmo salar. The blood plasma biochemical response to an acute hypoxic event (1 h at 31 39% O2saturation) was investigated in fish with and without a septum transversum to assess levels of anaerobic respiration (lactate) and the stress response (cortisol, glucose, osmolality, Na+, Cl- and K+). AST had no effect on body size parameters or relative ventricular mass. The hypoxic event increased the levels of anaerobic respiration and induced a typical stress response. Contrary to our expectations, AST had no effect on any plasma parameter in normoxia or following severe acute hypoxia. We conclude that in the current scenario, AST does not affect the levels of anaerobic respiration or the plasma stress response in Atlantic salmon. PMID- 25144122 TI - New trends of progestins treatment of endometriosis. AB - The management of endometriosis with OC or progestins is generally safe, effective and well-tolerated and should constitute the first line of medical treatment in symptomatic patients who do not want to have children. Progestins, synthetic progestational agents, have been used in the management of symptomatic endometriosis both as primary therapy and as an adjunct to surgical time. A variety of oral agents have been employed in this regard and investigators have demonstrated differing degrees of benefit. The lack of a standardized instrument to evaluate painful symptoms makes comparative analysis more difficult. Concern about efficacy and side effect has pushed the research on the development of new well-tolerated drugs and to develop new administration routes to minimize general side effects. Aim of the present review is to present the results of clinical studies on new trends of progestins in the treatment of endometriosis. PMID- 25144123 TI - Desorption of intrinsic cesium from smectite: inhibitive effects of clay particle organization on cesium desorption. AB - Fine clay particles have functioned as transport media for radiocesium in terrestrial environments after nuclear accidents. Because radiocesium is expected to be retained in clay minerals by a cation-exchange reaction, ascertaining trace cesium desorption behavior in response to changing solution conditions is crucially important. This study systematically investigated the desorption behavior of intrinsic Cs (13 nmol/g) in well-characterized Na-montmorillonite in electrolyte solutions (NaCl, KCl, CaCl2, and MgCl2) under widely differing cation concentrations (0.2 mM to 0.2 M). Batch desorption experiments demonstrated that Cs(+) desorption was inhibited significantly in the presence of the environmental relevant concentrations of Ca(2+) and Mg(2+) (>0.5 mM) and high concentrations of K(+). The order of ability for Cs desorption was Na(+) = K(+) > Ca(2+) = Mg(2+) at the highest cation concentration (0.2 M), which is opposite to the theoretical prediction based on the cation-exchange selectivity. Laser diffraction grain-size analyses revealed that the inhibition of Cs(+) desorption coincided with the increase of the clay tactoid size. Results suggest that radiocesium in the dispersed fine clay particles adheres on the solid phase when the organization of swelling clay particles occurs because of changes in solution conditions caused by both natural processes and artificial treatments. PMID- 25144124 TI - Laminated ultrathin chemical vapor deposition graphene films based stretchable and transparent high-rate supercapacitor. AB - Due to their exceptional flexibility and transparency, CVD graphene films have been regarded as an ideal replacement of indium tin oxide for transparent electrodes, especially in applications where electronic devices may be subjected to large tensile strain. However, the search for a desirable combination of stretchability and electrochemical performance of such devices remains a huge challenge. Here, we demonstrate the implementation of a laminated ultrathin CVD graphene film as a stretchable and transparent electrode for supercapacitors. Transferred and buckled on PDMS substrates by a prestraininig-then-buckling strategy, the four-layer graphene film maintained its outstanding quality, as evidenced by Raman spectra. Optical transmittance of up to 72.9% at a wavelength of 550 nm and stretchability of 40% were achieved. As the tensile strain increased up to 40%, the specific capacitance showed no degradation and even increased slightly. Furthermore, the supercapacitor demonstrated excellent frequency capability with small time constants under stretching. PMID- 25144125 TI - Inflammatory bowel disease in subfertile men and the effect of mesalazine on fertility. AB - This study aimed to examine the effect of mesalazine on fertility. In this retrospective analysis of 1,225 male subfertile patients, we reviewed the cases of inflammatory bowel disease (IBD) in the medical records and evaluated the prevalence of the disease in our reproduction center. Specifically, we examined IBD patients who ceased mesalazine during male infertility treatment, and compared the seminogram of these patients before and after discontinuation of mesalazine. We also analyzed pregnancy outcome after discontinuation. The prevalence rate of Crohn's disease and ulcerative colitis in our male infertile patients was 163 per 100,000 men and 490 per 100,000 men, respectively. Seven patients had taken mesalazine and six of them subsequently stopped the medication. The mean values of sperm concentration, sperm motility, percentage of normal formed sperm, semen volume, and total motile sperm count taken before discontinuation increased after discontinuation of mesalazine. Among these parameters, the sperm motility and total motile sperm count were significantly improved (p < 0.05) after discontinuation. Of the six patients who stopped the drug, four achieved pregnancy with their partners, with two of the four men showing significant improvement not only in the percentage of normal shaped sperm but also sperm motility and total motile sperm count. This study provides further insight into the rarely investigated relationship between male fertility and mesalazine. PMID- 25144127 TI - Safety of intracameral injection of moxifloxacin using total replacement technique (bag and chamber flushing). AB - PURPOSE: To assess the safety of intracameral injection of moxifloxacin (MFLX) using the total replacement technique [bag and chamber (BC) flushing]. METHODS: The anterior chamber including the area behind the intraocular lens was irrigated and replaced using BC flushing. In Group A, 36 patients received balanced salt solution irrigation in the right eye and intracameral MFLX (150 MUg/mL: 33-fold dilution of 0.5% eye drops) in the left eye. In Group B, 33 patients received intracameral MFLX in the right (500 MUg/mL: 10-fold dilution) and left eyes (150 MUg/mL: 33-fold dilution). Visual acuity, intraocular pressure, corneal endothelial cell density, corneal thickness, and foveal thickness were recorded before and up to 3 months after surgery. RESULTS: In either group, there were no statistically significant differences between the right and left eyes with respect to visual acuity, intraocular pressure, corneal endothelial cell count, and foveal thickness before and at 3 months after surgery. There was no difference in corneal thickness before and at 3 months after surgery. In patients who received 500 MUg/mL MFLX during surgery, central corneal thickness at 1 week after surgery was significantly reduced. CONCLUSIONS: In the present study, there was no adverse effect associated with intracameral injection of 150-500 MUg/mL MFLX. Moreover, our results supported the safety of BC flushing. Thus, BC flushing, which can irrigate the inside of the capsular bag and attain stable antibiotic concentrations, appears to be a favorable technique for intracameral injection of MFLX. PMID- 25144126 TI - Total fructose intake and risk of hypertension: a systematic review and meta analysis of prospective cohorts. AB - OBJECTIVES: Although most controlled feeding trials have failed to show an adverse effect of fructose on blood pressure, concerns continue to be raised regarding the role of fructose in hypertension. To quantify the association between fructose-containing sugar (high-fructose corn syrup, sucrose, and fructose) intake and incident hypertension, a systematic review and meta-analysis of prospective cohort studies was undertaken. METHODS: MEDLINE, EMBASE, CINAHL and the Cochrane Library (through February 5, 2014) were searched for relevant studies. Two independent reviewers reviewed and extracted relevant data. Risk estimates were aggregated comparing the lowest (reference) quintile with highest quintile of intake using inverse variance random effect models and expressed as risk ratios (RR) with 95% confidence intervals (CIs). Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I(2) statistic). The Newcastle Ottawa Scale assessed study quality. Clinicaltrials.gov NCT01608620. RESULTS: Eligibility criteria were met by 3 prospective cohorts (n = 37,375 men and 185,855 women) with 58,162 cases of hypertension observed over 2,502,357 person years of follow-up. Median fructose intake was 5.7-6.0% total energy in the lowest quintile and 13.9-14.3% total energy in the highest quintile. Fructose intake was not associated with incident hypertension (RR = 1.02, 95% CI, 0.99 1.04), with no evidence of heterogeneity (I(2) = 0%, p = 0.59). Spline curve modeling showed a U-shaped relationship with a negative association at intakes <=50th percentile (~10% total energy) and a positive association at higher intakes. CONCLUSIONS: Total fructose intake was not associated with an increased risk of hypertension in 3 large prospective cohorts of U.S. men and women. PMID- 25144128 TI - Matters of sex and gender in F. J. Gall's Organology: a primary approach. AB - The originator of phrenology, F. J. Gall (1758-1828), saw himself as a natural scientist and physiologist. His approach consisted of brain anatomy but also of palpating skulls and inferring mental faculties. Unlike some of the philosophical principles underlying Gall's work, his conception of sex/gender has not yet been examined in detail. In this article, I will focus on Gall's treatment of men and women, his idea of sex differences, and how far an assumed existence of dichotomous sexes influenced his work. In examining his primary writings, I will argue that Gall held some contradictory views concerning the origin and manifestation of sex/gender characteristics, which were caused by the collision of his naturalistic ideas and internalized gender stereotypes. I will conclude that Gall did not aim at deducing or legitimizing sex/gender relations scientifically, but that he tried to express metaphysical reasons for a given social order in terms of functional brain mechanisms. PMID- 25144129 TI - Biocompatibility of soft-templated mesoporous carbons. AB - Soft-templated mesoporous carbon is morphologically a non-nano type of carbon. It is a relatively newer variety of biomaterial, which has already demonstrated its successful role in drug delivery applications. To investigate the toxicity and biocompatibility, we introduced three types of mesoporous carbons with varying synthesis conditions and pore textural properties. We compared the Brunauer Emmett-Teller (BET) surface area and pore width and performed cytotoxicity experiments with HeLa cells, cell viability studies with fibroblast cells and hemocomapatibility studies. Cytotoxicity tests reveal that two of the carbons are not cytotoxic, with cell survival over 90%. The mesoporous carbon with the highest surface area showed slight toxicity (~ 70% cell survival) at the highest carbon concentration of 500 MUg/mL. Fibroblast cell viability assays suggested high and constant viability of over 98% after 3 days with no apparent relation with materials property and good visible cell-carbon compatibility. No hemolysis (<1%) was confirmed for all the carbon materials. Protein adsorption experiments with bovine serum albumin (BSA) and fibrinogen revealed a lower protein binding capacity of 0.2-0.6 mg/m(2) and 2-4 mg/m(2) for BSA and fibrinogen, respectively, with lower binding associated with an increase in surface area. The results of this study confirm the biocompatibility of soft-templated mesoporous carbons. PMID- 25144130 TI - Using testosterone and cortisol as biomarker for training individualization in elite basketball: a 4-year follow-up study. AB - The purpose of this study was to determine the responses of testosterone and cortisol, with special reference to playing positions, playing time (PT), and phase of the season. We performed a follow-up study during 4 consecutive seasons to investigate the effects of PT, positional role, and phase of the season on anabolic-catabolic biomarkers (plasma total testosterone -TT- and cortisol -C-) on 20 professional male basketball players (27.0 +/- 4.2 years; 24.4 +/- 1.2 kg.m). First blood samples were collected right after the off-season period and considered as baseline. Samples were taken periodically every 4-6 weeks, always after a 24- to 36-hour break after the last game played. Statistical procedures were nonparametric mainly. Hormonal status was playing position-dependent, power forward (PF) showed the lowest TT values (median +/- interquartile range [IQR]; PF: 18.1 +/- 4.9; nmol.L), and small forwards showed the highest ones of cortisol (0.55 +/- 0.118 MUmol.L). Players who played between 13 and 25 minutes per game showed the highest values of TT (22.8 +/- 6.9 nmol.L) and TT/C (47.1 +/- 21.2). March and April showed the most catabolic or stressed hormonal state (low TT/C values and high ones of cortisol) and that is necessary to take into account according to PT (>25-minute per game) and specific playing position. Monitoring plasma TT and cortisol is recommended to prevent excessive stress caused by professional basketball season requirements. PMID- 25144131 TI - Effect of intestinal microbiota on exercise performance in mice. AB - The antioxidant enzyme system helps protect against intense exercise-induced oxidative damage and is related to the physical status of athletes. Evidence suggests that intestinal microbiota may be an important environmental factor associated with host metabolism, physiology, and antioxidant endogenous defense. However, evidence of the effect of gut microbiota status on exercise performance and physical fatigue is limited. We investigated the association of intestinal bacteria and exercise performance in specific pathogen-free (SPF), germ-free (GF), and Bacteroides fragilis (BF) gnotobiotic mice. Endurance swimming time was longer for SPF and BF than GF mice, and the weight of liver, muscle, brown adipose, and epididymal fat pads was higher for SPF and BF than GF mice. The serum levels of glutathione peroxidase (GPx) and catalase were greater in SPF than GF mice. Serum superoxide dismutase activity was lower in BF than SPF and GF mice. In addition, hepatic GPx level was higher in SPF than GF and BF mice. Gut microbial status could be crucial for exercise performance and its potential action linked with the antioxidant enzyme system in athletes. PMID- 25144132 TI - Prediction of aerobic and anaerobic capacities of elite cyclists from changes in lactate during isocapnic buffering phase. AB - This study predicted aerobic and anaerobic capacities using relative changes of arterial blood lactate during the isocapnic buffering phase (relative [La]ISBP). Fourteen male professional cyclists (sprint-trained [n = 6] and endurance [n = 8]) performed 2 exercise sessions to exhaustion on a cycle ergometer; 1 incremental standard test to determine the isocapnic buffering phase, buffering capacities, and relative [La]ISBP and 1 supramaximal exercise test to determine maximal accumulated oxygen deficit (MAOD). The time between Lactate threshold (LT) and respiratory compensatory threshold (RCT) was considered to be the isocapnic buffering phase. Total buffering capacity was calculated as Delta[La].DeltapH. Bicarbonate buffering was calculated as Delta[HCO3].DeltapH, and the difference between -Delta[La].DeltapH and Delta[HCO3].DeltapH was considered as nonbicarbonate buffering. The lactate concentration for LT (p <= 0.05) and RCT (p <= 0.05), and relative [La]ISBP (p < 0.01) were significantly lower for endurance cyclists than for sprint-trained cyclists. A significant difference was found for bicarbonate buffering capacity between groups (p < 0.01). A significant correlation was found between relative [La]ISBP with (Equation is included in full-text article.)(r = -0.71, p <= 0.05) and MAOD (r = 0.73, p < 0.01). Relative [La]ISBP was useful for predicting aerobic power (R = 51%) and anaerobic capacity (R = 53%). These results demonstrated that relative [La]ISBP is an important variable in intermediary metabolism and in addition to (Equation is included in full-text article.)and LT is recommended for better evaluation of performance of athletes who show nearly equal contributions from the aerobic and anaerobic energy systems during exercise. PMID- 25144133 TI - Effect of caffeine ingestion on maximal voluntary contraction strength in upper- and lower-body muscle groups. AB - The effect of caffeine on strength-power performance is equivocal, especially with regard to maximal voluntary contraction (MVC) strength. This is partly related to differences in upper- and lower-body musculature. However, there is no evidence to suggest whether this is a product of muscle group location, muscle group size, or both. Consequently, the primary aim of this study was to establish whether the effect of caffeine ingestion on MVC strength in upper- and lower-body muscle groups is significantly different, and if so, to determine whether this is a product of muscle group size. In a randomized, subject-blind crossover manner, 16 resistance-trained men (estimated caffeine intake [mean +/- SD] 95.4 +/- 80.0 mg.d) received either 6 mg.kg of caffeine (CAF) or a placebo (PLA). Isokinetic peak torque of the knee extensors, ankle plantar flexors, elbow flexors and wrist flexors were measured at an angular velocity of 60 degrees .s. Statistical analyses revealed a significant increase in isokinetic peak torque from PLA to CAF (p = 0.011) and a significant difference in isokinetic peak torque between muscle groups (p < 0.001). However, there was no significant treatment * muscle group interaction (p = 0.056). Nonetheless, the %improvement in isokinetic peak torque with caffeine increased with muscle group size. In conclusion, a moderate dose of caffeine improves MVC strength in resistance-trained men regardless of muscle group location, whereas the influence of muscle group size remains uncertain. This research may be useful for competitive and recreational athletes aiming to increase strength-power performance. PMID- 25144134 TI - Effects of in-competitive season power-oriented and heavy resistance lower-body training on performance of elite female water polo players. AB - We examined the effect of 16 weeks of lower-body resistance and power-oriented training on key performance measures of elite female water polo players. Twenty one players were randomly assigned to 2 groups: control group (C) who did in water training only and a lower body strength (LBS) group, who performed resistance (full squat and split squat) and jump and power-oriented lower-body training (countermovement jump [CMJ] loaded and CMJ) sessions (twice per week) in addition to the same in-water training. In-water training was conducted 5 days per week for a total of 16 weeks. Twenty-meter maximal sprint swim (MSS), lower body strength during 1 repetition maximum (1RM) full squat (FS), in-water boost and CMJ, and Throwing speed (ThS) were measured before and after the training. Pretraining results showed no statistically significant differences between the groups in any of the variables tested. After 16 weeks, no statistically significant improvement was found in any of the variables measured in the C group, however, significant improvement was found in the LBS group: in-water boost (4.6 cm, 12.02%, effect size [ES] = 1.02), CMJ (2.4 cm, 8.66%, ES = 0.85), FS (12.7 kg, 20.99%, ES = 2.41), and ThS (3.4 km.h, 6.86%, ES = 3.44). Lower-body resistance and power-oriented training in female water polo players for 16 weeks produced significant improvements in performance qualities highly specific to water polo performance. Therefore, we propose modifications to current training methodology for female water polo players to include resistance and power oriented training during the competitive season in this sport. PMID- 25144135 TI - Cation ordering and flexibility of the BO42- tetrahedra in incommensurately modulated CaEu2(BO4)4 (B = Mo, W) scheelites. AB - The factors mediating cation ordering in the scheelite-based molybdates and tungstates are discussed on the basis of the incommensurately modulated crystal structures of the CaEu2(BO4)4 (B = Mo, W) red phosphors solved from high resolution synchrotron powder X-ray diffraction data. Monoclinic CaEu2(WO4)4 adopts a (3 + 1)-dimensionally modulated structure [superspace group I2/b(alphabeta0)00, a = 5.238 73(1)A, b = 5.266 35(1) A, c = 11.463 19(9) A, gamma = 91.1511(2) degrees , q = 0.56153(6)a* + 0.7708(9)b*, R(F) = 0.050, R(P) = 0.069], whereas tetragonal CaEu2(MoO4)4 is (3 + 2)-dimensionally modulated [superspace group I41/a(alphabeta0)00(-betaalpha0)00, a = 5.238 672(7) A, c = 11.548 43(2) A, q1 = 0.55331(8)a* + 0.82068(9)b*, q2 = -0.82068(9)a* + 0.55331(8)b*, R(F) = 0.061, R(P) = 0.082]. In both cases the modulation arises from the ordering of the Ca/Eu cations and the cation vacancies at the A sublattice of the parent scheelite ABO4 structure. The cation ordering is incomplete and better described with harmonic rather than with steplike occupational modulation functions. The structures respond to the variation of the effective charge and cation size at the A-position through the flexible geometry of the MoO4(2-) and WO4(2-) tetrahedra demonstrating an alternation of stretching the B-O bond lengths and bending the O-B-O bond angles. The tendency towards A site cation ordering in scheelites is rationalized using the difference in ionic radii and concentration of the A-site vacancies as parameters and presented in the form of a structure map. PMID- 25144136 TI - Fast colloidal synthesis of scalable Mo-rich hierarchical ultrathin MoSe(2-x) nanosheets for high-performance hydrogen evolution. AB - MoSe2 nanosheets have been extensively pursued due to the outstanding properties of this typical layered transition metal dichalcogenide (LTMD). In this work, we report a facile, fast strategy to synthesize scalable hierarchical ultrathin MoSe2-x (x ~ 0.47) nanosheets. The nanosheets possess 2-5 Se-Mo-Se atomic layers and were synthesised through a bottom-up colloidal route within 20 mins under mild conditions from the reaction of MoO2(acac)2 with dibenzyl diselenide. The as obtained hierarchical ultrathin MoSe2-x nanosheets are Mo-rich with a Se vacancy and show excellent HER performance with a small overpotential of ~170 mV, large cathodic currents, and a Tafel slope of 98 mV per decade. Such high performance has been attributed to the unique structure of the Se vacancy defect, large surface area, as well as the enhanced conductivity. Meanwhile, the pathway can be extended as a general strategy to prepare other metal selenides, such as ultrathin WSe2 and SnSe nanosheets, and PbSe nanocrystals. It will also pave a new way to synthesize scalable nanostructured materials for intriguing nanodevices and large-scale applications. PMID- 25144137 TI - Replication characteristics of infectious laryngotracheitis virus in the respiratory and conjunctival mucosa. AB - Avian infectious laryngotracheitis virus (ILTV) is an alphaherpesvirus of poultry that is spread worldwide. ILTV enters its host via the respiratory tract and the eyes. Although ILTV has been known for a long time, the replication characteristics of the virus in the respiratory and conjunctival mucosa are still poorly studied. To study these characteristics, two in vitro explant models were developed. Light microscopy and fluorescent terminal deoxynucleotidyl transferase dUTP nick end-labelling staining were used to evaluate the viability of mucosal explants, which were found to be viable up to the end of the experiment at 96 h of cultivation. The tracheal and conjunctival mucosal explants were inoculated with ILTV and collected at 0, 24, 48 and 72 h post inoculation (p.i.). ILTV spread in a plaque-wise manner in both mucosae. A reproducible quantitative analysis of this mucosal spread was evaluated by measuring plaque numbers, plaque latitude and invasion depth underneath the basement membrane. No major differences in plaque numbers were observed over time. Plaque latitude progressively increased to 70.4 +/- 12.9 MUm in the trachea and 97.8 +/- 9.5 MUm in the conjunctiva at 72 h p.i. The virus had difficulty crossing the basement membrane and was first observed only at 48 h p.i. The virus was observed at 72 h p.i. in 56% (trachea) and 74% (conjunctiva) of the plaques. Viability analysis of infected explants indicated that ILTV blocks apoptosis in infected cells of both mucosae but activates apoptosis in bystander cells. PMID- 25144138 TI - Levetiracetam as adjunctive therapy for acute alcohol withdrawal syndrome in hospitalized patients. AB - BACKGROUND: Benzodiazepines are often considered the standard of care for managing symptoms of acute alcohol withdrawal syndrome. Because of potential adverse effects, other agents have been evaluated in this patient population. Previous studies have produced mixed results on the efficacy of levetiracetam in alcohol withdrawal. OBJECTIVE: The objective of this study was to determine whether adjunctive levetiracetam reduces the amount of symptom-triggered benzodiazepines required by patients experiencing symptoms of alcohol withdrawal. METHODS: We conducted a retrospective chart review of patients who experienced symptoms of alcohol withdrawal while hospitalized. The outcomes of patients who received adjunctive levetiracetam were compared with those of patients who received only the standard of care (control group). RESULTS: Two hundred fifty patients (125 in each cohort) were included. No significant differences were found in the benzodiazepine requirements of the 2 cohorts. The control group required a median average daily dose of 2.0 mg of lorazepam (range, 0.1-17 mg/d) compared with the levetiracetam group, which required a median average daily dose of 1.3 mg of lorazepam (range, 0.0-53.5 mg/d) (P = 0.09). The patients in the control group required a median total of 6 mg of lorazepam during their hospitalization compared with a median total of 5.5 mg in the levetiracetam group. Both cohorts had a median length of stay of 3 days, although those in the levetiracetam group had a shorter length of intensive care unit stay and spent less time mechanically ventilated. CONCLUSIONS: The adjunctive use of levetiracetam does not significantly reduce the benzodiazepine requirements of patients experiencing symptoms of alcohol withdrawal in the inpatient setting. PMID- 25144139 TI - Chain and pore-blocking effects on matrix degradation in protein-loaded microgels. AB - Factors affecting matrix degradation in protein-loaded microgels were investigated for dextran-based microgels, the sugar-binding protein Concanavalin A (ConA), and the dextran-degrading enzyme Dextranase. For this system, effects of enzyme, protein, and glucose concentrations, as well as pH, were considered. Microgel network degradation was monitored by micromanipulator-assisted light microscopy, whereas enzyme and protein distributions were monitored by confocal microscopy. Results show that Dextranase-mediated microgel degradation increased with increasing enzyme concentration, whereas an increased ConA loading in the dextran microgels caused a concentration-dependent decrease in microgel degradation. In the presence of glucose, competitive release of microgel-bound ConA restored the microgel degradation observed in the absence of ConA. To clarify effects of mass transport limitations, microgel degradation was compared to that of non-cross-linked dextran, demonstrating that ConA limits enzyme substrate access in dextran microgels primarily through pore blocking and induction of pore shrinkage. The experimentally observed effects were qualitatively captured by a modified Michaelis-Menten approach for spherical symmetry, in which network blocking by ConA was included. Taken together, the results demonstrate that matrix degradation of protein-loaded microgels depends sensitively on a number of factors, which need to be considered in the use of microgels in biomedical applications. PMID- 25144140 TI - Care of the critically ill and injured during pandemics and disasters: groundbreaking results from the Task Force on Mass Critical Care. PMID- 25144141 TI - Atomistic force field for pyridinium-based ionic liquids: reliable transport properties. AB - Reliable force field (FF) is a central issue in successful prediction of physical chemical properties via computer simulations. This work introduces refined FF parameters for six popular ionic liquids (ILs) of the pyridinium family (butylpyridinium tetrafluoroborate, bis(trifluoromethanesulfonyl)imide, dicyanamide, hexafluorophosphate, triflate, chloride). We elaborate a systematic procedure, which allows accounting for specific cation-anion interactions in the liquid phase. Once these interactions are described accurately, all experimentally determined transport properties can be reproduced. We prove that three parameters per interaction site (atom diameter, depth of potential well, point electrostatic charge) provide a sufficient basis to predict thermodynamics (heat of vaporization, density), structure (radial distributions), and transport (diffusion, viscosity, conductivity) of ILs at room conditions and elevated temperature. The developed atomistic models provide a systematic refinement upon the well-known Canongia Lopes-Padua (CL&P) FF. Together with the original CL&P parameters the present models foster a computational investigation of ionic liquids. PMID- 25144142 TI - Ruthenium(II) complexes of N-heterocyclic carbenes derived from imidazolium linked cyclophanes. AB - The present work seeks to characterize, in the light of electronic structure calculations, an unusual metal-[(eta(1)-NHC)2:(eta(6)-arene)] bonding situation in a set of ruthenium(ii) complexes containing the ortho-xylylene-linked bis(NHC)cyclophane ligand (NHC-cyclophane) (), which binds to the ruthenium center through two carbene carbons and one of the arene rings. The nature of ruthenium(ii)-[(eta(1)-NHC)2:(eta(6)-arene)] bonding was investigated in the light of EDA-NOCV, NBO and QTAIM analyses by adopting as a model compound. The interplay between the ortho-cyclophane scaffold with different families of five membered carbenes, such as imidazole, , triazole-based NHCs (Enders' carbenes), , and P-heterocyclic carbenes (PHCs), , was investigated. The metal-[(eta(1) NHC)2:(eta(6)-arene)] bonding situation was also extended to heavier analogues, such as N-heterocyclic silylenes (NHSi) and N-heterocyclic germylenes (NHGe), in order to address how the basicity of NHC, NHSi and NHGe is affected by the cyclophane framework. The results reveal that ruthenium(ii)-[(eta(1) NHC)2:(eta(6)-arene)] is more covalently than electrostatically bonded and that the degree of covalence is larger in PHCs than in NHCs or Enders' carbenes. It is also revealed that the covalent character in the ruthenium(ii)-[(eta(1) NHGe)2:(eta(6)-arene)] and ruthenium(ii)-[(eta(1)-NHSi)2:(eta(6)-arene)] bonds is larger than in ruthenium(ii)-[(eta(1)-NHC)2:(eta(6)-arene)]. PMID- 25144143 TI - The role of electrical stimulation techniques in the management of the male patient with urgency incontinence. AB - PURPOSE OF REVIEW: Overactive bladder affects 10-27% of men, a significant portion of whom report urge urinary incontinence that is inadequately treated with first-line and second-line treatments. There is thus a substantial need to critically evaluate the alternative means of clinical management. RECENT FINDINGS: This review presents the current evidence for the use of sacral neuromodulation and percutaneous tibial nerve stimulation in the treatment of men with urge incontinence, as well as evaluates the financial implications of these treatments. Other alternative modes of electrical stimulation for urge incontinence are also briefly reviewed. SUMMARY: Both sacral neuromodulation and percutaneous tibial nerve stimulation prove to be viable, durable options for treating patients with refractory urge incontinence. Alternative modes of stimulation are also beginning to show promise. PMID- 25144144 TI - Application of guidelines to the evaluation of the male patient with urgency and/or incontinence. AB - PURPOSE OF REVIEW: To review and evaluate the evidence from contemporary evidence based guidelines regarding the assessment of men with urinary urgency and/or incontinence. RECENT FINDINGS: There are a number of evidence-based guidelines which describe the pathways for assessing men with the symptoms of urgency and/or incontinence. We summarize the conclusions of the European Association of Urology, American Urological Association and National Institute of Clinical Excellence guidelines. SUMMARY: All guidelines recommend a directed history, examination (including digital rectal examination), urinalysis and bladder diary as being essential in the assessment of men with lower urinary tract symptoms, although there are no high levels of evidence studies to support this. Creatinine estimation and prostate-specific antigen are recommended in selected groups of men, the latter after appropriate counselling. Uroflowmetry with postvoid residual assessment is recommended for at specialist assessment. Pad tests may be useful to quantify leakage. Ultrasound assessment of prostatic size and protrusion into the bladder base may be useful. Cystometry is recommended for men considering prostatic surgery, although there is a poor level of evidence underpinning this. Noninvasive surrogates for cystometry, such as penile plethysmography, lack sufficient evidence to allow recommendations to be made. PMID- 25144145 TI - Androgen-deprivation-associated bone disease. AB - PURPOSE OF REVIEW: Androgen deprivation therapy (ADT) remains a common treatment for prostate cancer, even in the nonmetastatic setting and in scenarios without evidence of efficacy. Increasing attention has focused on its adverse effects, of which bone disease in the form of osteoporosis and fractures has been one of the major concerns. Recently published articles are reviewed, focusing on ADT effects on bone and management of ADT-associated bone disease. RECENT FINDINGS: A range of strategies directed at ADT-associated bone disease are available, including antiresorptive agents such as denosumab and bisphosphonates, as well as complementary approaches such as calcium and vitamin D supplementation, exercise regimens, and multifaceted interventions incorporating several approaches. Most interventions used bone mineral density as a surrogate outcome, despite compelling evidence that it inadequately captures fracture risk. SUMMARY: The antiresorptive agents are clearly able to preserve bone mineral density in men on ADT, whereas other approaches have modest to no benefits. Unfortunately, despite intense research interest in this area, no approach has yet demonstrated a definitive and convincing reduction in clinically relevant fracture outcomes. This emphasizes the importance of restricting the use of ADT to settings in which its benefits are clearly established, in order to limit unnecessary complications. PMID- 25144146 TI - Bone health in living kidney donors. AB - PURPOSE OF REVIEW: Living kidney donors may experience changes in bone mineral metabolism, which adversely affect the skeletal system. In this review, we summarize the literature assessing the relationship between living kidney donation, changes in bone mineral metabolism, and skeletal fracture. RECENT FINDINGS: Living kidney donor nephrectomy may lower the concentration of 1,25 dihydroxyvitamin D and phosphate and raise the concentration of parathyroid hormone, with no appreciable effect on the concentration of calcium. There is conflicting evidence on whether the concentration of fibroblast growth factor 23 rises after kidney donation. Whether these changes in bone mineral metabolism alter skeletal fracture risk in living kidney donors is an open question. To date, a single study of over 2000 living kidney donors (median age 43 years) matched to a segment of the general population selected for good health has found that after a median follow-up of 6.6 years (maximum 17.7 years), the rate of fragility (osteoporotic) fractures is no higher in donors compared to nondonors. SUMMARY: Living kidney donors experience changes in bone mineral metabolism. Long term studies are needed to determine whether an association between living kidney donation and fracture exists. PMID- 25144147 TI - The use of pharmacotherapy for male patients with urgency and stress incontinence. AB - PURPOSE OF REVIEW: To summarize recent data on the medical treatment of men with incontinence due to overactive bladder or to stress urinary incontinence published in peer-reviewed journals. RECENT FINDINGS: Previous randomized controlled trials have shown that both antimuscarinic drugs and alpha1 adrenoceptor blockers can be useful for treatment of male lower urinary tract symptoms, including the overactive bladder syndrome, and that combination of the two principles may offer additional benefits over monotherapy with either agent. This has been further confirmed in several recent studies. There seems to be an associated increase in postvoid residual urine volume by the combinations, but not a significantly increased risk of retention. The efficacy of other combinations, for example, alpha1-adrenoceptor blocker and 5alpha-reductase inhibitor, has also been further documented. Recent evidence supports the use of mirabegron, alone or in combination with solifenacin, as a treatment alternative of male overactive bladder syndrome. Monotherapy with phosphodiesterase 5 inhibitors seems to be as effective as alpha1-adrenoceptor blockers in male lower urinary tract symptoms. Only a few recent studies have been performed on the pharmacological treatment of male stress urinary incontinence, confirming that duloxetine had a modest positive effect in men with postprostatectomy incontinence. SUMMARY: For treatment of storage symptoms in men with lower urinary tract symptoms, combinations of antimuscarinics and alpha1-adrenoceptor blockers have produced the most promising results. Duloxetine exerts only modest relief of male stress urinary incontinence, but may be recommended in some patients. PMID- 25144148 TI - Bone health in hypogonadal men. AB - PURPOSE OF REVIEW: To examine bone health in relation to testosterone and male hypogonadism. RECENT FINDINGS: An emerging area of research pertains to the newly described bone-testis axis. In particular, the peptide hormone osteocalcin, which is made by bone and fat, appears to play a role in testosterone production. Inconsistent weak associations have been noted between vitamin D deficiency or insufficiency and lower testosterone levels. Although a high prevalence of hypogonadism is associated with opioid use, HIV and transfusion-dependent thalassemia, the risk of fracture in these populations is unclear. In fact, one study found that the modest increase in fractures among opioid users was attributed to central nervous system adverse effects of the medications as opposed to chronic hypogonadism. In terms of therapy, many small studies have found that testosterone replacement therapy increases bone mineral density in hypogonadal men, including men with hypopituitarism. SUMMARY: Further research is needed on the cross-talk that occurs in the bone-testis axis. When it comes to managing men with hypogonadism, the benefit of testosterone replacement therapy on prevention of incident fractures is uncertain. Large, long-term randomized controlled trials are needed with fracture as the primary outcome. PMID- 25144149 TI - Clinical features of docetaxel chemotherapy-related lymphedema. AB - Lymphedema is a chronic, progressive, and multifactorial disease. The anticancer drug docetaxel (Taxotere) can lead to fluid retention, which is the main cause of peripheral edema of the extremities, pleural effusion, pericardial effusion, and ascites in patients undergoing chemotherapy. While there have been a few case reports documenting fluid retention-induced edema as a side effect of docetaxel, it is not yet clear whether docetaxel causes lymphedema directly. Here, we report cases of three patients who developed lymphedema after treatment with docetaxel. PMID- 25144150 TI - Discriminate sensing of pyrophosphate using a new tripodal tetramine-based dinuclear Zn(II) complex under an indicator displacement assay approach. AB - In this research, the dinuclear Zn(ii) complex of anthracene based tripodal tetramine Zn2L was synthesized, and its sensing abilities towards anions was investigated using the indicator displacement assay (IDA) approach with four complexometric indicators: pyrocatechol violet (PV), bromopyrogallol red (BPG), methylthymol blue (MTB) and xylenol orange (XO). UV-vis spectrophotometry results indicated that the Zn2L-MTB ensemble sensor could discriminate the pyrophosphate anion (PPi) from other phosphate containing anions. (1)H and (31)P NMR spectroscopy as well as DFT calculations confirmed that PPi bound to Zn2L in a 2 : 2 manner. Both NMR spectroscopy and UV-vis spectrophotometry suggested that the two bulky tripodal tetramine units in Zn2L played an important role to provide the ensemble cleft for MTB, giving rise to an ensemble that could be displaced exclusively by PPi. The detection limit of PPi for the reported IDA system was 0.3 MUM in 20% (v/v) water-acetonitrile buffered at pH 7.4 with HEPES. PMID- 25144151 TI - Fibular aplasia, tibial campomelia, and oligosyndactyly: a further patient with a 2-year follow-up. PMID- 25144152 TI - Partial monosomy 3q26.33-3q27.3 presenting with intellectual disability, facial dysmorphism, and diaphragm eventration: a case report. PMID- 25144153 TI - Mild phenotype of a large partial 13q trisomy. PMID- 25144154 TI - Congenital myotonic dystrophy: natural disease progression and facial dysmorphology. PMID- 25144155 TI - Deep eutectic solvents as novel extraction media for phenolic compounds from model oil. AB - Deep eutectic solvents (DES) as a new kind of green solvent were used for the first time to excellently extract phenolic compounds from model oil. It was also proved that DES could be used to extract other polar compounds from non-polar or weakly-polar solvents by liquid-phase microextraction. PMID- 25144156 TI - Synthesis of a chiral building block for highly functionalized polycyclic ethers. AB - An efficient procedure for preparing enantiopure polycyclic ethers is reported. The protocol is based on the photo-oxidation/conjugate addition sequence over a chiral functionalized furan, which was prepared from commercially available tri-O acetyl-D-glucal. The Michael addition step afforded two products with the same absolute configuration from a mixture of diastereomers. PMID- 25144157 TI - Short-term outcomes for preterm infants with surgical necrotizing enterocolitis. AB - OBJECTIVE: To characterize the population and short-term outcomes in preterm infants with surgical necrotizing enterocolitis (NEC). STUDY DESIGN: Preterm infants with surgical NEC were identified from 27 hospitals over 3 years using the Children's Hospitals Neonatal Database; infants with gastroschisis, volvulus, major congenital heart disease or surgical NEC that resolved prior to referral were excluded. Patient characteristics and pre-discharge morbidities were stratified by gestational age (<28 vs 28(0/7) to 36(6/7) weeks' gestation). RESULT: Of the 753 eligible infants, 60% were born at <28 weeks' gestation. The median age at referral was 14 days; only 2 infants were inborn. Male gender (61%) was overrepresented, whereas antenatal steroid exposure was low (46%). Although only 11% had NEC totalis, hospital mortality (<28 weeks' gestation: 41%; 28(0/7) to 36(6/7) weeks' gestation: 32%, P=0.02), short bowel syndrome (SBS)/intestinal failure (IF) (20% vs 26%, P=0.06) and the composite of mortality or SBS/IF (50% vs 49%, P=0.7) were prevalent. Also, white matter injury (11.7% vs 6.6%, P=0.02) and grade 3 to 4 intraventricular hemorrhages (23% vs 2.7%, P<0.01) were commonly diagnosed. After referral, the median length of hospitalization was longer for survivors (106 days; interquartile range (IQR) 79, 152) relative to non-survivors (2 days; IQR 1,17; P<0.001). These survivors were prescribed parenteral nutrition infrequently after hospital discharge (<28 weeks': 5.2%; 28(0/7) to 36(6/7) weeks': 9.9%, P=0.048). CONCLUSION: After referral for surgical NEC, the short term outcomes are grave, particularly for infants born <28 weeks' gestation. Although analyses to predict outcomes are urgently needed, these data suggest that affected infants are at a high risk for lengthy hospitalizations and adverse medical and neuro-developmental abnormalities. PMID- 25144158 TI - The Neonatal Pain, Agitation and Sedation Scale and the bedside nurse's assessment of neonates. AB - OBJECTIVE: To determine the reliability of an objective measure of pain, agitation and sedation using the Neonatal Pain, Agitation and Sedation Scale (N PASS) compared with nursing bedside assessment. STUDY DESIGN: Neonates admitted in neonatal intensive care unit over a 6-month period were eligible. Pain and sedation were assessed with N-PASS, and a subjective questionnaire was administered to the bedside nurse. RESULT: A total of 218 neonates were eligible (median: gestational age 34.6 weeks, age at assessment 7 days). N-PASS pain score correlated significantly with both nurses' pain score (Spearman coefficient (r)=0.37; P<0.001) and agitation score (r=0.56; P<0.001). N-PASS sedation score correlated with nurses' sedation score (r=-0.39; P<0.001). Adjusting for gestational age, day of life, intrauterine drug exposure and use of high frequency ventilation only slightly attenuated the correlations (r=0.36, 0.55 and -0.31, respectively). CONCLUSION: The N-PASS captures nursing assessment of pain, agitation and sedation in this broad population and provides a quantitative assessment of subjective descriptions that often drives patient therapy. PMID- 25144160 TI - Development of surfactant coacervation in aqueous solution. AB - Coacervation is a phenomenon in which a colloidal dispersion separates into two immiscible liquid phases: a liquid rich in colloidal phase in equilibrium with another diluted liquid phase. Surfactant coacervation here refers to coacervation whose main components are surfactants with low molecular weights. Over the past two decades, surfactants have been greatly developed and studies on coacervation in systems of novel surfactants have been reported. This review summarizes the development of coacervation occurring in monomeric surfactants, one-head and two tail surfactants, gemini surfactants and their mixtures. The effects of surfactant molecular structure and external conditions on critical conditions for coacervation, structures of precursors and coacervates, and their relationships are described. The effects of inorganic salts, alcohols and organic salts on surfactant coacervation are also reviewed. PMID- 25144159 TI - Packed red blood cell transfusion is not associated with increased risk of necrotizing enterocolitis in premature infants. AB - OBJECTIVE: Recent reports have posited a temporal association between blood transfusion with packed red blood cells (BT) and necrotizing enterocolitis (NEC). We evaluated the relationship between BT and NEC among infants at three hospitals who were consented at birth into a prospective observational study of NEC. STUDY DESIGN: We used a case-control design to match each case of NEC in our study population of infants born at<33 weeks postmenstrual age (PMA) to one control infant using hospital of birth, PMA, birth weight and date of birth. RESULT: The number of transfusions per infant did not differ between 42 NEC cases and their controls (4.0 +/- 4.6 vs 5.4 +/- 4.1, mean +/- s.d., P = 0.063). A matched-pair analysis did not identify an association of transfusion with NEC in either the 48 h or 7-day time periods before the onset of NEC. Stratifying on matched-sets, the Cox proportional hazard model did not identify any difference in the total number of BTs between the two groups (hazard ratio 0.78, 95% confidence interval 0.57 to 1.07, P = 0.11). CONCLUSION: In contrast to previous studies, our case-control study did not identify a significant temporal association between BT and NEC. Additional large prospective randomized studies are needed to clarify the relationship between BT and NEC. PMID- 25144162 TI - Higher levels of sex chromosome heteromorphism are associated with markedly stronger reproductive isolation. AB - The two 'rules of speciation', Haldane's rule and the large X-effect, describe the genetic basis of postzygotic isolation, and have led to the realization that sex chromosomes play an important role in this process. However, a range of sex determination mechanisms exists in nature, not always involving sex chromosomes. Based on these 'rules of speciation', I test the hypothesis that the presence of sex chromosomes will contribute to a faster evolution of intrinsic postzygotic isolation. I show that taxa that do not have sex chromosomes evolve lower levels of postzygotic isolation than taxa with sex chromosomes, at a similar amount of genetic divergence. Taxa with young homomorphic sex chromosomes show an intermediate pattern compared to taxa with heteromorphic sex chromosomes and taxa without sex chromosomes. These results are consistent with predictions from the two 'rules of speciation', and emphasize the importance of sex chromosomes for the evolution of intrinsic postzygotic isolation. PMID- 25144163 TI - Survival outcomes in advanced laryngeal cancer. AB - IMPORTANCE: Chemoradiation therapy has become increasingly popular in the treatment of advanced laryngeal cancer as part of an organ preservation protocol. However, several studies have reported a decline in survival, possibly attributable to the increased use of radiation and chemoradiation therapy. OBJECTIVE: To evaluate survival outcomes of laryngeal conservation vs surgical therapy in the treatment of advanced laryngeal cancer in the United States using a large population-based cancer database. DESIGN, SETTING, AND PARTICIPANTS: Population-based, nonconcurrent cohort study of 5394 patients who received a diagnosis of stage III or IV laryngeal squamous cell carcinoma between 1992 and 2009. Data were extracted from the Surveillance, Epidemiology, and End Results 18 Database. INTERVENTIONS: Surgical or nonsurgical therapy. MAIN OUTCOMES AND MEASURES: Overall survival (OS) and disease-specific survival (DSS). RESULTS: Patients who received surgical therapy had better 2-year and 5-year DSS (70% vs 64% and 55% vs 51%, respectively; P < .001) and 2-year and 5-year OS (64% vs 57% and 44% vs 39%, respectively; P < .001) than patients who received nonsurgical therapy. The difference in DSS and OS between treatment groups remained after stratification by year-of-diagnosis cohorts (P < .001). The survival gap consistently narrowed with subsequent year-of-diagnosis cohorts. On multivariable analysis, nonsurgical patients had worse DSS (hazard ratio [HR], 1.33 [95% CI, 1.21-1.45]) and OS (HR, 1.32 [95% CI, 1.22-1.43]) after adjustment for year of diagnosis, American Joint Committee on Cancer stage, age, sex, subsite, race, and marital status. Stage III disease (HR, 0.59 [95% CI, 0.54-0.65]), glottic subsite (HR, 0.74 [95% CI, 0.67-0.82]), 2004 to 2009 year-of-diagnosis cohort (HR, 0.79 [95% CI, 0.70-0.90]), female sex (HR, 0.80 [95% CI, 0.72-0.89]), and married status (HR, 0.68 [95% CI, 0.62-0.75]) positively affected DSS. Black race (HR, 1.17 [95% CI, 1.05-1.30]) and increased age (HR, 1.03 [95% CI, 1.02-1.03] for each year) negatively affected DSS. CONCLUSIONS AND RELEVANCE: Surgical therapy leads to better survival outcomes than nonsurgical therapy for patients with advanced laryngeal cancer. Patients need to be made aware of the modest but significant survival disadvantage associated with nonsurgical therapy as part of the shared decision-making process during treatment selection. PMID- 25144164 TI - Blood coagulation screening using a paper-based microfluidic lateral flow device. AB - A simple approach to the evaluation of blood coagulation using a microfluidic paper-based lateral flow assay (LFA) device for point-of-care (POC) and self monitoring screening is reported. The device utilizes whole blood, without the need for prior separation of plasma from red blood cells (RBC). Experiments were performed using animal (rabbit) blood treated with trisodium citrate to prevent coagulation. CaCl2 solutions of varying concentrations are added to citrated blood, producing Ca(2+) ions to re-establish the coagulation cascade and mimic different blood coagulation abilities in vitro. Blood samples are dispensed into a paper-based LFA device consisting of sample pad, analytical membrane and wicking pad. The porous nature of the cellulose membrane separates the aqueous plasma component from the large blood cells. Since the viscosity of blood changes with its coagulation ability, the distance RBCs travel in the membrane in a given time can be related to the blood clotting time. The distance of the RBC front is found to decrease linearly with increasing CaCl2 concentration, with a travel rate decreasing from 3.25 mm min(-1) for no added CaCl2 to 2.2 mm min(-1) for 500 mM solution. Compared to conventional plasma clotting analyzers, the LFA device is much simpler and it provides a significantly larger linear range of measurement. Using the red colour of RBCs as a visible marker, this approach can be utilized to produce a simple and clear indicator of whether the blood condition is within the appropriate range for the patient's condition. PMID- 25144166 TI - Reviewing effectiveness of ankle assessment techniques for use in robot-assisted therapy. AB - This article provides a comprehensive review of studies that investigated ankle assessment techniques to better understand those that can be used in the real time monitoring of rehabilitation progress for implementation in conjunction with robot-assisted therapy. Seventy-six publications published between January 1980 and August 2013 were selected based on eight databases. They were divided into two main categories (16 qualitative and 60 quantitative studies): 13 goniometer studies, 18 dynamometer studies, and 29 studies about innovative techniques. A total of 465 subjects participated in the 29 quantitative studies of innovative measurement techniques that may potentially be integrated in a real-time monitoring device, of which 19 studies included less than 10 participants. Results show that qualitative ankle assessment methods are not suitable for real time monitoring in robot-assisted therapy, though they are reliable for certain patients, while the quantitative methods show great potential. The majority of quantitative techniques are reliable in measuring ankle kinematics and kinetics but are usually available only for use in the sagittal plane. Limited studies determine kinematics and kinetics in all three planes (sagittal, transverse, and frontal) where motions of the ankle joint and the subtalar joint actually occur. PMID- 25144167 TI - Functional outcomes associated with expiratory muscle strength training: narrative review. AB - This review presents the available evidence for the effects of expiratory muscle strength training (EMST) with the use of a pressure threshold device. The investigators used computerized database searches for studies reporting the outcomes of pressure threshold EMST published after 1994. A total of 24 selected articles presented outcomes related but not limited to respiratory function, such as speech, swallow, voice, and cough function in persons with neurologic conditions such as Parkinson disease, multiple sclerosis, and Lance-Adams syndrome; in persons with respiratory diseases, such as chronic obstructive pulmonary disease; and in healthy young adults and sedentary and active elderly. Several studies demonstrated promising outcomes of EMST as a non-task-specific training for airway protection in persons with dysphagia secondary to neuromuscular impairments; however, further research is needed to confirm and generalize the reported findings. PMID- 25144161 TI - Engagement and education: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: Engagement and education of ICU clinicians in disaster preparedness is fragmented by time constraints and institutional barriers and frequently occurs during a disaster. We reviewed the existing literature from 2007 to April 2013 and expert opinions about clinician engagement and education for critical care during a pandemic or disaster and offer suggestions for integrating ICU clinicians into planning and response. The suggestions in this article are important for all of those involved in a pandemic or large-scale disaster with multiple critically ill or injured patients, including front-line clinicians, hospital administrators, and public health or government officials. METHODS: A systematic literature review was performed and suggestions formulated according to the American College of Chest Physicians (CHEST) Consensus Statement development methodology. We assessed articles, documents, reports, and gray literature reported since 2007. Following expert-informed sorting and review of the literature, key priority areas and questions were developed. No studies of sufficient quality were identified upon which to make evidence-based recommendations. Therefore, the panel developed expert opinion-based suggestions using a modified Delphi process. RESULTS: Twenty-three suggestions were formulated based on literature-informed consensus opinion. These suggestions are grouped according to the following thematic elements: (1) situational awareness, (2) clinician roles and responsibilities, (3) education, and (4) community engagement. Together, these four elements are considered to form the basis for effective ICU clinician engagement for mass critical care. CONCLUSIONS: The optimal engagement of the ICU clinical team in caring for large numbers of critically ill patients due to a pandemic or disaster will require a departure from the routine independent systems operating in hospitals. An effective response will require robust information systems; coordination among clinicians, hospitals, and governmental organizations; pre-event engagement of relevant stakeholders; and standardized core competencies for the education and training of critical care clinicians. PMID- 25144168 TI - Visual function, traumatic brain injury, and posttraumatic stress disorder. AB - Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are signature injuries of the Iraq and Afghanistan conflicts. The conditions can be comorbid and have overlapping signs and symptoms, making it difficult to diagnose and treat each. TBI is associated with numerous changes in vision function, but vision problems secondary to PTSD have not been documented. To address this shortcoming, we reviewed the medical records of 100 patients with a history of TBI, noting PTSD diagnoses, visual symptoms, vision function abnormalities, and medications with visual side effects. Forty-one patients had PTSD and 59 did not. High rates of binocular vision and oculomotor function deficits were measured in patients with a history of TBI, but no significant differences between patients with or without PTSD were evident. However, compared to patients without PTSD, patients with PTSD had more self-reported visual symptoms in all four assessments and the complaint rates were significantly higher for light sensitivity and reading problems. Together, these findings may be beneficial in understanding vision problems in patients with TBI and PTSD as comorbid conditions compared with those with TBI alone. PMID- 25144169 TI - Pain experience of Iraq and Afghanistan Veterans with comorbid chronic pain and posttraumatic stress. AB - Chronic pain and posttraumatic stress disorder (PTSD) co-occur at high rates, and Veterans from recent wars in Iraq and Afghanistan may be particularly vulnerable to both conditions. The objective of this study was to identify key aspects of chronic pain, cognitions, and psychological distress associated with comorbid PTSD among this sample of Veterans. Baseline data were analyzed from a randomized controlled trial testing a stepped-care intervention for chronic musculoskeletal pain. Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) Veterans with chronic pain only (n = 173) were compared with those with chronic pain and clinically significant posttraumatic stress symptoms (n = 68). Group differences on pain characteristics, pain cognitions, and psychological distress were evaluated. Results demonstrated that OIF/OEF Veterans with comorbid chronic musculoskeletal pain and PTSD experienced higher pain severity, greater pain related disability and increased pain interference, more maladaptive pain cognitions (e.g., catastrophizing, self-efficacy, pain centrality), and higher affective distress than those with chronic pain alone. Veterans of recent military conflicts in Iraq and Afghanistan may be particularly vulnerable to the compounded adverse effects of chronic pain and PTSD. These results highlight a more intense and disabling pain and psychological experience for those with chronic pain and PTSD than for those without PTSD. PMID- 25144170 TI - Posttraumatic stress disorder symptoms, levels of social support, and emotional hiding in returning veterans. AB - The current study examines the associations among levels of social support, emotional hiding, and screening positive for posttraumatic stress disorder (PTSD) within a sample of 536 Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) veterans. Michigan and Ohio OIF/OEF veterans were contacted to complete a postdeployment mental health screening questionnaire developed as part of the Department of Veterans Affairs Ann Arbor Healthcare System's Serving Returning Veterans Mental Health Program. Approximately 30% of veterans screened positive for PTSD. All sources of social support, as well as emotional hiding, were significantly associated with screening positive for PTSD. Each unit increase of emotional hiding from spouses or significant others, friends, and family was associated with a 32% to 44% increase in odds of screening positive for PTSD. Additional research is needed to examine constructs related to social support and PTSD, such as emotional hiding, in order to identify areas for intervention. PMID- 25144171 TI - Reliability of brain-computer interface language sample transcription procedures. AB - We tested the reliability of transcribing language samples of daily brain computer interface (BCI) communication recorded as language activity monitoring (LAM) logfiles. This study determined interrater reliability and interjudge agreement for transcription of communication of veterans with amyotrophic lateral sclerosis using a P300-based BCI as an augmentative and alternative communication (AAC) system. KeyLAM software recorded logfiles in a universal logfile format during use of BCI-controlled email and word processing applications. These logfiles were encrypted and sent to our laboratory for decryption, transcription, and analysis. The study reports reliability results on transcription of 345 daily logfile samples. The procedure was found to be accurate across transcribers/raters. Frequency of agreement ratios of 97.6% for total number of words and 93.5% for total utterances were found as measures of interrater reliability. Interjudge agreement was 100% for both measures. The results indicated that transcribing language samples using LAM data is highly reliable and the fidelity of the process can be maintained. LAM data supported the transcription of a large number of samples that could not have been completed using audio and video recordings of AAC speakers. This demonstrated efficiency of LAM tools to measure language performance benefits to BCI research and clinical communities. PMID- 25144172 TI - Reliability, agreement, and validity of digital weighing scale with MatScan in limb load measurement. AB - Limb loading measurements serve as an objective evaluation of asymmetrical weight bearing in the lower limb. Digital weighing scales (DWSs) could be used in clinical settings for measurement of static limb loading. However, ambiguity exists whether limb loading measurements of DWSs are comparable with a standard tool such as MatScan. A cross-sectional study composed of 33 nondisabled participants was conducted to investigate the reliability, agreement, and validity of DWSs with MatScan in static standing. Amounts of weight distribution and plantar pressure on the individual lower limb were measured using two DWSs (A, B) and MatScan during eyes open (EO) and eyes closed (EC) conditions. The results showed that intra- and interrater reliability (3, 1) were excellent (0.94 0.97) within and between DWS A and B. Bland-Altman plot revealed good agreement between DWS and MatScan in EO and EC conditions. The area under the receiver operating characteristic curve was significant and identified as 0.68 (p = 0.01). The measurements obtained with DWSs are valid and in agreement with MatScan measurements. Hence, DWSs could be used interchangeably with MatScan and could provide clinicians an objective measurement of limb loading suitable for clinical settings. PMID- 25144173 TI - Identifying position, visibility, dimensions, and angulation of the ear. AB - We selected 254 subjects between the ages of 18 and 30 yr to assess the ear position, angulations of the ear in relation to the nose, visibility from the frontal view, and dimensions of the ear by using various anthropometric points of the face. Subjects were divided into four groups based on facial form. A reference plane indicator, facial topographical measurements, metal ruler, and digital photography were used. While considering the position of the ear, in all facial forms except square tapering, the most samples showed a tendency for the subaurale being in line with subnasale. Regression analysis showed a tendency to gnathion distance is the most dependent variable with length of the ear kept as a constant predictor, while both interalar distance and exocanthion to endocanthion distance correlate highly significantly to the width of the ear. In all subjects, the visibility of the ear when viewed from the front was an average of 1.5 mm. Regardless of facial form, ear angulation was generally less than nose angulation. PMID- 25144174 TI - Development of a progressive audiologic tinnitus management program for Veterans with tinnitus. AB - Tinnitus is the most prevalent service-connected disability awarded to Veterans. However, clinical protocols for management of tinnitus have been inconsistent across Department of Veterans Affairs (VA) medical centers. A study was funded to develop and pilot test a protocol to provide tinnitus services consistently across VA audiology clinics. Drawing on a series of prior VA and external research projects, a clinical model was formulated, supporting materials in multimedia were developed, and a pilot study was conducted. Five hierarchical levels of care were defined and labeled the Progressive Audiologic Tinnitus Management (PATM) model. The model facilitates access to medical services for tinnitus and includes detailed protocols for evaluation, education, and counseling of patients. Patients at each level of care have the option to "progress" to the next level of PATM if further services are required. Clinical procedures were defined for each level and materials were produced for audiologists and patients. The PATM model was then piloted with clinical patients at the James A. Haley Veterans' Hospital (JAHVH) in Tampa, Florida. Throughout the pilot study, feedback from patients and clinicians was carefully noted. Training materials for audiologists, incorporation of the protocol into clinic activities, and patient outcomes were evaluated. The model was implemented within the JAHVH Audiology Clinic and to assist Veterans with tinnitus management. The most notable finding was how little tinnitus-specific intervention was required for the majority of patients. This finding supports a clinical model that offers stepped-care ("progressive") levels of care until tinnitus management is achieved by the patient. PMID- 25144175 TI - Assessment of gait stability, harmony, and symmetry in subjects with lower-limb amputation evaluated by trunk accelerations. AB - Analysis of upper-body accelerations is a promising and simple technique for quantitatively assessing some general features of gait such as stability, harmony, and symmetry. Despite the growing literature on elderly healthy populations and neurological patients, few studies have used accelerometry to investigate these features in subjects with lower-limb amputation. We enrolled four groups of subjects: subjects with transfemoral amputation who walked with a locked knee prosthesis, subjects with transfemoral amputation who walked with an unlocked knee prosthesis, subjects with transtibial amputation, and age-matched nondisabled subjects. We found statistically significant differences for stability (p < 0.001), harmony (p < 0.001), and symmetry (p < 0.001) of walking, with general trends following the noted order of subjects, but with the lowest laterolateral harmony in subjects with transtibial amputation. This study is the first to investigate upper-body acceleration of subjects with unilateral lower limb amputation during walking who were evaluated upon dismissal from a rehabilitation hospital; it is also the first study to differentiate the sample in terms of level of amputation and type of prosthesis used. PMID- 25144176 TI - Test-retest reliability and rater agreements of assessment of capacity for myoelectric control version 2.0. AB - The Assessment of Capacity for Myoelectric Control (ACMC) is an observation-based tool that evaluates ability to control a myoelectric prosthetic hand. Validity evidence led to ACMC version 2.0, but the test-retest reliability and minimal detectable change (MDC) of the ACMC have never been evaluated. Investigation of rater agreements in this version was also needed because it has new definitions in certain rating categories and items. Upper-limb prosthesis users (n = 25, 15 congenital, 10 acquired; mean age 27.5 yr) performed one standardized activity twice, 2 to 5 wk apart. Activity performances were videorecorded and assessed by two ACMC raters. Data were analyzed by weighted kappa, intraclass correlation coefficient (ICC), and Bland-Altman method. For test-retest reliability, weighted kappa agreements were fair to excellent (0.52 to 1.00), ICC2,1 was 0.94, and one user was located outside the limits of agreement in the Bland-Altman plot. MDC95 was less than or equal to 0.55 logits (1 rater) and 0.69 logits (2 raters). For interrater reliability, weighted kappa agreements were fair to excellent in both sessions (0.44 to 1.00), and ICC2,1 was 0.95 (test) and 0.92 (retest). Intrarater agreement (rater 1) was also excellent (ICC3,1 0.98). Evidence regarding the reliability of the ACMC is satisfactory and MDC95 can be used to indicate change. PMID- 25144177 TI - Inflammation-mediating cytokine response to acute handcycling exercise with/without functional electrical stimulation-evoked lower-limb cycling. AB - This feasibility study compared the plasma inflammation-mediating cytokine response to an acute bout of handcycling (HC) with and without the addition of functional electrical stimulation (FES)-evoked lower-limb cycling. On two separate occasions, five recreationally active, community-based participants with motor complete paraplegia (thoracic 5- 7) performed 30 min HC and hybrid exercise (HYB) at a fixed power output. Venous blood samples were collected at rest, immediately postexercise, 1 h postexercise (post+1) and 2 h postexercise (post+2). Plasma interleukin (IL)-6, IL-10, IL-1 receptor antagonist (IL-1ra), adrenaline, and cortisol concentrations were determined via enzyme-linked immunoassay. Plasma IL-6 concentrations were significantly (p < 0.04) elevated (~2.5-fold) at post+1 and post+2 in HYB only. A small (0.5-fold), nonsignificant (p > 0.05) increase in IL-6 was observed at post+1 in HC, with concentrations significantly higher in HYB at post+2 (p < 0.02). Plasma IL-1ra was unaffected in both trials. Although not reaching statistical significance (p = 0.15), a ~1-fold increase in IL-10 concentration was seen in HYB at post+2. In contrast, increases in adrenaline (p < 0.04) and cortisol (p = 0.08) were observed immediately postexercise in HC and HYB. Initial findings suggest paralyzed skeletal muscle releases IL-6 in response to FES-evoked contractions. HYB may provide a greater anti-inflammatory potential in individuals with a thoracic spinal cord injury compared with HC alone. PMID- 25144178 TI - Colitis after polytrauma: case report. AB - Across the medical literature, delayed diagnosis and treatment leads to more costly and worse outcomes. Rehabilitation patients, especially those with polytrauma, often have a complex mixture of medical, social, and psychological health problems that can impair effective diagnosis and treatment. The case presentation describes the procession toward the diagnosis of ulcerative colitis in a preinjury asymptomatic male, suggesting a potential mechanism for its emergence and describing the effect of delayed diagnosis on the efficiency of rehabilitative care. As such, the differential diagnosis for early posttraumatic diarrhea should remain broad, particularly if unexplained or ineffectively controlled. PMID- 25144179 TI - Botulinum toxin injection for bruxism associated with brain injury: case report. AB - Bruxism is involuntary grinding of the teeth and can occur as a complication of brain injury. If untreated, bruxism can lead to severe occlusal trauma. Herein, we present a patient with traumatic brain injury and nocturnal bruxism that was treated with botulinum toxin injection. A 21 yr old male patient with traumatic brain injury from a car accident was admitted to our inpatient rehabilitation unit. He had a history of coma for 2 wk in the intensive care unit. The initial cranial computed tomography scan indicated a superior thalamic hemorrhage. On admission to our department 3 mo postinjury, his mental status was good and he was able to walk without assistance, but he had mild ataxia. He complained about severe teeth grinding at night, which began 2 mo postinjury. Botulinum toxin-A was injected into the masseter muscles (20 U in each muscle) and temporalis muscles (15 U in each muscle) bilaterally. A decrease in bruxism was reported within 3 d. Clinical improvement persisted at assessment 4 mo posttreatment. Botulinum toxin injection can be used as an effective treatment for bruxism associated with brain injury. PMID- 25144180 TI - Guest editorial: Department of Veterans Affairs Amputations System of care:5 years of accomplishments and outcomes. PMID- 25144182 TI - Disruptive behaviors among physicians. PMID- 25144181 TI - Combining cationic liposomal delivery with MPL-TDM for cysteine protease cocktail vaccination against Leishmania donovani: evidence for antigen synergy and protection. AB - BACKGROUND: With the paucity of new drugs and HIV co-infection, vaccination remains an unmet research priority to combat visceral leishmaniasis (VL) requiring strong cellular immunity. Protein vaccination often suffers from low immunogenicity and poor generation of memory T cells for long-lasting protection. Cysteine proteases (CPs) are immunogenic proteins and key mediators of cellular functions in Leishmania. Here, we evaluated the vaccine efficacies of CPs against VL, using cationic liposomes with Toll like receptor agonists for stimulating host immunity against L. donovani in a hamster model. METHODOLOGY/PRINCIPAL FINDINGS: Recombinant CPs type I (cpb), II (cpa) and III (cpc) of L. donovani were tested singly and in combination as a triple antigen cocktail for antileishmanial vaccination in hamsters. We found the antigens to be highly immunoreactive and persistent anti-CPA, anti-CPB and anti-CPC antibodies were detected in VL patients even after cure. The liposome-entrapped CPs with monophosphoryl lipid A-Trehalose dicorynomycolate (MPL-TDM) induced significantly high nitric oxide (up to 4 fold higher than controls) mediated antileishmanial activity in vitro, and resulted in strong in vivo protection. Among the three CPs, CPC emerged as the most potent vaccine candidate in combating the disease. Interestingly, a synergistic increase in protection was observed with liposomal CPA, CPB and CPC antigenic cocktail which reduced the organ parasite burden by 1013-1016 folds, and increased the disease-free survival of >80% animals at least up to 6 months post infection. Robust secretion of IFN-gamma and IL-12, along with concomitant downregulation of Th2 cytokines, was observed in cocktail vaccinates, even after 3 months post infection. CONCLUSION/SIGNIFICANCE: The present study is the first report of a comparative efficacy of leishmanial CPs and their cocktail using liposomal formulation with MPL-TDM against L. donovani. The level of protection attained has not been reported for any other subcutaneous single or polyprotein vaccination against VL. PMID- 25144183 TI - Selenium-based S-adenosylmethionine analog reveals the mammalian seven-beta strand methyltransferase METTL10 to be an EF1A1 lysine methyltransferase. AB - Lysine methylation has been extensively studied in histones, where it has been shown to provide specific epigenetic marks for the regulation of gene expression; however, the molecular mechanism and physiological function of lysine methylation in proteins other than histones remains to be fully addressed. To better understand the substrate diversity of lysine methylation, S-adenosylmethionine (SAM) derivatives with alkyne-moieties have been synthesized. A selenium-based SAM analog, propargylic Se-adenosyl-l-selenomethionine (ProSeAM), has a wide spectrum of reactivity against various lysine methyltransferases (KMTs) with sufficient stability to support enzymatic reactions in vitro. By using ProSeAM as a chemical probe for lysine methylation, we identified substrates for two seven beta-strand KMTs, METTL21A and METTL10, on a proteomic scale in mammalian cells. METTL21A has been characterized as a heat shock protein (HSP)-70 methyltransferase. Mammalian METTL10 remains functionally uncharacterized, although its ortholog in yeast, See1, has been shown to methylate the translation elongation factor eEF1A. By using ProSeAM-mediated alkylation followed by purification and quantitative MS analysis, we confirmed that METTL21A labels HSP70 family proteins. Furthermore, we demonstrated that METTL10 also methylates the eukaryotic elongation factor EF1A1 in mammalian cells. Subsequent biochemical characterization revealed that METTL10 specifically trimethylates EF1A1 at lysine 318 and that siRNA-mediated knockdown of METTL10 decreases EF1A1 methylation levels in vivo. Thus, our study emphasizes the utility of the synthetic cofactor ProSeAM as a chemical probe for the identification of non-histone substrates of KMTs. PMID- 25144184 TI - A new method to infer causal phenotype networks using QTL and phenotypic information. AB - In the context of genetics and breeding research on multiple phenotypic traits, reconstructing the directional or causal structure between phenotypic traits is a prerequisite for quantifying the effects of genetic interventions on the traits. Current approaches mainly exploit the genetic effects at quantitative trait loci (QTLs) to learn about causal relationships among phenotypic traits. A requirement for using these approaches is that at least one unique QTL has been identified for each trait studied. However, in practice, especially for molecular phenotypes such as metabolites, this prerequisite is often not met due to limited sample sizes, high noise levels and small QTL effects. Here, we present a novel heuristic search algorithm called the QTL+phenotype supervised orientation (QPSO) algorithm to infer causal directions for edges in undirected phenotype networks. The two main advantages of this algorithm are: first, it does not require QTLs for each and every trait; second, it takes into account associated phenotypic interactions in addition to detected QTLs when orienting undirected edges between traits. We evaluate and compare the performance of QPSO with another state-of-the art approach, the QTL-directed dependency graph (QDG) algorithm. Simulation results show that our method has broader applicability and leads to more accurate overall orientations. We also illustrate our method with a real-life example involving 24 metabolites and a few major QTLs measured on an association panel of 93 tomato cultivars. Matlab source code implementing the proposed algorithm is freely available upon request. PMID- 25144185 TI - Dynamic modularity of host protein interaction networks in Salmonella Typhi infection. AB - BACKGROUND: Salmonella Typhi is a human-restricted pathogen, which causes typhoid fever and remains a global health problem in the developing countries. Although previously reported host expression datasets had identified putative biomarkers and therapeutic targets of typhoid fever, the underlying molecular mechanism of pathogenesis remains incompletely understood. METHODS: We used five gene expression datasets of human peripheral blood from patients suffering from S. Typhi or other bacteremic infections or non-infectious disease like leukemia. The expression datasets were merged into human protein interaction network (PIN) and the expression correlation between the hubs and their interacting proteins was measured by calculating Pearson Correlation Coefficient (PCC) values. The differences in the average PCC for each hub between the disease states and their respective controls were calculated for studied datasets. The individual hubs and their interactors with expression, PCC and average PCC values were treated as dynamic subnetworks. The hubs that showed unique trends of alterations specific to S. Typhi infection were identified. RESULTS: We identified S. Typhi infection specific dynamic subnetworks of the host, which involve 81 hubs and 1343 interactions. The major enriched GO biological process terms in the identified subnetworks were regulation of apoptosis and biological adhesions, while the enriched pathways include cytokine signalling in the immune system and downstream TCR signalling. The dynamic nature of the hubs CCR1, IRS2 and PRKCA with their interactors was studied in detail. The difference in the dynamics of the subnetworks specific to S. Typhi infection suggests a potential molecular model of typhoid fever. CONCLUSIONS: Hubs and their interactors of the S. Typhi infection-specific dynamic subnetworks carrying distinct PCC values compared with the non-typhoid and other disease conditions reveal new insight into the pathogenesis of S. Typhi. PMID- 25144186 TI - External validation of the simple clinical score and the HOTEL score, two scores for predicting short-term mortality after admission to an acute medical unit. AB - BACKGROUND: Clinical scores can be of aid to predict early mortality after admission to a medical admission unit. A developed scoring system needs to be externally validated to minimise the risk of the discriminatory power and calibration to be falsely elevated. We performed the present study with the objective of validating the Simple Clinical Score (SCS) and the HOTEL score, two existing risk stratification systems that predict mortality for medical patients based solely on clinical information, but not only vital signs. METHODS: Pre planned prospective observational cohort study. SETTING: Danish 460-bed regional teaching hospital. FINDINGS: We included 3046 consecutive patients from 2 October 2008 until 19 February 2009. 26 (0.9%) died within one calendar day and 196 (6.4%) died within 30 days. We calculated SCS for 1080 patients. We found an AUROC of 0.960 (95% confidence interval [CI], 0.932 to 0.988) for 24-hours mortality and 0.826 (95% CI, 0.774-0.879) for 30-day mortality, and goodness-of fit test, chi(2) = 2.68 (10 degrees of freedom), P = 0.998 and chi(2) = 4.00, P = 0.947, respectively. We included 1470 patients when calculating the HOTEL score. Discriminatory power (AUROC) was 0.931 (95% CI, 0.901-0.962) for 24-hours mortality and goodness-of-fit test, chi(2) = 5.56 (10 degrees of freedom), P = 0.234. CONCLUSION: We find that both the SCS and HOTEL scores showed an excellent to outstanding ability in identifying patients at high risk of dying with good or acceptable precision. PMID- 25144187 TI - Rosiglitazone inhibits TGF-beta 1 induced activation of human Tenon fibroblasts via p38 signal pathway. AB - PURPOSE: Transdifferentiation of human Tenon fibroblasts to myofibroblasts and subsequent deposition of extracellular matrix is a key step in the scarring after glaucoma filtration surgery. The p38 signaling pathway plays an important role in cell proliferation and differentiation, and its upstream regulators and downstream molecules are widely distributed in the eye. We aimed to investigate the role of p38 in the activation of Tenon fibroblasts and that of the anti fibrotic mechanism of rosiglitazone in the modulation of the p38 signaling pathway. METHODS: Cultured Tenon fibroblasts were stimulated with transforming growth factor (TGF)-beta1. Activation of p38 was examined by western blot analysis. Rosiglitazone and blocking of the p38 signaling pathway by SB203580 were used to antagonize stimulation by TGF-beta1. Fibroblast motility was examined by wound closure assay; alpha-smooth muscle actin, connective tissue growth factor, and collagen type I were determined by qPCR and western blot. Expression and localization of alpha-smooth muscle actin were determined by immunofluorescence staining. RESULTS: Phosphorylated p38 was upregulated in fibroblasts stimulated with TGF-beta1, and this effect was substantially inhibited by rosiglitazone. Proliferation and migration of fibroblasts were suppressed by rosiglitazone and SB203580. Expression of alpha-smooth muscle actin, connective tissue growth factor, and collagen type I were decreased at the mRNA and protein levels by rosiglitazone and SB203580. However, the inhibitory effect of SB203580 on transcription and protein expression was weaker than that of rosiglitazone. Similar phenomena were found on immunofluorescence microscopy of alpha-smooth muscle actin. CONCLUSIONS: The p38 signaling pathway mediates the TGF-beta1-induced transdifferentiation of human Tenon fibroblasts to myofibroblasts. Rosiglitazone can exert anti-fibrotic activity by interfering with the TGF-beta/p38 signaling pathway and might be useful for modulating scar formation after glaucoma filtration surgery. PMID- 25144188 TI - Event-related brain potentials during a semantic priming task in children with learning disabilities not otherwise specified. AB - Learning disabilities (LDs) are the most common psychiatric disorders in children. LDs are classified either as "Specific" or "Learning Disorder Not Otherwise Specified". An important hypothesis suggests a failure in general domain process (i.e., attention) that explains global academic deficiencies. The aim of this study was to evaluate event-related potential (ERP) patterns of LD Not Otherwise Specified children with respect to a control group. Forty-one children (8-10.6 years old) participated and performed a semantic judgment priming task while ERPs were recorded. Twenty-one LD children had significantly lower scores in all academic skills (reading, writing and arithmetic) than twenty controls. Different ERP patterns were observed for each group. Control group showed smaller amplitudes of an anterior P200 for unrelated than related word pairs. This P200 effect was followed by a significant early N400a effect (greater amplitudes for unrelated than related word pairs; 350-550 ms) with a right topographical distribution. By contrast, LD Not Otherwise Specified group did not show a P200 effect or a significant N400a effect. This evidence suggests that LD Not Otherwise Specified children might be deficient in reading, writing and arithmetic domains because of their sluggish shifting of attention to process the incoming information. PMID- 25144190 TI - Fourth international workshop on computational phantoms: special issue. PMID- 25144189 TI - Differential sensitivity of Src-family kinases to activation by SH3 domain displacement. AB - Src-family kinases (SFKs) are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12) to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3 based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo. PMID- 25144192 TI - Differential effects of omega-3 fatty acid docosahexaenoic acid and palmitate on the circadian transcriptional profile of clock genes in immortalized hypothalamic neurons. AB - Diets high in saturated fatty acids (SFAs) are associated with the development of circadian dysregulation, obesity, and Type 2 diabetes mellitus. Conversely, polyunsaturated fatty acids (PUFAs) have recently been identified to improve insulin sensitivity, reduce weight gain, and relieve obesity-induced inflammation. While saturated fatty acids, such as the prevalent dietary fatty acid palmitate, have been implicated in circadian disruption, there is a paucity of studies regarding the effects of PUFAs on circadian parameters. Therefore, the immortalized murine neuronal model, mHypoE-37, was utilized to examine the effects of the SFA palmitate and omega-3 PUFA docosahexaenoic acid (DHA) on circadian rhythms. The mHypoE-37 neurons express the core clock genes, Bmal1, Per2, and Rev-erbalpha, in a circadian manner. 25 MUM of palmitate significantly increased the transcriptional expression of Bmal1, without altering the expression of inflammatory markers TLR4, IkappaBalpha, and IL-6, nor the orexigenic neuropeptide AgRP, suggesting that the observed disruption of the molecular clock is the result of a mechanism distinct from that of hypothalamic cellular inflammation. Furthermore, treatment with the PUFA DHA resulted in alterations in the circadian expression profile of Bmal1, although differentially from the effects of palmitate. In the presence of DHA, the disruptive effects of palmitate on Bmal1 were less pronounced, suggesting a protective effect of DHA. These studies are the first to identify the potential for omega-3 PUFAs to protect against palmitate-mediated dysregulation of circadian parameters and will ultimately improve the understanding of circadian control mechanisms. PMID- 25144193 TI - SMA-causing missense mutations in survival motor neuron (Smn) display a wide range of phenotypes when modeled in Drosophila. AB - Mutations in the human survival motor neuron 1 (SMN) gene are the primary cause of spinal muscular atrophy (SMA), a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of phenotypic severities, similar to the human disease. Furthermore, specific interactions with other proteins known to be important for SMN's role in RNP assembly are conserved. Intragenic complementation analyses revealed that the three most severe mutations, all of which map to the YG box self-oligomerization domain of SMN, display a stronger phenotype than the null allele and behave in a dominant fashion. In support of this finding, the severe YG box mutants are defective in self-interaction assays, yet maintain their ability to heterodimerize with wild type SMN. When expressed at high levels, wild-type SMN is able to suppress the activity of the mutant protein. These results suggest that certain SMN mutants can sequester the wild-type protein into inactive complexes. Molecular modeling of the SMN YG box dimer provides a structural basis for this dominant phenotype. These data demonstrate that important structural and functional features of the SMN YG box are conserved between vertebrates and invertebrates, emphasizing the importance of self-interaction to the proper functioning of SMN. PMID- 25144194 TI - The safety and acceptance of the PrePex device for non-surgical adult male circumcision in Rakai, Uganda. A non-randomized observational study. AB - OBJECTIVES: To assess the safety and acceptance of the PrePex device for medical male circumcision (MMC) in rural Uganda. METHODS: In an observational study, HIV uninfected, uncircumcised men aged 18 and older who requested elective MMC were informed about the PrePex and dorsal slit methods and offered a free choice of their preferred procedure. 100 men received PrePex to assess preliminary safety (aim 1). An additional 329 men, 250 chose PrePex and 79 chose Dorsal slit, were enrolled following approval by the Safety Monitoring Committee (aim 2). Men were followed up at 7 days to assess adverse events (AEs) and to remove the PrePex device. Wound healing was assessed at 4 weeks, with subsequent weekly follow up until completed healing. RESULTS: The PrePex device was contraindicated in 5.7% of men due to a tight prepuce or phimosis/adhesions. Among 429 enrolled men 350 (82.0%) got the PrePex device and 79 (18.0%) the dorsal slit procedure. 250 of 329 men (76.0%) who were invited to choose between the 2 procedures chose Prepex. There were 9 AEs (2.6%) with the PrePex, of which 5 (1.4%) were severe complications, 4 due to patient self-removal of the device leading to edema and urinary obstruction requiring emergency surgical circumcision, and one due to wound dehiscence following device removal. 71.8% of men reported an unpleasant odor prior to PrePex removal. Cumulative rates of completed wound healing with the PrePex were 56.7% at week 4, 84.8% week 5, 97.6% week 6 and 98.6% week 7, compared to 98.7% at week 4 with dorsal slit (p<0.0001). CONCLUSION: The PrePex device was well accepted, but healing was slower than with dorsal slit surgery. Severe complications, primarily following PrePex self-removal, required rapid access to emergency surgical facilities. The need to return for removal and delayed healing may increase Program cost and client burden. PMID- 25144197 TI - The impact of early specialist management on outcomes of patients with in hospital stroke. AB - Delays in treatment of in-hospital stroke (IHS) adversely affect patient outcomes. We hypothesised that early referral and specialist management of IHS patients will improve outcomes at 90 days. Baseline characteristics, assessment delays, thrombolysis eligibility, 90-day functional outcomes and all-cause mortality were compared between IHS patients referred for specialist stroke management within 3 hours of symptom onset (early referrals) and later referrals. Patients were identified from a prospective stroke registry between January 2009 and December 2010. Inclusion criteria were primary admission with a non-stroke diagnosis, onset of new neurological deficits after admission and early ischaemic changes on CT or MR imaging. Eighty four (4.6%) of 1836 stroke patients had IHS (mean age 74 year; 51% male, median NIHSS score 10). There were no significant differences in baseline characteristics between 53 (63%) early and 31 (37%) late referrals. Thrombolysis was performed in 29 (76%) of the 37/78 (47%) potentially eligible patients; 7 patients were excluded because specialist referral was delayed beyond 4.5 hours despite symptom recognition within 3 hours of onset. Early referral improved functional outcomes (modified Rankin Scale 0-2 at 90 days 40% v 7%, p = 0.001) and was an independent predictor of mRS 0-2 at 90 days after adjusting for age, pre-morbid function, primary cause for hospital admission and stroke severity [OR 1.13 (95% C.I. = 1.10-1.27), p = 0.002]. Early referral and specialist management of IHS patients that includes thrombolysis is associated with better functional outcomes at 90 days. PMID- 25144196 TI - Ezrin mediates neuritogenesis via down-regulation of RhoA activity in cultured cortical neurons. AB - Neuronal morphogenesis is implicated in neuronal function and development with rearrangement of cytoskeletal organization. Ezrin, a member of Ezrin/Radixin/Moesin (ERM) proteins links between membrane proteins and actin cytoskeleton, and contributes to maintenance of cellular function and morphology. In cultured hippocampal neurons, suppression of both radixin and moesin showed deficits in growth cone morphology and neurite extensions. Down-regulation of ezrin using siRNA caused impairment of netrin-1-induced axon outgrowth in cultured cortical neurons. However, roles of ezrin in the neuronal morphogenesis of the cultured neurons have been poorly understood. In this report, we performed detailed studies on the roles of ezrin in the cultured cortical neurons prepared from the ezrin knockdown (Vil2(kd/kd)) mice embryo that showed a very small amount of ezrin expression compared with the wild-type (Vil2(+/+)) neurons. Ezrin was mainly expressed in cell body in the cultured cortical neurons. We demonstrated that the cultured cortical neurons prepared from the Vil2(kd/kd) mice embryo exhibited impairment of neuritogenesis. Moreover, we observed increased RhoA activity and phosphorylation of myosin light chain 2 (MLC2), as a downstream effector of RhoA in the Vil2(kd/kd) neurons. In addition, inhibition of Rho kinase and myosin II rescued the impairment of neuritogenesis in the Vil2(kd/kd) neurons. These data altogether suggest a novel role of ezrin in the neuritogenesis of the cultured cortical neurons through down-regulation of RhoA activity. PMID- 25144195 TI - Delineating the importance of serum opsonins and the bacterial capsule in affecting the uptake and killing of Burkholderia pseudomallei by murine neutrophils and macrophages. AB - Infection of susceptible hosts by the encapsulated Gram-negative bacterium Burkholderia pseudomallei (Bp) causes melioidosis, with septic patients attaining mortality rates >= 40%. Due to its high infectivity through inhalation and limited effective therapies, Bp is considered a potential bioweapon. Thus, there is great interest in identifying immune effectors that effectively kill Bp. Our goal is to compare the relative abilities of murine macrophages and neutrophils to clear Bp, as well as determine the importance of serum opsonins and bacterial capsule. Our findings indicate that murine macrophages and neutrophils are inherently unable to clear either unopsonized Bp or the relatively-avirulent acapsular bacterium B. thailandensis (Bt). Opsonization of Bp and Bt with complement or pathogen-specific antibodies increases macrophage-uptake, but does not promote clearance, although antibody-binding enhances complement deposition. In contrast, complement opsonization of Bp and Bt causes enhanced uptake and killing by neutrophils, which is linked with rapid ROS induction against bacteria exhibiting a threshold level of complement deposition. Addition of bacteria specific antibodies enhances complement deposition, but antibody-binding alone cannot elicit neutrophil clearance. Bp capsule provides some resistance to complement deposition, but is not anti-phagocytic or protective against reactive oxygen species (ROS)-killing. Macrophages were observed to efficiently clear Bp only after pre-activation with IFNgamma, which is independent of serum- and/or antibody-opsonization. These studies indicate that antibody-enhanced complement activation is sufficient for neutrophil-clearance of Bp, whereas macrophages are ineffective at clearing serum-opsonized Bp unless pre-activated with IFNgamma. This suggests that effective immune therapies would need to elicit both antibodies and Th1-adaptive responses for successful prevention/eradication of melioidosis. PMID- 25144198 TI - NLR-associating transcription factor bHLH84 and its paralogs function redundantly in plant immunity. AB - In plants and animals, nucleotide-binding and leucine-rich repeat domain containing (NLR) immune receptors are utilized to detect the presence or activities of pathogen-derived molecules. However, the mechanisms by which NLR proteins induce defense responses remain unclear. Here, we report the characterization of one basic Helix-loop-Helix (bHLH) type transcription factor (TF), bHLH84, identified from a reverse genetic screen. It functions as a transcriptional activator that enhances the autoimmunity of NLR mutant snc1 (suppressor of npr1-1, constitutive 1) and confers enhanced immunity in wild-type backgrounds when overexpressed. Simultaneously knocking out three closely related bHLH paralogs attenuates RPS4-mediated immunity and partially suppresses the autoimmune phenotypes of snc1, while overexpression of the other two close paralogs also renders strong autoimmunity, suggesting functional redundancy in the gene family. Intriguingly, the autoimmunity conferred by bHLH84 overexpression can be largely suppressed by the loss-of-function snc1-r1 mutation, suggesting that SNC1 is required for its proper function. In planta co immunoprecipitation revealed interactions between not only bHLH84 and SNC1, but also bHLH84 and RPS4, indicating that bHLH84 associates with these NLRs. Together with previous finding that SNC1 associates with repressor TPR1 to repress negative regulators, we hypothesize that nuclear NLR proteins may interact with both transcriptional repressors and activators during immune responses, enabling potentially faster and more robust transcriptional reprogramming upon pathogen recognition. PMID- 25144199 TI - Psychological stress exerts effects on pathogenesis of hepatitis B via type 1/type-2 cytokines shift toward type-2 cytokine response. AB - BACKGROUND: Psychological and physical stress has been demonstrated to have an impact on health through modulation of immune function. Despite high prevalence of stress among patients with hepatitis B virus (HBV) infection, little is known about whether and how stress exerts an effect on the course of hepatitis B. METHODS: Eighty patients with chronic hepatitis B(CHB) completed the Perceived Stress Scale-10(PSS-10) and State-Trait Anxiety Inventory(STAI). Fresh whole blood was subject to flow cytometry for lymphocytes count. Plasma samples frozen at -80 degrees C were thawed for cytokines, alanine aminotransferase (ALT), and virus load. These patients were grouped into high or low perceived stress, state anxiety and trait anxiety groups according to the scale score. Sociodemographic, disease-specific characteristics, lymphocytes count and cytokines were compared. RESULTS: Firstly, a negative association between ALT and stress (t = -4.308; p = .000), state anxiety (t = -3.085; p = .003) and trait anxiety (t = -4.925; p = .000) were found. As ALT is a surrogate marker of hepatocytes injury, and liver injury is a consequence of immune responses. Next, we tested the relationship between stress/anxiety and lymphocytes. No statistical significance were found with respect to counts of total T cells, CD4+ T cell, CD8+ T cell, NK cell, and B cell count between high and low stress group. Type-2 cytokine interleukin-10 (IL-10) level was significantly higher in high stress group relative to lower counterpart (t = 6.538; p = 0.000), and type-1 cytokine interferon-gamma (IFN-gamma) level shown a decreased tendency in high stress group (t = -1.702; p = 0.093). Finally, INF-gamma:IL-10 ratio displayed significant decrease in high perceived stress(t = -4.606; p = 0.000), state anxiety(t = -5.126; p = 0.000) and trait anxiety(t = -4.670; p = 0.000) groups relative to low counterparts. CONCLUSION: Our data show stress is not related to the lymphocyte cells count in CHB patients, however, stress induces a shift in the type-1/type-2 cytokine balance towards a type-2 response, which implicated a role of psychological stress in the course of HBV related immune-pathogenesis. PMID- 25144200 TI - The role of emotion in musical improvisation: an analysis of structural features. AB - One of the primary functions of music is to convey emotion, yet how music accomplishes this task remains unclear. For example, simple correlations between mode (major vs. minor) and emotion (happy vs. sad) do not adequately explain the enormous range, subtlety or complexity of musically induced emotions. In this study, we examined the structural features of unconstrained musical improvisations generated by jazz pianists in response to emotional cues. We hypothesized that musicians would not utilize any universal rules to convey emotions, but would instead combine heterogeneous musical elements together in order to depict positive and negative emotions. Our findings demonstrate a lack of simple correspondence between emotions and musical features of spontaneous musical improvisation. While improvisations in response to positive emotional cues were more likely to be in major keys, have faster tempos, faster key press velocities and more staccato notes when compared to negative improvisations, there was a wide distribution for each emotion with components that directly violated these primary associations. The finding that musicians often combine disparate features together in order to convey emotion during improvisation suggests that structural diversity may be an essential feature of the ability of music to express a wide range of emotion. PMID- 25144201 TI - Development of a prokaryotic universal primer for simultaneous analysis of Bacteria and Archaea using next-generation sequencing. AB - For the analysis of microbial community structure based on 16S rDNA sequence diversity, sensitive and robust PCR amplification of 16S rDNA is a critical step. To obtain accurate microbial composition data, PCR amplification must be free of bias; however, amplifying all 16S rDNA species with equal efficiency from a sample containing a large variety of microorganisms remains challenging. Here, we designed a universal primer based on the V3-V4 hypervariable region of prokaryotic 16S rDNA for the simultaneous detection of Bacteria and Archaea in fecal samples from crossbred pigs (Landrace * Large white * Duroc) using an Illumina MiSeq next-generation sequencer. In-silico analysis showed that the newly designed universal prokaryotic primers matched approximately 98.0% of Bacteria and 94.6% of Archaea rRNA gene sequences in the Ribosomal Database Project database. For each sequencing reaction performed with the prokaryotic universal primer, an average of 69,330 (+/- 20,482) reads were obtained, of which archaeal rRNA genes comprised approximately 1.2% to 3.2% of all prokaryotic reads. In addition, the detection frequency of Bacteria belonging to the phylum Verrucomicrobia, including members of the classes Verrucomicrobiae and Opitutae, was higher in the NGS analysis using the prokaryotic universal primer than that performed with the bacterial universal primer. Importantly, this new prokaryotic universal primer set had markedly lower bias than that of most previously designed universal primers. Our findings demonstrate that the prokaryotic universal primer set designed in the present study will permit the simultaneous detection of Bacteria and Archaea, and will therefore allow for a more comprehensive understanding of microbial community structures in environmental samples. PMID- 25144204 TI - A bulky mass in the neck. PMID- 25144202 TI - Introduction and executive summary: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - Natural disasters, industrial accidents, terrorism attacks, and pandemics all have the capacity to result in large numbers of critically ill or injured patients. This supplement provides suggestions for all of those involved in a disaster or pandemic with multiple critically ill patients, including front-line clinicians, hospital administrators, professional societies, and public health or government officials. The current Task Force included a total of 100 participants from nine countries, comprised of clinicians and experts from a wide variety of disciplines. Comprehensive literature searches were conducted to identify studies upon which evidence-based recommendations could be made. No studies of sufficient quality were identified. Therefore, the panel developed expert-opinion-based suggestions that are presented in this supplement using a modified Delphi process. The ultimate aim of the supplement is to expand the focus beyond the walls of ICUs to provide recommendations for the management of all critically ill or injured adults and children resulting from a pandemic or disaster wherever that care may be provided. Considerations for the management of critically ill patients include clinical priorities and logistics (supplies, evacuation, and triage) as well as the key enablers (systems planning, business continuity, legal framework, and ethical considerations) that facilitate the provision of this care. The supplement also aims to illustrate how the concepts of mass critical care are integrated across the spectrum of surge events from conventional through contingency to crisis standards of care. PMID- 25144206 TI - Patterns of shoulder imbalance in adolescent idiopathic scoliosis: a retrospective observational study. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To study the relationship between the proximal spine and shoulder levels in adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: It has been frequently observed that the shoulder levels do not correspond to the spinal curve direction in AIS. MATERIALS AND METHODS: Eighty-five operated cases of AIS were analyzed retrospectively of which 69 were Lenke type I and II curves. Preoperative anteroposterior standing x rays of the spine and clinical photographs were studied. T1 tilt and intercoracoid line (ICL) tilt and their mutual relationship were documented. The curve type (Lenke), magnitude, and direction of the proximal and main thoracic (PT and MT) curves were also noted. RESULTS: The shoulder level as depicted by the ICL showed 3 patterns-horizontal, left side elevated, or right side elevated. The T1-ICL relationship was either concordant or discordant. In the concordant case the T1 was tilted to the same side as the ICL; and vice versa in the discordant. The shoulder level was dependent on the MT curve if the ICL tilted to the same side as the MT curve and it was dependent on the PT curve if it tilted to the same side as the PT curve. This relationship appeared unrelated to curve type. CONCLUSIONS: Preoperative shoulder levels in AIS may be concordant with the T1 or discordant-each can have left or right shoulder elevation or balanced shoulders. Further, the shoulder might be MT dependent or PT dependent. Theoretically therefore, surgical balancing of the shoulder and upper instrumented vertebra placement should not depend only on the magnitude and stiffness of the PT curve. PMID- 25144207 TI - Protein crystalline frameworks with controllable interpenetration directed by dual supramolecular interactions. AB - Protein crystalline frameworks are attractive for biomimetic and nanotechnological studies because they could augment the useful functionalities of numerous proteins through dense packing and uniform orientation. However, their formation and precise structural control is challenging. Here we present novel protein crystalline frameworks with controllable interpenetration. The homotetrameric lectin concanavalin A is crosslinked by predetermined inducing ligands containing monosaccharide and rhodamine groups connected by an oligo(ethylene oxide) spacer. Two non-covalent interactions, that is, sugar lectin binding and the dimerization of RhB, are responsible for the framework formation. The three-dimensional structure of the framework is fully characterized by X-ray crystallographic methods. For the first time, either interpenetrating or non-interpenetrating frameworks are obtained, and they are controlled by the spacer length of the inducing ligand. Further kinetics and mechanistic investigations reveal that, in the self-assembly process, the carbohydrate-protein binding occurs first, followed by RhB dimerization. This sequence favours rapid crystallization with a high yield when an excess amount of inducing ligand is used. In short, by using well-controlled dual non-covalent interactions, fast and versatile preparation of protein crystalline framework was achieved with high crystallization ratio of the proteins, which may shed light on protein crystallization in near future. PMID- 25144203 TI - Legal preparedness: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: Significant legal challenges arise when health-care resources become scarce and population-based approaches to care are implemented during severe disasters and pandemics. Recent emergencies highlight the serious legal, economic, and health impacts that can be associated with responding in austere conditions and the critical importance of comprehensive, collaborative health response system planning. This article discusses legal suggestions developed by the American College of Chest Physicians (CHEST) Task Force for Mass Critical Care to support planning and response efforts for mass casualty incidents involving critically ill or injured patients. The suggestions in this chapter are important for all of those involved in a pandemic or disaster with multiple critically ill or injured patients, including front-line clinicians, hospital administrators, and public health or government officials. METHODS: Following the CHEST Guidelines Oversight Committee's methodology, the Legal Panel developed 35 key questions for which specific literature searches were then conducted. The literature in this field is not suitable to provide support for evidence-based recommendations. Therefore, the panel developed expert opinion-based suggestions using a modified Delphi process resulting in seven final suggestions. RESULTS: Acceptance is widespread for the health-care community's duty to appropriately plan for and respond to severe disasters and pandemics. Hospitals, public health entities, and clinicians have an obligation to develop comprehensive, vetted plans for mass casualty incidents involving critically ill or injured patients. Such plans should address processes for evacuation and limited appeals and reviews of care decisions. To legitimize responses, deter independent actions, and trigger liability protections, mass critical care (MCC) plans should be formally activated when facilities and practitioners shift to providing MCC. Adherence to official MCC plans should contribute to protecting hospitals and practitioners who act in good faith from liability. Finally, to address anticipated staffing shortages during severe and prolonged disasters and pandemics, governments should develop approaches to formally expand the availability of qualified health-care workers, such as through using official foreign medical teams. CONCLUSIONS: As a fundamental element of health-care and public health emergency planning and preparedness, the law underlies critical aspects of disaster and pandemic responses. Effective responses require comprehensive advance planning efforts that include assessments of complex legal issues and authorities. Recent disasters have shown that although law is a critical response tool, it can also be used to hold health-care stakeholders who fail to appropriately plan for or respond to disasters and pandemics accountable for resulting patient or staff harm. Claims of liability from harms allegedly suffered during disasters and pandemics cannot be avoided altogether. However, appropriate planning and legal protections can help facilitate sound, consistent decision-making and support response participation among health-care entities and practitioners. PMID- 25144208 TI - Trans-regulation of oligodendrocyte myelination by neurons through small GTPase Arf6-regulated secretion of fibroblast growth factor-2. AB - The small G protein ADP-ribosylation factor 6 (Arf6) plays important roles in a wide variety of membrane dynamics-based cellular events such as neurite outgrowth and spine formation in vitro. However, little is known about physiological function of Arf6 in vivo. Here we generate conditional knockout mice lacking Arf6 in neurons, oligodendrocytes, or both cell lineages, and unexpectedly find that Arf6 expression in neurons, but not in oligodendrocytes, is crucial for oligodendrocyte myelination in the hippocampal fimbria and the corpus callosum during development, and that this is through the regulation of secretion of fibroblast growth factor-2, a guidance factor for migration of oligodendrocyte precursor cells (OPCs). These results suggest that Arf6 in neurons plays an important role in OPC migration through regulation of FGF-2 secretion during neuronal development. PMID- 25144209 TI - Smoking behaviour: investigation of the coaction of environmental and genetic risk factors. PMID- 25144210 TI - Comparing spectral-domain optical coherence tomography and standard automated perimetry to diagnose glaucomatous optic neuropathy. AB - PURPOSE: To compare the abilities of standard automated perimetry (SAP) and spectral-domain optical coherence tomography (SDOCT) in diagnosing eyes with glaucomatous optic neuropathy (GON). METHODS: In a cross-sectional study, 280 eyes of 175 subjects referred to tertiary eye care center by general ophthalmologists for a glaucoma evaluation underwent retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) imaging with SDOCT. All subjects had at least 2 reliable and repeatable SAP. Two glaucoma experts masked to clinical and SAP results classified the optic nerves into GON and nonglaucomatous groups based on digital optic disc photographs. Ability of SDOCT parameters and SAP to discriminate GON eyes from nonglaucomatous eyes was evaluated using sensitivity, specificity, and likelihood ratios (LR). RESULTS: Experts classified 179 eyes into GON and 101 eyes into nonglaucomatous group. Sensitivity of SAP (69.8%) was significantly lower (P<0.05) than that of inferior quadrant RNFL thickness (83.8%), average RNFL thickness (77.2%), GCC focal loss volume (FLV, 81.5%), and global loss volume (GLV, 82.6%). Specificity and positive LR of SAP (95% and14.1, respectively) were significantly greater than those of all RNFL parameters, FLV (84.2% and 5.1) and GLV (82.2% and 4.6). Negative LR of SAP (0.32) was significantly inferior to that of inferior quadrant RNFL thickness (0.22), FLV (0.22), and GLV (0.21). CONCLUSIONS: Most of the RNFL and GCC parameters of SDOCT had better sensitivities and negative LRs to diagnose GON compared with SAP. The specificities and positive LRs of most SDOCT parameters were inferior to that of SAP. PMID- 25144211 TI - Comparison of Optic Nerve Head Topographic Parameters in Patients With Primary Open-Angle Glaucoma With and Without Diabetes Mellitus. AB - PURPOSE: To evaluate the optic nerve head (ONH) parameters of primary open-angle glaucoma (POAG) patients with and without diabetes and to investigate the effect of the metabolic control of diabetes on ONH topography. MATERIALS AND METHODS: A study group of 60 eyes of 60 POAG patients with type 2 diabetes mellitus and a control group of 41 eyes of 41 POAG patients without diabetes were recruited for the study. Complete ophthalmic examinations of all patients were performed and the quantitative optic disc parameters were evaluated with Heidelberg retina tomography (HRT) III. HbA1c measurements of diabetic patients were assessed on the same day when the ophthalmic assessments were performed. RESULTS: Mean rim area and rim volume of the study group was statistically higher than the control group (P=0.04 for rim area and P=0.02 for rim volume). The difference in other parameters of the HRT between the groups were insignificant (P>0.05). In the study group, the duration of the diabetes was not significantly correlated to rim area and rim volume (r=0.03, P=0.81 for rim area; r=0.03, P=0.79 for rim volume). Analysis of covariance showed insignificant effects of age, sex, MD, and PSD values over rim area and rim volume (P>0.05). There were weak but statistically significant correlations between HbA1c levels and some HRT parameters including disc area, cup area, cup volume, and cup shape measure (r=0.35 and P=0.006 for disc area; r=0.35 and P=0.006 for cup area; r=0.32 and P=0.01 for cup volume; r=0.32 and P=0.01 for cup shape measure). CONCLUSIONS: The results of this study imply the protective effect of diabetes over glaucomatous optic nerve damage in POAG patients. However, larger and controlled studies are warranted to confirm those findings. PMID- 25144212 TI - Baerveldt 250 mm2 Glaucoma Drainage Devices in Eyes With Preexisting Scleral Buckles. AB - PURPOSE: To evaluate eyes with preexisting scleral buckles (SBs) that underwent placement of a 250 mm Baerveldt glaucoma drainage device (GDD). PATIENTS AND METHODS: Records of all patients with a preexisting SB who underwent 250 mm Baerveldt GDD placement at the Kellogg Eye Center between January 1, 2005 and September 30, 2012 were reviewed. Outcome measures included visual acuity (VA), intraocular pressure (IOP), and number of glaucoma medications prescribed. RESULTS: Seventeen eyes of 17 patients were analyzed. Mean follow-up was 23.9 months. Twelve eyes (70.6%) achieved successful control of IOP (<22 mm Hg, not requiring additional IOP reduction procedures, and no devastating complications). Preoperatively, mean IOP was 25.5 mm Hg, mean number of glaucoma medications was 3.5, and mean logMAR VA was 1.1 (Snellen equivalent 20/200). At 1 and 2 years postoperatively, mean IOP was 9.2 and 8.8 mm Hg (P<0.001), and mean number of glaucoma medications was 0.9 and 0.3 (P<0.001), respectively. There were no statistically significant changes in logMAR VA at 1 and 2 years postoperatively (P=0.45 and 0.99, respectively). Complications included conjunctival dehiscence (4 eyes, 24%), wound leak (2 eyes, 12%), tube and plate exposure requiring removal of drainage device (2 eyes, 12%), phthisis (2 eyes, 12%), and hemorrhagic choroidal detachment (1 eye, 6%). CONCLUSIONS: In eyes with preexisting SBs, the Baerveldt 250 mm GDD effectively lowers IOP and reduces the number of glaucoma medications. Complications related to conjunctival dehiscence are not uncommon in these eyes with significantly scarred conjunctiva. PMID- 25144213 TI - Transcatheter aortic valve replacement: establishing a comprehensive program model for hybrid cardiac catheterization laboratories in the Department of Veterans Affairs. AB - Aortic valve disease, especially aortic stenosis, becomes progressively debilitating and carries a high mortality risk if it is categorized as severe and symptomatic (J Thorac Cardiovas Surg. 2012;144(3):e29-e84). In the past, the only treatment for aortic stenosis was surgical aortic valve replacement. Surgical treatment may require several hours of cardioplegia, and if the patient has comorbidities, such as renal failure or chronic obstructive pulmonary disease, their operative mortality percentage increases.In 2011, the US Food and Drug Administration approved the use of a transcatheter aortic valve replacement (TAVR) procedure for patients who were deemed high risk or inoperative for the routine surgical aortic valve replacement surgery. More than 20, 000 TAVRs have been performed in patients worldwide since 2002 when Dr Alain Cribier performed the first-in-man TAVR (Arch Cardiovasc Dis. 2012;105(3):145-152). The Edwards Lifesciences SAPIEN XT valve and the Medtronic CoreValve are commercially available.The clinical findings and economic statistic have supported the expansion of the TAVR procedure. However, there has been considerable controversy over where the procedure is to occur and who is directly responsible for directing the TAVR care. This debate has identified barriers to the implementation of a TAVR program. The operating rooms and a cardiac catheterization laboratory are underprepared for the hybrid valve replacement therapy. Because of the barriers identified, the Department of Veterans Affairs determined a need for a systematic approach to review the programs that applied for this structural heart disease program. A centralized team was developed to ensure room readiness and staff competency. The use of the Health Failure Mode and Effects Analysis can define high-risk clinical processes and conduct a hazard analysis. Worksheets can show potential failure modes and their probabilities, along with actions and outcome measures, team collaboration, extensive screening, and selection process. The TAVR program begins implementation with data entry with each case into CART-CL (Cardiovascular Assessment, Reporting and Tracking System for Cath Labs, Veteran Administration database for interventional cardiology procedures). If an untoward event occurs, within 24 hours the CART-CL Quality Assessment Team is activated to begin the review process. This provides real-time review and feedback to the local facility in an expeditious manner. Cardiac catheterization laboratories have been inundated with rapidly changing technological advances in the past decade. The era for structural heart repair is rapidly mobilizing from a surgical/operating room setting to a transcatheter/hybrid catheterization laboratory suite. The use of the new hybrid catheterization laboratories will continue to expand as the approval of future transcatheter therapies evolve. Editor's note: Due to the volume of important information presented in each table, only the first table is included in the print version of the article, however, all tables may be viewed in their entirety free of charge on the online version of this article: http://journals.lww.com/dccnjournal/pages/default.aspx. PMID- 25144215 TI - Increased MIBG activity in the uterine cervix due to menstruation. AB - A 21-year-old woman with history of presacral ganglioneuroblastoma underwent I MIBG scan for restaging. Planar images revealed increased MIBG activity in the upper pelvis, suggestive of disease recurrence. Complementary SPECT/CT images, however, localized the activity to the uterine cervix. Upon further questioning, it has been established that the patient was menstruating. Subsequent follow-up scans proved normal, confirming the benign etiology of these findings. The case shows that radioactive blood accumulation in the uterine cervix can interfere with MIBG scan interpretation in menstruating patients. PMID- 25144214 TI - A pilot study of the value of 18F-fluoro-deoxy-thymidine PET/CT in predicting viable lymphoma in residual 18F-FDG avid masses after completion of therapy. AB - BACKGROUND: Despite its success in diagnosing and staging lymphoma, F-FDG PET/CT can be falsely positive in areas of posttreatment inflammation. 3'-F-fluoro-3' deoxy-l-thymidine (F-FLT) is a structural analog of the DNA constituent thymidine; its uptake correlates with cellular proliferation. This pilot study evaluates the ability of F-FLT PET/CT to distinguish viable lymphoma from posttreatment inflammatory changes in F-FDG avid residual masses. METHODS: Twenty one patients with lymphoma with at least 1 F-FDG avid residual mass after therapy underwent F-FLT PET/CT imaging. F-FDG and F-FLT uptake values were compared, including quantitative pharmacokinetic parameters extracted from the F-FLT time activity curves generated from dynamic data using graphical and nonlinear compartmental modeling. RESULTS: The true nature of the residual mass was confirmed by biopsy in 12 patients (8 positive and 4 negative for viable lymphoma and by follow-up CT and/or repeat F-FDG PET/CT imaging over 1 year); among the remaining 9 patients, 7 lesions resolved or decreased and 2 showed growth indicative of lymphoma. F-FLT PET SUVest.max was significantly higher in tumors than in benign lesions (5.5 [2.2] vs 1.7 [0.6]; P < 0.0001), whereas the difference in F-FDG SUVs was not significant (malignant, 7.8 [3.8] vs benign, 5.4 [2.4]; P = 0.11). All of the benign lesions had an F-FLT SUVest.max of less than 3.0. CONCLUSIONS: F-FLT shows improved specificity over F-FDG in distinguishing residual lymphoma from posttreatment inflammation and may be useful in the evaluation of patients with residual F-FDG-positive masses after completing therapy. PMID- 25144216 TI - Nonsurgical considerations for addressing periocular aesthetics: a conceptual dimensional approach. PMID- 25144217 TI - Myocardial and microvascular inflammation/infection in patients with HIV associated pulmonary artery hypertension. AB - BACKGROUND: Right ventricle compromise affects survival of patients with HIV associated pulmonary artery hypertension (PAH). DESIGN: Myocardial histology with viral assessment may clarify the mechanism of right ventricular deterioration and provide clues on PAH origin. METHODS: Fifteen patients with HIV infection, PAH and right ventricular dysfunction underwent cardiac magnetic resonance, catheterization, coronary with ventricular angiography and biventricular endomyocardial biopsy. Endothelial expression of HLA-DR, ICAM-1, E-selectin and VCAM-1 was semi-quantitatively evaluated. PCR for HIV, hepatitis C virus, human herpes virus-6, human herpes virus-8, Epstein-Barr virus, adenovirus, cytomegalovirus, enterovirus, influenza A/B and parvovirus B19 was performed. In PCR-positive hearts, viral protein adenovirus-1 and TORDJI-22 were assessed by immunohistology. RESULTS: New York Heart Association class was 2.4 +/- 0.5, mean pulmonary artery pressure 49.93 +/- 10.15 mmHg and wedge pressure 9.5 +/- 2.19 mmHg. Coronaries were normal with slow flow. Left ventricular and/or right ventricular micro-aneurysms were seen in eight patients. Cardiac magnetic resonance documented increased right ventricular end-diastolic volume with reduced ejection fraction, normal left ventricular end-diastolic volume and left ventricular ejection fraction. Subepicardial/mesocardial oedema and delayed enhancement in the inter-ventricular junction and/or left ventricular inferolateral wall was detected in eight patients. Histology showed active lymphocytic myocarditis in 12 patients, with microvasculitis in three. Endothelial adhesion molecules were over-expressed in all patients. PCR was positive in four patients for hepatitis C virus and in two for adenovirus, and viruses localized both in cardiomyocytes and endothelial cells. CONCLUSIONS: Inflammation/infection of myocardium and intramural vessels is detectable in patients with HIV-associated PAH. It may adversely affect right ventricular function and have a role in the compromised pulmonary circulation. PMID- 25144219 TI - The importance of monocytes and macrophages in HIV pathogenesis, treatment, and cure. AB - Monocytes and macrophages play critical roles in HIV transmission, viral spread early in infection, and as a reservoir of virus throughout infection. There has been a recent resurgence of interest in the biology of monocyte subsets and macrophages and their role in HIV pathogenesis, partly fuelled by efforts to understand difficulties in achieving HIV eradication. This article examines the importance of monocyte subsets and tissue macrophages in HIV pathogenesis. Additionally, we will review the role of monocytes and macrophages in the development of serious non-AIDS events including cardiovascular disease and neurocognitive impairment, their significance in viral persistence, and how these cells represent an important obstacle to achieving HIV eradication. PMID- 25144218 TI - Independent assessment of candidate HIV incidence assays on specimens in the CEPHIA repository. AB - OBJECTIVE: Cross-sectional HIV incidence surveillance, using assays that distinguish 'recent' from 'nonrecent' infections, has been hampered by inadequate performance and characterization of incidence assays. In this study, the Consortium for the Evaluation and Performance of HIV Incidence Assays presents results of the first independent evaluation of five incidence assays (BED, Limiting Antigen Avidity, Less-sensitive Vitros, Vitros Avidity and BioRad Avidity). DESIGN: A large repository of diverse specimens from HIV-positive patients was established, multiple assays were run on 2500 selected specimens, and data were analyzed to estimate assay characteristics relevant for incidence surveillance. METHODS: The mean duration of recent infection (MDRI, average time 'recent' while infected for less than some time cut-off T) was estimated from longitudinal data on seroconverters by regression. The false-recent rate (FRR, probability of testing 'recent' when infected for longer than T) was explored by measuring the proportions of 'recent' results in various subsets of patients. RESULTS: Assays continue to fail to attain the simultaneously large MDRI and small FRR demanded by existing performance guidelines. All assays produce high FRRs amongst virally suppressed patients (>40%), including elite controllers and treated patients. CONCLUSIONS: Results from this first independent evaluation provide valuable information about the current performance of assays, and suggest the need for further optimization. Variation of 'recent'/'nonrecent' thresholds and the use of multiple antibody-maturation assays, as well as other biomarkers, can now be explored, using the rich data generated by the Consortium for the Evaluation and Performance of HIV Incidence Assays. Consistently high FRRs amongst those virally suppressed suggest that viral load will be a particularly valuable supplementary marker. PMID- 25144220 TI - ICRP Publication 116--the first ICRP/ICRU application of the male and female adult reference computational phantoms. AB - ICRP Publication 116 on 'Conversion coefficients for radiological protection quantities for external radiation exposures', provides fluence-to-dose conversion coefficients for organ-absorbed doses and effective dose for various types of external exposures (ICRP 2010 ICRP Publication 116). The publication supersedes the ICRP Publication 74 (ICRP 1996 ICRP Publication 74, ICRU 1998 ICRU Report 57), including new particle types and expanding the energy ranges considered. The coefficients were calculated using the ICRP/ICRU computational phantoms (ICRP 2009 ICRP Publication 110) representing the reference adult male and reference adult female (ICRP 2002 ICRP Publication 89), together with a variety of Monte Carlo codes simulating the radiation transport in the body. Idealized whole-body irradiation from unidirectional and rotational parallel beams as well as isotropic irradiation was considered for a large variety of incident radiations and energy ranges. Comparison of the effective doses with operational quantities revealed that the latter quantities continue to provide a good approximation of effective dose for photons, neutrons and electrons for the 'conventional' energy ranges considered previously (ICRP 1996, ICRU 1998), but not at the higher energies of ICRP Publication 116. PMID- 25144222 TI - Quantifying the validity of routine neonatal healthcare data in the Greater Accra Region, Ghana. AB - OBJECTIVES: The District Health Information Management System-2 (DHIMS-2) is the database for storing health service data in Ghana, and similar to other low and middle income countries, paper-based data collection is being used by the Ghana Health Service. As the DHIMS-2 database has not been validated before this study aimed to evaluate its validity. METHODS: Seven out of ten districts in the Greater Accra Region were randomly sampled; the district hospital and a polyclinic in each district were recruited for validation. Seven pre-specified neonatal health indicators were considered for validation: antenatal registrants, deliveries, total births, live birth, stillbirth, low birthweight, and neonatal death. Data were extracted on these health indicators from the primary data (hospital paper-registers) recorded from January to March 2012. We examined all the data captured during this period as these data have been uploaded to the DHIMS-2 database. The differences between the values of the health indicators obtained from the primary data and that of the facility and DHIMS-2 database were used to assess the accuracy of the database while its completeness was estimated by the percentage of missing data in the primary data. RESULTS: About 41,000 data were assessed and in almost all the districts, the error rates of the DHIMS-2 data were less than 2.1% while the percentages of missing data were below 2%. At the regional level, almost all the health indicators had an error rate below 1% while the overall error rate of the DHIMS-2 database was 0.68% (95% C I = 0.61 0.75) and the percentage of missing data was 3.1% (95% C I = 2.96-3.24). CONCLUSION: This study demonstrated that the percentage of missing data in the DHIMS-2 database was negligible while its accuracy was close to the acceptable range for high quality data. PMID- 25144221 TI - VIB1, a link between glucose signaling and carbon catabolite repression, is essential for plant cell wall degradation by Neurospora crassa. AB - Filamentous fungi that thrive on plant biomass are the major producers of hydrolytic enzymes used to decompose lignocellulose for biofuel production. Although induction of cellulases is regulated at the transcriptional level, how filamentous fungi sense and signal carbon-limited conditions to coordinate cell metabolism and regulate cellulolytic enzyme production is not well characterized. By screening a transcription factor deletion set in the filamentous fungus Neurospora crassa for mutants unable to grow on cellulosic materials, we identified a role for the transcription factor, VIB1, as essential for cellulose utilization. VIB1 does not directly regulate hydrolytic enzyme gene expression or function in cellulosic inducer signaling/processing, but affects the expression level of an essential regulator of hydrolytic enzyme genes, CLR2. Transcriptional profiling of a Deltavib-1 mutant suggests that it has an improper expression of genes functioning in metabolism and energy and a deregulation of carbon catabolite repression (CCR). By characterizing new genes, we demonstrate that the transcription factor, COL26, is critical for intracellular glucose sensing/metabolism and plays a role in CCR by negatively regulating cre-1 expression. Deletion of the major player in CCR, cre-1, or a deletion of col-26, did not rescue the growth of Deltavib-1 on cellulose. However, the synergistic effect of the Deltacre-1; Deltacol-26 mutations circumvented the requirement of VIB1 for cellulase gene expression, enzyme secretion and cellulose deconstruction. Our findings support a function of VIB1 in repressing both glucose signaling and CCR under carbon-limited conditions, thus enabling a proper cellular response for plant biomass deconstruction and utilization. PMID- 25144223 TI - Cerebellar integrity in the amyotrophic lateral sclerosis-frontotemporal dementia continuum. AB - Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology. PMID- 25144224 TI - Detection of MPLW515L/K mutations and determination of allele frequencies with a single-tube PCR assay. AB - A gain-of-function mutation in the myeloproliferative leukemia virus (MPL) gene, which encodes the thrombopoietin receptor, has been identified in patients with essential thrombocythemia and primary myelofibrosis, subgroups of classic myeloproliferative neoplasms (MPNs). The presence of MPL gene mutations is a critical diagnostic criterion for these diseases. Here, we developed a rapid, simple, and cost-effective method of detecting two major MPL mutations, MPLW515L/K, in a single PCR assay; we termed this method DARMS (dual amplification refractory mutation system)-PCR. DARMS-PCR is designed to produce three different PCR products corresponding to MPLW515L, MPLW515K, and all MPL alleles. The amplicons are later detected and quantified using a capillary sequencer to determine the relative frequencies of the mutant and wild-type alleles. Applying DARMS-PCR to human specimens, we successfully identified MPL mutations in MPN patients, with the exception of patients bearing mutant allele frequencies below the detection limit (5%) of this method. The MPL mutant allele frequencies determined using DARMS-PCR correlated strongly with the values determined using deep sequencing. Thus, we demonstrated the potential of DARMS PCR to detect MPL mutations and determine the allele frequencies in a timely and cost-effective manner. PMID- 25144226 TI - Causes of death among commercially insured multiple sclerosis patients in the United States. AB - BACKGROUND: Information on causes of death (CODs) for patients with multiple sclerosis (MS) in the United States is sparse and limited by standard categorizations of underlying and immediate CODs on death certificates. Prior research indicated that excess mortality among MS patients was largely due to greater mortality from infectious, cardiovascular, or pulmonary causes. OBJECTIVE: To analyze disease categories in order to gain insight to pathways, which lead directly to death in MS patients. METHODS: Commercially insured MS patients enrolled in the OptumInsight Research database between 1996 and 2009 were matched to non-MS comparators on age/residence at index year and sex. The cause most-directly leading to death from the death certificate, referred to as the "principal" COD, was determined using an algorithm to minimize the selection of either MS or cardiac/pulmonary arrest as the COD. Principal CODs were categorized into MS, cancer, cardiovascular, infectious, suicide, accidental, pulmonary, other, or unknown. Infectious, cardiovascular, and pulmonary CODs were further subcategorized. RESULTS: 30,402 MS patients were matched to 89,818 controls, with mortality rates of 899 and 446 deaths/100,000 person-years, respectively. Excluding MS, differences in mortality rate between MS patients and non-MS comparators were largely attributable to infections, cardiovascular causes, and pulmonary problems. Of the 95 excessive deaths (per 100,000 person years) related to infectious causes, 41 (43.2%) were due to pulmonary infections and 45 (47.4%) were attributed to sepsis. Of the 46 excessive deaths (per 100,000 person-years) related to pulmonary causes, 27 (58.7%) were due to aspiration. No single diagnostic entity predominated for the 60 excessive deaths (per 100,000 person-years) attributable to cardiac CODs. CONCLUSIONS: The principal COD algorithm improved on other methods of determining COD in MS patients from death certificates. A greater awareness of the common CODs in MS patients will allow physicians to anticipate potential problems and, thereby, improve the care that they provide. PMID- 25144225 TI - The effect of (-)-epigallocatechin 3-O--gallate in vitro and in vivo in Leishmania braziliensis: involvement of reactive oxygen species as a mechanism of action. AB - BACKGROUND: Leishmaniasis is a parasitic disease associated with extensive mortality and morbidity. The treatment for leishmaniasis is currently based on pentavalent antimonials and amphotericin B; however, these drugs result in numerous adverse side effects. Natural compounds have been used as novel treatments for parasitic diseases. In this paper, we evaluated the effect of (-) epigallocatechin 3-O-gallate (EGCG) on Leishmania braziliensis in vitro and in vivo and described the mechanism of EGCG action against L. braziliensis promastigotes and intracellular amastigotes. METHODOLOGY/PRINCIPAL FINDING: In vitro activity and reactive oxygen species (ROS) measurements were determined during the promastigote and intracellular amastigote life stages. The effect of EGCG on mitochondrial membrane potential (DeltaPsim) was assayed using JC-1, and intracellular ATP concentrations were measured using a luciferin-luciferase system. The in vivo experiments were performed in infected BALB/c mice orally treated with EGCG. EGCG reduced promastigote viability and the infection index in a time- and dose-dependent manner, with IC50 values of 278.8 uM and 3.4 uM, respectively, at 72 h and a selectivity index of 149.5. In addition, EGCG induced ROS production in the promastigote and intracellular amastigote, and the effects were reversed by polyethylene glycol (PEG)-catalase. Additionally, EGCG reduced DeltaPsim, thereby decreasing intracellular ATP concentrations in promastigotes. Furthermore, EGCG treatment was also effective in vivo, demonstrating oral bioavailability and reduced parasitic loads without altering serological toxicity markers. CONCLUSIONS/SIGNIFICANCE: In conclusion, our study demonstrates the leishmanicidal effects of EGCG against the two forms of L. braziliensis, the promastigote and amastigote. In addition, EGCG promotes ROS production as a part of its mechanism of action, resulting in decreased DeltaPsim and reduced intracellular ATP concentrations. These actions ultimately culminate in parasite death. Furthermore, our data suggest that EGCG is orally effective in the treatment of L. braziliensis-infected BALB/c mice without altering serological toxicity markers. PMID- 25144227 TI - Presence of antigen-experienced T cells with low grade of differentiation and proliferative potential in chronic Chagas disease myocarditis. AB - BACKGROUND: The main consequence of chronic Trypanosoma cruzi infection is the development of myocarditis in approximately 20-30% of infected individuals but not until 10-20 years after the initial infection. We have previously shown that circulating interferon-gamma-secreting T cells responsive to Trypanosoma cruzi antigens in chronic Chagas disease patients display a low grade of differentiation and the frequency of these T lymphocytes decreases along with the severity of heart disease. This study thought to explore the expression of inhibitory receptors, transcription factors of type 1 or regulatory T cells, and markers of T cell differentiation, immunosenescence or active cell cycle in cardiac explants from patients with advanced Chagas disease myocarditis. METHODOLOGY/PRINCIPAL FINDINGS: The expression of different markers for T and B cells as well as for macrophages was evaluated by immunohistochemistry and immunofluorescence techniques in cardiac explants from patients with advanced chronic Chagas disease submitted to heart transplantation. Most infiltrating cells displayed markers of antigen-experienced T cells (CD3(+), CD4(+), CD8(+), CD45RO(+)) with a low grade of differentiation (CD27(+), CD57(-), CD45RA(-), PD( )1(-)). A skewed T helper1/T cytotoxic 1 profile was supported by the expression of T-bet; whereas FOXP3(+) cells were scarce and located only in areas of severe myocarditis. In addition, a significant proliferative capacity of CD3(+) T cells, assessed by Ki67 staining, was found. CONCLUSIONS/SIGNIFICANCE: The quality of T cell responses and immunoregulatory mechanisms might determine the pattern of the cellular response and the severity of disease in chronic Trypanosoma cruzi infection. PMID- 25144228 TI - Late engagement of CD86 after influenza virus clearance promotes recovery in a FoxP3+ regulatory T cell dependent manner. AB - Influenza A virus (IAV) infection in the respiratory tract triggers robust innate and adaptive immune responses, resulting in both virus clearance and lung inflammation and injury. After virus clearance, resolution of ongoing inflammation and tissue repair occur during a distinct recovery period. B7 family co-stimulatory molecules such as CD80 and CD86 have important roles in modulating T cell activity during the initiation and effector stages of the host response to IAV infection, but their potential role during recovery and resolution of inflammation is unknown. We found that antibody-mediated CD86 blockade in vivo after virus clearance led to a delay in recovery, characterized by increased numbers of lung neutrophils and inflammatory cytokines in airways and lung interstitium, but no change in conventional IAV-specific T cell responses. However, CD86 blockade led to decreased numbers of FoxP3+ regulatory T cells (Tregs), and adoptive transfer of Tregs into alphaCD86 treated mice rescued the effect of the blockade, supporting a role for Tregs in promoting recovery after virus clearance. Specific depletion of Tregs late after infection mimicked the CD86 blockade phenotype, confirming a role for Tregs during recovery after virus clearance. Furthermore, we identified neutrophils as a target of Treg suppression since neutrophil depletion in Treg-depleted mice reduced excess inflammatory cytokines in the airways. These results demonstrate that Tregs, in a CD86 dependent mechanism, contribute to the resolution of disease after IAV infection, in part by suppressing neutrophil-driven cytokine release into the airways. PMID- 25144229 TI - Unmet need for family planning, contraceptive failure, and unintended pregnancy among HIV-infected and HIV-uninfected women in Zimbabwe. AB - BACKGROUND: Prevention of unintended pregnancies among women living with HIV infection is a strategy recommended by the World Health Organization for prevention of mother-to-child transmission of HIV (PMTCT). We assessed pregnancy intentions and contraceptive use among HIV-positive and HIV-negative women with a recent pregnancy in Zimbabwe. METHODS: We analyzed baseline data from the evaluation of Zimbabwe's Accelerated National PMTCT Program. Eligible women were randomly sampled from the catchment areas of 157 health facilities offering PMTCT services in five provinces. Eligible women were >=16 years old and mothers of infants (alive or deceased) born 9 to 18 months prior to the interview. Participants were interviewed about their HIV status, intendedness of the birth, and contraceptive use. RESULTS: Of 8,797 women, the mean age was 26.7 years, 92.8% were married or had a regular sexual partner, and they had an average of 2.7 lifetime births. Overall, 3,090 (35.1%) reported that their births were unintended; of these women, 1,477 (47.8%) and 1,613 (52.2%) were and were not using a contraceptive method prior to learning that they were pregnant, respectively. Twelve percent of women reported that they were HIV-positive at the time of the survey; women who reported that they were HIV-infected were significantly more likely to report that their pregnancy was unintended compared to women who reported that they were HIV-uninfected (44.9% vs. 33.8%, p<0.01). After adjustment for covariates, among women with unintended births, there was no association between self-reported HIV status and lack of contraception use prior to pregnancy. CONCLUSIONS: Unmet need for family planning and contraceptive failure contribute to unintended pregnancies among women in Zimbabwe. Both HIV infected and HIV-uninfected women reported unintended pregnancies despite intending to avoid or delay pregnancy, highlighting the need for effective contraceptive methods that align with pregnancy intentions. PMID- 25144230 TI - The Sch9 kinase regulates conidium size, stress responses, and pathogenesis in Fusarium graminearum. AB - Fusarium head blight caused by Fusarium graminearum is an important disease of wheat and barley worldwide. In a previous study on functional characterization of the F. graminearum kinome, one protein kinase gene important for virulence is orthologous to SCH9 that is functionally related to the cAMP-PKA and TOR pathways in the budding yeast. In this study, we further characterized the functions of FgSCH9 in F. graminearum and its ortholog in Magnaporthe oryzae. The DeltaFgsch9 mutant was slightly reduced in growth rate but significantly reduced in conidiation, DON production, and virulence on wheat heads and corn silks. It had increased tolerance to elevated temperatures but became hypersensitive to oxidative, hyperosmotic, cell wall, and membrane stresses. The DeltaFgsch9 deletion also had conidium morphology defects and produced smaller conidia. These results suggest that FgSCH9 is important for stress responses, DON production, conidiogenesis, and pathogenesis in F. graminearum. In the rice blast fungus Magnaporthe oryzae, the DeltaMosch9 mutant also was defective in conidiogenesis and pathogenesis. Interestingly, it also produced smaller conidia and appressoria. Taken together, our data indicate that the SCH9 kinase gene may have a conserved role in regulating conidium size and plant infection in phytopathogenic ascomycetes. PMID- 25144231 TI - RNA interference mitigates motor and neuropathological deficits in a cerebellar mouse model of Machado-Joseph disease. AB - Machado-Joseph disease or Spinocerebellar ataxia type 3 is a progressive fatal neurodegenerative disorder caused by the polyglutamine-expanded protein ataxin-3. Recent studies demonstrate that RNA interference is a promising approach for the treatment of Machado-Joseph disease. However, whether gene silencing at an early time-point is able to prevent the appearance of motor behavior deficits typical of the disease when initiated before onset of the disease had not been explored. Here, using a lentiviral-mediated allele-specific silencing of mutant ataxin-3 in an early pre-symptomatic cerebellar mouse model of Machado-Joseph disease we show that this strategy hampers the development of the motor and neuropathological phenotypic characteristics of the disease. At the histological level, the RNA specific silencing of mutant ataxin-3 decreased formation of mutant ataxin-3 aggregates, preserved Purkinje cell morphology and expression of neuronal markers while reducing cell death. Importantly, gene silencing prevented the development of impairments in balance, motor coordination, gait and hyperactivity observed in control mice. These data support the therapeutic potential of RNA interference for Machado-Joseph disease and constitute a proof of principle of the beneficial effects of early allele-specific silencing for therapy of this disease. PMID- 25144233 TI - Inhibitory phenotype of HBV-specific CD4+ T-cells is characterized by high PD-1 expression but absent coregulation of multiple inhibitory molecules. AB - BACKGROUND: T-cell exhaustion seems to play a critical role in CD8+ T-cell dysfunction during chronic viral infections. However, up to now little is known about the mechanisms underlying CD4+ T-cell dysfunction during chronic hepatitis B virus (CHB) infection and the role of inhibitory molecules such as programmed death 1 (PD-1) for CD4+ T-cell failure. METHODS: The expression of multiple inhibitory molecules such as PD-1, CTLA-4, TIM-3, CD244, KLRG1 and markers defining the grade of T-cell differentiation as CCR7, CD45RA, CD57 and CD127 were analyzed on virus-specific CD4+ T-cells from peripheral blood using a newly established DRB1*01-restricted MHC class II Tetramer. Effects of in vitro PD-L1/2 blockade were defined by investigating changes in CD4+ T-cell proliferation and cytokine production. RESULTS: CD4+ T-cell responses during chronic HBV infection was characterized by reduced Tetramer+CD4+ T-cell frequencies, effector memory phenotype, sustained PD-1 but low levels of CTLA-4, TIM-3, KLRG1 and CD244 expression. PD-1 blockade revealed individualized patterns of in vitro responsiveness with partly increased IFN-gamma, IL-2 and TNF-alpha secretion as well as enhanced CD4+ T-cell expansion almost in treated patients with viral control. CONCLUSION: HBV-specific CD4+ T-cells are reliably detectable during different courses of HBV infection by MHC class II Tetramer technology. CD4+ T cell dysfunction during chronic HBV is basically linked to strong PD-1 upregulation but absent coregulation of multiple inhibitory receptors. PD-L1/2 neutralization partly leads to enhanced CD4+ T-cell functionality with heterogeneous patterns of CD4+ T-cell rejunivation. PMID- 25144232 TI - Mechanisms of regulation of olfactory transduction and adaptation in the olfactory cilium. AB - Olfactory adaptation is a fundamental process for the functioning of the olfactory system, but the underlying mechanisms regulating its occurrence in intact olfactory sensory neurons (OSNs) are not fully understood. In this work, we have combined stochastic computational modeling and a systematic pharmacological study of different signaling pathways to investigate their impact during short-term adaptation (STA). We used odorant stimulation and electroolfactogram (EOG) recordings of the olfactory epithelium treated with pharmacological blockers to study the molecular mechanisms regulating the occurrence of adaptation in OSNs. EOG responses to paired-pulses of odorants showed that inhibition of phosphodiesterases (PDEs) and phosphatases enhanced the levels of STA in the olfactory epithelium, and this effect was mimicked by blocking vesicle exocytosis and reduced by blocking cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) and vesicle endocytosis. These results suggest that G-coupled receptors (GPCRs) cycling is involved with the occurrence of STA. To gain insights on the dynamical aspects of this process, we developed a stochastic computational model. The model consists of the olfactory transduction currents mediated by the cyclic nucleotide gated (CNG) channels and calcium ion (Ca(2+))-activated chloride (CAC) channels, and the dynamics of their respective ligands, cAMP and Ca(2+), and it simulates the EOG results obtained under different experimental conditions through changes in the amplitude and duration of cAMP and Ca(2+) response, two second messengers implicated with STA occurrence. The model reproduced the experimental data for each pharmacological treatment and provided a mechanistic explanation for the action of GPCR cycling in the levels of second messengers modulating the levels of STA. All together, these experimental and theoretical results indicate the existence of a mechanism of regulation of STA by signaling pathways that control GPCR cycling and tune the levels of second messengers in OSNs, and not only by CNG channel desensitization as previously thought. PMID- 25144234 TI - Neonatal injury at cephalic vaginal delivery: a retrospective analysis of extent of association with shoulder dystocia. AB - PURPOSE: To describe the risk factors and labor characteristics of Clavicular fracture (CF) and brachial plexus injury (BPI); and compare antenatal and labor characteristics and prognosis of obstetrical BPI associated with shoulder dystocia with obstetrical BPI not associated with shoulder dystocia. METHODS: This retrospective study consisted of women who gave birth to an infant with a fractured clavicle or BPI between January 2009 and June 2013. Antenatal and neonatal data were compared between groups. The control group (1300) was composed of the four singleton vaginal deliveries that immediately followed each birth injury. A multivariable logistic regression model, with backward elimination, was constructed in order to find independent risk factors associated with BPI and CF. A subgroup analysis involved comparison of features of BPI cases with or without associated shoulder dystocia. RESULTS: During the study period, the total number of vaginal deliveries was 44092. The rates of CF, BPI and shoulder dystocia during the study period were 0,6%, 0,16% and 0,29%, respectively. In the logistic regression model, shoulder dystocia, GDM, multiparity, gestational age >42 weeks, protracted labor, short second stage of labor and fetal birth weight greater than 4250 grams increased the risk of CF independently. Shoulder dystocia and protracted labor were independently associated with BPI when controlled for other factors. Among neonates with BPI whose injury was not associated with shoulder dystocia, five (12.2%) sustained permanent injury, whereas one neonate (4.5%) with BPI following shoulder dystocia sustained permanent injury (p = 0.34). CONCLUSION: BPI not associated with shoulder dystocia might have a higher rate of concomitant CF and permanent sequelae. PMID- 25144236 TI - Size dependency of post-disturbance recovery of multi-stemmed resprouting trees. AB - In frequently burned ecosystems, many plants persist by repeated resprouting from basal or belowground buds. This strategy requires that plants reach a balance between biomass loss and recovery, which depends on the shape of the relationship between pre- and post-fire size. Previous analyses of this relationship, however, have focused on the size of the largest stem, which ignores the importance of the multi-stem growth habit that is common in pyrogenic ecosystems. We hypothesized that the presence of multiple stems causes a substantial shift in the relationship between pre- and post-fire size and in the relationship between pre fire size and size recovery. We measured the height and basal diameter, then calculated volume and biomass, of all stems of six tree species before and nine months after complete removal of aboveground biomass via coppicing. The number of resprouts was correlated with the original number of stems for four species. For all species, the relationship between pre-coppicing and resprout size fit a positive curvilinear function, and the shape of this curve did not differ for maximum and total stem size. Smaller individuals recovered a larger proportion of their pre-coppicing size than larger individuals, but the shape of the size recovery curves were the same regardless of whether the analysis was performed with all stems or only the largest stem. Our results indicate that measuring only the largest stem of multi-stemmed individuals is sufficient to assess the ability of individuals to recover after complete loss of aboveground biomass and persist under frequent burning. PMID- 25144235 TI - Infection with MERS-CoV causes lethal pneumonia in the common marmoset. AB - The availability of a robust disease model is essential for the development of countermeasures for Middle East respiratory syndrome coronavirus (MERS-CoV). While a rhesus macaque model of MERS-CoV has been established, the lack of uniform, severe disease in this model complicates the analysis of countermeasure studies. Modeling of the interaction between the MERS-CoV spike glycoprotein and its receptor dipeptidyl peptidase 4 predicted comparable interaction energies in common marmosets and humans. The suitability of the marmoset as a MERS-CoV model was tested by inoculation via combined intratracheal, intranasal, oral and ocular routes. Most of the marmosets developed a progressive severe pneumonia leading to euthanasia of some animals. Extensive lesions were evident in the lungs of all animals necropsied at different time points post inoculation. Some animals were also viremic; high viral loads were detected in the lungs of all infected animals, and total RNAseq demonstrated the induction of immune and inflammatory pathways. This is the first description of a severe, partially lethal, disease model of MERS-CoV, and as such will have a major impact on the ability to assess the efficacy of vaccines and treatment strategies as well as allowing more detailed pathogenesis studies. PMID- 25144238 TI - Genetic diversity and molecular evolution of Plum bark necrosis stem pitting associated virus from China. AB - Plum bark necrosis stem pitting-associated virus (PBNSPaV), a member of the genus Ampelovirus in the family Closteroviridae, infects different Prunus species and has a worldwide distribution. Yet the population structure and genetic diversity of the virus is still unclear. In this study, sequence analyses of a partial heat shock protein 70 homolog (HSP70h) gene and coat protein (CP) gene of PBNSPaV isolates from seven Prunus species grown in China revealed a highly divergent Chinese PBNSPaV population, sharing nucleotide similarities of 73.1-100% with HSP70h gene, and 83.9-98.6% with CP gene. Phylogenetic analysis of HSP70h and CP sequences revealed segregation of global PBNSPaV isolates into four phylo-groups (I-IV), of which two newly identified groups, II and IV, solely comprised Chinese isolates. Complete genome sequences of three PBNSPaV isolates, Pch-WH-1 and Pch GS-3 from peaches, and Plm-WH-3 from a plum tree, were determined. The three isolates showed overall nucleotide identities of 90.0% (Pch-GS-3) and 96.4% (Pch WH-1) with the type isolate PL186, and the lowest identity of 70.2-71.2% with isolate Nanjing. For the first time, to the best of our knowledge, we report evidence of significant recombination in the HSP70h gene of PBNSPaV variant Pch2 by using five programs implemented in RDP3; in addition, five codon positions in its CP gene (3, 8, 44, 57, and 88) were identified that appeared to be under positive selection. Collectively, these results indicate a divergent Chinese PBNSPaV population. In addition, our findings provide a foundation for elucidating the epidemiological characteristics of virus population. PMID- 25144237 TI - Recognition of Bungarus multicinctus venom by a DNA aptamer against beta bungarotoxin. AB - Antibody-based technology is the main method for diagnosis and treatment of snake bite envenoming currently. However, the development of an antibody, polyclonal or monoclonal, is a complicated and costly procedure. Aptamers are single stranded oligonucleotides that recognize specific targets such as proteins and have shown great potential over the years as diagnostic and therapeutic agents. In contrast to antibodies, aptamers can be selected in vitro without immunization of animals, and synthesized chemically with extreme accuracy, low cost and high degree of purity. In this study we firstly report on the identification of DNA aptamers that bind to beta-bungarotoxin (beta-BuTx), a neurotoxin from the venom of Bungarus multicinctus. A plate-SELEX method was used for the selection of beta BuTx specific aptamers. After 10 rounds of selection, four aptamer candidates were obtained, with the dissociation constant ranged from 65.9 nM to 995 nM measured by fluorescence spectroscopy. Competitive binding assays using both the fluorescently labeled and unlabeled aptamers revealed that the four aptamers bound to the same binding site of beta-BuTx. The best binder, betaB-1, bound specifically to beta-BuTx, but not to BSA, casein or alpha-Bungarotoxin. Moreover, electrophoretic mobility shift assay and enzyme-linked aptamer assay demonstrated that betaB-1 could discriminate B. multicinctus venom from other snake venoms tested. The results suggest that aptamer betaB-1 can serve as a useful tool for the design and development of drugs and diagnostic tests for beta BuTx poisoning and B. multicinctus bites. PMID- 25144241 TI - A functional polymorphism in CSF1R gene is a novel susceptibility marker for lung cancer among never-smoking females. AB - INTRODUCTION: It has been estimated that the proportion of never-smokers among females with lung cancer is 53% worldwide and 75% in Korea. We conducted a two stage study to identify genetic factors responsible for lung cancer susceptibility in female never-smokers. MATERIALS AND METHODS: In a discovery set, 1969 potentially functional single nucleotide polymorphisms (SNPs) of 1151 genes, which were related to cancer development and progression, were evaluated using the Affymetrix custom-made GeneChip in 181 female never-smokers with lung cancer and 179 controls. A replication study was performed on an independent cohort of 596 cases and 1194 healthy controls. RESULTS: Sixteen SNPs with p < 0.05 for genotype distribution in the discovery set were enrolled in the replication study. Among 16 SNPs, three SNPs (colony-stimulating factor 1 receptor [CSF1R] rs10079250A>G, tumor protein p63 [TP63] rs7631358G>A, and corepressor interacting with RBPJ 1 [CIR1] rs13009079T>C) were found to be significantly associated with lung cancer in the same direction as the discovery set. Homology-based model for CSF1R indicated that the rs10079250A>G leads to increased positive charge of CSF-binding region of CSF1R, thereby increasing the chance of binding between CSF and CSF1R. In addition, this SNP was found to increase the phosphorylation of a mitogen-activated protein kinase, JNK. CONCLUSIONS: Our results suggest that the three SNPs, particularly CSF1R rs10079250, may contribute to lung cancer susceptibility in never-smoking females. PMID- 25144242 TI - A novel mechanism of EML4-ALK rearrangement mediated by chromothripsis in a patient-derived cell line. AB - INTRODUCTION: EML4-ALK is a driver oncogene in non-small-cell lung cancer (NSCLC) and has been developed into a promising molecular target for antitumor agents. Although EML4-ALK is reported to be formed by inversion of chromosome 2, other mechanisms of this gene fusion remain unknown. This study aimed to examine the mechanism of EML4-ALK rearrangement using a novel cell line with the EML4-ALK fusion gene. METHODS: An EML4-ALK-positive cell line, termed JFCR-LC649, was established from pleomorphic carcinoma, a rare subtype of NSCLC. We investigated the chromosomal aberrations using fluorescence in situ hybridization and comparative genomic hybridization (CGH). Alectinib/CH5424802, a selective ALK inhibitor, was evaluated in the antitumor activity against JFCR-LC649 in vitro and in vivo xenograft model. RESULTS: We established an EML4-ALK-positive cell line, termed JFCR-LC649, derived from a patient with NSCLC and revealed that the JFCR-LC649 cells harbor variant 3 of the EML4-ALK fusion with twofold copy number gain. Interestingly, comparative genomic hybridization and metaphase-fluorescence in situ hybridization analysis showed that in addition to two normal chromosome 2, JFCR-LC649 cells contained two aberrant chromosome 2 that were fragmented and scattered. These observations provided the first evidence that EML4-ALK fusion in JFCR-LC649 cells was formed in chromosome 2 by a distinct mechanism of genomic rearrangement, termed chromothripsis. Furthermore, a selective ALK inhibitor alectinib/CH5424802 suppressed tumor growth of the JFCR-LC649 cells through inhibition of phospho-ALK in vitro and in vivo in a xenograft model. CONCLUSION: Our results suggested that chromothripsis may be a mechanism of oncogenic rearrangement of EML4-ALK. In addition, alectinib was effective against EML4-ALK positive tumors with ALK copy number gain mediated by chromothripsis. PMID- 25144240 TI - Stress-induced enzyme activation primes murine embryonic stem cells to differentiate toward the first extraembryonic lineage. AB - Extracellular stresses influence transcription factor (TF) expression and therefore lineage identity in the peri-implantation mouse embryo and its stem cells. This potentially affects pregnancy outcome. To understand the effects of stress signaling during this critical period of pregnancy, we exposed cultured murine embryonic stem cells (mESCs) to hyperosmotic stress. We then measured stress-enzyme-dependent regulation of key pluripotency and lineage TFs. Hyperosmotic stress slowed mESC accumulation due to slowing of the cell cycle over 72 h, after a small apoptotic response within 12 h. Phosphoinositide 3 kinase (PI3K) enzymatic signaling was responsible for stem cell survival under stressed conditions. Stress initially triggered mESC differentiation after 4 h through MEK1, c-Jun N-terminal kinase (JNK), and PI3K enzymatic signaling, which led to proteasomal degradation of Oct4, Nanog, Sox2, and Rex1 TF proteins. Concurrent with this post-transcriptional effect was the decreased accumulation of potency TF mRNA transcripts. After 12-24 h of stress, cells adapted, cell cycle resumed, and Oct4 and Nanog mRNA and protein expression returned to approximately normal levels. The TF protein recovery was mediated by p38MAPK and PI3K signaling, as well as by MEK2 and/or MEK1. However, due to JNK signaling, Rex1 expression did not recover. Probing for downstream lineages revealed that although mESCs did not differentiate morphologically during 24 h of stress, they were primed to differentiate by upregulating markers of the first lineage differentiating from mESCs, extraembryonic endoderm. Thus, although two to three TFs that mark pluripotency recover expression by 24 h of stress, there is nonetheless sustained Rex1 suppression and a priming of mESCs for differentiation to the earliest lineage. PMID- 25144243 TI - The oncofetal protein IMP3: a useful marker to predict poor clinical outcome in neuroendocrine tumors of the lung. AB - INTRODUCTION: We evaluated the expression of the oncofetal protein IMP3 in a series of neuroendocrine tumors of the lung, correlating our results with proliferating index Ki67 and with the expression of the two most studied stem cell markers in lung cancer, Nanog and Oct3/4. METHODS: A total of 74 patients with a diagnosis of neuroendocrine tumor including 46 cases of typical carcinoid, nine cases of atypical carcinoids, 13 cases of large cell neuroendocrine carcinomas and six cases of small cell carcinomas were enrolled. RESULTS: IMP3 was expressed in 50% of small cell carcinomas, 84% of large cell neuroendocrine carcinomas, 55% of atypical carcinoids and 10% of typical carcinoids. IMP3 positive cases showed significantly decreased overall and disease-free survival time compared with IMP3-negative cases. Nanog was expressed in 50% of small cell carcinomas, 31% of large cell neuroendocrine carcinomas, 33% of atypical carcinoids and 15% of typical carcinoids, and 68% of IMP3-positive tumors were also enriched for Nanog expression. Conversely, Oct3/4 expression could not be detected in all the analyzed series. When combining Ki67 and IMP3 expression we demonstrated that all the cases with a Ki67 index higher than 4% were also IMP3 positive, and their simultaneous expression was a poor prognostic factor. CONCLUSIONS: IMP3 is a marker of poor outcome in lung neuroendocrine tumors; its correlation with Nanog expression suggest an implication of IMP3 in stem cell processes and its association with a Ki67 labeling index higher than 4% stratifies a subset of atypical carcinoids with a higher risk of recurrence and mortality. PMID- 25144244 TI - Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23. AB - Polyglutamine repeat expansion in ataxin-3 causes neurodegeneration in the most common dominant ataxia, spinocerebellar ataxia type 3 (SCA3). Since reducing levels of disease proteins improves pathology in animals, we investigated how ataxin-3 is degraded. Here we show that, unlike most proteins, ataxin-3 turnover does not require its ubiquitination, but is regulated by ubiquitin-binding site 2 (UbS2) on its N terminus. Mutating UbS2 decreases ataxin-3 protein levels in cultured mammalian cells and in Drosophila melanogaster by increasing its proteasomal turnover. Ataxin-3 interacts with the proteasome-associated proteins Rad23A/B through UbS2. Knockdown of Rad23 in cultured cells and in Drosophila results in lower levels of ataxin-3 protein. Importantly, reducing Rad23 suppresses ataxin-3-dependent degeneration in flies. We present a mechanism for ubiquitination-independent degradation that is impeded by protein interactions with proteasome-associated factors. We conclude that UbS2 is a potential target through which to enhance ataxin-3 degradation for SCA3 therapy. PMID- 25144245 TI - Amino acid sequence in constitutionally isomeric tetrapeptide amphiphiles dictates architecture of one-dimensional nanostructures. AB - The switching of two adjacent amino acids can lead to differences in how proteins fold thus affecting their function. This effect has not been extensively explored in synthetic peptides in the context of supramolecular self-assembly. Toward this end, we report here the use of isomeric peptide amphiphiles as molecular building blocks to create one-dimensional (1D) nanostructures. We show that four peptide amphiphile isomers, with identical composition but a different sequence of their four amino acids, can form drastically different types of 1D nanostructures under the same conditions. We found that molecules with a peptide sequence of alternating hydrophobic and hydrophilic amino acids such as VEVE and EVEV self assemble into flat nanostructures that can be either helical or twisted. On the other hand, nonalternating isomers such as VVEE and EEVV result in the formation of cylindrical nanofibers. Furthermore, we also found that when the glutamic acid is adjacent to the alkyl tail the supramolecular assemblies appear to be internally flexible compared to those with valine as the first amino acid. These results clearly demonstrate the significance of peptide side chain interactions in determining the architectures of supramolecular assemblies. PMID- 25144247 TI - Optical coherence tomography of a cystic retinal tuft. PMID- 25144248 TI - Second harmonic generation from tryptophan-rich short peptides: W(n)K(m) and gramicidin A. AB - We report the first hyperpolarizability of a series of tryptophan-rich short peptides with the respective sequence KWK, KWWK, KWWWK, KWWKWWK, where W and K stand for tryptophan and lysine. The measurements were performed with the technique of hyper-Rayleigh scattering in the bulk of an aqueous Tris buffer solution at a pH of 8.5 and a salt concentration of 150 mM at the non-resonant fundamental wavelength of 784 nm. The first hyperpolarizability of the different peptides follows a simple additive model scaling with the number of tryptophan residues contained in the peptide. However, it appears that the first hyperpolarizability response of a single tryptophan residue in the peptide strongly differs from that of an isolated tryptophan. Hence, it is therefore demonstrated that the local environment of the tryptophan residues within the peptide strongly influences its nonlinear optical response. A comparison with the first hyperpolarizability of the natural peptide gramicidin A measured in trifluoroethanol (TFE) further confirms the key role of the local environment on the first hyperpolarizability of tryptophan residues in peptides. PMID- 25144246 TI - Methodology: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: Natural disasters, industrial accidents, terrorism attacks, and pandemics all have the capacity to result in large numbers of critically ill or injured patients. This supplement provides suggestions for all those involved in a disaster or pandemic with multiple critically ill patients, including front line clinicians, hospital administrators, professional societies, and public health or government officials. The field of disaster medicine does not have the required body of evidence needed to undergo a traditional guideline development process. In result, consensus statement-development methodology was used to capture the highest-caliber expert opinion in a structured, scientific approach. METHODS: Task Force Executive Committee members identified core topic areas regarding the provision of care to critically ill or injured patients from pandemics or disasters and subsequently assembled an international panel for each identified area. International disaster medicine experts were brought together to identify key questions (in a population, intervention, comparator, outcome [PICO] based format) within each of the core topic areas. Comprehensive literature searches were then conducted to identify studies upon which evidence-based recommendations could be made. No studies of sufficient quality were identified. Therefore, the panel developed expert opinion-based suggestions that are presented in this supplement using a modified Delphi process. RESULTS: A total of 315 suggestions were drafted across all topic groups. After two rounds of a Delphi consensus-development process, 267 suggestions were chosen by the panel to include in the document and published in a total of 12 manuscripts composing the core chapters of this supplement. Draft manuscripts were prepared by the topic editor and members of the working groups for each of the topics, producing a total of 11 papers. Once the preliminary drafts were received, the Executive Committee (Writing Committee) then met to review, edit, and promote alignment of all of the primary drafts of the manuscripts prepared by the topic editors and their groups. The topic editors then revised their manuscripts based on the Executive Committee's edits and comments. The Writing Committee subsequently reviewed the updated drafts and prepared the final manuscripts for submission to the Guidelines Oversight Committee (GOC). The manuscripts subsequently underwent review by the GOC, including external review as well as peer review for the journal publication. The Writing Committee received the feedback from the reviewers and modified the manuscripts as required. CONCLUSIONS: Based on a robust and transparent process, this project used rigorous methodology to produce clinically relevant, trustworthy consensus statements, with the aim to provide needed guidance on treatment and procedures for practitioners, hospital administrators, and public health and government officials when addressing the care of critically ill or injured patients in disasters or pandemics. PMID- 25144249 TI - Synthesis of the 6-azaindole containing HIV-1 attachment inhibitor pro-drug, BMS 663068. AB - The development of a short and efficient synthesis of a complex 6-azaindole, BMS 663068, is described. Construction of the 6-azaindole core is quickly accomplished starting from a simple pyrrole, via a regioselective Friedel-Crafts acylation, Pictet-Spengler cyclization, and a radical-mediated aromatization. The synthesis leverages an unusual heterocyclic N-oxide alpha-bromination to functionalize a critical C-H bond, enabling a highly regioselective copper mediated Ullmann-Goldberg-Buchwald coupling to install a challenging triazole substituent. This strategy resulted in an efficient 11 step linear synthesis of this complex clinical candidate. PMID- 25144250 TI - The leisure-noise dilemma: hearing loss or hearsay? What does the literature tell us? AB - The authors undertook a review of the literature, focussing on publications describing the following: (1) Pure tone threshold data for adolescents/young adults; (2) Measurements/estimates of noise exposure from leisure activities; and (3) The relationship between hearing threshold levels (HTLs) and leisure-noise exposure. There is a large volume of published materials relevant to these topics, and opinion among authors regarding the relationship between leisure noise exposure and HTLs varies significantly. At one extreme is the view that the effects of leisure-noise are minimal. The opposing belief is that as a direct result of leisure-noise exposure, significant HTL shifts and possibly significant hearing disability are occurring in a large (and increasing) proportion of young people. It has been claimed that behaviors relating to leisure-noise are "as threatening to young people's health as more traditional risk behaviors" (, p. 55). This view has been reiterated by the popular media. This review revealed that while sufficient data confirm that some leisure pursuits provide potentially hazardous noise levels, the nature of the exposure-injury relationship for leisure-noise is yet to be determined. Specific information about the quality-of life effects of threshold shift related to leisure-noise exposure is also lacking. The scope and limitations of a large sample of relevant publications and an overview of the methodological issues in this area of research are briefly presented. Considerations for future research are raised. PMID- 25144253 TI - Synthesis of peroxo-titanium decorated H-titanate-nanotube-based hierarchical microspheres with enhanced visible-light photocatalytic activity in degradation of Rhodamine B. AB - Peroxo-titanium decorated H-titanate-nanotube-based hierarchical microspheres (PTHM) with a large surface area (368 m(2) g(-1)) and mesoporous structure were prepared by an alkaline hydrothermal method in the presence of H2O2 followed by acid wash, and they exhibited improved activity in degradation of Rhodamine B under visible light irradiation. PMID- 25144252 TI - Binaural enhancement for bilateral cochlear implant users. AB - OBJECTIVES: Bilateral cochlear implant (BCI) users receive limited binaural cues and, thus, show little improvement to speech intelligibility from spatial cues. The feasibility of a method for enhancing the binaural cues available to BCI users is investigated. This involved extending interaural differences of levels, which typically are restricted to high frequencies, into the low-frequency region. DESIGN: Speech intelligibility was measured in BCI users listening over headphones and with direct stimulation, with a target talker presented to one side of the head in the presence of a masker talker on the other side. Spatial separation was achieved by applying either naturally occurring binaural cues or enhanced cues. RESULTS: In this listening configuration, BCI patients showed greater speech intelligibility with the enhanced binaural cues than with naturally occurring binaural cues. CONCLUSIONS: In some situations, it is possible for BCI users to achieve greater speech intelligibility when binaural cues are enhanced by applying interaural differences of levels in the low frequency region. PMID- 25144251 TI - Vestibular perception and the vestibulo-ocular reflex in young and older adults. AB - OBJECTIVES: Quantification of the perceptual thresholds to vestibular stimuli may offer valuable complementary information to that provided by measures of the vestibulo-ocular reflex (VOR). Perceptual thresholds could be particularly important in evaluating some subjects, such as the elderly, who might have a greater potential of central as well as peripheral vestibular dysfunction. The authors hypothesized that perceptual detection and discrimination thresholds would worsen with aging, and that there would be a poor relation between thresholds and traditional measures of the angular VOR represented by gain and phase on rotational chair testing. DESIGN: The authors compared the detection and discrimination thresholds of 19 younger and 16 older adults in response to earth vertical, 0.5 Hz rotations. Perceptual results of the older subjects were then compared with the gain and phase of their VOR in response to earth-vertical rotations over the frequency range from 0.025 to 0.5 Hz. RESULTS: Detection thresholds were found to be 0.69 +/- 0.29 degree/sec (mean +/- standard deviation) for the younger participants and 0.81 +/- 0.42 degree/sec for older participants. Discrimination thresholds in younger and older adults were 4.83 +/- 1.80 degree/sec and 4.33 +/- 1.57 degree/sec, respectively. There was no difference in either measure between age groups. Perceptual thresholds were independent of the gain and phase of the VOR. CONCLUSIONS: These results indicate that there is no inevitable loss of vestibular perception with aging. Elevated thresholds among the elderly are therefore suggestive of pathology rather than normal consequences of aging. Furthermore, perceptual thresholds offer additional insight, beyond that supplied by the VOR alone, into vestibular function. PMID- 25144254 TI - Social Determinants and Their Impact on Visual Impairment in Southern Mexico. AB - PURPOSE: Visual impairment in disadvantaged populations in Mexico has been scarcely reported. We compared the prevalence of visual impairment and its associated risk factors in populations in rural compared to urban areas of the Mexican southern state of Chiapas. METHODS: In a population-based study, the prevalence of visual impairment in rural and urban areas of Comitan, Chiapas, was estimated. All eligible individuals aged >=20 years living in rural areas were invited to participate; persons from urban areas were chosen randomly. Individuals were considered of indigenous (IND) origin either by self-report or if they spoke an IND language. Visual acuity (VA) and pinhole VA were measured using a tumbling E chart. VA was defined as normal (better than or equal to 20/60), moderate impairment (worse than 20/60 but better than or equal to 20/200), severe impairment (worse than 20/200 but better than or equal to 20/400), or blindness (worse than 20/400). RESULTS: Data on VA were obtained from 969 persons (610 rural, 359 urban) whose mean age was 43.3 years (standard deviation 15.6 years). Prevalence of moderate visual impairment was higher in rural (10.2%, 95% confidence interval, CI, 7.2-14.2%) than urban (3.9%, 95% CI 1.9-7.9%) areas (p < 0.001). Persons with moderate visual impairment were older and less educated (both p < 0.001). Rural individuals aged 50 years and older had 4.4 times (95% CI 1.8-11.3, p = 0.002) the likelihood of having moderate visual impairment compared with urban persons. CONCLUSION: Unfavorable socioeconomic conditions were associated with higher prevalence of moderate visual impairment in rural compared with urban populations in Mexico. PMID- 25144255 TI - The relation of visualization of internal mammary lymph nodes on lymphoscintigraphy to axillary lymph node metastases in breast cancer. AB - BACKGROUND: A few studies about lymphoscintigraphy in breast cancer patients have reported a correlation between decreased sentinel lymph node (LN) uptake and increased risk of axillary involvement with the hypothesis of blocked lymphatic passage of radiotracers by metastatic burden. This study is designed to investigate whether the visible internal mammary LN of lymphoscintigraphy (IM LPS) is related to axillary LN metastasis, rather than identifying sentinel LN in the internal mammary area. METHODS: We retrospectively reviewed medical records of 401 breast cancer patients who underwent sentinel lymphoscintigraphy using Tc 99m phytate and subsequent axillary LN dissection. The IM-LPS was divided into positive or negative groups, and axillary lymphoscintigraphy (A-LPS) was visually graded into four groups according to the method suggested by Lee et al. (1) To evaluate the relation of positive IM-LPS and A-LPS pattern with axillary LN metastasis, multivariate logistic regression analysis was done with covariates of Memorial Sloan-Kettering Cancer Center model. RESULTS: Positive IM-LPS was found in 32 patients. On the univariate logistic regression analysis, positive IM-LPS (p=0.01) and A-LPS pattern (p<0.05) successfully predicted the axillary LN status. On the multivariate logistic regression model, positive IM-LPS (OR 2.6362; 95% CI 1.0382-6.6938; p=0.04) and group II A-LPS (OR 1.9773; 95% CI 1.1336-3.4491; p=0.01) remained statistically significant variables for the predictor of axillary LN metastasis. CONCLUSION: This study suggests that IM-LPS and A-LPS pattern might be useful to show the burden of axillary LN metastasis in breast cancer patients, as an indicator of altered lymphatic pathway. PMID- 25144256 TI - Development of neural systems for reading in the monolingual and bilingual brain: new insights from functional near infrared spectroscopy neuroimaging. AB - What neural changes underlie reading development in monolingual and bilingual children? We examined neural activation patterns of younger (ages 6-8) and older (ages 8-10) children and adults to see whether early-life language experience influences the development of neural systems for reading. Using functional Near Infrared Spectroscopy, we observed an age-related shift in neural recruitment of language areas (left inferior frontal gyrus [LIFG], superior temporal gyrus [STG]). Bilinguals showed a greater extent and variability of neural activation in bilateral IFG and STG, and higher cognitive areas (dorsolateral prefrontal cortex, rostrolateral prefrontal cortex). This bilingual "neural signature" reveals the extent that neural systems underlying reading development can be modified through differences in early-life language experience. PMID- 25144257 TI - The differential role of verbal and spatial working memory in the neural basis of arithmetic. AB - We examine the relations of verbal and spatial working memory (WM) ability to the neural bases of arithmetic in school-age children. We independently localize brain regions subserving verbal versus spatial representations. For multiplication, higher verbal WM ability is associated with greater recruitment of the left temporal cortex, identified by the verbal localizer. For multiplication and subtraction, higher spatial WM ability is associated with greater recruitment of right parietal cortex, identified by the spatial localizer. Depending on their WM ability, children engage different neural systems that manipulate different representations to solve arithmetic problems. PMID- 25144258 TI - MR spectroscopic evidence of brain injury in the non-diagnosed collision sport athlete. AB - With growing evidence of long-term neurological damage in individuals enduring repetitive head trauma, it is critical to detect lower-level damage accumulation for the early diagnosis of injury in at-risk populations. Proton magnetic resonance spectroscopic scans of the dorsolateral prefrontal cortex and primary motor cortex were collected from high school American (gridiron) football athletes, prior to and during their competition seasons. Although no concussions were diagnosed, significant metabolic deviations from baseline and non-collision sport controls were revealed. Overall the findings indicate underlying biochemical changes, consequential to repetitive hits, which have previously gone unnoticed due to a lack of traditional neurological symptoms. PMID- 25144260 TI - Pathogenesis of Gallibacterium anatis in a natural infection model fulfils Koch's postulates: 1. Folliculitis and drop in egg production are the predominant effects in specific pathogen free layers. AB - Pathogenicity of Gallibacterium anatis was studied in specific pathogen free layers in a controlled environment, applying the intranasal route for experimental infection. At 30 weeks, 37 hens were infected with 0.4 ml of 1.53 * 10(8) colony-forming units/ml suspension of G. anatis strain 07990 whereas equal numbers of hens were left uninfected for control. Following experimental infection, clinical signs and the number and weight of the eggs were recorded daily until 5 weeks post infection. Three birds from each group were killed at 3, 7, 10, 28 and 38 days post infection (d.p.i.) for necropsy and sampling for bacteriological and histopathological examinations. Additionally, necropsy examination was performed on all remaining birds at 38 d.p.i. G. anatis infection was found to have an immediate and severe effect on egg production, showing early and persistent colonization in respiratory and reproductive organs as well as in the gut of infected layers. In birds killed at various time points, G. anatis infection caused focal necrosis in the liver (1/37), folliculitis (2/37), pericarditis (3/37), haemorrhagic follicles (2/37), ruptured follicles (20/37), yolk in the body cavity (2/37) and egg peritonitis (1/37). The inflammation of the ovaries could be further confirmed by histopathological examination. Recovery of G. anatis from yolk at 10 d.p.i. indicates the potential of vertical transmission. Altogether, lesions reflect typical findings of G. anatis infection reported in natural cases. Thus, for the first time, lesions and the consecutive disease caused by G. anatis infection have been reproduced experimentally in a natural infection model. PMID- 25144259 TI - ERP responses to face repetition during passive viewing: a nonverbal measure of social motivation in children with autism and typical development. AB - This study examined whether individual differences in social motivation affect the extent of processing of social versus nonsocial information. Event-related potentials were recorded in 13 children with autism spectrum disorder and 11 typically developing children during passive viewing of unfamiliar faces and houses. One image in each category was presented repeatedly, the rest were shown once. Analyses indicated no group differences in the early perceptual responses. Only typical children evidenced larger P600 for the repeated faces. These results were replicated during a retest session. Individual differences in memory for the repeated faces correlated with standardized behavioral assessments of social skills. PMID- 25144261 TI - Natural products in medicine: transformational outcome of synthetic chemistry. AB - This review brings to the forefront key synthetic modifications on natural products (NPs) that have yielded successful drugs. The emphasis is placed on the power of targeted chemical transformations in enhancing the therapeutic value of NPs through optimization of pharmacokinetics, stability, potency, and/or selectivity. Multiple classes of NPs such as macrolides, opioids, steroids, and beta-lactams used to treat a variety of conditions such as cancers, infections, inflammation are exemplified. Molecular modeling or X-ray structures of NP/protein complexes supporting the observed boost in therapeutic value of the modified NPs are also discussed. Significant advancement in synthetic chemistry, in structure determination, and in the understanding of factors controlling pharmacokinetics can now better position drug discovery teams to undertake NPs as valuable leads. We hope that the beneficial NPs synthetic modifications outlined here will reignite medicinal chemists' interest in NPs and their derivatives. PMID- 25144264 TI - Cockroach allergy and allergen-specific immunotherapy in asthma: potential and pitfalls. AB - PURPOSE OF REVIEW: To provide a summary and discussion of cockroach allergy and clinical trials of cockroach allergen immunotherapy. RECENT FINDINGS: Cockroach allergen exposure among sensitized children is increasingly recognized as a key factor contributing to asthma morbidity. Recent trials suggest that cockroach immunotherapy holds promise as a treatment strategy with studies demonstrating immunomodulatory and clinical effects. However, a few obstacles need to be overcome to realize the full potential of this treatment modality as cockroach allergic patients often exhibit complex sensitization patterns to multiple cockroach-associated proteins, and an immunodominant allergen has not been identified. These factors have made it difficult to produce standardized cockroach allergen extracts that are potent and provide the broad allergen profiles needed for optimal treatment. There have been important advances in the identification and cloning of cockroach allergens, and several strategies are being developed to provide therapeutic cockroach allergen products with enhanced clinical efficacy. SUMMARY: Allergen immunotherapy has the capability of modulating the immune response to cockroach allergen and has potential as a valuable treatment modality. Further studies of the clinical efficacy, along with the development of improved therapeutic products, are needed to advance our knowledge and realize the full potential of this promising therapy. PMID- 25144265 TI - The Efficacy of Palonosetron Plus Dexamethasone in Preventing Chemoradiotherapy induced Nausea and Emesis in Patients Receiving Daily Low-dose Cisplatin-based Concurrent Chemoradiotherapy for Uterine Cervical Cancer: A Phase II Study. AB - OBJECTIVES: The prevention of chemotherapy-induced and radiotherapy-induced emesis is recommended by several guidelines; however, there are no evidence-based recommendations for the use of antiemetics in concurrent chemoradiotherapy (CCRT). The aim of the present study was to evaluate the efficacy and safety of antiemetic therapy comprising palonosetron and dexamethasone during CCRT. METHODS: This is a nonrandomized, prospective, single-center, open phase II study.Twenty-six consecutive patients with cervical carcinoma were treated with daily low-dose cisplatin (8 mg/m/d)-based CCRT (2 Gy/d, 25 fractions, 5 times a week). All patients received 0.75 mg of palonosetron on day 1 of each week and 4 mg of oral dexamethasone daily. The primary endpoint was the percentage of patients achieving a complete response, which was defined as no emetic episodes and no antiemetic rescue medication during treatment. RESULTS: Planned daily low dose cisplatin-based CCRT was successful without delay or interruption in 46% (12/26) of the patients. The mean dose of total cisplatin was 184 (range, 136 to 200) mg/m.No patient vomited during the treatment period. The complete response rate during CCRT was 100%. A total of 81% patients were completely free from nausea. All patients tolerated the combination of palonosetron and dexamethasone and completed the scheduled regimen. Five patients exhibited grade 1 Cushingoid features that resolved after treatment. CONCLUSIONS: Antiemetic therapy comprising palonosetron and dexamethasone provided complete protection from nausea and vomiting in patients with cervical cancer receiving daily low-dose cisplatin-based CCRT. PMID- 25144266 TI - Gene Expression Profiling of Tumors From Heavily Pretreated Patients With Metastatic Cancer for the Selection of Therapy: A Pilot Study. AB - BACKGROUND: Recently, it has been shown that it is possible to identify tumor profiles of sensitivity for potentially useful drugs, both conventional and experimental, based on whole oligonucleotide microarray gene expression studies in heavily pretreated patients with metastatic solid tumors. METHODS: Fresh frozen tumor biopsies for molecular profiling (MP) were obtained from patients with advanced and refractory cancer. Total tumor and control tissue RNA was hybridized to a whole human genome oligonucleotide microarray. Differentially expressed genes interacting with potential therapeutic targets were identified. Results were complemented with DNA sequencing of selected driver genes and with immunohistochemistry and fluorescent "in situ" hybridization. The results were used to guide experimental treatment. RESULTS: MP assays led to a potentially active available drug in 91.2% of the patients. The median number of available active drugs per tumor was 5 (range, 1 to 9). Nine treated patients were not evaluable for response. Partial response was observed in 18 patients (33%), stable disease in 22 patients (40%) (clinical benefit rate of 73%), and progression in 15 (27%). Overall median progression-free survival and overall survival were 8 and 13 months, respectively. CONCLUSION: MP-guided therapy is feasible and seems to improve the clinical outcome of extensively pretreated patients but prospective and confirmatory trials are needed. PMID- 25144262 TI - Ethical considerations: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: Mass critical care entails time-sensitive decisions and changes in the standard of care that it is possible to deliver. These circumstances increase provider uncertainty as well as patients' vulnerability and may, therefore, jeopardize disciplined, ethical decision-making. Planning for pandemics and disasters should incorporate ethics guidance to support providers who may otherwise make ad hoc patient care decisions that overstep ethical boundaries. This article provides consensus-developed suggestions about ethical challenges in caring for the critically ill or injured during pandemics or disasters. The suggestions in this article are important for all of those involved in any pandemic or disaster with multiple critically ill or injured patients, including front-line clinicians, hospital administrators, and public health or government officials. METHODS: We adapted the American College of Chest Physicians (CHEST) Guidelines Oversight Committee's methodology to develop suggestions. Twenty-four key questions were developed, and literature searches were conducted to identify evidence for suggestions. The detailed literature reviews produced 144 articles. Based on their expertise within this domain, panel members also supplemented the literature search with governmental publications, interdisciplinary workgroup consensus documents, and other information not retrieved through PubMed. The literature in this field is not suitable to support evidence-based recommendations. Therefore, the panel developed expert opinion-based suggestions using a modified Delphi process. RESULTS: We report the suggestions that focus on five essential domains: triage and allocation, ethical concerns of patients and families, ethical responsibilities to providers, conduct of research, and international concerns. CONCLUSIONS: Ethics issues permeate virtually all aspects of pandemic and disaster response. We have addressed some of the most pressing issues, focusing on five essential domains: triage and allocation, ethical concerns of patients and families, ethical responsibilities to providers, conduct of research, and international concerns. Our suggestions reflect the consensus of the Task Force. We recognize, however, that some suggestions, including those related to end-of-life care, may be controversial. We highlight the need for additional research and dialogue in articulating values to guide health-care decisions during disasters. PMID- 25144267 TI - Phase II Study of Modified FOLFOX6 With Bevacizumab in Metastatic Gastroesophageal Adenocarcinoma. AB - BACKGROUND: The median survival for patients with metastatic gastroesophageal adenocarcinoma is <12 months. Bevacizumab has demonstrated promising activity in metastatic gastroesophageal adenocarcinoma when used in combination with cisplatin-based regimens for patients from the Americas. We conducted a prospective phase II trial to investigate the efficacy of bevacizumab in combination with the oxaliplatin-based regimen, modified FOLFOX6, in patients with metastatic gastroesophageal adenocarcinoma. METHODS: Patients with untreated metastatic adenocarcinoma of the stomach, gastroesophageal junction, or distal esophagus received mFOLFOX6 (leucovorin 400 mg/m, fluorouracil 400 mg/m bolus and 2400 mg/m continuous infusion over 46 h, oxaliplatin 85 mg/m) and bevacizumab (10 mg/kg) every 2 weeks until disease progression or intolerance. Response by RECIST was evaluated by CT scan every 8 weeks. The primary objective was progression free survival (PFS); secondary objectives were safety, response rate, and overall survival (OS). RESULTS: A total of 39 patients with untreated metastastic gastroesophageal adenocarcinoma were enrolled between September 2008 and June 2012. Median number of cycles administered was 12 (range, 4 to 86). The confirmed response rate was 56.4% (3 complete response and 19 partial response). The median PFS was 7.8 months and median OS was 14.7 months. Three patients remain on treatment, and 11 patients are alive, of whom 6 have survived >24 months. Treatment-related grade 3/4 toxicities included neutropenia (33.3%), neuropathy (20.5%), thromboembolism (VTE) (7.7%), thrombocytopenia (7.7%), anemia (2.6%), hypertension (2.6%), and proteinuria (2.6%). We observed no GI perforations or grade 3/4 GI hemorrhagic events. CONCLUSIONS: First-line mFOLFOX6 with bevacizumab for metastatic gastroesophageal adenocarcinoma was well tolerated and associated with longer PFS and OS compared with historical data from similar populations treated without bevacizumab. Our results suggest that the addition of bevacizumab to mFOLFOX6 may provide clinical benefit in American patients with metastatic gastroesophageal adenocarcinoma, a finding consistent with previous studies of first-line bevacizumab in combination with chemotherapy for this disease. PMID- 25144268 TI - Efficient cobalt-catalyzed C-N cross-coupling reaction between benzamide and aryl iodide in water. AB - A practical and efficient strategy for the N-arylation of benzamide catalysed by a Co(C2O4).2H2O/dmeda system in water is reported. Under the optimized conditions, a wide variety of N-arylated products were obtained in good yields (up to 92%) using substituted aryl iodides. PMID- 25144269 TI - A robust chromatin immunoprecipitation protocol for studying transcription factor DNA interactions and histone modifications in wood-forming tissue. AB - Woody cells and tissues are recalcitrant to standard chromatin immunoprecipitation (ChIP) procedures. However, we recently successfully implemented ChIP in wood-forming tissue of the model woody plant Populus trichocarpa. Here we provide the detailed ChIP protocol optimized for wood forming tissue that we used in those studies. By using stem-differentiating xylem (SDX; a wood-forming tissue), we identified all steps that were ineffective in standard ChIP protocols and systematically modified them to develop and optimize a robust ChIP protocol. The protocol includes tissue collection, cross-linking, nuclear isolation, chromatin extraction, DNA fragmentation, immunoprecipitation, DNA purification and sequence analysis. The protocol takes 2.5 d to complete and allows a robust 8-10-fold enrichment of transcription factor (TF)-bound genomic fragments (~150 ng/g of SDX) over nonspecific DNAs. The enriched DNAs are of high quality and can be used for subsequent PCR and DNA-seq analyses. We used this protocol to identify genome-wide specific TF-DNA interactions during wood formation and histone modifications associated with regulation of wood formation. Our protocol, which may be suitable for many tissue types, is so far the only working ChIP system for wood-forming tissue. PMID- 25144270 TI - A simple improved-throughput xylem protoplast system for studying wood formation. AB - Isolated protoplasts serve as a transient expression system that is highly representative of stable transgenics in terms of transcriptome responses. They can also be used as a cellular system to study gene transactivation and nucleocytoplasmic protein trafficking. They are particularly useful for systems studies in which stable transgenics and mutants are unavailable. We present a protocol for the isolation and transfection of protoplasts from wood-forming tissue, the stem-differentiating xylem (SDX), in the model woody plant Populus trichocarpa. The method involves tissue preparation, digestion of SDX cell walls, protoplast isolation and DNA transfection. Our approach is markedly faster and provides better yields than previous protocols; small (milligrams)- to large (20 g)-scale SDX preparations can be achieved in ~60 s, with isolation of protoplasts and their subsequent transfection taking ~50 min. Up to ten different samples can be processed simultaneously in this time scale. Our protocol gives a high yield (~2.5 * 10(7) protoplasts per g of SDX) of protoplasts sharing 96% transcriptome identity with intact SDX. PMID- 25144271 TI - Tethered particle analysis of supercoiled circular DNA using peptide nucleic acid handles. AB - This protocol describes how to monitor individual naturally supercoiled circular DNA plasmids bound via peptide nucleic acid (PNA) handles between a bead and a surface. The protocol was developed for single-molecule investigation of the dynamics of supercoiled DNA, and it allows the investigation of both the dynamics of the molecule itself and of its interactions with a regulatory protein. Two bis PNA clamps designed to bind with extremely high affinity to predetermined homopurine sequence sites in supercoiled DNA are prepared: one conjugated with digoxigenin for attachment to an anti-digoxigenin-coated glass cover slide, and one conjugated with biotin for attachment to a submicron-sized streptavidin coated polystyrene bead. Plasmids are constructed, purified and incubated with the PNA handles. The dynamics of the construct is analyzed by tracking the tethered bead using video microscopy: less supercoiling results in more movement, and more supercoiling results in less movement. In contrast to other single molecule methodologies, the current methodology allows for studying DNA in its naturally supercoiled state with constant linking number and constant writhe. The protocol has potential for use in studying the influence of supercoils on the dynamics of DNA and its associated proteins, e.g., topoisomerase. The procedure takes ~4 weeks. PMID- 25144272 TI - A comparative cross-linking strategy to probe conformational changes in protein complexes. AB - Chemical cross-linking, together with mass spectrometry (MS), is a powerful combination for probing subunit interactions within static protein assemblies. To probe conformational changes in response to stimuli, we have developed a comparative cross-linking strategy, using lysine-specific deuterated and nondeuterated bis(sulfosuccinimidyl)suberate cross-linking reagents (BS3). Here we describe the experimental procedures as well as the data analysis, validation and interpretation. The protocol involves first assigning cross-linked peptides in the complex without ligand binding, or with post-translational modifications (PTMs) at natural abundance, using a standard procedure with labeled cross linkers, proteolysis and assignment of cross-linked peptides after liquid chromatography-tandem MS (LC-MS/MS) and database searching. An aliquot of the protein complex is then exposed to a stimulus: either ligand binding or incubation with a phosphatase or kinase to bring about changes in PTMs. Two solutions--one containing the apo/untreated complex and the other containing the enzymatically modified/ligand-bound complex--are then cross-linked independently. Typically, nondeuterated BS3-d0 is used for the untreated complex and deuterated BS3-d4 is used for the experiment. The two aliquots are then incubated at equal concentrations, digested and processed as before. The ratios of labeled and unlabeled cross-linked peptides provide a direct readout of the effect of the stimulus. We exemplify our method by quantifying changes in subunit interactions induced by dephosphorylation of an ATP synthase. The protocol can also be used to determine the conformational changes in protein complexes induced by various stimuli including ligand/drug binding, oligomerization and other PTMs. Application of the established protocol takes ~9 d, including protein complex purification. PMID- 25144273 TI - Role of polymeric endosomolytic agents in gene transfection: a comparative study of poly(L-lysine) grafted with monomeric L-histidine analogue and poly(L histidine). AB - Endosomal entrapment is one of the main barriers that must be overcome for efficient gene expression along with cell internalization, DNA release, and nuclear import. Introducing pH-sensitive ionizable groups into the polycationic polymers to increase gene transfer efficiency has proven to be a useful method; however, a comparative study of introducing equal numbers of ionizable groups in both polymer and monomer forms, has not been reported. In this study, we prepared two types of histidine-grafted poly(L-lysine) (PLL), a stacking form of poly(L histidine) (PLL-g-PHis) and a mono-L-histidine (PLL-g-mHis) with the same number of imidazole groups. These two types of histidine-grafted PLL, PLL-g-PHis and PLL g-mHis, showed profound differences in hemolytic activity, cellular uptake, internalization, and transfection efficiency. Cy3-labeled PLL-g-PHis showed strong fluorescence in the nucleus after internalization, and high hemolytic activity upon pH changes was also observed from PLL-g-PHis. The arrangement of imidazole groups from PHis also provided higher gene expression than mHis due to its ability to escape the endosome. mHis or PHis grafting reduced the cytotoxicity of PLL and changed the rate of cellular uptake by changing the quantity of free epsilon-amines available for gene condensation. The subcellular localization of PLL-g-PHis/pDNA measured by YOYO1-pDNA intensity was highest inside the nucleus, while the lysotracker, which stains the acidic compartments was lowest among these polymers. Thus, the polymeric histidine arrangement demonstrate the ability to escape the endosome and trigger rapid release of polyplexes into the cytosol, resulting in a greater amount of pDNA available for translocation to the nucleus and enhanced gene expression. PMID- 25144275 TI - Breast cancer brain metastases: one step at a time. PMID- 25144274 TI - Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity. AB - Etiological agents of acute, persistent, or relapsing clinical infections are often refractory to antibiotics due to multidrug resistance and/or antibiotic tolerance. Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen that causes recalcitrant and severe acute chronic and persistent human infections. Here, we target the MvfR-regulated P. aeruginosa quorum sensing (QS) virulence pathway to isolate robust molecules that specifically inhibit infection without affecting bacterial growth or viability to mitigate selective resistance. Using a whole-cell high-throughput screen (HTS) and structure-activity relationship (SAR) analysis, we identify compounds that block the synthesis of both pro-persistence and pro-acute MvfR-dependent signaling molecules. These compounds, which share a benzamide-benzimidazole backbone and are unrelated to previous MvfR-regulon inhibitors, bind the global virulence QS transcriptional regulator, MvfR (PqsR); inhibit the MvfR regulon in multi-drug resistant isolates; are active against P. aeruginosa acute and persistent murine infections; and do not perturb bacterial growth. In addition, they are the first compounds identified to reduce the formation of antibiotic-tolerant persister cells. As such, these molecules provide for the development of next-generation clinical therapeutics to more effectively treat refractory and deleterious bacterial-human infections. PMID- 25144276 TI - Updates on the management of breast cancer brain metastases. AB - Breast cancer brain metastases (BCBMs) are common in patients with advanced disease. Breast cancer subtype and performance status are the major determinants of the course of the disease and survival time following a diagnosis of brain metastasis. Unique challenges specific to the management of BCBMs include overcoming the blood-brain barrier and resistance to conventional systemic therapies, as BCBMs typically occur in the pretreated patient population. The development of new systemic therapies for breast cancer, coupled with improvements in trial design, imaging modalities, and methods of defining and measuring clinical endpoints, has led to a renewed interest in developing novel therapeutic approaches for BCBMs. In this overview, we will review recent developments in the management of BCBMs and current prospective trials of systemic therapies specifically for patients with BCBMs, with a focus on novel pathway-specific therapies. PMID- 25144277 TI - Approaches for optimal drug development and clinical trial design for breast cancer brain metastasis. PMID- 25144278 TI - Management of breast cancer brain metastases is moving forward, but new options are still needed. PMID- 25144279 TI - Assessing the 'fit' older patient for chemotherapy. AB - Oncologists are called on daily to assess "fit" older persons for cancer therapy. An individual's level of physiological reserve becomes unmasked during cancer therapy when the need arises to rely on this reserve. An in-depth assessment is essential in quantifying the level of an older adult's fitness. Tools can assist with this evaluation, including chemotherapy toxicity calculators and web-based geriatric assessment scales. Integrating these tools into oncology practice will be well worth the time and effort for both the patient and the oncology care team. PMID- 25144280 TI - Extended lymph node dissection in prostate cancer: a procedure with therapeutic utility. PMID- 25144281 TI - Extended pelvic lymph node dissection for prostate cancer: do more nodes mean better survival? PMID- 25144282 TI - Is surgery always necessary in rectal cancer? AB - Rectal cancer is a major health problem around the world, representing about one third of the total colorectal cancer cases. Because of its anatomical location, there is a higher risk of local recurrence, and treatment often requires a complex multidisciplinary approach which includes neoadjuvant radiotherapy, chemotherapy, and a radical surgical procedure that commonly leads to a permanent colostomy. The cure rate with this strategy is good, with some patients having no residual disease in the surgical specimen. While the prognosis for those patients is excellent, their quality of life is permanently compromised. In this article, we review risks and benefits of the standard treatment approach and compare standard treatment with alternative methods aimed at rectal preservation. PMID- 25144283 TI - 'Watch-and-wait' for rectal cancer: what's the way forward? PMID- 25144284 TI - Nonoperative strategies for rectal cancer following a complete clinical response to preoperative chemoradiation: a few considerations. PMID- 25144285 TI - Metastatic adrenocortical carcinoma with a prolonged response to mitotane. PMID- 25144286 TI - Surgery for primary central nervous system lymphoma: is it time for reevaluation? AB - The overall survival rate for primary central nervous system lymphoma (PCNSL) has improved significantly. This prolongation in survival is related mainly to advances in chemotherapy regimens and radiotherapy. In contrast, the role of surgery in PCNSL has been limited because tumors are frequently not amenable to resection and because most studies have failed to show that resection is beneficial. A recent analysis of the German Primary CNS Lymphoma Study Group 1 (G PCNSL-SG-1) trial has challenged this convention by showing that the survival of patients with PCNSL may actually be prolonged if tumors are resected. While there are a number of weaknesses in the analysis, many authorities now feel that an attempt at gross total resection is reasonable for patients with solitary lesions that can be removed without morbidity. However, even if resection does benefit some patients, the diagnosis of lymphoma is almost always made in retrospect, and there are few occasions when a neurosurgeon will actually need to make a decision whether or not to resect a known PCNSL. PMID- 25144287 TI - Primary CNS lymphoma: the role of resection. PMID- 25144288 TI - Role of surgical resection in primary CNS lymphoma: a resurrected discussion. PMID- 25144289 TI - Inside ASCO 2014. PMID- 25144290 TI - The first case. PMID- 25144291 TI - Adherence to cancer prevention guidelines in 18 African countries. AB - BACKGROUND: Cancer rates in Africa are projected to double by 2030 due to aging and increased exposure to cancer risk factors, including modifiable risk factors. We assessed adherence to 5 modifiable cancer risk factors across 18 African countries. METHODS: Data on adults 18 years and older were obtained from the 2002 2004 World Health Survey. Adherence to current World Cancer Research Fund guidelines on smoking, alcohol, body weight, physical activity, and nutrition was assessed. Adherence scores ranged from 0 (no guideline met) to 5 (all guidelines met). Determinants of adherence were assessed using multivariable linear regression adjusted for individual and country level characteristics. RESULTS: Across all countries, adherence to the guidelines among adults was high for smoking (72%-99%) and alcohol (85%-100%), but low for body weight (1.8%-78%), physical activity (3.4%-84%) and nutrition (1.4%-61%). Overall adherence score ranged from 2.32 in Mali to 3.72 in Comoros. In multivariable models, residing in low versus high SES households was associated with reduced adherence by 0.24 and 0.21 points for men and women respectively after adjusting for age, gender, education, and marital status (p<0.001). Every % increase in GDP spent on health was associated with increased adherence by 0.03 in men and 0.09 in women (p<0.001). CONCLUSIONS: The wide variation in adherence to cancer prevention guidelines observed across countries and between population sub-groups suggests the need for targeted public health efforts to improve behaviors related to body weight, physical activity and nutrition. PMID- 25144292 TI - Occupational noise annoyance linked to depressive symptoms and suicidal ideation: a result from nationwide survey of Korea. AB - BACKGROUND: Noise, or undesirable sound, is one of the most common environmental stressors, and it can cause various health effects. Beyond the auditory consequences of occupational noise exposure, extra-auditory effects such as psychological problems have also been found. The aim of the current study is to elucidate the association between occupational noise annoyance and psychological symptoms, including symptoms of depression and suicidal ideation. METHODS: A total of 10,020 participants (5,410 men and 4,610 women) were included in the current analysis, using data from the fourth Korean National Health and Nutrition Examination Survey (KNHANES). Self-report questionnaires were used to assess noise annoyance levels, depressive symptoms, and suicidal ideation. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for psychosocial symptoms were calculated using multiple logistic regression models. RESULTS: Compared to the no noise annoyance group, ORs (95% CI) of the severe annoyance groups were 1.58 (1.12-2.23) and 1.76 (1.29-2.40) in men and 1.49 (1.05-2.11) and 1.41 (1.01-1.97) in women for depressive symptoms and suicidal ideation, respectively. The ORs (95% CI) for severe noise annoyance in those with less than five hours of sleep were 2.95 (1.46-5.96) and 2.05 (1.01-4.16) in men and women, respectively, compared with those with no noise annoyance and a sleep time of more than five hours. CONCLUSION: Our study shows that occupational noise annoyance is significantly related to mental health, including depressive symptoms and suicidal ideation after controlling for individual and socio-demographic characteristics even with gender stratification. However, prospective studies with quantified noise exposure assessment were needed to elucidate the causality on the association between noise annoyance and psychological symptoms. PMID- 25144293 TI - Distinct kinetics in the frequency of peripheral CD4+ T cells in patients with ulcerative colitis experiencing a flare during treatment with mesalazine or with a herbal preparation of myrrh, chamomile, and coffee charcoal. AB - BACKGROUND: We found the first evidence of the efficacy of a herbal treatment with myrrh, dry extract of chamomile flowers, and coffee charcoal for ulcerative colitis (UC). However, the impact of the herbal treatment on the CD4+ T-cell compartment, which is essential for both the induction of UC and the maintenance of tolerance in the gut, is not well understood. AIM: To analyze the frequency and functional phenotype of CD4+ T cells and of immune-suppressive CD4+CD25high regulatory T cells (Tregs) in healthy control subjects, patients with UC in remission, and patients with clinical flare of UC. METHODS: Patients in clinical remission were treated with either mesalazine or the herbal preparation for 12 months. The frequencies of whole CD4+ T cells, CD4+CD25med effector T cells, and Tregs and the expression of Foxp3 within the CD4+CD25hig Tregs were determined by flow cytometry at 6 time points. We determined the suppressive capability of Tregs from healthy control subjects and from patients in remission or clinical flare. RESULTS: A total of 79 patients (42 women, 37 men; mean age, 48.5 years; 38 with clinical flare) and 5 healthy control subjects were included in the study. At baseline the frequencies of whole CD4+ T cells, CD4+CD25med effector cells, and Tregs did not differ between the two treatment groups and the healthy control subjects. In addition, patients with UC in sustained clinical remission showed no alteration from baseline after 1, 3, 6, 9, or 12 months of either treatment. In contrast, CD4+ T cells, CD4+CD25med effector T cells, and Tregs demonstrated distinctly different patterns at time points pre-flare and flare. The mesalazine group showed a continuous but not statistically significant increase from baseline to pre-flare and flare (p = ns). In the herbal treatment group, however, the percentage of the CD4+ T cells was lower at pre-flare than at baseline. This decrease was completely reversed after flare, when a significant increase was seen (CD4+CD25med pre-flare/flare p = 0.0461; CD4+CD25high baseline/flare p = 0.0269 and pre-flare/flare p = 0.0032). In contrast, no changes in the expression of Foxp3 cells were detected within the subsets of CD4+CD25high regulatory T cells. Of note, no alterations were detected in the suppressive capability of CD4+CD25high regulatory T cells isolated from the peripheral blood of healthy donors, from patients in remission, or from patients with clinical flare. CONCLUSIONS: In patients with UC experiencing acute flare, the CD4+ T compartment demonstrates a distinctly different pattern during treatment with myrrh, chamomile extract, and coffee charcoal than during treatment with mesalazine. These findings suggest an active repopulation of regulatory T cells during active disease. TRIAL REGISTRATION: EU Clinical Trials Register 2007-007928-18/DE. PMID- 25144294 TI - From dandruff to deep-sea vents: Malassezia-like fungi are ecologically hyper diverse. PMID- 25144295 TI - Predicting out-of-office blood pressure level using repeated measurements in the clinic: an observational cohort study. AB - OBJECTIVES: Identification of people with lower (white-coat effect) or higher (masked effect) blood pressure at home compared to the clinic usually requires ambulatory or home monitoring. This study assessed whether changes in SBP with repeated measurement at a single clinic predict subsequent differences between clinic and home measurements. METHODS: This study used an observational cohort design and included 220 individuals aged 35-84 years, receiving treatment for hypertension, but whose SBP was not controlled. The characteristics of change in SBP over six clinic readings were defined as the SBP drop, the slope and the quadratic coefficient using polynomial regression modelling. The predictive abilities of these characteristics for lower or higher home SBP readings were investigated with logistic regression and repeated operating characteristic analysis. RESULTS: The single clinic SBP drop was predictive of the white-coat effect with a sensitivity of 90%, specificity of 50%, positive predictive value of 56% and negative predictive value of 88%. Predictive values for the masked effect and those of the slope and quadratic coefficient were slightly lower, but when the slope and quadratic variables were combined, the sensitivity, specificity, positive and negative predictive values for the masked effect were improved to 91, 48, 24 and 97%, respectively. CONCLUSION: Characteristics obtainable from multiple SBP measurements in a single clinic in patients with treated hypertension appear to reasonably predict those unlikely to have a large white-coat or masked effect, potentially allowing better targeting of out-of office monitoring in routine clinical practice. PMID- 25144297 TI - Challenges of hypertension and hypertension treatment. PMID- 25144298 TI - Identification and validation of suitable housekeeping genes for normalizing quantitative real-time PCR assays in injured peripheral nerves. AB - Injury to the peripheral nerve induces dramatic changes in terms of cellular composition that are reflected on RNA quality and quantity, making messenger RNA expression analysis very complex. Several commonly used housekeeping genes are regulated following peripheral nerve injury and are thus not suitable for quantitative real-time PCR normalization; moreover, the presence of pseudogenes in some of them impairs their use. To deal with this problem, we have developed a new method to identify new stable housekeeping genes based on publicly available microarray data on normal and injured nerves. Four new candidate stable genes were identified and validated by quantitative real-time PCR analysis on nerves during the different phases after nerve injury: nerve degeneration, regeneration and remyelination. The stability measure of these genes was calculated with both NormFinder and geNorm algorithms and compared with six commonly used housekeeping genes. This procedure allowed us to identify two new and highly stable genes that can be employed for normalizing injured peripheral nerve data: ANKRD27 and RICTOR. Besides providing a tool for peripheral nerve research, our study also describes a simple and cheap procedure that can be used to identify suitable housekeeping genes in other tissues and organs. PMID- 25144299 TI - Macronutrient intake as a mediator with FTO to increase body mass index. AB - BACKGROUND: The fat mass and obesity-associated (FTO) single nucleotide polymorphisms (SNPs; rs1421085, rs17817449, rs9939609, rs8050136) and macronutrient intake (carbohydrate, protein, fat, total calories) are associated with body mass index (BMI). However, the mechanism for this relationship has not been fully elucidated. OBJECTIVE: This study examined whether macronutrient intake mediates the association between FTO SNPs and BMI. DESIGN: Baseline cross sectional data from the Atherosclerosis Risk in Communities (ARIC) study of whites (n = 10,176) and African Americans (n = 3641) aged 45 to 64 years were analyzed. RESULTS: In linear regression models with BMI as the dependent variable, FTO SNPs were significantly associated with higher BMI after adjusting for covariates. The addition of energy-adjusted macronutrients attenuated the FTO effect estimates, indicating partial mediation. In whites, beta ranged from 0.40 (95% confidence interval [CI], 0.20, 0.60) for rs17817449 heterozygous carriers to 0.93 (95% CI, 0.64, 122) for rs8050136 homozygous carriers; for African Americans rs17817449 homozygous carriers beta was 0.65 (95% CI, 0.03, 1.27). In models with macronutrient intake as the dependent variable, all FTO SNPs were associated with higher protein intake for homozygous carriers after adjusting for BMI and other covariates. Among whites, beta ranged from 1.44 (95% CI, 0.51, 2.37) for rs8050136 to 1.73 (95% CI, 0.85, 2.61) for rs17817449; among African American rs8050136 homozygous carriers beta was 2.46 (95% CI, 0.77, 4.14). In mediation analysis, in whites only, FTO high-risk alleles were associated with higher BMI partly through their small effects on carbohydrate and protein intake. CONCLUSIONS: These findings suggest that in adults, the relationship between FTO variants and BMI is not primarily through mediation of food intake. PMID- 25144300 TI - Cr(OH)3(s) oxidation induced by surface catalyzed Mn(II) oxidation. AB - We examined the feasibility of Cr(OH)3(s) oxidation mediated by surface catalyzed Mn(II) oxidation under common groundwater pH conditions as a potential pathway of natural Cr(VI) contaminations. Dissolved Mn(II) (50 MUM) was reacted with or without synthesized Cr(OH)3(s) (1.0 g/L) at pH 7.0-9.0 under oxic or anoxic conditions. Homogeneous Mn(II) oxidation by dissolved O2 was not observed at pH <= 8.0 for 50 days. At pH 9.0, by contrast, dissolved Mn(II) was completely removed within 8 days and precipitated as hausmannite. When Cr(OH)3(s) was present, this solid was oxidized and released substantial amounts of Cr(VI) as dissolved Mn(II) was added into the suspension at pH >= 8.0 under oxic conditions. Production of Cr(VI) was attributed to Cr(OH)3(s) oxidation by a newly formed Mn oxide via Mn(II) oxidation catalyzed on Cr(OH)3(s) surface. XANES results indicated that this surface-catalyzed Mn(II) oxidation produced a mixed valence Mn(III/IV) solid phase. Our results suggest that toxic Cr(VI) can be naturally produced via Cr(OH)3(s) oxidation coupled with the oxidation of dissolved Mn(II). In addition, this study evokes the potential environmental hazard of sparingly soluble Cr(OH)3(s), which has been considered the most common and a stable remediation product of Cr(VI) contamination. PMID- 25144296 TI - Nifedipine plus candesartan combination increases blood pressure control regardless of race and improves the side effect profile: DISTINCT randomized trial results. AB - OBJECTIVES: DISTINCT (reDefining Intervention with Studies Testing Innovative Nifedipine GITS - Candesartan Therapy) aimed to determine the dose-response and tolerability of nifedipine GITS and/or candesartan cilexetil therapy in participants with hypertension. METHODS: In this 8-week, multinational, multicentre, randomized, double-blind, placebo-controlled study, adults with mean seated DBP of at least 95 to less than 110 mmHg received combination or monotherapy with nifedipine GITS (N) 20, 30 or 60 mg and candesartan cilexetil (C) 4, 8, 16 or 32 mg, or placebo. The primary endpoint, change in DBP from baseline to Week 8, was analysed using the response surface model (RSM); this analysis was repeated for mean seated SBP. RESULTS: Overall, 1381 participants (mean baseline SBP/DBP: 156.5/99.6 mmHg) were randomized. Both N and C contributed independently to SBP/DBP reductions [P < 0.0001 (RSM)]. A positive dose-response was observed, with all combinations providing statistically better blood pressure (BP) reductions from baseline versus respective monotherapies (P < 0.05) and N60C32 achieving the greatest reduction [-23.8/-16.5 mmHg; P < 0.01 versus placebo (-5.3/-6.7 mmHg) and component monotherapies]. Even very low-dose (N20 and C4) therapy provided significant BP-lowering, and combination therapy was similarly effective in different racial groups. N/C combination demonstrated a lower incidence of vasodilatory adverse events than N monotherapy (18.3 versus 23.6%), including headache (5.5 versus 11.0%; P = 0.003, chi-square test) and peripheral oedema over time (3.6 versus 5.8%; n.s.). CONCLUSION: N/C combination was effective in participants with hypertension and showed an improved side effect profile compared with N monotherapy. PMID- 25144301 TI - Hyperglycemia promotes K-Ras-induced lung tumorigenesis through BASCs amplification. AB - Oncogenic K-Ras represents the most common molecular change in human lung adenocarcinomas, the major histologic subtype of non-small cell lung cancer (NSCLC). The presence of K-Ras mutation is associated with a poor prognosis, but no effective treatment strategies are available for K-Ras -mutant NSCLC. Epidemiological studies report higher lung cancer mortality rates in patients with type 2 diabetes. Here, we use a mouse model of K-Ras-mediated lung cancer on a background of chronic hyperglycemia to determine whether elevated circulating glycemic levels could influence oncogenic K-Ras-mediated tumor development. Inducible oncogenic K-Ras mouse model was treated with subtoxic doses of streptozotocin (STZ) to induce chronic hyperglycemia. We observed increased tumor mass and higher grade of malignancy in STZ treated diabetic mice analyzed at 4, 12 and 24 weeks, suggesting that oncogenic K-Ras increased lung tumorigenesis in hyperglycemic condition. This promoting effect is achieved by expansion of tumor initiating lung bronchio-alveolar stem cells (BASCs) in bronchio-alveolar duct junction, indicating a role of hyperglycemia in the activity of K-Ras-transformed putative lung stem cells. Notably, after oncogene K-Ras activation, BASCs show upregulation of the glucose transporter (Glut1/Slc2a1), considered as an important player of the active control of tumor cell metabolism by oncogenic K Ras. Our novel findings suggest that anti-hyperglycemic drugs, such as metformin, may act as therapeutic agent to restrict lung neoplasia promotion and progression. PMID- 25144303 TI - A highly ordered meso@microporous carbon-supported sulfur@smaller sulfur core shell structured cathode for Li-S batteries. AB - For lithium-sulfur batteries, commercial application is hindered by the insulating nature of sulfur and the dissolution of the reaction intermediates of polysulfides. Here, we present an ordered meso-microporous core-shell carbon (MMCS) as a sulfur container, which combines the advantages of both mesoporous and microporous carbon. With large pore volume and highly ordered porous structure, the "core" promises a sufficient sulfur loading and a high utilization of the active material, while the "shell" containing microporous carbon and smaller sulfur acts as a physical barrier and stabilizes the cycle capability of the entire S/C composite. Such a S/MMCS composite exhibits a capacity as high as 837 mAh g(-1) at 0.5 C after 200 cycles with a capacity retention of 80% vs the second cycle (a decay of only 0.1% per cycle), demonstrating that the diffusion of the polysulfides into the bulk electrolyte can be greatly reduced. We believe that the tailored highly ordered meso-microporous core-shell structured carbon can also be applicable for designing some other electrode materials for energy storage. PMID- 25144302 TI - High content image-based screening of a protease inhibitor library reveals compounds broadly active against Rift Valley fever virus and other highly pathogenic RNA viruses. AB - High content image-based screening was developed as an approach to test a protease inhibitor small molecule library for antiviral activity against Rift Valley fever virus (RVFV) and to determine their mechanism of action. RVFV is the causative agent of severe disease of humans and animals throughout Africa and the Arabian Peninsula. Of the 849 compounds screened, 34 compounds exhibited >= 50% inhibition against RVFV. All of the hit compounds could be classified into 4 distinct groups based on their unique chemical backbone. Some of the compounds also showed broad antiviral activity against several highly pathogenic RNA viruses including Ebola, Marburg, Venezuela equine encephalitis, and Lassa viruses. Four hit compounds (C795-0925, D011-2120, F694-1532 and G202-0362), which were most active against RVFV and showed broad-spectrum antiviral activity, were selected for further evaluation for their cytotoxicity, dose response profile, and mode of action using classical virological methods and high-content imaging analysis. Time-of-addition assays in RVFV infections suggested that D011 2120 and G202-0362 targeted virus egress, while C795-0925 and F694-1532 inhibited virus replication. We showed that D011-2120 exhibited its antiviral effects by blocking microtubule polymerization, thereby disrupting the Golgi complex and inhibiting viral trafficking to the plasma membrane during virus egress. While G202-0362 also affected virus egress, it appears to do so by a different mechanism, namely by blocking virus budding from the trans Golgi. F694-1532 inhibited viral replication, but also appeared to inhibit overall cellular gene expression. However, G202-0362 and C795-0925 did not alter any of the morphological features that we examined and thus may prove to be good candidates for antiviral drug development. Overall this work demonstrates that high-content image analysis can be used to screen chemical libraries for new antivirals and to determine their mechanism of action and any possible deleterious effects on host cellular biology. PMID- 25144304 TI - Microfluidic serpentine antennas with designed mechanical tunability. AB - This paper describes the design and characterization of microfluidic serpentine antennas with reversible stretchability and designed mechanical frequency modulation (FM). The microfluidic antennas are designed based on the Poisson's ratio of the elastomer in which the liquid alloy antenna is embedded, to controllably decrease, stabilize or increase its resonance frequency when being stretched. Finite element modelling was used in combination with experimental verification to investigate the effects of substrate dimensions and antenna aspect ratios on the FM sensitivity to uniaxial stretching. It could be designed within the range of -1.2 to 0.6 GHz per 100% stretch. When the aspect ratio of the serpentine antenna is between 1.0 and 1.5, the resonance frequency is stable under stretching, bending, and twisting. The presented microfluidic serpentine antenna design could be utilized in the field of wireless mobile communication for the design of wearable electronics, with a stable resonance frequency under dynamic applied strain up to 50%. PMID- 25144305 TI - Hoarseness after metastatic colon cancer treatment. PMID- 25144306 TI - Magnetic resonance imaging of the ear for patient-specific reconstructive surgery. AB - INTRODUCTION: Like a fingerprint, ear shape is a unique personal feature that should be reconstructed with a high fidelity during reconstructive surgery. Ear cartilage tissue engineering (TE) advantageously offers the possibility to use novel 3D manufacturing techniques to reconstruct the ear, thus allowing for a detailed auricular shape. However it also requires detailed patient-specific images of the 3D cartilage structures of the patient's intact contralateral ear (if available). Therefore the aim of this study was to develop and evaluate an imaging strategy for acquiring patient-specific ear cartilage shape, with sufficient precision and accuracy for use in a clinical setting. METHODS AND MATERIALS: Magnetic resonance imaging (MRI) was performed on 14 volunteer and six cadaveric auricles and manually segmented. Reproducibility of cartilage volume (Cg.V), surface (Cg.S) and thickness (Cg.Th) was assessed, to determine whether raters could repeatedly define the same volume of interest. Additionally, six cadaveric auricles were harvested, scanned and segmented using the same procedure, then dissected and scanned using high resolution micro-CT. Correlation between MR and micro-CT measurements was assessed to determine accuracy. RESULTS: Good inter- and intra-rater reproducibility was observed (precision errors <4% for Cg.S and <9% for Cg.V and Cg.Th). Intraclass correlations were good for Cg.V and Cg.S (>0.82), but low for Cg.Th (<0.23) due to similar average Cg.Th between patients. However Pearson's coefficients showed that the ability to detect local cartilage shape variations is unaffected. Good correlation between clinical MRI and micro-CT (r>0.95) demonstrated high accuracy. DISCUSSION AND CONCLUSION: This study demonstrated that precision and accuracy of the proposed method was high enough to detect patient-specific variation in ear cartilage geometry. The present study provides a clinical strategy to access the necessary information required for the production of 3D ear scaffolds for TE purposes, including detailed patient-specific shape. Furthermore, the protocol is applicable in daily clinical practice with existing infrastructure. PMID- 25144307 TI - High-value utilization of lignin to synthesize Ag nanoparticles with detection capacity for Hg2+. AB - This study reports the rapid preparation of silver nanoparticles (AgNPs) from Tollens' reagent under microwave irradiation. In the synthesis, lignin with reducing groups and spatial three-dimensional structure was used as reducing and stabilizing agents without other chemical reagents, and the effects of the ratio of lignin to Ag(+), reaction temperature, and heating time on the synthesis of AgNPs were investigated. The obtained AgNPs were further characterized by UV-vis, Malvern particle size, TEM, XRD, and XPS analyses. The structural changes of lignin before and after reaction were also studied by FT-IR, (1)H NMR, (13)C NMR, and GC-MS. The results revealed that the obtained AgNPs were mostly spherical with diameters of around 24 nm. The optimum reaction conditions were a ratio 50 mg of lignin to 0.3 mM of Ag(+), a microwave irradiation temperature of 60 degrees C, and a heating time of 10 min. Moreover, AgNPs redispersed well in water and ethanol after centrifugation for the removal of lignin. During the formation of AgNPs, lignin was oxidized, and the side chains of lignin were partly disrupted into small molecules, such as hydrocarbon and alcohol. The resultant lignin-AgNPs showed highly selective sensing detection for Hg(2+), and the color of the lignin-AgNP solution containing Hg(2+) decreased gradually with increasing amounts of Hg(2+) within seconds, but the other 19 metal ions had little effect on the color and surface plasmon absorption band of the lignin AgNPs. Also, there was a linear relationship between the absorbance and Hg(2+) concentration, with a limit of detection concentration of 23 nM. This study provides not only a new way to take advantage of agricultural and forestry residues, but also a green and rapid method for the synthesis of AgNPs to detect the toxic ion Hg(2+) selectively and sensitively. PMID- 25144309 TI - Prognostic evaluation of DNA index in HIV-HPV co-infected women cervical samples attending in reference centers for HIV-AIDS in Recife. AB - INTRODUCTION: Persistence of cervical infection caused by human papillomavirus (HPV) types with high oncogenic risk may lead to cervical intraepithelial neoplasia (CIN). The aim of the present study was to evaluate whether, in HIV positive women, the presence of aneuploidy in cervical cell samples is associated with presence and evolution of CIN. METHODS: The present study had two stages. In the first stage, comprising a cross-sectional study, the association between the presence of aneuploidy seen via flow cytometry and sociodemographic characteristics, habits and characteristics relating to HPV and HIV infection was analyzed. In the second stage, comprising a cohort study, it was investigated whether aneuploidy was predictive of CIN evolution. RESULTS: No association was observed between the presence of aneuploidy and HPV infection, or between its presence and alterations seen in oncotic cytological analysis. On the other hand, aneuploidy was associated with the presence of CIN (p = 0.030) in histological analysis and with nonuse of antiretroviral therapy (p = 0.001). Most of the HIV positive women (234/272) presented normal CD4+ T lymphocyte counts (greater than 350 cells/mm3) and showed a greater aneuploidy regression rate (77.5%) than a progression rate (23.9%) over a follow-up of up to two years. CONCLUSION: Although there was an association between the presence of cervical tissue lesions and the DNA index, the latter was not predictive of progression of the cervical lesion. This suggests that progression of the cervical lesion to cancer in HIV positive women may also be changed through improvement of the immunological state enabled by using antiretroviral therapy. PMID- 25144310 TI - Assessment of mouse germinal vesicle stage oocyte quality by evaluating the cumulus layer, zona pellucida, and perivitelline space. AB - To improve the outcome of assisted reproductive technology (ART) for patients with ovulation problems, it is necessary to retrieve and select germinal vesicle (GV) stage oocytes with high developmental potential. Oocytes with high developmental potential are characterized by their ability to undergo proper maturation, fertilization, and embryo development. In this study, we analyzed morphological traits of GV stage mouse oocytes, including cumulus cell layer thickness, zona pellucida thickness, and perivitelline space width. Then, we assessed the corresponding developmental potential of each of these oocytes and found that it varies across the range measured for each morphological trait. Furthermore, by manipulating these morphological traits in vitro, we were able to determine the influence of morphological variation on oocyte developmental potential. Manually altering the thickness of the cumulus layer showed strong effects on the fertilization and embryo development potentials of oocytes, whereas manipulation of zona pellucida thickness effected the oocyte maturation potential. Our results provide a systematic detailed method for selecting GV stage oocytes based on a morphological assessment approach that would benefit for several downstream ART applications. PMID- 25144311 TI - Systematic regional variations in Purkinje cell spiking patterns. AB - In contrast to the uniform anatomy of the cerebellar cortex, molecular and physiological studies indicate that significant differences exist between cortical regions, suggesting that the spiking activity of Purkinje cells (PCs) in different regions could also show distinct characteristics. To investigate this possibility we obtained extracellular recordings from PCs in different zebrin bands in crus IIa and vermis lobules VIII and IX in anesthetized rats in order to compare PC firing characteristics between zebrin positive (Z+) and negative (Z-) bands. In addition, we analyzed recordings from PCs in the A2 and C1 zones of several lobules in the posterior lobe, which largely contain Z+ and Z- PCs, respectively. In both datasets significant differences in simple spike (SS) activity were observed between cortical regions. Specifically, Z- and C1 PCs had higher SS firing rates than Z+ and A2 PCs, respectively. The irregularity of SS firing (as assessed by measures of interspike interval distribution) was greater in Z+ bands in both absolute and relative terms. The results regarding systematic variations in complex spike (CS) activity were less consistent, suggesting that while real differences can exist, they may be sensitive to other factors than the cortical location of the PC. However, differences in the interactions between SSs and CSs, including the post-CS pause in SSs and post-pause modulation of SSs, were also consistently observed between bands. Similar, though less strong trends were observed in the zonal recordings. These systematic variations in spontaneous firing characteristics of PCs between zebrin bands in vivo, raises the possibility that fundamental differences in information encoding exist between cerebellar cortical regions. PMID- 25144313 TI - Highly sensitive naphthalene-based two-photon fluorescent probe for in situ real time bioimaging of ultratrace cyclooxygenase-2 in living biosystems. AB - Detecting and imaging of ultratrace cyclooxygenase-2 in living biosystems could provide much important valuable information for the diagnosis and intervention of cancer. Molecular probes, whose fluorescent signals are generated by cyclooxygenase-2, hold great potential for identification and enumeration of cyclooxygenase-2 in living biosystems. Although quite a few fluorescent probes have been reported for cyclooxygenase-2, the use fluorogenic probe with the excellent two-photon properties for the determination of ultratrace cyclooxygenase-2 has been scarce. Herein, an "off-on" fluorescence probe (BTDAN COX-2), able to report and image the presence of ultratrace cyclooxygenase-2 in living biosystems, has been designed and evaluated. In order to improve sensitivity and specific selectivity of probe for ultratrace cyclooxygenase-2, BTDAN-COX-2 employed cyclooxygenase-2's inhibitor as recognition group, because it is a classical and efficient recognition group for cyclooxygenase-2. A polarity-sensitive naphthalene derivative (BTDAN) as fluorophore was introduced into the molecule to enhance two-photon properties of BTDAN-COX-2. In the absent of cyclooxygenase-2, BTDAN-COX-2 mainly exists in a folded conformation where probe fluorescence is quenched through photoinduced electron transfer between the fluorophore and the recognition group. Under the condition of existence of cyclooxygenase-2, fluorescence of probe is turned on, because photoinduced electron transfer between the fluorophore and the recognition group is restrained. BTDAN-COX-2 provides high signal-to-background staining for the ultratrace cyclooxygenase-2 and has been successfully used to rapidly detect and image ultratrace cyclooxygenase-2 in living biosystems. PMID- 25144314 TI - Hydrothermal fabrication of MnCO3@rGO composite as an anode material for high performance lithium ion batteries. AB - The layer structure of graphene or reduced graphene oxide (rGO) opens an avenue for the development of advanced functional materials. In this paper, a MnCO3@rGO composite (MGC) was fabricated by anchoring MnCO3 nanoparticles (NPs) on rGO sheets in the hydrothermal reduction process of graphene oxide by using NaBH4. MnCO3 NPs with an average diameter of 8-20 nm were anchored onto the surface of rGO. The layer structure of rGO was maintained in MGC. The MGC was employed as an anode active material for lithium ion batteries. Excellent performances were obtained with a high specific capacity up to 857 mA.h.g(-1) after 100 cycles. The various charging-discharging current rates of 0.2-5.0 C exhibited no clear negative effect on the recycling stability of the MGC. The enhanced structure stability and ion and electron conductivity of the MGC are responsible for the superior electrochemical properties. PMID- 25144312 TI - Chemo-predictive assay for targeting cancer stem-like cells in patients affected by brain tumors. AB - Administration of ineffective anticancer therapy is associated with unnecessary toxicity and development of resistant clones. Cancer stem-like cells (CSLCs) resist chemotherapy, thereby causing relapse of the disease. Thus, development of a test that identifies the most effective chemotherapy management offers great promise for individualized anticancer treatments. We have developed an ex vivo chemotherapy sensitivity assay (ChemoID), which measures the sensitivity of CSLCs as well as the bulk of tumor cells to a variety of chemotherapy agents. Two patients, a 21-year old male (patient 1) and a 5-month female (patient 2), affected by anaplastic WHO grade-III ependymoma were screened using the ChemoID assay. Patient 1 was found sensitive to the combination of irinotecan and bevacizumab, which resulted in a prolonged disease progression free period of 18 months. Following recurrence, the combination of various chemotherapy drugs was tested again with the ChemoID assay. We found that benzyl isothiocyanate (BITC) greatly increased the chemosensitivity of the ependymoma cells to the combination of irinotecan and bevacizumab. After patient 1 was treated for two months with irinotecan, bevacizumab and supplements of cruciferous vegetable extracts containing BITC, we observed over 50% tumoral regression in comparison with pre ChemoID scan as evidenced by MRI. Patient 2 was found resistant to all treatments tested and following 6 cycles of vincristine, carboplatin, cyclophosphamide, etoposide, and cisplatin in various combinations, the tumor of this patient rapidly progressed and proton beam therapy was recommended. As expected animal studies conducted with patient derived xenografts treated with ChemoID screened drugs recapitulated the clinical observation. This assay demonstrates that patients with the same histological stage and grade of cancer may vary considerably in their clinical response, suggesting that ChemoID testing which measures the sensitivity of CSLCs as well as the bulk of tumor cells to a variety of chemotherapy agents could lead to more effective and personalized anticancer treatments in the future. PMID- 25144315 TI - Serum diamine oxidase as a hemorrhagic shock biomarker in a rabbit model. AB - BACKGROUND: In prolonged hemorrhagic shock, reductions in intestinal mucosal blood perfusion lead to mucosal barrier damage and systemic inflammation. Gastrointestinal failure in critically ill patients has a poor prognosis, so early assessment of mucosal barrier injury in shock patients is clinically relevant. Unfortunately, there is no serum marker that can accurately assess intestinal ischemia-reperfusion injury. OBJECTIVE: The aim of this study was to assess if serum diamine oxidase levels can reflect intestinal mucosal injury subsequent to prolonged hemorrhagic shock. METHODS: Thirty New Zealand white rabbits were divided into three groups: a control group, a medium blood pressure (BP) group (exsanguinated to a shock BP of 50 to 41 mm Hg), and a low BP group (exsanguinated to a shock blood pressure of 40 to 31 mm Hg), in which the shock BP was sustained for 180 min prior to fluid resuscitation. RESULTS: The severity of hemorrhagic shock in the low BP group was significantly greater than that of the medium BP group according to the post-resuscitation BP, serum tumor necrosis factor (TNF)-alpha, and arterial lactate. Intestinal damage was significantly more severe in the low BP group according to Chiu's scoring, claudin-1, intercellular adhesion molecule (ICAM)-1, and myeloperoxidase expression. Serum diamine oxidase was significantly increased in the low BP group compared to the medium BP and control groups and was negatively correlated with shock BP. CONCLUSION: Serum diamine oxidase can be used as a serological marker in evaluating intestinal injury and shows promise as an indicator of hemorrhagic shock severity. PMID- 25144316 TI - In vivo evaluation of adeno-associated virus gene transfer in airways of mice with acute or chronic respiratory infection. AB - Patients with cystic fibrosis (CF) often suffer chronic lung infection with concomitant inflammation, a setting that may reduce the efficacy of gene transfer. While gene therapy development for CF often involves viral-based vectors, little is known about gene transfer in the context of an infected airway. In this study, three mouse models were established to evaluate adeno associated virus (AAV) gene transfer in such an environment. Bordetella bronchiseptica RB50 was used in a chronic, nonlethal respiratory infection in C57BL/6 mice. An inoculum of ~10(5) CFU allowed B. bronchiseptica RB50 to persist in the upper and lower respiratory tracts for at least 21 days. In this infection model, administration of an AAV vector on day 2 resulted in 2.8-fold reduction of reporter gene expression compared with that observed in uninfected controls. Postponement of AAV administration to day 14 resulted in an even greater (eightfold) reduction of reporter gene expression, when compared with uninfected controls. In another infection model, Pseudomonas aeruginosa PAO1 was used to infect surfactant protein D (SP-D) or surfactant protein A (SP-A) knockout (KO) mice. With an inoculum of ~10(5) CFU, infection persisted for 2 days in the nasal cavity of either mouse model. Reporter gene expression was approximately ~2.5 fold lower compared with uninfected mice. In the SP-D KO model, postponement of AAV administration to day 9 postinfection resulted in only a two fold reduction in reporter gene expression, when compared with expression seen in uninfected controls. These results confirm that respiratory infections, both ongoing and recently resolved, decrease the efficacy of AAV-mediated gene transfer. PMID- 25144318 TI - The development of Nanoscale. PMID- 25144317 TI - How far are we from visceral leishmaniasis elimination in Bangladesh? An assessment of epidemiological surveillance data. AB - INTRODUCTION: In 2005, Bangladesh, India, and Nepal joined forces to eliminate Visceral Leishmaniasis (or kala-azar) from the region by 2015. In Bangladesh the elimination target is set at less than one new case per 10,000 population per year at upazila (sub-district) level. As the deadline approaches, we review the status of the elimination initiative in this country. METHODS: We collected all available disease surveillance data at the Disease Control Unit of the Directorate General of Health Services, Government of Bangladesh from 1994 to 2013. Additionally, we retrieved data from the Civil Surgeon Office from the Mymensingh district, one of the most heavily affected areas in Bangladesh. RESULTS: Between 1994 and 2013, 109,266 kala-azar cases causing 329 deaths were reported from 37 endemic districts in Bangladesh. Only 16 districts reported cases every year. The Mymensingh district was the most affected with 53,582 (49.04%) cases. Between 2008 and 2013 only 16 upazilas showed incidence rates above the elimination target in which they ranged from 1.06 to 18.25 per 10,000 people per year. DISCUSSION: While clear progress has been made towards eliminating VL, 16 upazilas in Bangladesh had not yet reached the target in 2013, based on official notification data that probably suffered from under-reporting bias. The elimination initiative urgently needs to establish methods to ascertain and monitor the elimination target. PMID- 25144320 TI - Experimental verification of carrier multiplication in graphene. AB - We report on the first direct experimental observation of carrier multiplication in graphene reaching a multiplication factor of up to 2 and persisting on a picoseconds time scale. Exploiting multicolor pump-probe measurement techniques, the excited nonequilibrium carrier distribution is retrieved on an ultrafast time scale. This provides access to the temporal evolution of the optically excited carrier density and thus allows quantitative conclusions on possible carrier multiplication. Microscopic time- and momentum-resolved calculations on the ultrafast relaxation dynamics of optically excited carriers confirm the observation of carrier multiplication under corresponding experimental conditions, suggesting graphene as a promising material for novel high-efficiency photodetection devices. PMID- 25144319 TI - Characterization of DNA repair deficient strains of Chlamydomonas reinhardtii generated by insertional mutagenesis. AB - While the mechanisms governing DNA damage response and repair are fundamentally conserved, cross-kingdom comparisons indicate that they differ in many aspects due to differences in life-styles and developmental strategies. In photosynthetic organisms these differences have not been fully explored because gene-discovery approaches are mainly based on homology searches with known DDR/DNA repair proteins. Here we performed a forward genetic screen in the green algae Chlamydomonas reinhardtii to identify genes deficient in DDR/DNA repair. We isolated five insertional mutants that were sensitive to various genotoxic insults and two of them exhibited altered efficiency of transgene integration. To identify genomic regions disrupted in these mutants, we established a novel adaptor-ligation strategy for the efficient recovery of the insertion flanking sites. Four mutants harbored deletions that involved known DNA repair factors, DNA Pol zeta, DNA Pol theta, SAE2/COM1, and two neighbouring genes encoding ERCC1 and RAD17. Deletion in the last mutant spanned two Chlamydomonas-specific genes with unknown function, demonstrating the utility of this approach for discovering novel factors involved in genome maintenance. PMID- 25144322 TI - The UF/NCI family of hybrid computational phantoms representing the current US population of male and female children, adolescents, and adults--application to CT dosimetry. AB - Substantial increases in pediatric and adult obesity in the US have prompted a major revision to the current UF/NCI (University of Florida/National Cancer Institute) family of hybrid computational phantoms to more accurately reflect current trends in larger body morphometry. A decision was made to construct the new library in a gridded fashion by height/weight without further reference to age-dependent weight/height percentiles as these become quickly outdated. At each height/weight combination, circumferential parameters were defined and used for phantom construction. All morphometric data for the new library were taken from the CDC NHANES survey data over the time period 1999-2006, the most recent reported survey period. A subset of the phantom library was then used in a CT organ dose sensitivity study to examine the degree to which body morphometry influences the magnitude of organ doses for patients that are underweight to morbidly obese in body size. Using primary and secondary morphometric parameters, grids containing 100 adult male height/weight bins, 93 adult female height/weight bins, 85 pediatric male height/weight bins and 73 pediatric female height/weight bins were constructed. These grids served as the blueprints for construction of a comprehensive library of patient-dependent phantoms containing 351 computational phantoms. At a given phantom standing height, normalized CT organ doses were shown to linearly decrease with increasing phantom BMI for pediatric males, while curvilinear decreases in organ dose were shown with increasing phantom BMI for adult females. These results suggest that one very useful application of the phantom library would be the construction of a pre-computed dose library for CT imaging as needed for patient dose-tracking. PMID- 25144321 TI - Rapidly self-renewing human multipotent marrow stromal cells (hMSC) express sialyl Lewis X and actively adhere to arterial endothelium in a chick embryo model system. AB - BACKGROUND: There have been conflicting observations regarding the receptors utilized by human multipotent mesenchymal bone marrow stromal cells (hMSC) to adhere to endothelial cells (EC). To address the discrepancies, we performed experiments with cells prepared with a standardized, low-density protocol preserving a sub-population of small cells that are rapidly self-renewing. METHODS: Sialyl Lewis X (SLeX) and alpha4 integrin expression were determined by flow cytometry. Fucosyltransferase expression was determined by quantitative realtime RT-PCR. Cell adhesion assays were carried out with a panel of endothelial cells from arteries, veins and the microvasculature in vitro. In vivo experiments were performed to determine single cell interactions in the chick embryo chorioallantoic membrane (CAM). The CAM is a well-characterized respiratory organ allowing for time-lapse image acquisition of large numbers of cells treated with blocking antibodies against adhesion molecules expressed on hMSC. RESULTS: hMSC expressed alpha4 integrin, SLeX and fucosyltransferase 4 and adhered to human EC from arteries, veins and the microvasculature under static conditions in vitro. In vivo, hMSC rolled on and adhered to arterioles in the chick embryo CAM, whereas control melanoma cells embolized. Inhibition of alpha4 integrin and/or SLeX with blocking antibodies reduced rolling and adhesion in arterioles and increased embolism of hMSC. CONCLUSIONS: The results demonstrated that rapidly self-renewing hMSC were retained in the CAM because they rolled on and adhered to respiratory arteriolar EC in an alpha4 integrin- and SLeX dependent manner. It is therefore important to select cells based on their cell adhesion receptor profile as well as size depending on the intended target of the cell and the injection route. PMID- 25144324 TI - Obstructive sleep apnea and cardiovascular comorbidities: a large epidemiologic study. AB - Obstructive sleep apnea (OSA) is a common disorder, characterized by cyclic cessation of airflow for 10 seconds or more. There is growing awareness that OSA is related to the development and progression of cardiovascular disease. However, only a few studies have associated OSA directly to major cardiovascular events. The aim of this study was to evaluate the relationship between OSA and cardiovascular morbidity in a well defined population of patients.The electronic database of the central district of a major health management organization was searched for all patients diagnosed with OSA in 2002-2010. For each patient identified, an age- and sex-matched patient was randomly selected from the members of the same health management organization who did not have OSA. Data on demographics, socioeconomic status, and relevant medical parameters were collected as well.The study population included 2797 patients, average age 58.1, in which 76.6% were males. There was a significant correlation between OSA and the presence of ischemic heart disease (P < 0.001), pulmonary hypertension (P < 0.001), congestive heart failure (P < 0.001), cardiomyopathy (P = 0.003), and arrhythmia (P < 0.001). OSA was also significantly correlated with low socioeconomic status (P < 0.001).OSA and cardiovascular disease were strongly correlated. As such, early diagnosis and treatment of OSA may change the course of both diseases. We suggest that sleep disordered breathing should be routinely assessed in patients with cardiovascular problems. An ear-nose-throat evaluation may also be important to rule out anatomic disorders that cause upper airway obstruction. PMID- 25144325 TI - A case of severe chlorite poisoning successfully treated with early administration of methylene blue, renal replacement therapy, and red blood cell transfusion: case report. AB - The case of a 55-year-old man who attempted suicide by ingesting <100 mL of 28% sodium chlorite solution is presented. On arrival in the intensive care unit, the patient appeared cyanotic with lowered consciousness and displayed anuria and chocolate brown serum.Initial laboratory tests revealed 40% of methemoglobin. The formation of methemoglobin was effectively treated with methylene blue (10% after 29 hours).To remove the toxin, and because of the anuric acute renal failure, the patient received renal replacement therapy. Despite these therapeutic measures, the patient developed hemolytic anemia and disseminated intravascular coagulation, which were treated with red blood cell transfusion and intermittent hemodialysis. These interventions led to the improvement of his condition and the patient eventually fully recovered. Patient gave written informed consent.This is the third known case of chlorite poisoning that has been reported. Based upon this case, we suggest the management of sodium chlorite poisoning to comprise the early administration of methylene blue, in addition to renal replacement therapy and transfusion of red blood cells. PMID- 25144326 TI - Intestinal insufflation of small volume of oxygen increases systemic oxygenation in acute respiratory distress sundrome patients. PMID- 25144323 TI - Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation. AB - The mechanisms underlying cardiac automaticity are still incompletely understood and controversial. Here we report the complete conditional and time-controlled silencing of the 'funny' current (If) by expression of a dominant-negative, non conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific If silencing caused altered [Ca(2+)]i release and Ca(2+) handling in the sinoatrial node, impaired pacemaker activity and symptoms reminiscent of severe human disease of pacemaking. The effects of If silencing critically depended on the activity of the autonomic nervous system. We were able to rescue the failure of impulse generation and conduction by additional genetic deletion of cardiac muscarinic G protein-activated (GIRK4) channels in If-deficient mice without impairing heartbeat regulation. Our study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels, thus offering a new therapeutic strategy for the treatment of heart rhythm diseases. PMID- 25144327 TI - Fibreoptic tracheal intubation training using bronchoscopy simulation. PMID- 25144328 TI - The energetics of isomerisation in Keggin-series aluminate cations. AB - Electronic-structure calculations show that the epsilon-isomer of the polyoxoaluminate ion in the Keggin structure [AlO4-(Al(OH)2(H2O))12](7+) is the thermodynamically favoured one. Direct interconversion between the epsilon- and delta-isomers via cap rotation has a prohibitively high energy barrier in vacuo, suggesting that isomerisation in solution either proceeds via a dissolution precipitation pathway, or that solvation and/or coordination to counterions reduces the barrier significantly. The implications for the formation of the [Al2O8Al28(OH)56(H2O)26](18+) ion are discussed. PMID- 25144329 TI - Positron emission tomography in CNS drug discovery and drug monitoring. AB - Molecular imaging methods such as positron emission tomography (PET) are increasingly involved in the development of new drugs. Using radioactive tracers as imaging probes, PET allows the determination of the pharmacokinetic and pharmacodynamic properties of a drug candidate, via recording target engagement, the pattern of distribution, and metabolism. Because of the noninvasive nature and quantitative end point obtainable by molecular imaging, it seems inherently suited for the examination of a pharmaceutical's behavior in the brain. Molecular imaging, most especially PET, can therefore be a valuable tool in CNS drug research. In this Perspective, we present the basic principles of PET, the importance of appropriate tracer selection, the impact of improved radiopharmaceutical chemistry in radiotracer development, and the different roles that PET can fulfill in CNS drug research. PMID- 25144330 TI - In situ X-ray absorption spectroscopy studies of kinetic interaction between platinum(II) ions and UiO-66 series metal-organic frameworks. AB - The interaction of guest Pt(II) ions with UiO-66-X (X = NH2, H, NO2, OMe, F) series metal-organic frameworks (MOFs) in aqueous solution was investigated using in situ X-ray absorption spectroscopy. All of these MOFs were found to be able to coordinate with Pt(II) ions. The Pt(II) ions in UiO-66-X MOFs generally coordinate with 1.6-2.4 Cl and 1.4-2.4 N or O atoms. We also studied the time evolution of the coordination structure and found that Pt(II) maintained a coordination number of 4 throughout the whole process. Furthermore, the kinetic parameters of the interaction of Pt(II) ions with UiO-66-X series MOFs (X = NH2, H, NO2, OMe, F) were determined by combinational linear fitting of extended X-ray absorption fine structure (EXAFS) spectra of the samples. The Pt(II) adsorption rate constants were found to be 0.063 h(-1) for UiO-66-NH2 and 0.011-0.017 h(-1) for other UiO-66-X (X = H, NO2, OMe, F) MOFs, which means that Pt(II) adsorption in UiO-66-NH2 is 4-6 times faster than that in other UiO-66 series MOFs. FTIR studies suggested that the carboxyl groups could be the major host ligands binding with Pt(II) ions in UiO-66 series MOFs, except for UiO-66-NH2, in which amino groups coordinate with Pt(II) ions. PMID- 25144332 TI - Emerging roles of RNA processing factors in regulating long non-coding RNAs. AB - Long non-coding RNAs (lncRNAs) can be important regulators of various biological processes such as RNA-directed DNA methylation (RdDM). In the RdDM pathway, recruitment of the DNA methylation complex is mediated through complementary pairing between scaffold RNAs and Argonaute-associated siRNAs. Scaffold RNAs are chromatin-associated lncRNAs transcribed by RNA polymerase Pol V or Pol II, while siRNAs originate from Pol IV- or Pol II-dependent production of lncRNAs. In contrast to the vast literature on co-transcriptional and post-transcriptional processing of mRNAs, information is limited for lncRNA regulation that enables their production and function. Recently Arabidopsis RRP6L1, a plant paralog of the conserved nuclear RNA surveillance protein Rrp6, was shown to mediate RdDM through retention of lncRNAs in the chromatin, thereby revealing that accumulation of functional lncRNAs requires more than simply RNA polymerases. By focusing on the canonical RdDM pathway, here we summarize recent evidence that indicate co-transcriptional and/or post-transcriptional regulation of lncRNAs, and highlight the emerging theme of lncRNA regulation by RNA processing factors. PMID- 25144333 TI - Atypical lymphocytic angiitis of the optic nerve and central nervous system. PMID- 25144335 TI - Effect of CYP2C9 genetic polymorphism on the metabolism of flurbiprofen in vitro. AB - CYP2C9 is an important member of the cytochrome P450 enzyme superfamily, and 57 cytochrome P450 2C9 alleles have been previously reported. To examine the enzymatic activity of the CYP2C9 alleles, kinetic parameters for 4' hydroxyflurbiprofen were determined using recombinant human P450s CYP2C9 microsomes from insect cells Sf21 carrying wild-type CYP2C9*1 and other variants. The results showed that the enzyme activity of most of the variants decreased comparing with the wild type as the previous studies reported, while the enzyme activity of some of them increased, which were not in accordance with the previous researches. Of the 36 tested CYP2C9 allelic isoforms, two variants (CYP2C9*53 and CYP2C9*56) showed a higher intrinsic clearance value than the wild type protein, especially for CYP2C9*56, exhibited much higher intrinsic clearance (197.3%) relative to wild-type CYP2C9*1, while the remaining 33 CYP2C9 allelic isoforms exhibited significantly decreased clearance values (from 0.6 to 83.8%) compared to CYP2C9*1. This study provided the most comprehensive data on the enzymatic activities of all reported CYP2C9 variants in the Chinese population with regard to the commonly used non-steroidal anti-inflammatory drug, flurbiprofen (FP). The results indicated that most of the tested rare alleles decreased the catalytic activity of CYP2C9 variants toward FP hydroxylation in vitro. This is the first report of all these rare alleles for FP metabolism providing fundamental data for further clinical studies on CYP2C9 alleles for FP metabolism in vivo. PMID- 25144336 TI - A continuous-flow protocol for light-induced benzylic fluorinations. AB - A continuous-flow protocol for the light-induced fluorination of benzylic compounds is presented. The procedure uses Selectfluor as the fluorine source and xanthone as an inexpensive and commercially available photoorganocatalyst. The flow photoreactor is based on transparent fluorinated ethylene propylene tubing and a household compact fluorescent lamp. The combination of xanthone with black light irradiation results in very efficient fluorination. Good to excellent isolated yields were obtained for a variety of substrates bearing different functional groups applying residence times below 30 min. PMID- 25144334 TI - Surge capacity principles: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: This article provides consensus suggestions for expanding critical care surge capacity and extension of critical care service capabilities in disasters or pandemics. It focuses on the principles and frameworks for expansion of intensive care services in hospitals in the developed world. A companion article addresses surge logistics, those elements that provide the capability to deliver mass critical care in disaster events. The suggestions in this article are important for all who are involved in large-scale disasters or pandemics with injured or critically ill multiple patients, including front-line clinicians, hospital administrators, and public health or government officials. METHODS: The Surge Capacity topic panel developed 23 key questions focused on the following domains: systems issues; equipment, supplies, and pharmaceuticals; staffing; and informatics. Literature searches were conducted to identify evidence on which to base key suggestions. Most reports were small scale, were observational, or used flawed modeling; hence, the level of evidence on which to base recommendations was poor and did not permit the development of evidence-based recommendations. Therefore, the panel developed expert opinion-based suggestions using a modified Delphi process. Suggestions from the previous task force were also included for validation by the expert panel. RESULTS: This article presents 10 suggestions pertaining to the principles that should guide surge capacity and capability planning for mass critical care, including the role of critical care in disaster planning; the surge continuum; targets of surge response; situational awareness and information sharing; mitigating the impact on critical care; planning for the care of special populations; and service deescalation/cessation (also considered as engineered failure). CONCLUSIONS: Future reports on critical care surge should emphasize population-based outcomes as well as logistical details. Planning should be based on the projected number of critically ill or injured patients resulting from specific scenarios. This should include a consideration of ICU patient care requirements over time and must factor in resource constraints that may limit the ability to provide care. Standard ICU management forms and patient data forms to assess ICU surge capacity impacts should be created and used in disaster events. PMID- 25144338 TI - The Helicobacter pylori resistance rate to clarithromycin in Iran. AB - BACKGROUND: Clarithromycin is the most commonly suggested antibiotic in Helicobacter pylori eradication regimens. Increasing antibiotic resistance rate to clarithromycin is the main reason for therapeutic failure. The resistance is associated with mutations in the 23S rRNA gene. AIM: The purpose of this study was to determine the clarithromycin resistance rate of isolated H. pylori strains from referral patients in Kashan, Iran. METHODS: In total 95 H. pylori strains isolated from gastric mucosa of 246 patients with different clinical signs underwent gastroscopy in Kashan, Iran in 2013. The Epsilometer test was used to determine the minimum inhibitory concentrations (MICs) of clarithromycin (CLR) in isolated H. pylori strains. Occurrence of mutation in 23S rRNA gene of clarithromycin-resistant strains was investigated with polymerase chain reaction sequencing method. RESULTS: Antibiotic susceptibility pattern showed that 32 strains (33.7%) were resistant to clarithromycin (MICs >=1 MUg/ml), 33.7% were intermediate resistant, while 31 of H. pylori strains (32.6%) were susceptible. The 23S rRNA gene mutations at positions A2143G and A2142G were detected in H. pylori clarithromycin-resistant strains. CONCLUSION: The resistance rate to clarithromycin in Iran is high. H. pylori clarithromycin-resistant strains were not associated with sex, age, and disease. The A2143G mutation in clarithromycin resistant H. pylori strains was the predominant finding. PMID- 25144340 TI - Coronary bypass surgery: from variability to standardization? AB - PURPOSE OF REVIEW: The review summarizes recent literature on standardization of care in coronary artery bypass grafting (CABG), with particular attention to the impact of standardization on outcomes and resource utilization. RECENT FINDINGS: An increasing number of studies have demonstrated potential advantages to standardization in CABG. Certain process measures such as specific medications at discharge, selection and duration of antibiotic prophylaxis, and use of the internal mammary artery have been advocated as quality indicators in CABG and have contributed to standardized care and improvement in outcomes. In addition, as the potentially harmful consequences of blood transfusions are increasingly being recognized, efforts to standardize transfusion practices in CABG have been undertaken. Nevertheless, despite recognition that uniformity of care improves outcomes, evidence suggests that there continues to be substantial variability between hospitals in the delivery of care to the CABG patient. SUMMARY: There continue to be opportunities for further identification and implementation of cost-effective pathways to lower overall resource utilization while improving outcomes in CABG patients. PMID- 25144341 TI - Postthrombotic syndrome: a 2014 update. AB - PURPOSE OF REVIEW: Postthrombotic syndrome (PTS) is the most frequent complication of deep vein thrombosis. Its pathophysiology is incompletely understood and therapeutic options are limited. This review aims to present and discuss recently published studies that have improved our knowledge related to PTS. RECENT FINDINGS: From a prognostic point of view, some polymorphisms of plasminogen activator inhibitor-1 and platelet endothelial cell adhesion molecule 1 influence the degree of thrombus resolution after deep vein thrombosis and the subsequent rate of PTS, and could help in predicting the risk of PTS. From a therapeutic point of view, the results of a large multicenter placebo-controlled trial suggest an absence of effectiveness of elastic compression stockings to prevent PTS. In addition, although the Cavent trial of catheter-directed thrombolysis to treat ilio-femoral deep vein thrombosis showed significant reduction in the incidence of PTS that was cost-effective, secondary analyses did not show dramatic improvements in quality of life associated with use of catheter directed thrombolysis. SUMMARY: Choice of anticoagulant to treat deep vein thrombosis may represent a new cornerstone of PTS therapeutic management. Studies are needed to assess the impact of new oral anticoagulants and the benefit of extended courses of low molecular weight heparins on the risk of PTS. PMID- 25144337 TI - Resource-poor settings: infrastructure and capacity building: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: Planning for mass critical care (MCC) in resource-poor or constrained settings has been largely ignored, despite their large populations that are prone to suffer disproportionately from natural disasters. Addressing MCC in these settings has the potential to help vast numbers of people and also to inform planning for better-resourced areas. METHODS: The Resource-Poor Settings panel developed five key question domains; defining the term resource poor and using the traditional phases of disaster (mitigation/preparedness/response/recovery), literature searches were conducted to identify evidence on which to answer the key questions in these areas. Given a lack of data upon which to develop evidence based recommendations, expert-opinion suggestions were developed, and consensus was achieved using a modified Delphi process. RESULTS: The five key questions were then separated as follows: definition, infrastructure and capacity building, resources, response, and reconstitution/recovery of host nation critical care capabilities and research. Addressing these questions led the panel to offer 33 suggestions. Because of the large number of suggestions, the results have been separated into two sections: part 1, Infrastructure/Capacity in this article, and part 2, Response/Recovery/Research in the accompanying article. CONCLUSIONS: Lack of, or presence of, rudimentary ICU resources and limited capacity to enhance services further challenge resource-poor and constrained settings. Hence, capacity building entails preventative strategies and strengthening of primary health services. Assistance from other countries and organizations is needed to mount a surge response. Moreover, planning should include when to disengage and how the host nation can provide capacity beyond the mass casualty care event. PMID- 25144342 TI - Vitamin D and atherosclerosis. AB - PURPOSE OF REVIEW: To provide an overview of the association between vitamin D deficiency and atherosclerosis. RECENT FINDINGS: Vitamin D exerts protective effects on atherosclerosis through multiple mechanisms. It has been shown to protect against endothelial dysfunction, vascular smooth muscle cell proliferation and migration, and modulation of the immune system, as well as the inflammatory response. In addition, vitamin D has been shown to have systemic effects on insulin resistance, dyslipidemia, and hypertension. SUMMARY: Vitamin D deficiency is widely prevalent in the United States and worldwide. Although deficiency of this fat-soluble vitamin is usually associated with musculoskeletal disorder, it is associated with a wide range of disease processes that include multiple organ systems. Recently, there has been mounting evidence linking vitamin D deficiency to cardiovascular disease and atherosclerosis. PMID- 25144343 TI - Perspectives on the management of antiplatelet therapy in patients with coronary artery disease requiring cardiac and noncardiac surgery. AB - PURPOSE OF REVIEW: To provide an updated overview on the management of antiplatelet therapy in patients with coronary stents undergoing cardiac and noncardiac surgery. RECENT FINDINGS: Surgical procedures are frequently performed in patients with coronary stents and are associated with an increased risk of ischemic and bleeding complications in the perioperative period. Given the lack of well-designed prospective randomized trials, guidelines recommendations are currently derived from observational studies and expert consensus. Defining the optimal balance between the risk of thrombotic events following discontinuation of antiplatelet therapy and the risk of hemorrhagic complications of having a surgical procedure while on antiplatelet therapy is pivotal. Elective surgery should be postponed for at least 4 weeks after bare metal stent implantation and 6-12 months after drug-eluting stent. If this is not possible, aspirin should be continued in the perioperative period, although the management of P2Y12 inhibitors should be individualized according to the individual patient and type of surgery. SUMMARY: In the absence of well-defined recommendations deriving from prospective randomized clinical trials, the perioperative management of antiplatelet therapy should be based on the balance between the specific thrombotic and hemorrhagic risks that characterize each patient and each surgical procedure. PMID- 25144344 TI - Downregulation of clusterin mediates sensitivity to protein kinase inhibitors in breast cancer cells. AB - The efficacy of protein kinase inhibitors (PKIs) has been shown in clinical assays for cancer, but as isolated agents, they only have a modest effect. One of the most important characteristics of mitogen-activated PKIs is their ability to decrease the apoptotic threshold of cancer cells, sensitizing them to the action of other antiapoptotic agents. The secretory clusterin protein is an inhibitor of apoptosis with a cytoprotective function. We describe the use of clusterin specific antisense oligonucleotides and siRNA to sensitize breast carcinoma cells to several PKIs. MCF-7 and MDA-MB-231 cells were treated with antisense oligonucleotide or siRNA to clusterin and the following PKIs: H-89, chelerythrine and genistein. The three inhibitors used in this study upregulated clusterin expression and treatments that included antisense oligonucleotide or siRNA to clusterin reduced the number of viable cells more effectively than did treatment with the drugs alone. Therefore, treatment with such combinations may benefit patients with breast cancer. PMID- 25144345 TI - Feasibility of radiotherapy or chemoradiotherapy after taxane-based induction chemotherapy for nonoperated locally advanced head and neck squamous cell carcinomas. AB - To assess the use of radiotherapy (RT) or concurrent chemoradiotherapy (CRT) following taxane-based induction chemotherapy (T-ICT) in locally advanced head and neck squamous cell carcinoma (LAHNSCC) and to evaluate the tolerability of CRT after T-ICT. From 01/2006 to 08/2012, 173 LAHNSCC patients treated as a curative intent by T-ICT, followed by definitive RT/CRT were included in this analysis. There was an 86% objective response (OR) after ICT among 154 evaluable patients. Forty-four patients received less than three cycles (25%) and 20 received only one cycle of T-ICT. The 3-year actuarial overall survival (OS) was 49% and there was no OS difference according to the type of ICT (regimen or number of cycle) or the addition of concurrent CT (cisplatin, carboplatin, or cetuximab) to RT. In multivariate analysis (MVA), clinically involved lymph node (cN+), age more than 60 years, the absence of OR after ICT, and performance status of at least 1 predicted for a decreased OS, with hazard ratios (HR) of 2.8, 2.2, 2.1, and 2, respectively. The 3-year actuarial locoregional control (LRC) and distant control (DC) rates were 52 and 73%, respectively. In MVA, the absence of OR after ICT (HR: 3.2), cN+ (HR: 3), and age more than 60 years (HR: 1.7) were prognostic for a lower LRC whereas cN+ (HR: 4.2) and carboplatin-based T-ICT (HR: 2.9) were prognostic for a lower DC. The number of cycles (<= 2) received during ICT was borderline significant for DC in the MVA (P=0.08). Among patients receiving less than or equal to three cycles of ICT, higher outcomes were observed in patients who received cisplatin-based T-ICT (vs. carboplatin based T-ICT) or subsequent CRT (vs. RT). T-ICT in our experience, followed by RT or CRT, raises several questions on the role and type of induction, and the efficacy of CRT over RT. The role of RT or CRT following induction, although feasible in these advanced patients, awaits answers from randomized trials. PMID- 25144346 TI - Bioavailability of cyclophosphamide and vincristine after intraperitoneal administration in cats. AB - Cyclophosphamide and vincristine are widely used intravenous chemotherapeutic agents in both human and veterinary oncology. Although intravenous administration of these chemotherapeutics is the gold standard in most treatment protocols, this route of administration has several disadvantages (e.g. long infusion times and risk of extravasation). Therefore, alternative routes have been explored in the past. Recently, good clinical results were achieved with intraperitoneal (i.p.) administration of cyclophosphamide and vincristine in cats. However, the bioavailability following i.p. administration of cyclophosphamide and vincristine providing proof of principle has not been investigated and is the focus of the present study. The pharmacokinetics of cyclophosphamide and vincristine after i.p. and intravenous administration was investigated in six cats in a cross-over study by analysis of plasma levels of cyclophosphamide and vincristine after simultaneously administration of 0.6 mg/m vincristine and 200 mg/m cyclophosphamide. The median bioavailability on i.p. administration was 76% for cyclophosphamide and 100% for vincristine. Median areas under the curve for i.p. and intravenous administration were 11.4 and 16.0 ng h/ml for cyclophosphamide and 16.7 and 16.5 ng h/ml for vincristine, respectively. No specific i.p. administration-related adverse events were observed after i.p. administration. The high bioavailability of both cyclophosphamide and vincristine after i.p. administration and the absence of specific i.p. administration-related side effects suggest that i.p. administration is a suitable route of systemic chemotherapy for both chemotherapeutics. These results are promising and may serve as a stepping stone for the investigation of the pharmacology, safety, and efficacy of i.p. administration of cyclophosphamide and vincristine in humans. PMID- 25144347 TI - Micro-heterogeneity metrics for diffusion in soft matter. AB - Passive particle tracking of diffusive paths in soft matter, coupled with analysis of the path data, is firmly established as a fundamental methodology for characterization of both diffusive transport properties (the focus here) and linear viscoelasticity. For either focus, particle time series are typically analyzed by ensemble averaging over paths, a perfectly natural protocol for homogeneous materials or for applications where mean properties are sufficient. Many biological materials, however, are heterogeneous over length scales above the probe diameter, and the implications of heterogeneity for biologically relevant transport properties (e.g. diffusive passage times through a complex fluid layer) motivate this paper. Our goals are three-fold: first, to detect heterogeneity as reflected by the ensemble path data; second, to further decompose the ensemble of particle paths into statistically distinct clusters; and third, to fit the path data in each cluster to a model for the underlying stochastic process. After reviewing current best practices for detection and assessment of heterogeneity in diffusive processes, we introduce our strategy toward the first two goals with methods from the statistics and machine learning literature that have not found application thus far to passive particle tracking data. We apply an analysis based solely on the path data that detects heterogeneity and yields a decomposition of particle paths into statistically distinct clusters. After these two goals are achieved, one can then pursue model fitting. We illustrate these heterogeneity metrics on diverse datasets: for numerically generated and experimental particle paths, with tunable and unknown heterogeneity, on numerical models for simple diffusion and anomalous sub diffusion, and experimentally on sucrose, hyaluronic acid, agarose, and human lung culture mucus solutions. PMID- 25144348 TI - Enzymatically cross-linked hyperbranched polyglycerol hydrogels as scaffolds for living cells. AB - Although several strategies are now available to enzymatically cross-link linear polymers to hydrogels for biomedical use, little progress has been reported on the use of dendritic polymers for the same purpose. Herein, we demonstrate that horseradish peroxidase (HRP) successfully catalyzes the oxidative cross-linking of a hyperbranched polyglycerol (hPG) functionalized with phenol groups to hydrogels. The tunable cross-linking results in adjustable hydrogel properties. Because the obtained materials are cytocompatible, they have great potential for encapsulating living cells for regenerative therapy. The gel formation can be triggered by glucose and controlled well under various environmental conditions. PMID- 25144350 TI - Severe tracheobronchial injuries: our experience. AB - INTRODUCTION: Severe tracheobronchial injuries (TBI) in children are usually traumatic or iatrogenic. However, they can also be caused by mediastinal infections that lead to critical situations. We herein report our experience in the treatment of these lesions. METHODS: A retrospective study was conducted for patients treated at our center from 2008 to 2014. TBI was diagnosed by imaging studies and bronchoscopy. Treatment was initially conservative (drainage of air and secretions, mechanical ventilation with minimal pressures, and an early extubation) with a limited use of surgical procedures whenever necessary. RESULTS: A total of 10 patients (7 males and 3 females) with a median age of 7.5 years (range, 3-17 years) suffered TBI. The mechanism was traumatic in six (three accidental and three iatrogenic) and mediastinal infection in four (three mycotic and one bacterial abscesses). All traumatic cases responded to conservative measures, except one iatrogenic lesion, which was surgically repaired. There were no complications or residual damages. Two patients with mediastinal infection presented with sudden cardiorespiratory arrest, one with hemoptysis caused by an arteriotracheal fistula and the other because of carinal rupture. Both died before any therapeutic measures could be taken. The other two patients were treated, one with previous extracorporeal membrane oxygenation support, underwent arterial embolization, but ultimately died, and the other one survived, but required esophagectomy and creation of a thoracostome for secondary wound closure of the bronchocutaneous fistula. CONCLUSION: Conservative treatment with gentle respiratory support suffices in most traumatic cases of TBI. Infectious abscesses with involvement of adjacent structures sometimes require complex surgery and are life-threatening. PMID- 25144351 TI - Ulcerative ileitis after proctocolectomy in children: a complication of ulcerative colitis or a disease in itself after ileoanal pullthrough? AB - Ulcerative ileitis (UI) after restorative proctocolectomy (RPC) and ileoanal pullthrough procedure (IAPP) is a rare condition described as inflammation of the terminal ileum proximal to the anastomosis. It is mostly observed in ulcerative colitis (UC) and is designated as prepouch ileitis; sometimes with pouchitis, but not necessarily all the time. Its incidence in adults is less than 5%, but the information in children is limited. Pathogenesis is unknown, it has been considered as a disease by itself, independently on the underlying disease. It involves additional morbidity and impacts negatively on quality of life because there is no effective treatment so far. This study aims to review the cases of UI in our institution and to summarize their clinical features and management. A descriptive retrospective study of UI patients between 1990 and 2013 was conducted. Children with RPC and IAPP with clinical and pathological diagnosis of UI were included. Sociodemographic and clinical data, diagnostic, and therapeutic procedures were collected through medical records. UI was diagnosed in eight patients (six males) after RCP; four had UC, two had total colonic aganglionosis (TCA), and two had complex anorectal malformations (one cloacal exstrophy and one omphalopagus twin with bladder exstrophy). Different surgical techniques were used in each case: UC patients underwent IAPP, 50% with J-reservoir and 50% without it; posterior sagittal pullthrough was performed in those with anorectal malformations; one Soave and one Swenson procedure in those with TCA. In summary, three patients had reservoir and five did not. The median age at the IAPP and ostomy closure was 6 years (range 2 months-8 years) and 7 years (range 6 months-9 years), respectively. UI was found after a median of 23 months (range 1-48 months), all of them after digestive tract continuity was reestablished. The leading symptom was lower GI or gastrointestinal, both of them bleeding with abdominal pain, followed by abdominopelvic abscesses and malabsorption with weight loss. Pathology showed nonspecific inflammatory changes. Treatment included antibiotics, corticosteroids and/or immunosuppressive agents with variable response, requiring a new ileostomy in five cases. Ileitis disappeared after diversion. In our experience, UI after colectomy is not an exclusive feature of UC as has been previously described. Although it appears with pouchitis, the presence of a reservoir is not a must, suggesting that this is a different entity. No medical treatment has been really effective in our patients and diversion above this level stopped the process. Further studies on its pathogenesis and treatment strategies are necessary. PMID- 25144352 TI - Tertiary surgery for complicated repair of esophageal atresia. AB - AIM: The ideal repair of esophageal atresia (EA) is primary anastomosis with closure of the fistula if present. Long gap or local circumstances prompt other procedures that occasionally lead to disastrous complications. The aim of this study was to analyze the management of these complications in a tertiary referral center. PATIENTS AND METHODS: A retrospective review of patients treated for EA between 1993 and 2013 was conducted. Both the patients were primarily treated by us, and referrals from elsewhere after two or more failed operations were included. RESULTS: In total, 23 patients were included (3/176 cases of EA treated primarily by us and 20 referrals). Of the 23 patients, 6 had type I EA, 15 type III (four long gaps), 1 type IV, and 1 type V. Cardiac anomalies were associated in seven cases, duodenal atresia in three, and Down syndrome in two patients. Primary anastomosis was initially achieved in 12 patients. Primary or secondary Foker lengthening was used in seven cases. The causes of the failure were anastomotic leaks in nine, unmanageable strictures in seven, and refistulization in five patients. These patients required 66 reoperations (median of 3 [2-7]) before inclusion in the study. Radical tertiary treatment consisted of 15 esophageal replacements (11 colonic grafts and 4 gastric pull-ups), and 1 esophageal-gastric disconnection. Five patients previously treated with esophageal replacement and referred for graft problems required 13 interventions. Two families did not give consent for one replacement and one disconnection. Complications appeared in 12 patients, and 9 additional operations were required in 7 patients. With a follow-up of 31 months (range, 4-139 months) 15 patients take all their meals per os, 5 occasionally use the gastrostomy, and 2 and 1 are fed exclusively via gastrostomy or jejunostomy. All tracheoesophageal fistulas were closed, but 15 cases are below p3 for weight and 12 for height. Three patients (13%) ultimately died 32 months (range, 9-56 months) after the first operation (due to aspiration in one, and for causes unrelated to it in the other two [tracheostomy obstruction and Guillain-Barre syndrome]). CONCLUSIONS: When repeated complications appear after EA repair, radical surgical attitudes may be justified. If esophageal continuity cannot be reestablished, the native esophagus may have to be discarded and replaced. Many complications should be expected, but the end result can be good. These patients should be referred to centers with large experience in the management of this complex condition. PMID- 25144353 TI - Problems during the long-term follow-up after surgery for pediatric solid malignancies. AB - INTRODUCTION: With the recent improvements in the prognosis of pediatric malignancies, the number of patients surviving long-term after surgery has been increasing. Therefore, the late effects of cancer treatments are important issues. In this study, we analyzed the problems associated with the treatment of pediatric patients during the long-term follow-up after surgery. PATIENTS AND METHODS: A total of 64 patients with pediatric malignancies who underwent surgical treatment and were followed up for more than 5 years and who were older than 13 years of age were included in this study. The average age was 20.8 (13 33) years, and the follow-up ranged from 5 to 31 years (mean, 17.7 years). Twenty one patients (32.3%) received high-dose chemotherapy (HDC) and nine (14.1%) received radiotherapy. RESULTS: In this study, 46 patients (71.9%) developed at least one problem during the follow-up period. With regard to the surgical problems, 14 patients underwent nephrectomy, and 1 of them developed renal failure. One patient received cystectomy with urinary tract reconstruction. One patient received a partial vaginectomy. Two cases with ovarian tumors received oophorectomy, one of whom also received partial hysterectomy. Other complications such as ileus, scoliosis, and leg length discrepancies were seen in some patients. In terms of the medical problems, 15 patients showed growth retardation and 2 were treated with growth hormone therapy. Gonadal dysfunction was observed in 23 patients, and 8 of them were treated with hormone replacement therapy. Six patients developed hypothyroidism, two of whom were treated with thyroid hormone replacement therapy. Other medial issues, such as hearing impairment, low bone mineral density, and hepatitis, were seen in some patients. The rate of growth retardation, gonadal dysfunction, and hypothyroidism were significantly higher in the patients who received HDC (p<0.05). There was one case of second malignancy of the parotid gland. CONCLUSION: Various treatment-related complications may occur even many years after treatment, especially in patients who receive HDC. Medical problems, especially endocrine disorders, appear to be more serious than surgery-related problems. Lifetime medical surveillance and continuous follow-up by not only pediatric surgeons but also by various specialists, such as pediatric oncologists, pediatric endocrinologists, urologists, and gynecologists, are necessary. PMID- 25144354 TI - Thyroid Surgery in Children: Clinical Outcomes. AB - AIM: The aim of this study was to review the outcomes of thyroid surgery in children operated for both benign and malignant conditions. PATIENTS AND METHOD: Demography, clinical features, and surgical outcomes were noted retrospectively for operations performed during the last 23 years. Results were analyzed using Fisher exact test and Woolf (logit) method with p value < 0.05 considered as significant. RESULTS: In total, 61 children (43 girls and 18 boys) underwent thyroidectomy for benign (70%) and malignant (30%) conditions. Median follow-up period was 1.4 years. In the benign group, 84% children had Graves disease and 16% had other conditions. In this study, 42% children had total, 22% had near total, 27% had subtotal, and 9% had type 2 hemithyroidectomy. In the malignant group, 50% had multiple endocrine neoplasia, 33% had papillary, 11% had follicular cancer, and 6% had B-cell lymphoma. Fifty percent children had prophylactic thyroidectomy, 44% had total thyroidectomy plus lymphadenectomy, and 6% had hemithyroidectomy. At the time of surgery, children with benign conditions were older than those with malignancy (median, 12 vs. 7.5 years). There were no incidents of postoperative bleeding or infection. Hypocalcemia was significantly more frequent in the malignant group (39 vs. 9%, p value = 0.01). The type of recurrent laryngeal nerve (RLN) injury was more serious in the benign group (one bilateral and one unilateral permanent injury) than in the malignant group (transient hoarseness in three). Overall rate of complications was higher for operations for malignancy (56 vs. 28%, p value = 0.07). In Graves disease, the subtotal thyroidectomies had a recurrence of 30% but no recurrence was seen following total or near-total thyroidectomy group (p value = 0.01). There was no recurrence in the malignant group. Children operated after 2000 were younger than those operated before 2000 (median age, 9 vs. 14 years). Malignant conditions were more common in children operated after 2000 in comparison to before 2000 (55 vs. 10%). CONCLUSION: Benign conditions are commonest indications for thyroid surgery in children but the incidence of surgery for malignant conditions is rising. Overall rate of complications, especially hypocalcemia, is higher after surgery for malignancy but all cases of permanent RLN injury were in benign group. Total or near total thyroidectomy prevents recurrence of thyrotoxicosis and is an operation of choice for Graves disease. PMID- 25144355 TI - Simulation-based education and performance assessments for pediatric surgeons. AB - Education in the knowledge, skills, and attitudes necessary for a surgeon to perform at an expert level in the operating room, and beyond, must address all potential cognitive and technical performance gaps, professionalism and personal behaviors, and effective team communication. Educational strategies should also seek to replicate the stressors and distractions that might occur during a high risk operation or critical care event. Finally, education cannot remain fixed in an apprenticeship model of "See one, do one, teach one," whereby patients are exposed to the risk of harm inherent to any learning curve. The majority of these educational goals can be achieved with the addition of simulation-based education (SBE) as a valuable adjunct to traditional training methods. This article will review relevant principles of SBE, explore currently available simulation-based educational tools for pediatric surgeons, and finally make projections for the future of SBE and performance assessments for pediatric surgeons. PMID- 25144356 TI - Second-toe transfer for traumatic thumb amputation in children under 5 years: bone and soft-tissue growth. AB - BACKGROUND: Posttraumatic thumb amputations in children under 5 years are uncommon. The final clinical long-term results have been reported shortly in literature. We report our clinical experience in children under 5 years with traumatic amputation of the thumb that were reconstructed using a second-toe transfer. MATERIALS AND METHODS: There were 7 boys and 2 girls between the ages of 1 and 5 years. The follow-up was between 6 and 14 years. The average age at the time of transfer was 2.8 years, and the average follow-up was 10.7 years (range, between 6 and 14 y). The most frequent cause of amputation was avulsion (33.3%). RESULTS: All the transferred toes survived and achieved bone union and static 2-point discrimination was averaged at 5 mm. They acquired good prehensile pinch and grasp. All of the structures of the transferred toes showed substantial growth. CONCLUSIONS: Second-toe transfer for traumatic amputation of the thumb continues to be one of the best choices. Children require secondary procedures less often and in some cases late functional recovery can be expected. It is a safe procedure and there are fewer complications and a better success rate. PMID- 25144357 TI - Pronator teres opposition transfer through Guyon's canal: a technique. AB - Restoration of thumb opposition in the setting of peripheral nerve or brachial plexus injury is critical to upper limb function. When commonly utilized opposition donors are unavailable for clinical use, the pronator teres represents a good and reliable tendon for restoration of thumb opposition. Here we describe our rational and technique for pronator teres opposition transfer using Guyon's canal as a pulley. PMID- 25144358 TI - Postictal agitation syndrome or anxiety symptoms. PMID- 25144359 TI - Tracing the evolution of lineage-specific transcription factor binding sites in a birth-death framework. AB - Changes in cis-regulatory element composition that result in novel patterns of gene expression are thought to be a major contributor to the evolution of lineage specific traits. Although transcription factor binding events show substantial variation across species, most computational approaches to study regulatory elements focus primarily upon highly conserved sites, and rely heavily upon multiple sequence alignments. However, sequence conservation based approaches have limited ability to detect lineage-specific elements that could contribute to species-specific traits. In this paper, we describe a novel framework that utilizes a birth-death model to trace the evolution of lineage-specific binding sites without relying on detailed base-by-base cross-species alignments. Our model was applied to analyze the evolution of binding sites based on the ChIP-seq data for six transcription factors (GATA1, SOX2, CTCF, MYC, MAX, ETS1) along the lineage toward human after human-mouse common ancestor. We estimate that a substantial fraction of binding sites (~58-79% for each factor) in humans have origins since the divergence with mouse. Over 15% of all binding sites are unique to hominids. Such elements are often enriched near genes associated with specific pathways, and harbor more common SNPs than older binding sites in the human genome. These results support the ability of our method to identify lineage specific regulatory elements and help understand their roles in shaping variation in gene regulation across species. PMID- 25144361 TI - Forecasting nutrition research in 2020. PMID- 25144360 TI - Cooperation between Epstein-Barr virus immune evasion proteins spreads protection from CD8+ T cell recognition across all three phases of the lytic cycle. AB - CD8+ T cell responses to Epstein-Barr virus (EBV) lytic cycle expressed antigens display a hierarchy of immunodominance, in which responses to epitopes of immediate-early (IE) and some early (E) antigens are more frequently observed than responses to epitopes of late (L) expressed antigens. It has been proposed that this hierarchy, which correlates with the phase-specific efficiency of antigen presentation, may be due to the influence of viral immune-evasion genes. At least three EBV-encoded genes, BNLF2a, BGLF5 and BILF1, have the potential to inhibit processing and presentation of CD8+ T cell epitopes. Here we examined the relative contribution of these genes to modulation of CD8+ T cell recognition of EBV lytic antigens expressed at different phases of the replication cycle in EBV transformed B-cells (LCLs) which spontaneously reactivate lytic cycle. Selective shRNA-mediated knockdown of BNLF2a expression led to more efficient recognition of immediate-early (IE)- and early (E)-derived epitopes by CD8+ T cells, while knock down of BILF1 increased recognition of epitopes from E and late (L) expressed antigens. Contrary to what might have been predicted from previous ectopic expression studies in EBV-negative model cell lines, the shRNA-mediated inhibition of BGLF5 expression in LCLs showed only modest, if any, increase in recognition of epitopes expressed in any phase of lytic cycle. These data indicate that whilst BNLF2a interferes with antigen presentation with diminishing efficiency as lytic cycle progresses (IE>E>>L), interference by BILF1 increases with progression through lytic cycle (IE=25 kg/m2) and normal weight (BMI<25 kg/m2) patients. RESULTS: Of 239 patients, 129 (54%) were overweight or obese. Overweight or obese patients were younger, more likely to have a history of nonparoxysmal AF, hypertension, and diabetes mellitus. Levels of NT-proBNP were significantly lower in overweight or obese than in normal weight subjects (P<0.05). The relationship of obesity and decreased NT-proBNP levels persisted in subgroup of hypertension, both gender and both age levels (>=65 yrs and <65 yrs).Multivariate linear regression identified BMI as an independent negative correlate of LogNT-proBNP level. CONCLUSIONS: An inverse relationship between BMI and plasma NT-proBNP concentrations have been demonstrated in AF patients without heart failure. Overweight or obese patients with AF appear to have lower NT proBNP levels than normal weight patients. PMID- 25144362 TI - Upregulation of intermediate-conductance Ca2+-activated K+ channels (KCNN4) in porcine coronary smooth muscle requires NADPH oxidase 5 (NOX5). AB - AIMS: NADPH oxidase (NOX) is the primary source of reactive oxygen species (ROS) in vascular smooth muscle cells (SMC) and is proposed to play a key role in redox signaling involved in the pathogenesis of cardiovascular disease. Growth factors and cytokines stimulate coronary SMC (CSMC) phenotypic modulation, proliferation, and migration during atherosclerotic plaque development and restenosis. We previously demonstrated that increased expression and activity of intermediate conductance Ca(2+)-activated K(+) channels (KCNN4) is necessary for CSMC phenotypic modulation and progression of stenotic lesions. Therefore, the purpose of this study was to determine whether NOX is required for KCNN4 upregulation induced by mitogenic growth factors. METHODS AND RESULTS: Dihydroethidium micro fluorography in porcine CSMCs demonstrated that basic fibroblast growth factor (bFGF) increased superoxide production, which was blocked by the NOX inhibitor apocynin (Apo). Apo also blocked bFGF-induced increases in KCNN4 mRNA levels in both right coronary artery sections and CSMCs. Similarly, immunohistochemistry and whole cell voltage clamp showed bFGF-induced increases in CSMC KCNN4 protein expression and channel activity were abolished by Apo. Treatment with Apo also inhibited bFGF-induced increases in activator protein-1 promoter activity, as measured by luciferase activity assay. qRT-PCR demonstrated porcine coronary smooth muscle expression of NOX1, NOX2, NOX4, and NOX5 isoforms. Knockdown of NOX5 alone prevented both bFGF-induced upregulation of KCNN4 mRNA and CSMC migration. CONCLUSIONS: Our findings provide novel evidence that NOX5-derived ROS increase functional expression of KCNN4 through activator protein-1, providing another potential link between NOX, CSMC phenotypic modulation, and atherosclerosis. PMID- 25144365 TI - Near-road modeling and measurement of cerium-containing particles generated by nanoparticle diesel fuel additive use. AB - Cerium oxide nanoparticles (nCe) are used as a fuel-borne catalyst in diesel engines to reduce particulate emissions, yet the environmental and human health impacts of the exhaust particles are not well understood. To bridge the gap between emission measurements and ambient impacts, size-resolved measurements of particle composition and mass concentration have been performed in Newcastle-upon Tyne, United Kingdom, where buses have used an nCe additive since 2005. These observations show that the noncrustal cerium fraction thought to be associated with the use of nCe has a mass concentration ~ 0.3 ng m(-3) with a size distribution peaking at 100-320 nm in aerodynamic diameter. Simulations with a near-roadway multicomponent sectional aerosol dynamic model predict that the use of nCe additives increases the number concentration of nuclei mode particles (<50 nm in diameter) while decreasing the total mass concentration. The near-road model predicts a downwind mass size distribution of cerium-containing particles peaking at 150 nm in aerodynamic diameter, a value similar to that measured for noncrustal cerium in Newcastle. This work shows that both the emission and atmospheric transformation of cerium-containing particles needs to be taken into account by regional modelers, exposure scientists, and policymakers when determining potential environmental and human health impacts. PMID- 25144364 TI - Poly(ADP-ribose) polymerase 1 (PARP1) overexpression in human breast cancer stem cells and resistance to olaparib. AB - BACKGROUND: Breast cancer stem cells (BCSCs) have been recognized as playing a major role in various aspects of breast cancer biology. To identify specific biomarkers of BCSCs, we have performed comparative proteomics of BCSC-enriched and mature cancer cell populations from the human breast cancer cell line (BCL), BrCA-MZ-01. METHODS: ALDEFLUOR assay was used to sort BCSC-enriched (ALDH+) and mature cancer (ALDH-) cell populations. Total proteins were extracted from both fractions and subjected to 2-Dimensional Difference In-Gel Electrophoresis (2-D DIGE). Differentially-expressed spots were excised and proteins were gel extracted, digested and identified using MALDI-TOF MS. RESULTS: 2-D DIGE identified poly(ADP-ribose) polymerase 1 (PARP1) as overexpressed in ALDH+ cells from BrCA-MZ-01. This observation was confirmed by western blot and extended to four additional human BCLs. ALDH+ cells from BRCA1-mutated HCC1937, which had the highest level of PARP1 overexpression, displayed resistance to olaparib, a specific PARP1 inhibitor. CONCLUSION: An unbiased proteomic approach identified PARP1 as upregulated in ALDH+, BCSC-enriched cells from various human BCLs, which may contribute to clinical resistance to PARP inhibitors. PMID- 25144366 TI - Ly6Chi monocyte recruitment is responsible for Th2 associated host-protective macrophage accumulation in liver inflammation due to schistosomiasis. AB - Accumulation of M2 macrophages in the liver, within the context of a strong Th2 response, is a hallmark of infection with the parasitic helminth, Schistosoma mansoni, but the origin of these cells is unclear. To explore this, we examined the relatedness of macrophages to monocytes in this setting. Our data show that both monocyte-derived and resident macrophages are engaged in the response to infection. Infection caused CCR2-dependent increases in numbers of Ly6Chi monocytes in blood and liver and of CX3CR1+ macrophages in diseased liver. Ly6Chi monocytes recovered from liver had the potential to differentiate into macrophages when cultured with M-CSF. Using pulse chase BrdU labeling, we found that most hepatic macrophages in infected mice arose from monocytes. Consistent with this, deletion of monocytes led to the loss of a subpopulation of hepatic CD11chi macrophages that was present in infected but not naive mice. This was accompanied by a reduction in the size of egg-associated granulomas and significantly exacerbated disease. In addition to the involvement of monocytes and monocyte-derived macrophages in hepatic inflammation due to infection, we observed increased incorporation of BrdU and expression of Ki67 and MHC II in resident macrophages, indicating that these cells are participating in the response. Expression of both M2 and M1 marker genes was increased in liver from infected vs. naive mice. The M2 fingerprint in the liver was not accounted for by a single cell type, but rather reflected expression of M2 genes by various cells including macrophages, neutrophils, eosinophils and monocytes. Our data point to monocyte recruitment as the dominant process for increasing macrophage cell numbers in the liver during schistosomiasis. PMID- 25144368 TI - Whole-body prepulse inhibition protocol to test sensorymotor gating mechanisms in monkeys. AB - Prepulse inhibition (PPI) is the decrease of startle reflex amplitude when a slight stimulus is previously generated. This paradigm may provide valuable information about sensorimotor gating functionality. Here we aimed at determining the inhibited and uninhibited startle response of capuchin monkeys (Sapajus spp.), and to evaluate the role of the superior colliculus in PPI. Capuchin monkeys were tested in a whole-body protocol, to determine the best startle amplitude and interstimuli interval. Additionally we tested two subjects with bilateral superior colliculus damage in this protocol. Results show that 115 dB auditory pulse has induced the best startle response. In contrast to reports in other species, no habituation to the auditory stimuli was observed here in capuchins. Also, startle reflex inhibition was optimal after 120 msec interstimuli interval. Finally, there was a downward tendency of percentage inhibition in superior colliculus-lesioned monkeys. Our data provides the possibility of further studies with whole-body protocol in capuchin monkeys and reinforces the importance of the superior colliculus in PPI. PMID- 25144367 TI - Anti-obesity effects of granulocyte-colony stimulating factor in Otsuka-Long Evans-Tokushima fatty rats. AB - Granulocyte-colony stimulating factor (G-CSF) has molecular structures and intracellular signaling pathways that are similar to those of leptin and ciliary neurotropic factor (CNTF). It also has immune-modulatory properties. Given that leptin and CNTF play important roles in energy homeostasis and that obesity is an inflammatory condition in adipose tissue, we hypothesized that G-CSF could also play a role in energy homeostasis. We treated 12 38-week-old male Otsuka-Long Evans-Tokushima fatty rats (OLETF, diabetic) and 12 age-matched male Long-Evans Tokushima rats (LETO, healthy) with 200 ug/day G-CSF or saline for 5 consecutive days. Body weight reduction was greater in G-CSF-treated OLETF (G-CSF/OLETF) than saline-treated OLETF (saline/OLETF) following 8 weeks of treatment (-6.9+/-1.6% vs. -3.1+/-2.2%, p<0.05). G-CSF treatment had no effect on body weight in LETO or on food intake in either OLETF or LETO. Body fat in G-CSF/OLETF was more reduced than in saline/OLETF (-32.2+/-3.1% vs. -20.8+/-6.2%, p<0.05). Energy expenditure was higher in G-CSF/OLETF from 4 weeks after the treatments than in saline/OLETF. Serum levels of cholesterol, triglyceride, interleukin-6 and tumor necrosis factor-alpha were lower in G-CSF/OLETF than in saline/OLETF. Uncoupling protein-1 (UCP-1) expression in brown adipose tissue (BAT) was higher in G-CSF/OLETF than in saline/OLETF, but was unaffected in LETO. Immunofluorescence staining and PCR results revealed that G-CSF receptors were expressed in BAT. In vitro experiments using brown adipocyte primary culture revealed that G-CSF enhanced UCP-1 expression from mature brown adipocytes via p38 mitogen-activated protein kinase pathway. In conclusion, G-CSF treatment reduced body weight and increased energy expenditure in a diabetic model, and enhanced UCP-1 expression and decreased inflammatory cytokine levels may be associated with the effects of G-CSF treatment. PMID- 25144369 TI - Photothermal heating enabled by plasmonic nanostructures for electrokinetic manipulation and sorting of particles. AB - Plasmonic nanostructures support strong electromagnetic field enhancement or optical "hot spots" that are accompanied by local heat generation. This heating effect is generally seen as an obstacle to stable trapping of particles on a plasmonic substrate. In this work, instead of treating the heating effect as a hindrance, we utilized the collective photoinduced heating of the nanostructure array for high-throughput trapping of particles on a plasmonic nanostructured substrate. The photoinduced heating of the nanostructures is combined with an ac electric field of less than 100 kHz, which results in creation of a strong electrothermal microfluidic flow. This flow rapidly transports suspended particles toward the plasmonic substrate, where they are captured by local electric field effects. This work is envisioned to have application in biosensing and surface-enhanced spectroscopies such as SERS. PMID- 25144370 TI - Integrative taxonomy and species delimitation in harvestmen: a revision of the western North American genus Sclerobunus (Opiliones: Laniatores: Travunioidea). AB - Alpha taxonomy, and specifically the delimitation of species, is becoming increasingly objective and integrative. The use of coalescent-based methods applied to genetic data is providing new tools for the discovery and delimitation of species. Here, we use an integrative approach via a combination of discovery based multivariate morphological analyses to detect potential new species. These potential species are then used as a priori species in hypothesis-driven validation analyses with genetic data. This research focuses on the harvestmen genus Sclerobunus found throughout the mountainous regions of western North America. Based on our analyses, we conduct a revision of Sclerobunus resulting in synonymy of Cyptobunus with Sclerobunus including transfer of S. cavicolens comb. nov. and elevation of both subspecies of S. ungulatus: S. ungulatus comb. nov. and S. madhousensis comb. nov., stat. nov. The three subspecies of S. robustus are elevated, S. robustus, S. glorietus stat. nov., and S. idahoensis stat. nov. Additionally, five new species of Sclerobunus are described from New Mexico and Colorado, including S. jemez sp. nov., S. klomax sp. nov., S. skywalkeri sp. nov., S. speoventus sp. nov., and S. steinmanni sp. nov. Several of the newly described species are single-cave endemics, and our findings suggest that further exploration of western North American cave habitats will likely yield additional new species. PMID- 25144371 TI - Wnt-mediated repression via bipartite DNA recognition by TCF in the Drosophila hematopoietic system. AB - The Wnt/beta-catenin signaling pathway plays many important roles in animal development, tissue homeostasis and human disease. Transcription factors of the TCF family mediate many Wnt transcriptional responses, promoting signal-dependent activation or repression of target gene expression. The mechanism of this specificity is poorly understood. Previously, we demonstrated that for activated targets in Drosophila, TCF/Pangolin (the fly TCF) recognizes regulatory DNA through two DNA binding domains, with the High Mobility Group (HMG) domain binding HMG sites and the adjacent C-clamp domain binding Helper sites. Here, we report that TCF/Pangolin utilizes a similar bipartite mechanism to recognize and regulate several Wnt-repressed targets, but through HMG and Helper sites whose sequences are distinct from those found in activated targets. The type of HMG and Helper sites is sufficient to direct activation or repression of Wnt regulated cis-regulatory modules, and protease digestion studies suggest that TCF/Pangolin adopts distinct conformations when bound to either HMG-Helper site pair. This repressive mechanism occurs in the fly lymph gland, the larval hematopoietic organ, where Wnt/beta-catenin signaling controls prohemocytic differentiation. Our study provides a paradigm for direct repression of target gene expression by Wnt/beta-catenin signaling and allosteric regulation of a transcription factor by DNA. PMID- 25144372 TI - Identification and biochemical characterization of an acid sphingomyelinase-like protein from the bacterial plant pathogen Ralstonia solanacearum that hydrolyzes ATP to AMP but not sphingomyelin to ceramide. AB - Acid sphingomyelinase (aSMase) is a human enzyme that catalyzes the hydrolysis of sphingomyelin to generate the bioactive lipid ceramide and phosphocholine. ASMase deficiency is the underlying cause of the genetic diseases Niemann-Pick Type A and B and has been implicated in the onset and progression of a number of other human diseases including cancer, depression, liver, and cardiovascular disease. ASMase is the founding member of the aSMase protein superfamily, which is a subset of the metallophosphatase (MPP) superfamily. To date, MPPs that share sequence homology with aSMase, termed aSMase-like proteins, have been annotated and presumed to function as aSMases. However, none of these aSMase-like proteins have been biochemically characterized to verify this. Here we identify RsASML, previously annotated as RSp1609: acid sphingomyelinase-like phosphodiesterase, as the first bacterial aSMase-like protein from the deadly plant pathogen Ralstonia solanacearum based on sequence homology with the catalytic and C-terminal domains of human aSMase. A biochemical characterization of RsASML does not support a role in sphingomyelin hydrolysis but rather finds RsASML capable of acting as an ATP diphosphohydrolase, catalyzing the hydrolysis of ATP and ADP to AMP. In addition, RsASML displays a neutral, not acidic, pH optimum and prefers Ni2+ or Mn2+, not Zn2+, for catalysis. This alters the expectation that all aSMase-like proteins function as acid SMases and expands the substrate possibilities of this protein superfamily to include nucleotides. Overall, we conclude that sequence homology with human aSMase is not sufficient to predict substrate specificity, pH optimum for catalysis, or metal dependence. This may have implications to the biochemically uncharacterized human aSMase paralogs, aSMase-like 3a (aSML3a) and aSML3b, which have been implicated in cancer and kidney disease, respectively, and assumed to function as aSMases. PMID- 25144373 TI - GlnR negatively regulates the transcription of the alanine dehydrogenase encoding gene ald in Amycolatopsis mediterranei U32 under nitrogen limited conditions via specific binding to its major transcription initiation site. AB - Ammonium assimilation is catalyzed by two enzymatic pathways, i.e., glutamine synthetase/glutamate synthase (GS/GOGAT) and alanine dehydrogenase (AlaDH) in Amycolatopsis mediterranei U32. Under nitrogen-rich conditions, the AlaDH pathway is the major route for ammonium assimilation, while the GS/GOGAT pathway takes over when the extracellular nitrogen supply is limited. The global nitrogen regulator GlnR was previously characterized to activate the transcription of the GS encoding gene glnA in response to nitrogen limitation and is demonstrated in this study as a repressor for the transcription of the AlaDH encoding gene ald, whose regulation is consistent with the switch of the ammonium assimilation pathways from AlaDH to GS/GOGAT responding to nitrogen limitation. Three transcription initiation sites (TISs) of ald were determined with primer extension assay, among which transcription from aldP2 contributed the major transcripts under nitrogen-rich conditions but was repressed to an undetectable level in response to nitrogen limitation. Through DNase I footprinting assay, two separate regions were found to be protected by GlnR within ald promoter, within which three GlnR binding sites (a1, b1 sites in region I and a2 site in region II) were defined. Interestingly, the major TIS aldP2 is located in the middle of a2 site within region II. Therefore, one may easily conclude that GlnR represses the transcription of ald via specific binding to the GlnR binding sites, which obviously blocks the transcription initiation from aldP2 and therefore reduces ald transcripts. PMID- 25144374 TI - HIV-associated histoplasmosis early mortality and incidence trends: from neglect to priority. AB - BACKGROUND: Histoplasmosis is an endemic fungal infection in French Guiana. It is the most common AIDS-defining illness and the leading cause of AIDS-related deaths. Diagnosis is difficult, but in the past 2 decades, it has improved in this French overseas territory which offers an interesting model of Amazonian pathogen ecology. The objectives of the present study were to describe the temporal trends of incidence and mortality indicators for HIV-associated histoplasmosis in French Guiana. METHODS: A retrospective study was conducted to describe early mortality rates observed in persons diagnosed with incident cases of HIV-associated Histoplasma capsulatum var. capsulatum histoplasmosis admitted in one of the three main hospitals in French Guiana between 1992 and 2011. Early mortality was defined by death occurring within 30 days after antifungal treatment initiation. Data were collected on standardized case report forms and analysed using standard statistical methods. RESULTS: There were 124 deaths (45.3%) and 46 early deaths (16.8%) among 274 patients. Three time periods of particular interest were identified: 1992-1997, 1998-2004 and 2005-2011. The two main temporal trends were: the proportion of early deaths among annual incident histoplasmosis cases significantly declined four fold (chi2, p<0.0001) and the number of annual incident histoplasmosis cases increased three fold between 1992 1997 and 1998-2004, and subsequently stabilized. CONCLUSION: From an occasional exotic diagnosis, AIDS-related histoplasmosis became the top AIDS-defining event in French Guiana. This was accompanied by a spectacular decrease of early mortality related to histoplasmosis, consistent with North American reference center mortality rates. The present example testifies that rapid progress could be at reach if awareness increases and leads to clinical and laboratory capacity building in order to diagnose and treat this curable disease. PMID- 25144375 TI - Increased antigen presentation but impaired T cells priming after upregulation of interferon-beta induced by lipopolysaccharides is mediated by upregulation of B7H1 and GITRL. AB - Dendritic cells are able to present Ag-derived peptides on MHC class I and II molecules and induce T cells priming. Lipopolysaccharides (LPS), an activator of Toll-like 4 receptor (TLR4) signaling, has been demonstrated to facilitate Ag presentation, up-regulate surface molecules expression but impair T cells priming. In this study, we investigated the effect of LPS on nicotine-enhanced DCs-dependent T cells priming and the mechanisms of LPS orchestrating the immunosuppressive program. We could demonstrate that the treatment with LPS resulted in increased surface molecules expression, enhanced Ag-presentation, up regulated release of TGF-beta, TNF-alpha, IL-6, and IFN-beta. Concomititantly, the upregulation of IFN-beta in DCs induces the up-regulation of coinhibitory molecules B7H1 and GITRL, which cause an impaired activation of naive Ag-specific T cells and the induction of T cell tolerance by enhancing B7H1-PD-1 interactions and promoting GITRL-GITL facilitated Treg generation, respectively. These data provide a mechanistic basis for the immunomodulatory action of IFN-beta which might open new possibilities in the development of therapeutic approaches aimed at the control of excessive immune response and persistent infection. PMID- 25144377 TI - A soft microchannel decreases polydispersity of droplet generation. AB - We study the effect of softness of the microchannel on the process of droplet generation in two-phase flows in a T-junction microchannel. One side of the microchannel has a flexible thin PDMS layer, which vibrates naturally while droplets are generated; the deformation frequency coincides with the frequency of droplet formation. Furthermore, we compare the polydispersity of water-in-oil droplets formed with a microchannel with one soft wall with those formed in a conventional rigid microchannel. We show that deformation of the soft wall reduces the polydispersity in the droplet size. PMID- 25144376 TI - Effects of GWAS-associated genetic variants on lncRNAs within IBD and T1D candidate loci. AB - Long non-coding RNAs are a new class of non-coding RNAs that are at the crosshairs in many human diseases such as cancers, cardiovascular disorders, inflammatory and autoimmune disease like Inflammatory Bowel Disease (IBD) and Type 1 Diabetes (T1D). Nearly 90% of the phenotype-associated single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) lie outside of the protein coding regions, and map to the non-coding intervals. However, the relationship between phenotype-associated loci and the non-coding regions including the long non-coding RNAs (lncRNAs) is poorly understood. Here, we systemically identified all annotated IBD and T1D loci-associated lncRNAs, and mapped nominally significant GWAS/ImmunoChip SNPs for IBD and T1D within these lncRNAs. Additionally, we identified tissue-specific cis-eQTLs, and strong linkage disequilibrium (LD) signals associated with these SNPs. We explored sequence and structure based attributes of these lncRNAs, and also predicted the structural effects of mapped SNPs within them. We also identified lncRNAs in IBD and T1D that are under recent positive selection. Our analysis identified putative lncRNA secondary structure-disruptive SNPs within and in close proximity (+/-5 kb flanking regions) of IBD and T1D loci-associated candidate genes, suggesting that these RNA conformation-altering polymorphisms might be associated with diseased-phenotype. Disruption of lncRNA secondary structure due to presence of GWAS SNPs provides valuable information that could be potentially useful for future structure-function studies on lncRNAs. PMID- 25144378 TI - Alternative splicing of Arabidopsis IBR5 pre-mRNA generates two IBR5 isoforms with distinct and overlapping functions. AB - The INDOLE-3-BUTYRIC ACID RESPONSE5 (IBR5) gene encodes a dual specificity phosphatase that regulates plant auxin responses. IBR5 has been predicted to generate two transcripts through alternative splicing, but alternative splicing of IBR5 has not been confirmed experimentally. The previously characterized ibr5 1 null mutant exhibits many auxin related defects such as auxin insensitive primary root growth, defective vascular development, short stature and reduced lateral root development. However, whether all these defects are caused by the lack of phosphatase activity is not clear. Here we describe two new auxin insensitive IBR5 alleles, ibr5-4, a catalytic site mutant, and ibr5-5, a splice site mutant. Characterization of these new mutants indicates that IBR5 is post transcriptionally regulated to generate two transcripts, AT2G04550.1 and AT2G04550.3, and consequently two IBR5 isoforms, IBR5.1 and IBR5.3. The IBR5.1 isoform exhibits phosphatase catalytic activity that is required for both proper degradation of Aux/IAA proteins and auxin-induced gene expression. These two processes are independently regulated by IBR5.1. Comparison of new mutant alleles with ibr5-1 indicates that all three mutant alleles share many phenotypes. However, each allele also confers distinct defects implicating IBR5 isoform specific functions. Some of these functions are independent of IBR5.1 catalytic activity. Additionally, analysis of these new mutant alleles suggests that IBR5 may link ABP1 and SCF(TIR1/AFBs) auxin signaling pathways. PMID- 25144379 TI - Patients undergoing total laryngectomy: an at-risk population for 30-day unplanned readmission. AB - IMPORTANCE: Patients undergoing total laryngectomy are at high risk for hospital readmission. Hospital readmissions are increasingly scrutinized because they are used as a metric of quality care and are subject to financial penalties. OBJECTIVE: To determine the rate of, reasons for, and risk factors that predict 30-day unplanned readmission for patients undergoing total laryngectomy. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study at a single academic tertiary referral medical center. The study population comprised 155 patients who underwent total laryngectomy with or without flap closure between January 2007 and December 2012 as either a primary treatment or salvage treatment for prior nonsurgical management. INTERVENTIONS: Total laryngectomy. MAIN OUTCOMES AND MEASURES: Rate of 30-day unplanned readmission, readmission diagnoses, and risk factors for unplanned readmission. Univariable and multivariable logistic regression were performed to identify risk factors for unplanned readmission within 30 days of discharge. RESULTS: The 30-day unplanned readmission rate for patients following discharge after total laryngectomy was 26.5% (41 of 155). The most common readmission diagnoses were pharyngocutaneous fistula (27% of readmissions; n = 11) and stomal cellulitis (16% of readmissions; n = 7). The median time to unplanned readmission was 7 days. Thirty-four percent of readmissions (14 of 41) occurred within 3 days of discharge. Significant predictors of 30-day unplanned readmission on multivariable analysis were postoperative complication after discharge (odds ratio [OR], 11.50; 95% CI, 4.10 32.28), visit to the emergency department within 30 days after discharge (OR, 5.25; 95% CI, 1.84-14.99), salvage total laryngectomy (OR, 3.52; 95% CI, 1.56 13.12), and chyle fistula during the index hospitalization (OR, 5.25; 95% CI, 0.86-29.92). The discriminative ability of the model to predict unplanned readmission, as measured by the C statistic, was 0.88. CONCLUSIONS AND RELEVANCE: Patients undergoing total laryngectomy are an at-risk patient population with a high rate of unplanned readmission within 30 days of discharge. By identifying the risk factors that predict 30-day unplanned readmission, these data can be used to design and implement quality-improvement interventions to decrease readmissions. PMID- 25144381 TI - An Al/P-based frustrated Lewis pair as an efficient ambiphilic ligand: coordination of boron trihalides, rearrangement, and formation of HBX2 complexes (X = Br, I). AB - The Al/P-based frustrated Lewis pair (FLP) Mes2P-C(?CH-Ph)-Al(CMe3)2 (1) reacted with boron halides BX3 (X = F, Cl, Br, I) as an ambiphilic ligand to form complexes (2-5) in which the boron atoms were coordinated to phosphorus and one of the halogen atoms to aluminum. Nonplanar five-membered heterocycles resulted that had five different ring atoms (AlCPBX). The distance of the bridging halogen atoms to the AlCPB plane increased steadily with the radius of the halogen atoms. Only the BF3 adduct showed a dynamic behavior in solution at room temperature with equivalent tert-butyl or mesityl groups in the NMR spectra, while in other cases, the rigid conformation led to the magnetic inequivalence of the substituents at Al and P with well-resolved signals for each group. The BBr3 and BI3 complexes underwent in solution at room temperature a spontaneous stereoselective rearrangement with the concomitant release of isobutene. The obtained products, Mes2P-(MU-C?CH-Ph)(MU-HBX2)-AlX(CMe3) (6 and 7) may be viewed as unique adducts of a modified new Al/P-based FLP, Mes2P-C(?CH-Ph)-AlX(CMe3) (X = Br, I), with dihalogenboranes, HBX2. The trapped boranes are either completely unknown (X = I) or unstable in the free form. Quantum-chemical calculations suggest an ionic rearrangement mechanism via the formation of a borenium cation, beta-hydride elimination, and hydride transfer. The bromine migration from boron to aluminum corresponds to a formal suprafacial 1,3-sigmatropic rearrangement. PMID- 25144380 TI - Visceral leishmaniasis and HIV coinfection in the Mediterranean region. AB - Visceral leishmaniasis is hypoendemic in Mediterranean countries, where it is caused by the flagellate protozoan Leishmania infantum. VL cases in this area account for 5%-6% of the global burden. Cases of Leishmania/HIV coinfection have been reported in the Mediterranean region, mainly in France, Italy, Portugal, and Spain. Since highly active antiretroviral therapy was introduced in 1997, a marked decrease in the number of coinfected cases in this region has been reported. The development of new diagnostic methods to accurately identify level of parasitemia and the risk of relapse is one of the main challenges in improving the treatment of coinfected patients. Clinical trials in the Mediterranean region are needed to determine the most adequate therapeutic options for Leishmania/HIV patients as well as the indications and regimes for secondary prophylaxis. This article reviews the epidemiological, diagnostic, clinical, and therapeutic aspects of Leishmania/HIV coinfection in the Mediterranean region. PMID- 25144382 TI - Size and surface functionalization of iron oxide nanoparticles influence the composition and dynamic nature of their protein corona. AB - Nanoparticles (NPs) adsorb proteins when in the biological matrix, and the resulted protein corona could affect NP-cell interactions. The corona has a dynamic nature with the adsorbed proteins constantly exchanging with the free proteins in the matrix at various rates. The rapidly exchanging proteins compose the soft corona, which responds more dynamically to environment changes than the hard corona established by the ones with slow exchange rates. In the present study, the corona formed on the superparamagnetic iron oxide NPs (SPIONs) in human serum was studied by flow field-flow fractionation and ultracentrifugation, which rapidly differentiated the corona proteins based on their exchange rates. By varying the surface hydrophobicity of the SPIONs with a core size around 10 nm, we found out that, the more hydrophobic surface ligand attracted proteins with higher surface hydrophobicity and formed a more dynamic corona with a larger portion of the involved proteins with fast exchange rates. Increasing the core diameter of the SPIONs but keeping the surface ligand the same could also result in a more dynamic corona. A brief investigation of the effect on the cellular uptake of SPIONs using one selected corona protein, transferrin, was conducted. The result showed that, only the stably bound transferrin could significantly enhance cellular uptake, while transferrin bound in a dynamic nature had negligible impact. Our study has led to a better understanding of the relationship between the particle properties and the dynamic nature of the corona, which can help with design of nanomaterials with higher biocompatibility and higher efficacy in biosystems for biomedical applications. PMID- 25144385 TI - Development of 1-year-old computational phantom and calculation of organ doses during CT scans using Monte Carlo simulation. AB - With the rapidly growing number of CT examinations, the consequential radiation risk has aroused more and more attention. The average dose in each organ during CT scans can only be obtained by using Monte Carlo simulation with computational phantoms. Since children tend to have higher radiation sensitivity than adults, the radiation dose of pediatric CT examinations requires special attention and needs to be assessed accurately. So far, studies on organ doses from CT exposures for pediatric patients are still limited. In this work, a 1-year-old computational phantom was constructed. The body contour was obtained from the CT images of a 1-year-old physical phantom and the internal organs were deformed from an existing Chinese reference adult phantom. To ensure the organ locations in the 1-year-old computational phantom were consistent with those of the physical phantom, the organ locations in 1-year-old computational phantom were manually adjusted one by one, and the organ masses were adjusted to the corresponding Chinese reference values. Moreover, a CT scanner model was developed using the Monte Carlo technique and the 1-year-old computational phantom was applied to estimate organ doses derived from simulated CT exposures. As a result, a database including doses to 36 organs and tissues from 47 single axial scans was built. It has been verified by calculation that doses of axial scans are close to those of helical scans; therefore, this database could be applied to helical scans as well. Organ doses were calculated using the database and compared with those obtained from the measurements made in the physical phantom for helical scans. The differences between simulation and measurement were less than 25% for all organs. The result shows that the 1-year-old phantom developed in this work can be used to calculate organ doses in CT exposures, and the dose database provides a method for the estimation of 1-year-old patient doses in a variety of CT examinations. PMID- 25144386 TI - Development of a new generation of ammonia sensors on printed polymeric hotplates. AB - Conducting polyaniline-based chemiresistors on printed polymeric micro-hotplates were developed, showing sensitive and selective detection of ammonia vapor in air. The devices consist of a fully inkjet-printed silver heater and interdigitated electrodes on a polyethylene naphthalate substrate, separated by a thin dielectric film. The integrated heater allowed operation at elevated temperatures, enhancing the ammonia sensing performance. The printed sensor designs were optimized over two different generations, to improve the thermal performance through careful design of the shape and dimension of the heater element. A vapor-phase deposition polymerization technique was adapted to produce polyaniline sensing layers doped with poly(4-styrenesulfonic acid). The resulting sensor had better thermal stability and sensing performance when compared with conventional polyaniline-based sensors, and this was attributed to the polymeric dopant used in this study. Improved long-term stability of the sensors was achieved by electrodeposition of gold on the silver electrodes. Response to sub parts-per-million concentrations of ammonia even under humid conditions was observed. PMID- 25144384 TI - Genetic variations in two seahorse species (Hippocampus mohnikei and Hippocampus trimaculatus): evidence for middle Pleistocene population expansion. AB - Population genetic of seahorses is confidently influenced by their species specific ecological requirements and life-history traits. In the present study, partial sequences of mitochondrial cytochrome b (cytb) and control region (CR) were obtained from 50 Hippocampus mohnikei and 92 H. trimaculatus from four zoogeographical zones. A total of 780 base pairs of cytb gene were sequenced to characterize mitochondrial DNA (mtDNA) diversity. The mtDNA marker revealed high haplotype diversity, low nucleotide diversity, and a lack of population structure across both populations of H. mohnikei and H. trimaculatus. A neighbour-joining (NJ) tree of cytb gene sequences showed that H. mohnikei haplotypes formed one cluster. A maximum likelihood (ML) tree of cytb gene sequences showed that H. trimaculatus belonged to one lineage. The star-like pattern median-joining network of cytb and CR markers indicated a previous demographic expansion of H. mohnikei and H. trimaculatus. The cytb and CR data sets exhibited a unimodal mismatch distribution, which may have resulted from population expansion. Mismatch analysis suggested that the expansion was initiated about 276,000 years ago for H. mohnikei and about 230,000 years ago for H. trimaculatus during the middle Pleistocene period. This study indicates a possible signature of genetic variation and population expansion in two seahorses under complex marine environments. PMID- 25144388 TI - The Cerebral Palsy Kinematic Assessment Tool (CPKAT): feasibility testing of a new portable tool for the objective evaluation of upper limb kinematics in children with cerebral palsy in the non-laboratory setting. AB - PURPOSE: Efficacy of treatment to improve upper-limb activity of children with cerebral palsy (CP) is typically evaluated outside clinical/laboratory environments through functional outcome measures (e.g. ABILHAND kids). This study evaluates CPKAT, a new portable laptop-based tool designed to objectively measure upper-limb kinematics in children with CP. METHODS: Seven children with unilateral CP (2 females; mean age 10 years 2 months (SD 2 years 3 months), median age 9 years 6 months, range 6 years 5 months, MACS II-IV) were evaluated on copying, tracking and tracing tasks at their homes using CPKAT. CPKAT recorded parameters relating to spatiotemporal hand movement: path length, movement time, smoothness, path accuracy and root mean square error. The Wilcoxon signed ranks test explored whether CPKAT could detect differences between the affected and less-affected limb. RESULTS: CPKAT detected intra-limb differences for movement time and smoothness (aiming), and path length (tracing). No intra-limb tracking differences were found, as hypothesised. These findings are consistent with other studies showing that movements of the impaired upper limb in unilateral CP are slower and less smooth. CONCLUSION: CPKAT provides a potential solution for home based assessment of upper limb kinematics in children with CP to supplement other measures and assess functional intervention outcomes. Further validation is required. Implications for Rehabilitation This paper demonstrates the feasibility of evaluating upper limb kinematics in home using CPKAT, a portable laptop-based evaluation tool. We found that CPKAT is easy to set-up and use in home environments and yields useful kinematic measures of upper limb function. CPKAT can complement less responsive patient reported or subjectively evaluated functional measures for a more complete evaluation of children with cerebral palsy. Thus, CPKAT can help guide a multi-disciplinary team to more effective intervention and rehabilitation for children with cerebral palsy. PMID- 25144389 TI - Ligand/cluster/support catalytic complexes in heterogeneous ultrananocatalysis: NO oxidation on Ag3/MgO(100). AB - In the present work we explore via first-principles simulations whether the ligand/cluster/support catalytic complex generated by CO oxidation over silver trimers deposited on the regular MgO(100) surface - i.e. a Ag3/carbonate or Ag3(CO3)/MgO(100) species - can be used as a catalyst in a different reaction: the selective oxidation of NO to NO2 (or NOox). The Ag3(CO3)/MgO(100) complex is first shown to be reasonably stable at room temperature in terms of both disaggregation and sintering, and that it can be generated from Ag3 adsorbed onto an oxygen vacancy defect of the regular MgO(100) surface under oxidation conditions. It is then found that the Ag3(CO3)/MgO(100) species transforms under NOox conditions into an even more complex aggregate, a mixed carbonate/double nitrite Ag3(CO3)(NO2)2/MgO(100) species, which can then act as an efficient catalyst of NOox. It is noteworthy that under NOox reaction conditions a different ligand/cluster/support catalytic complex is formed with respect to the original COox one. These findings prove the diversity of the catalytic chemistry of subnanometer (or ultranano) metal clusters deposited on oxide substrates, associated with the formation of many different ligand/cluster/support aggregates, the vast amount of combinatorial possibilities thus opening, and the need for computational approaches to perform systematic structural and stoichiometric searches in order to cope with such a multiform diversity. PMID- 25144391 TI - Direct current brain stimulation enhances navigation efficiency in individuals with low spatial sense of direction. AB - The aim of this study was to evaluate the influence of right versus left temporal transcranial direct current stimulation (tDCS) on navigation efficiency and spatial memory in individuals with low versus high spatial skills. A mixed design administered low (0.5 mA) versus high (2.0 mA) anodal tDCS (within-participants) over the right or the left temporal lobe (between-participants), centered at electrode site T8 (right) or T7 (left). During stimulation, participants navigated virtual environments in search of specified landmarks, and data were logged in terms of current position and heading over time. Following stimulation, participants completed pointing and map-drawing spatial memory tests. Individual differences in sense of direction reliably and inversely predicted navigation advantages in the 2.0 versus 0.5 mA right hemisphere stimulation condition (R=0.45, P<0.01); in other words, individuals with lower sense of direction showed increased navigation efficiency in the 2.0 versus 0.5 mA condition. Spatial memory tests also showed the development of relatively comprehensive spatial memories: bidimensional regression indicated lower distortion in sketch maps drawn following 2.0 versus 0.5 mA right temporal lobe stimulation (F=8.7, P<0.05). Data provide the first demonstration that right temporal anodal tDCS may hold potential for enhancing navigation efficiency in otherwise poor navigators. Data support neuroimaging studies showing the engagement of right temporal brain regions in developing and applying spatial memories during complex navigation tasks, and uniquely suggest that continuing research may find value in optimizing stimulation parameters (intensity, focality) as a function of individual differences. PMID- 25144390 TI - High susceptibility to fatty liver disease in two-pore channel 2-deficient mice. AB - Endolysosomal organelles play a key role in trafficking, breakdown and receptor mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites. PMID- 25144392 TI - Bimanual coordination of force enhances interhemispheric inhibition between the primary motor cortices. AB - The purpose of this study was to elucidate whether bimanual coordination of force affects interhemispheric inhibition (IHI) between the primary motor cortices (M1s). IHI with the index fingers isometrically abducted against a fixed plate (AAP task) was compared with IHI with the index fingers isometrically abducted against each other (AAF task). The index fingers were held stationary at the midline and activity levels of the first dorsal interosseous muscles were equalized between the tasks. The abduction force of each index finger was individually controlled during the AAP task, and bimanually coordinated during the AAF task. IHI during the AAF task was significantly higher than that during the AAP task. IHI between the M1s is related not only to the suppression of unwanted activity of the M1 contralateral to the active M1 but also to bimanual coordination of force. PMID- 25144393 TI - Dynamics of sodium channel Nav1.5 expression in astrocytes in mouse models of multiple sclerosis. AB - Astrocytes actively participate in the response of the central nervous system to injury, including in multiple sclerosis. Astrocytes can play both beneficial and detrimental roles in response to neuroinflammation; however, in extreme cases, astrogliosis can result in the formation of a glial scar, which can impede the regeneration of injured neurons. Although astrocytes do not express the voltage gated sodium channel Nav1.5 in the nonpathological human brain, they exhibit robust upregulation of Nav1.5 within acute and chronic multiple sclerosis lesions. Recent work has indicated that Nav1.5 contributes to the pathways that regulate glial scar formation in vitro through modulation of intracellular Ca levels. However, the temporal dynamics of astrocytic Nav1.5 channel expression in response to neuroinflammatory pathologies has not been investigated. We examined astrocytes from mice with monophasic and chronic-relapsing (CR) experimental autoimmune encephalomyelitis (EAE) by immunohistochemical analysis to determine whether Nav1.5 is expressed in these cells, and whether the expression correlates with the severity of disease and/or phases of relapse and remission. Our results demonstrate that Nav1.5 is upregulated in astrocytes in situ in a temporal manner that correlates with disease severity in both monophasic and CR EAE. Further, in CR EAE, Nav1.5 expression is upregulated during relapses and subsequently attenuated during periods of remission. These observations are consistent with the suggestion that Nav1.5 can play a role in the response of astrocytes to inflammatory pathologies in the central nervous system and suggest Nav1.5 may be a potential therapeutic target to modulate reactive astrogliosis in vivo. PMID- 25144394 TI - Chemokine-like factor 1 promotes the migration of rat primary cortical neurons by the induction of actin polymerization. AB - Chemokine-like factor 1 (CKLF1), a newly cloned chemotactic cytokine, plays an essential role in immune cell migration. However, the potential role of CKLF1 in the cortical neuronal migration remains unclear. In the present research, by measuring the distance between the margin of brain slices and the leading population of migrating cells, we showed that the extent of cell migration was markedly enhanced in response to CKLF1 treatment, which was significantly inhibited by the simultaneous addition of anti-CKLF1 antibody. By immunofluorescence staining, it was found that CKLF1 induced actin polymerization in primary cerebral cortical neurons. By wound-healing assays, it was found that CKLF1 stimulated the migration of cortical neurons in a dose-dependent manner. In conclusion, our data suggest that CKLF1 promotes the migration of rat primary cerebral cortical neurons by the induction of actin polymerization. PMID- 25144395 TI - Cerebellum-specific 18F-FDG PET analysis for the detection of subregional glucose metabolism changes in spinocerebellar ataxia. AB - The cerebellum (CB) consists of complex anatomical and functional subregions. To better investigate the complicated functional anatomy, a detailed subregional analysis and/or a precise spatial normalization of the fluorine-18 fluorodeoxyglucose (F-FDG) PET imaging data are essential. Here, the 28 MRIcron CB volumes of interests (VOIs) template merged into eight cerebellar subregional VOIs (bilateral anterior, superior, and inferior posterior lobes of the CB cortex, and the superior and inferior vermis) on mean F-FDG PET templates. We also developed a new spatial normalization method using a study-specific and CB specific template (CBSST) to better localize the VOIs and to minimize interparticipant differences for the locations of whole and subregional CB VOIs, as well as to increase the accuracy of the subregional mean F-FDG uptake. Using VOIs of individual F-FDG PET images normalized to the F-FDG template, we analyzed subregional cerebellar glucose metabolism in patients with spinocerebellar ataxia, a representative disease involving the spinocerebellum, and compared them with age-matched and sex-matched healthy normal controls. We achieved significant improvement over the Montreal Neurological Institute template in spatial normalization accuracy using our CBSST approach for CB VOI location agreement increases (79 vs. 90%) and VOI uptake error decreases in many CB subregions. We also found significant decreases in the anterior/posterior ratio of F-FDG uptake in patients with spinocerebellar ataxia (0.45) compared with those in normal controls (0.73) only using our CBSST approach. Therefore, we established an accurate CB subregional VOI analysis framework, and this may be useful for understanding and differentiating many of the cerebellar ataxia diseases. PMID- 25144397 TI - Coexisting differentiated neuroblastoma and ossifying renal tumor of infancy in a patient. AB - We presented a 5-month-old boy with differentiated neuroblastoma and ossifying renal tumor of infancy (ORTI) arising at the left adrenal gland and upper pole of the ipsilateral kidney, respectively. They were located in the adjacent organs with different morphology and immunohistochemistry characteristics. To our best knowledge, coexistence of differentiated neuroblastoma and ORTI in a patient has never been reported. In our report, two contiguous lesions might be represented collision tumor, originated from the same clusters of immature cells and triggered by different mechanism. PMID- 25144396 TI - Penumbra pattern assessment in acute stroke patients: comparison of quantitative and non-quantitative methods in whole brain CT perfusion. AB - BACKGROUND AND PURPOSE: While penumbra assessment has become an important part of the clinical decision making for acute stroke patients, there is a lack of studies measuring the reliability and reproducibility of defined assessment techniques in the clinical setting. Our aim was to determine reliability and reproducibility of different types of three-dimensional penumbra assessment methods in stroke patients who underwent whole brain CT perfusion imaging (WB CTP). MATERIALS AND METHODS: We included 29 patients with a confirmed MCA infarction who underwent initial WB-CTP with a scan coverage of 100 mm in the z axis. Two blinded and experienced readers assessed the flow-volume-mismatch twice and in two quantitative ways: Performing a volumetric mismatch analysis using OsiriX imaging software (MM(VOL)) and visual estimation of mismatch (MM(EST)). Complementarily, the semiquantitative Alberta Stroke Programme Early CT Score for CT perfusion was used to define mismatch (MM(ASPECTS)). A favorable penumbral pattern was defined by a mismatch of >= 30% in combination with a cerebral blood flow deficit of <= 90 ml and an MM(ASPECTS) score of >= 1, respectively. Inter- and intrareader agreement was determined by Kappa-values and ICCs. RESULTS: Overall, MM(VOL) showed considerably higher inter-/intrareader agreement (ICCs: 0.751/0.843) compared to MM(EST) (0.292/0.749). In the subgroup of large (>= 50 mL) perfusion deficits, inter- and intrareader agreement of MM(VOL) was excellent (ICCs: 0.961/0.942), while MM(EST )interreader agreement was poor (0.415) and intrareader agreement was good (0.919). With respect to penumbra classification, MM(VOL) showed the highest agreement (interreader agreement: 25 agreements/4 non agreements/kappa: 0.595; intrareader agreement 27/2/0.833), followed by MM(EST) (22/7/0.471; 23/6/0.577), and MM(ASPECTS) (18/11/0.133; 21/8/0.340). CONCLUSION: The evaluated approach of volumetric mismatch assessment is superior to pure visual and ASPECTS penumbra pattern assessment in WB-CTP and helps to precisely judge the extent of 3-dimensional mismatch in acute stroke patients. PMID- 25144398 TI - Predictive accuracy and feasibility of risk stratification scores for 28-day mortality of patients with sepsis in an emergency department. AB - OBJECTIVES: Sepsis is associated with high mortality. Because early therapy has proven to decrease mortality, a risk stratification tool that quickly and easily quantifies mortality risk of patients will be helpful to guide appropriate treatment. We investigated five scores in terms of (a) predicting 28-day mortality and (b) their feasibility for use in the emergency department (ED). MATERIALS AND METHODS: We carried out a historical cohort study in the ED of Maastricht University Medical Centre (MUMC). Patients who fulfilled the criteria for sepsis were included if they had been admitted to the hospital by an internist between August 2009 and August 2010. The Mortality in Emergency Department Sepsis (MEDS), Confusion, Urea, Respiratory rate, Blood pressure, age>65 (CURB-65), Acute Physiology And Chronic Health Evaluation II (APACHE II), Rapid Acute Physiology Score (RAPS), and Rapid Emergency Medicine Score (REMS) scores were calculated using ED charts. The primary outcome was total 28-day mortality. Receiver operating characteristic curves and calibration plots were constructed to evaluate predictive accuracy. Feasibility was defined as the proportion of patients for whom all data were available. RESULTS: We included 600 patients, of whom 90 (15%) died within 28 days. Discriminating ability for total 28-day mortality of the MEDS [area under the curve (AUC): 0.82, 95% confidence interval (CI) 0.78-0.87], CURB-65 (AUC: 0.78, 95% CI 0.73-0.83), and APACHE II (AUC: 0.71, 95% CI 0.64-0.79) was the highest, but only the difference between the MEDS and REMS (P=0.007) and the RAPS score (P<0.001) was significant. Both the MEDS and the CURB-65 had higher AUCs for predicting 28-day in-hospital mortality than the other three scores, but this was only significant for the MEDS score compared with the RAPS (P=0.003). Both the MEDS and the CURB-65 underestimated mortality, especially for the higher scores. The MEDS, CURB-65, REMS, and RAPS were most feasible as they could be calculated in more than 96% of patients. CONCLUSION: The MEDS and CURB-65 scores are the most adequate and feasible tools for the prediction of total 28-day mortality in septic patients presenting at the ED, but they need local recalibration before use in the ED. PMID- 25144399 TI - Predictors of intensive care unit transfer or death in emergency department patients with suspected infection. AB - OBJECTIVES: The aim of this study was to identify predictors of ICU transfer or death within 48 h obtainable within 4 h of admission in emergency department (ED) patients with suspected infection. PATIENTS AND METHODS: This was a nested case control study based on a prospective cohort of adult patients admitted to the ED at Aarhus University Hospital, in 2011, who had a blood culture drawn upon admission. Cases met the composite endpoint of ICU transfer or death within 4-48 h of admission. We identified up to three controls for each case, matched by age and admission month. We collected data on possible predictors from medical records. Univariate and multivariate logistic regressions were performed to identify predictors. RESULTS: A total of 1578 patients had a blood culture drawn in the ED. Among these, 61 (4%) patients were transferred to an ICU and 15 (1%) patients died within 4-48 h of admission. We could obtain complete data on 59 cases, which were matched to 165 controls. Significant predictors of ICU transfer or death within 4-48 h included temperature as a continuous variable, and neurologic (altered mental status), respiratory, and cardiovascular dysfunction. CONCLUSION: Readily available clinical and laboratory variables at arrival in the ED can support identification of late deterioration leading to ICU transfer or death within 48 h of admission. PMID- 25144401 TI - DNA fragment conformations in adducts with Kiteplatin. AB - The anticancer activity of cisplatin is triggered by its formation of intrastrand adducts involving adjacent G residues of DNA. To obtain information on the different conformers that can be formed, carrier ligands such as 2,2' bipiperidine, which provide large steric bulk near the platinum coordination plane and decrease the dynamic motion about the Pt-N7 bonds, were introduced ("retro-modelling" approach). In the present study we investigate the effect of cis-1,4-diaminocyclohexane (cis-1,4-DACH) on the formation, stability, and stereochemistry of (cis-1,4-DACH)Pt(ss-oligo) adducts (ss-oligo = d(GpG) with 3'- and/or 5'-substituents). Interesting features of this ligand, absent in previous retro-modelling studies, include the large bite angle (expected to impede the ease of interconversion between possible conformers), the presence of two protons on each nitrogen (a characteristic associated with antitumor activity), and the absence of chiral centres. The use of cis-1,4-DACH has made it possible to detect different conformers in a system containing a primary diamine carrier ligand associated with anticancer activity and to confirm the previous hypothesis that the coexistence of different conformers established in studies of retro models having relatively bulky ligands is not an artefact resulting from carrier-ligand bulk. Moreover, the data for the (cis-1,4-DACH)Pt(d(GpG)) and (cis-1,4 DACH)Pt(d(GGTTT)) adducts indicate that at a temperature close to the physiological one (40 degrees C) HH1 and DeltaHT1 conformers are present in comparable amounts. In contrast, at low temperature (close to 0 degrees C) the equilibrium shifts dramatically toward the more stable HH1 conformer (for the (cis-1,4-DACH)Pt(d(TGGT)) adduct the HH1 conformer is always dominant, even at high temperature). Notably, (cis-1,4-DACH)PtCl2 (Kiteplatin) has been recently reinvestigated and found to be particularly active against colorectal cancer (including oxaliplatin-resistant phenotypes). PMID- 25144400 TI - The sole cysteine residue (Cys301) of tetrathionate hydrolase from Acidithiobacillus ferrooxidans does not play a role in enzyme activity. AB - Cysteine residues are absolutely indispensable for the reactions of almost all enzymes involved in the dissimilatory oxidation pathways of reduced inorganic sulfur compounds. Tetrathionate hydrolase from the acidophilic iron- and sulfur oxidizing bacterium Acidithiobacillus ferrooxidans (Af-Tth) catalyzes tetrathionate hydrolysis to generate elemental sulfur, thiosulfate, and sulfate. Af-Tth is a key enzyme in the dissimilatory sulfur oxidation pathway in this bacterium. Only one cysteine residue (Cys301) has been identified in the deduced amino acid sequence of the Af-Tth gene. In order to clarify the role of the sole cysteine residue, a site-specific mutant enzyme (C301A) was generated. No difference was observed in the retention volumes of the wild-type and mutant Af Tth enzymes by gel-filtration column chromatography, and surprisingly the enzyme activities measured in the cysteine-deficient and wild-type enzymes were the same. These results suggest that the sole cysteine residue (Cys301) in Af-Tth is involved in neither the tetrathionate hydrolysis reaction nor the subunit assembly. Af-Tth may thus have a novel cysteine-independent reaction mechanism. PMID- 25144402 TI - Gold-nanoparticle-decorated hybrid mesoflowers: an efficient surface-enhanced Raman scattering substrate for ultra-trace detection of prostate specific antigen. AB - We demonstrate a method for making highly sensitive hybrid gold mesoflower (MF) based surface-enhanced Raman scattering (SERS) substrate via programmed assembly of spherical gold nanoparticles (AuNPs) onto a highly anisotropic silica-coated MF. This imparts a new signal enhancing mechanism for the ultrasensitive detection of molecules from highly complex molecular environments. This substrate has been utilized as an ideal platform for the detection of Raman features corresponding to the prostate specific antigen (PSA) of a concentration as low as 2.5 ng/mL without the aid of any labels. We also demonstrated the possible conformational modifications of PSA on the hybrid MF surface and the influence of various parameters on obtaining reproducible SERS spectra of proteins. This is critical in SERS based label-free detection of biomarkers from a diagnostic perspective. PMID- 25144403 TI - Using an Educational Multimedia Application to Prepare Children for Outpatient Surgeries. AB - Surgery is a highly stressful event for children and caregivers. Extensive effort has been made to improve preoperative care in order to alleviate worry about the surgical procedure itself. This study tested the impact of an educational multimedia intervention on the cognitive, emotional, and physiological responses of children undergoing surgery, as well as on parental state anxiety. Children (n = 90) were assigned to three different groups: an educational multimedia intervention (experimental group), an entertainment video game intervention (comparison group), and a control group (no intervention). Children who received the educational multimedia intervention reported lower level of worries about hospitalization, medical procedures, illness, and negative consequences than those in the control and in the comparison groups. Parental state anxiety was also lower in the both the educational and the entertainment video game interventions compared to the control group. These findings suggest that providing information to children regarding medical procedures and hospital rules and routines is important to reduce their preoperative worries, and also relevant for parental anxiety. PMID- 25144405 TI - Cerebrospinal fluid in the upper eyelid: an "abscess" of a different kind. PMID- 25144406 TI - N-heterocyclic carbene-stabilized palladium complexes as organometallic catalysts for bioorthogonal cross-coupling reactions. AB - A small library of water-soluble N-heterocyclic carbene (NHC)-stabilized palladium complexes was prepared and applied for cross-couplings of biomolecules under mild conditions in water. Pd-NHC complexes bearing hydrophilic groups were demonstrated to be efficient catalysts for the Suzuki-Miyaura coupling of various unnatural amino acids and proteins bearing p-iodophenyl functional groups. We further utilized this catalytic system for the rapid bioorthogonal labeling of proteins on the surfaces of mammalian cells. These results demonstrated that NHC stabilized metal complexes have potential utility in cellular systems. PMID- 25144404 TI - Characterization of RNA binding and chaperoning activities of HIV-1 Vif protein. Importance of the C-terminal unstructured tail. AB - The viral infectivity factor (Vif) is essential for the productive infection and dissemination of HIV-1 in non-permissive cells, containing the cellular anti-HIV defense cytosine deaminases APOBEC3 (A3G and A3F). Vif neutralizes the antiviral activities of the APOBEC3G/F by diverse mechanisms including their degradation through the ubiquitin/proteasome pathway and their translational inhibition. In addition, Vif appears to be an active partner of the late steps of viral replication by interacting with Pr55(Gag), reverse transcriptase and genomic RNA. Here, we expressed and purified full-length and truncated Vif proteins, and analyzed their RNA binding and chaperone properties. First, we showed by CD and NMR spectroscopies that the N-terminal domain of Vif is highly structured in solution, whereas the C-terminal domain remains mainly unfolded. Both domains exhibited substantial RNA binding capacities with dissociation constants in the nanomolar range, whereas the basic unfolded C-terminal domain of Vif was responsible in part for its RNA chaperone activity. Second, we showed by NMR chemical shift mapping that Vif and NCp7 share the same binding sites on tRNA(Lys) 3, the primer of HIV-1 reverse transcriptase. Finally, our results indicate that Vif has potent RNA chaperone activity and provide direct evidence for an important role of the unstructured C-terminal domain of Vif in this capacity. PMID- 25144409 TI - Using FOCUS PDSA to improve antipsychotic medication management. PMID- 25144411 TI - Novel platelet storage conditions: additive solutions, gas, and cold. AB - PURPOSE OF REVIEW: Platelets are a frequently requested blood product today and are often in limited supply because of a shelf life of 5-7 days, depending on the country. Room temperature storage is associated with an increased risk of transfusion-transmitted infection. Plasma used for platelet storage is unavailable for other uses, and allogeneic plasma carries with it risks for adverse transfusion reactions. This review looks at recent activities evaluating alternative conditions for the storage of platelets. RECENT FINDINGS: New generation platelet additive solutions are being evaluated and applied as a strategy to reduce the volume of allogeneic plasma transfused and to support storage following pathogen reduction treatments. There is a renewed interest in refrigerator temperature and frozen storage of platelets to improve availability, to reduce septic transfusion risk, and to enhance hemostatic efficacy in the bleeding patient. SUMMARY: Use of platelet additive solutions has been shown to reduce the incidence of allergic and nonhemolytic febrile transfusion reactions in two large studies. Results of ongoing research and new clinical trials in cold storage methods will be forthcoming and may present solutions for platelet availability problems and new choices for therapeutic transfusion of the bleeding patient. PMID- 25144412 TI - Expanding functionality of recombinant human collagen through engineered non native cysteines. AB - Collagen is the most abundant protein in extracellular matrices and is commonly used as a tissue engineering scaffold. However, collagen and other biopolymers from native sources can exhibit limitations when tuning mechanical and biological properties. Cysteines do not naturally occur within the triple-helical region of any native collagen. We utilized a novel modular synthesis strategy to fabricate variants of recombinant human collagen that contained 2, 4, or 8 non-native cysteines at precisely defined locations within each biopolymer. This bottom-up approach introduced capabilities using sulfhydryl chemistry to form hydrogels and immobilize bioactive factors. Collagen variants retained their triple-helical structure and supported cellular adhesion. Hydrogels were characterized using rheology, and the storage moduli were comparable to fibrillar collagen gels at similar concentrations. Furthermore, the introduced cysteines functioned as anchoring sites, with TGF-beta1-conjugated collagens promoting myofibroblast differentiation. This approach demonstrates the feasibility to produce custom designed collagens with chemical functionality not available from native sources. PMID- 25144407 TI - Surge capacity logistics: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: Successful management of a pandemic or disaster requires implementation of preexisting plans to minimize loss of life and maintain control. Managing the expected surges in intensive care capacity requires strategic planning from a systems perspective and includes focused intensive care abilities and requirements as well as all individuals and organizations involved in hospital and regional planning. The suggestions in this article are important for all involved in a large-scale disaster or pandemic, including front-line clinicians, hospital administrators, and public health or government officials. Specifically, this article focuses on surge logistics-those elements that provide the capability to deliver mass critical care. METHODS: The Surge Capacity topic panel developed 23 key questions focused on the following domains: systems issues; equipment, supplies, and pharmaceuticals; staffing; and informatics. Literature searches were conducted to identify studies upon which evidence-based recommendations could be made. The results were reviewed for relevance to the topic, and the articles were screened by two topic editors for placement within one of the surge domains noted previously. Most reports were small scale, were observational, or used flawed modeling; hence, the level of evidence on which to base recommendations was poor and did not permit the development of evidence based recommendations. The Surge Capacity topic panel subsequently followed the American College of Chest Physicians (CHEST) Guidelines Oversight Committee's methodology to develop suggestion based on expert opinion using a modified Delphi process. RESULTS: This article presents 22 suggestions pertaining to surge capacity mass critical care, including requirements for equipment, supplies, and pharmaceuticals; staff preparation and organization; methods of mitigating overwhelming patient loads; the role of deployable critical care services; and the use of transportation assets to support the surge response. CONCLUSIONS: Critical care response to a disaster relies on careful planning for staff and resource augmentation and involves many agencies. Maximizing the use of regional resources, including staff, equipment, and supplies, extends critical care capabilities. Regional coalitions should be established to facilitate agreements, outline operational plans, and coordinate hospital efforts to achieve predetermined goals. Specialized physician oversight is necessary and if not available on site, may be provided through remote consultation. Triage by experienced providers, reverse triage, and service deescalation may be used to minimize ICU resource consumption. During a temporary loss of infrastructure or overwhelmed hospital resources, deployable critical care services should be considered. PMID- 25144410 TI - Resource-poor settings: response, recovery, and research: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: Planning for mass critical care in resource-poor and constrained settings has been largely ignored, despite large, densely crowded populations who are prone to suffer disproportionately from natural disasters. As a result, disaster response has been suboptimal and in many instances hampered by lack of planning, education and training, information, and communication. METHODS: The Resource-Poor Settings panel developed five key question domains; defining the term resource poor and using the traditional phases of the disaster cycle (mitigation/preparedness/response/recovery). Literature searches were conducted to identify evidence to answer the key questions in these areas. Given a lack of data on which to develop evidence-based recommendations, expert-opinion suggestions were developed, and consensus was achieved using a modified Delphi process. RESULTS: The five key questions were as follows: definition, capacity building and mitigation, what resources can we bring to bear to assist/surge, response, and reconstitution and recovery of host nation critical care capabilities. Addressing these led the panel to offer 33 suggestions. Because of the large number of suggestions, the results have been separated into two sections: part I, Infrastructure/Capacity in the accompanying article, and part II, Response/Recovery/Research in this article. CONCLUSIONS: A lack of rudimentary ICU resources and capacity to enhance services plagues resource-poor or constrained settings. Capacity building therefore entails preventative strategies and strengthening of primary health services. Assistance from other countries and organizations is often needed to mount a surge response. Moreover, the disengagement of these responding groups and host country recovery require active planning. Future improvements in all phases require active research activities. PMID- 25144414 TI - Evaluation of Antibiotic Irrigation Versus Saline Irrigation in Reducing the Long Term Incidence and Severity of Capsular Contraction After Primary Augmentation Mammoplasty. AB - BACKGROUND: Capsular contracture is the most frequent complication after primary augmentation mammoplasty. The practice of irrigating implant pockets with a triple antibiotic solution has been widely adopted in an attempt to prevent capsular contracture, despite a limited understanding of the inciting pathophysiology. Capsular contracture is commonly attributed to subclinical infection, immunologic response to breast implants, and chronic inflammatory changes caused by the presence of the implants. The purpose of this study was to evaluate if antibiotic irrigation was superior to saline in reducing the long term incidence and severity of capsular contracture after primary augmentation mammoplasty. METHODS: A retrospective cohort study enrolling patients having undergone primary augmentation mammoplasty by the authors between 2011 and 2012 for all women satisfying inclusion and exclusion criteria was conducted using prospectively collected quality assurance data. Surgical technique between surgeons was controlled such that the only difference was the use of antibiotic irrigation in the treatment group. Analysis with predetermined 95% confidence intervals was performed using chi test and analysis of variance. RESULTS: Fifty five patients underwent surgery. Twenty-eight patients treated with saline (control) were included, ranging in age from 22 to 50 years with a mean follow-up time of 2.8 years. Twenty-seven patients were treated with triple antibiotic solution (treatment) ranging in age from 22 to 56 years with a mean follow-up time of 2.6 years. Rates of capsular contracture were 3.6% (control group) and 3.7% (treatment group). chi statistic was found to be 0.0014 (P = 0.97) and analysis of variance F value was 1 (P = 0.39). CONCLUSIONS: There was no difference between triple antibiotic and saline irrigation in the incidence or severity of capsular contracture at 2.8 years follow-up when high-quality surgical technique is used. PMID- 25144413 TI - Metabolic effect and receptor signalling profile of a non-metabolisable insulin glargine analogue. AB - CONTEXT: Insulin glargine (GLA) is rapidly metabolized in vivo to metabolite M1, which has in vitro metabolic and mitogenic profiles comparable with human insulin (HI). OBJECTIVE: To investigate the pharmacologic and signalling profiles of a non-metabolizable analogue (A21Gly,DiD-Arg) insulin (D-GLA). METHODS: Rats were injected s.c. with 1, 12.5 or 200 U/kg of GLA or D-GLA; blood glucose and phosphorylation status of the insulin receptor (IR), Akt and IGF-1 receptor (IGF1R) in tissue samples were investigated after 1 h. Plasma samples were analysed for insulin by LC-MS/MS. RESULTS: Blood glucose lowering was prolonged with D-GLA. D-GLA comprised >=98% of insulin after D-GLA injection; M1 comprised 76-92% after GLA injection. IR and Akt phosphorylation were comparable with GLA and D-GLA. Neither analogue stimulated IGF1R phosphorylation. CONCLUSIONS: Suprapharmacological doses of D-GLA did not activate IGF1R in vivo. Mitogenic effects of insulin and insulin analogues might be solely based on IR growth promoting activity. PMID- 25144415 TI - Outcomes of Gastro-omental Free Flap Reconstruction for Salvage Laryngopharyngectomy for Pharyngeal and Laryngeal Cancer After Concurrent Chemoradiotherapy. AB - BACKGROUND: In the case of salvage laryngopharyngectomy, replacement of the pharyngoesophageal segment is mostly performed with fasciocutaneous or jejunal flaps. However, these options do not represent the best surgical technique of reconstruction in some occasions. Thus, the gastro-omental free flap could serve as an alternative procedure. METHODS: A retrospective review was conducted on patients who underwent pharyngoesophageal reconstruction using gastro-omental free flap after salvage laryngopharyngectomy for recurrent pharyngeal or laryngeal carcinoma between 1992 and 2012 at Bellvitge Universitary Hospital. The perioperative morbidity, mortality, functional outcomes, and oncological outcomes were evaluated. RESULTS: Twenty-six patients were included and followed up at our hospital for a mean of 43.4 months (range, 12-184 months). Survival rate was 94% after 1-year follow-up and 89% after 3 years. Abdominal evisceration was observed in 2 cases, whereas no abdominal complications occurred to the other patients. Total flap necrosis was observed in 3 (11.5%) patients. Postoperative course was uneventful in 20 patients. Moreover, esophageal continuity without fistula was confirmed by barium swallow test. CONCLUSIONS: The gastro-omental flap represents a useful method for reconstruction of the pharyngoesophageal segment in a surgical field compromised by previous multimodal therapy. Despite being useful, the complication rate is relevant. PMID- 25144416 TI - Lateral Nail Fold Incision Technique for Venous Anastomosis in Fingertip Replantation. AB - BACKGROUND: Successful venous anastomosis is one of the most important factors in fingertip replantation. Volar veins in the fingertip course proximally in a random pattern, which makes it difficult to find out the exact locations. Although dorsal veins in the lateral nail fold have constant location and adequate diameter for anastomosis, they have been known as hard to dissect from the immobile subcutaneous tissue. The authors present a new lateral nail fold incision technique for venous anastomosis in the fingertip amputations. METHODS: From February 2010 to October 2010, 9 replantations using the new incision and venous anastomosis technique were performed in 9 patients. The levels of amputations were from the nail base to half of the nail bed. After repairing the proper digital arteries, a skin incision was made along the junction between the lateral nail fold and nail bed. Careful dissection was performed to isolate the veins in the lateral nail fold. After evaluation of the suitability of the vessel, venous anastomosis was performed. RESULTS: Seven male and 2 female patients were enrolled in this study. Appropriate dorsal veins for anastomosis could be found in 8 of 9 patients. All the replanted stumps survived without venous congestion and following additional procedures. A sizable volar or dorsal vein could not be found in 1 patient. The salvage technique was required in this patient. CONCLUSIONS: Dorsal veins in the lateral nail fold can be found easily because of the constant anatomical location. The new incision on the lateral nail fold provides not only sufficient operative field for anastomosis but also additional opportunity of successful venous anastomosis in the selected cases. The authors, therefore, propose this technique as an effective method for an alternative venous anastomosis in the zone I replantation. PMID- 25144417 TI - Perioperative Antibiotics in the Setting of Oropharyngeal Reconstruction: Less Is More. AB - BACKGROUND: Recipient-site infection after oropharyngeal reconstruction is a potentially disastrous complication. Although studies suggest that perioperative antibiotics reduces infection rates in these patients from 87% to 20%, there is no consensus regarding what constitutes the most appropriate antibiotic regimen and duration of treatment. METHODS: A retrospective review of perioperative antibiotic administration was performed of all patients who underwent local, pedicled, or free flap oropharyngeal reconstruction after oncologic resection by a single surgeon at a single institution between 2007 and 2013 to assess for recipient-site complications. RESULTS: Ninety-seven patients underwent 100 reconstructions (61 free flap reconstructions, 39 pedicled/local flap reconstructions) and all received a combination of intravenous (IV) antibiotic agents designed to cover oral flora. There were 23 (23%) recipient-site complications, which included cellulitis (9%), mucocutaneous fistula (5%), abscess (5%), and wound dehiscence (4%). Duration of antibiotic prophylaxis, defined as less than 48 hours (short-course) or greater than 48 hours (long course), was not a significant predictor of recipient-site complication. Significant risk factors for recipient-site complications were clindamycin prophylaxis (P < 0.008), increased duration of surgery (P < 0.047), and advanced age (P < 0.034). Recipient-site complication was found to be a significant predictor of both increased length of hospital stay (P < 0.001) and increased time to the resumption of enteral feeds (P < 0.035). CONCLUSIONS: These data suggest that extended courses of perioperative antibiotics do not confer additional benefits in patients undergoing oropharyngeal reconstruction. We recommend a limited 48-hour course of prophylactic antibiotics with sufficient aerobic and anaerobic coverage to help minimize the incidence of antibiotic related morbidities. PMID- 25144418 TI - Comparison of Extension Orthosis Versus Percutaneous Pinning of the Distal Interphalangeal Joint for Closed Mallet Injuries. AB - We compared a static extension orthosis with percutaneous pinning of the distal interphalangeal joint (DIPJ) for treatment of closed mallet injuries. After receiving counsel about treatment options, 44 patients (25 women and 19 men; mean age, 57 years) freely chose orthosis and 18 patients (5 women and 13 men; mean age, 51 years) chose pinning. Both the extension orthosis and the pin remained in place for 6 weeks; the pin then was removed, and the care in both groups was transitioned to nighttime orthosis use for an additional 6 weeks. The patients in the pin group were allowed to immediately resume unrestricted activity postoperatively. The mean follow-up was 32 months in the orthosis group and 19 months in the pin group. Final residual extensor lag was better in the pin group (5 vs 10 degrees, P = 0.048). Improvement between the groups was in favor of percutaneous pinning (36 vs 17 degrees, P = 0.001). No correlation was seen between time to treatment (<=14 vs >14 days from injury) and final extensor lag in either group (P = 0.85). The final mean DIPJ flexion was 53 degrees for orthosis and 46 degrees for pinning. Among the patients, 93% of the orthosis group and 100% of the pin group said that they would choose the same treatment again. Both groups had a mean of 5 hand therapy visits during treatment. Two complications occurred in the orthosis group (5%) and 3 (17%) occurred in the pin group. Extension orthotics and pinning are both well-tolerated, effective treatments of mallet injury. The techniques produce satisfactory correction of extensor lag and have high patient satisfaction. Pinning allows better correction of DIPJ extensor lag and results in a smaller degree of final extensor lag. Pinning is more expensive and may result in more DIPJ stiffness (ie, loss of active flexion), but it may be justified in certain patients (eg, medical professionals, food service workers) who would have difficulty working with an orthosis. PMID- 25144419 TI - Manipulation of Human Primary Endothelial Cell and Osteoblast Coculture Ratios to Augment Vasculogenesis and Mineralization. AB - Tissue-engineering scaffolds are often seeded with a single type of cell, but there has been more focus on cocultures to improve angiogenesis and bone formation for craniofacial applications. Investigation of bone-derived osteoblasts (OBs) is important because of the use of bone grafts and migration of OBs from native bone into constructs in vivo and therefore, their contribution to bone formation in vivo. The limitation of primary OBs has been their inability to mineralize without osteogenic factors in vitro. Through coculture of OBs and endothelial cells (ECs) and manipulation of the coculture ratio, mineralization can be achieved without osteogenic media or additional growth factors, thus enhancing their utility for tissue-engineering applications. An optimal ratio of EC/OB for vasculogenesis and mineralization has not been determined for human primary cells. Human umbilical vein ECs were cultured with normal human primary OBs in different EC/OB ratios, namely, 10:1, 5:1, 1:1, 1:5, and 1:10 with EC and OB monocultures as controls. The number of vasculogenic networks in a collagen matrix was highest in ratios of 5:1 and 1:1. ECs lined up and formed capillary like networks by day 10, which was not seen in the other groups. On polystyrene, cells were cocultured with ECs and OBs in direct contact (direct coculture) or separated by a transwell membrane (indirect coculture). At day 21, Alizarin Red staining showed mineralization on the 1:5 and 1:10 direct coculture ratios, with 1:5 having more mineralization nodules present than 1:10. No mineralization was seen in other direct coculture ratios or in any of the indirect coculture ratios. Alkaline phosphatase secretion was highest in the 1:5 direct coculture group. Vascular endothelial growth factor secretion from OBs was present in the 1:5 and 1:10 direct coculture ratios at all time points and inhibited after day 1 in other coculture groups. To improve vasculogenesis, cocultures of primary human ECs and OBs in ratios of 5:1 should be used, but to improve bone formation, the 1:5 direct coculture ratio results in most mineralization. PMID- 25144420 TI - How to avoid pectus bar displacement in the MIRPE or MOVARPE technique: results of 12 years' experience. PMID- 25144421 TI - Acute marjolin ulcers: a nebulous diagnosis: reply. PMID- 25144422 TI - Botulinum Toxin Type A Inhibits alpha-Smooth Muscle Actin and Myosin II Expression in Fibroblasts Derived From Scar Contracture. AB - BACKGROUND: Scar contracture (SC) is one of the most common complications resulting from major burn injuries. Numerous treatments are currently available but they do not always yield excellent therapeutic results. Recent reports suggest that botulinum toxin type A (BTXA) is effective at reducing SC clinically, but the molecular mechanism for this action is unknown. alpha-Smooth muscle actin (alpha-SMA) and myosin II are the main components of stress fibers, which are the contractile structures of fibroblasts. The effects of BTXA on alpha SMA and myosin II in SC are still unknown. This study aimed to explore the effect of BTXA on alpha-SMA and myosin II expression in fibroblasts derived from SC and to elucidate its actual mechanism further. METHODS: Fibroblasts were isolated from tissue specimens of SC. Fibroblasts were cultured in Dulbecco modified Eagle medium with different concentrations of BTXA and their proliferation was analyzed through the tetrazolium-based colorimetric method at 1, 4, and 7 days. Proteins of alpha-SMA and myosin II were checked using Western blot in fibroblasts treated with different concentrations of BTXA at 1, 4, and 7 days. RESULTS: Fibroblasts without BTXA treatment had a higher proliferation than that in other groups, which indicated that the proliferation of fibroblasts was significantly inhibited by BTXA (P < 0.05). Proteins of alpha-SMA and myosin II between fibroblasts with BTXA and fibroblasts without BTXA are statistically significant (P < 0.05). CONCLUSIONS: These results suggest that BTXA effectively inhibited the growth of fibroblasts derived from SC and reduced the expression of alpha-SMA and myosin II, which provided theoretical support for the application of BTXA to control SC. PMID- 25144423 TI - Experiences with end-of-life care in Paraguay. PMID- 25144426 TI - Drag reduction using lubricant-impregnated surfaces in viscous laminar flow. AB - Lubricant-impregnated surfaces (LIS), where micro/nanotextured surfaces are impregnated with lubricating liquids, have received significant attention for their robust, superslippery properties. In this study, we systematically demonstrate the potential for LIS to reduce drag in laminar flows. We present a scaling model that incorporates the viscosity of the lubricant and elucidates the dependence of drag reduction on the ratio of the viscosity of the working fluid to that of the lubricant. We experimentally validate this dependence in a cone and plate rheometer and demonstrate a drag reduction of 16% and slip length of 18 MUm in the case where the ratio of working fluid viscosity to lubricant viscosity is 260. PMID- 25144424 TI - Add-on treatment with teneligliptin ameliorates glucose fluctuations and improves glycemic control index in Japanese patients with type 2 diabetes on insulin therapy. AB - BACKGROUND: This study investigated whether teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, ameliorated glucose fluctuations in hospitalized Japanese patients with type 2 diabetes receiving insulin therapy, with or without other antidiabetes drugs, and using continuous glucose monitoring (CGM). PATIENTS AND METHODS: Twenty-six patients with type 2 diabetes were admitted for glycemic control. After admission, patients continued to be treated with optimal dietary therapy plus insulin therapy, with or without other antidiabetes drugs, until they achieved stable glycemic control. CGM measurements were made for 7 consecutive days. On Days 1-3, patients received insulin with or without other antidiabetes drugs, and on Days 4-7, teneligliptin 20 mg once daily at breakfast was added to ongoing therapy. Doses of insulin were fixed during the study. Levels of serum glycated albumin (GA), 1,5-anhydro-d-glucitol (1,5-AG), and high sensitivity C-reactive protein (hsCRP) were measured. RESULTS: Add-on treatment with teneligliptin led to significant improvements in 24-h mean glucose levels, the proportion of time in normoglycemia, mean amplitude of glycemic excursions, and total area under the curve within 2 h after each meal. The proportion of time in hypoglycemia and hsCRP levels did not increase significantly compared with before teneligliptin. Values of 1,5-AG and GA were significantly improved by treatment with teneligliptin. CONCLUSIONS: Addition of teneligliptin to insulin therapy led to a significant improvement in diurnal glycemic control and significant reductions in glucose fluctuations in 24-h periods without increasing hypoglycemia in Japanese patients with type 2 diabetes on insulin therapy, with or without other antidiabetes agents. PMID- 25144427 TI - Microencapsulation of krill oil using complex coacervation. AB - The research work was aimed at the development of a process to yield gelatin-gum Arabic multinuclear microcapsules of krill oil (KO), via complex coacervation. On the basis of the experimental results of the screening trials, a three-level-by three-factor Box-Behnken design was used to evaluate the effects of the ratio of the core material to the wall (RCW; x1), the stirring speed (SP; x2) and the pH (x3) on the encapsulation efficiency (EE). The experimental findings indicated that x3 has the most significant linear and quadratic effects on the EE of KO and a bilinear effect with x1, whereas x2 did not have any significant effect. The optimal conditions for a 92% of EE were: 1.75:1 for RCW, 3.8 for pH and 3 for SP. The microcapsules, formed by complex coacervation and without any cross-linking agent, were multinucleated, circular in shape and had sufficient stability to maintain their structure. PMID- 25144428 TI - Acute cholecystitis. AB - INTRODUCTION: Of people admitted to hospital for biliary tract disease, 20% have acute cholecystitis. Up to the age of 50 years, acute calculous cholecystitis is three times more common in women than in men, and about one and a half times more common in women than in men thereafter. About 95% of people with acute cholecystitis have gallstones. Optimal therapy for acute cholecystitis, based on timing and severity of presentation, remains controversial. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute cholecystitis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 18 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: early cholecystectomy, laparoscopic cholecystectomy, observation alone, open cholecystectomy, and percutaneous cholecystostomy. PMID- 25144429 TI - Energy costs & performance of transtibial amputees & non-amputees during walking & running. AB - This study compared energy costs and performance differences of walking and running for transtibial amputee (TTA) and matched non-amputee runners. TTA were tested with 3 prosthetic feet: traditional foot, SACH; general purpose, energy storing and return (ESAR) foot, Renegade; running-specific ESAR foot, Nitro. During walking, VO2 and gait efficiency (GE) were similar between prosthetic feet. VO2 was increased (21-33%) and GE was decreased for TTA compared to controls. Self-selected walking speed (SSWS) was slower for SACH (4-6%) compared to Renegade and Nitro but SSWS for TTA was slower (16-22%) than controls. During running, VO2 was increased (8-18%) and GE was decreased using SACH and Renegade, compared to Nitro. During running, VO2 was greater (9-38%), GE was decreased and SSRS was slower (17-30%) for TTA, than controls. VO2 peak was similar for controls and TTA using Nitro, but peak running speed was slower for TTA. In conclusion, during walking energy costs are mostly similar between prosthetic feet, but ESAR feet likely provide faster SSWS for TTA. During running, energy costs and performance are improved for TTA using Nitro. Nonetheless, for all prosthetic feet conditions, TTA demonstrated an energy cost and performance disadvantage during walking and running compared to non-amputee runners. PMID- 25144430 TI - Correlation between acute and chronic 24-hour blood pressure response to resistance training in adult women. AB - The purpose of the present study was to correlate the acute and chronic decrease in blood pressure (BP) following resistance training (RT). 13 normotensive women (18-49 years) completed an acute whole body RT session with 3 sets of 10 repetitions at 60% 1RM and then 8 weeks of RT as follows: 3/week, 3 sets of 8-12 repetitions maximum. Systolic (SBP) and diastolic BP (DBP) were measured up to 60 min and 24 h following RT (acute and chronic). The greatest acute decrease of SBP (108.5+/-7.0 mmHg) and DBP (71.5+/-6.4 mmHg) values over the 60-min period were reduced compared to pre-exercise (117.3+/-11.7 and 79.3+/-8.2 mmHg, respectively; p<0.05). The chronic effect on resting BP was observed only for those presenting acute post-exercise hypotension (PEH). The change in both SBP and DBP following acute RT was correlated with the chronic change in resting SBP and DBP (r>0.5; p<=0.05). The change in 24 h BP after acute RT was correlated with the chronic reduction in SBP (r=0.74) and DBP (r=0.80). The magnitude of PEH is a promising candidate for the prediction of individual BP-related training efficacy. PMID- 25144431 TI - Self-selecting fluid intake while maintaining high carbohydrate availability does not impair half-marathon performance. AB - We aimed to test the hypothesis that self-selecting fluid intake but maintaining high exogenous CHO availability (60 g/h) does not compromise half-marathon performance. 15 participants completed 3 half-marathons while drinking a 6% CHO solution to guidelines (DRINK) or a non-caloric solution in self-selected volumes when consuming 3*glucose (20 g) gels (G-GEL) or glucose-fructose (13 g glucose+7 g fructose) gels (GF-GEL) per hour. Fluid intake (DRINK: 1 557+/-182, G-GEL: 473+/-234, GF-GEL: 404+/-144 ml) and percent body mass loss (DRINK: - 0.8+/-0.9, G-GEL: - 2.0+/-0.6, GF-GEL: -2.3+/-1.1) were different (P<0.05) between conditions, though race time did not differ (DRINK: 110.6+/-14.4, G-GEL: 110.3+/ 14.6, GF-GEL: 113.7+/-12.8 min). In G-GEL, there was a positive correlation (P<0.05) between body mass loss and race time. Plasma glucose was lower (P<0.05) in GF-GEL compared with other conditions, and total CHO oxidation (DRINK: 3.2+/ 0.5, G-GEL: 3.0+/-0.4, GF-GEL: 2.6+/-0.4 g/min) was lower (P=0.06) in this trial. Self-selecting fluid intake but maintaining high CHO availability does not impair half-marathon performance. Additionally, consuming glucose-fructose mixtures in sub-optimal amounts reduces plasma glucose and total rates of CHO oxidation. PMID- 25144432 TI - Functional movement ScreenTM--normative values in healthy distance runners. AB - Recreational runners have an estimated overuse injury incidence rate of up to 79% and 90% for marathoners. A pre-participation screening tool that can identify risk for injury may help reduce overuse injury in runners. The Functional Movement Screen (FMS(TM)) is a reliable clinical tool used with athletes to help predict injury. To date, the FMS(TM) has not been used with endurance athletes. The purpose of this article is to establish normative FMS(TM) values for distance runners. 45 healthy runners performed the FMS(TM). Descriptive statistics were calculated; independent t-tests were performed to examine the effect of gender, experience and injury on scores. A Chi-square test was used to evaluate whether significant differences in scores exist for any component of the FMS(TM). The mean FMS(TM) score was 13.13+/-1.8. No significant differences in FMS(TM) scores were found between novice and experienced runners (p=0.71) or runners with a history of injury and those without (p=0.20). While male and female runners did not differ significantly in their total FMS(TM) score (p=0.65), significant differences were found in the deep squat (p<0.05), trunk stability push-up (p<0.001) and active straight leg raise components (p=0.002). This study provides normative values for FMS(TM) scores when testing uninjured distance runners. PMID- 25144433 TI - The association between hallux valgus and proximal joint alignment in young female dancers. AB - Very little is known about the relationship between proximal joint alignment and hallux valgus among young dancers. This study sought to determine the extent to which spinal and lower extremity alignments are involved in hallux valgus, and to identify predicting variables for its development in young dancers. A group of 1336 young female dancers aged 8-16 years, and 226 control participants of the same age cohort were screened for the presence of hallux valgus, body physique characteristics, joint range of motion, and anatomical anomalies. Hallux valgus was common in the 2 young female populations studied. Among the dancers, 40.0% had bilateral hallux valgus and 7.3% unilateral. Among the controls, 32.3% had bilateral and 1.8% unilateral hallux valgus (chi2=8.27, df=1, p=0.004). Following logistic regression analysis, age (OR=1.028, 95% CI=0.968-1.091), genu varum (OR=1.514; CI=1.139-2.013) and scoliosis (OR=2.089; CI=1.113-3.921) were found to be significant predicting factors for hallux valgus in the dancer group, whereas in the control group, the predicting factors were age (OR=0.911, 95% CI=0.801 1.036) and ankle plantar flexion range of motion (OR=0.972; CI=0.951-0.992). In conclusion, it was found that spinal deformity, lower extremity alignment, and joint range of motion are strongly related to hallux valgus. PMID- 25144434 TI - Influence of acute exercise on the osmotic stability of the human erythrocyte membrane. AB - This study evaluated the effects of 2 different types of acute aerobic exercise on the osmotic stability of human erythrocyte membrane and on different hematological and biochemical variables that are associated with this membrane property. The study population consisted of 20 healthy and active men. Participants performed single sessions of 2 types of exercise. The first session consisted of 60 min of moderate-intensity continuous exercise (MICE). The second session, executed a week later, consisted of high-intensity interval exercise (HIIE) until exhaustion. The osmotic stability of the erythrocyte membrane was represented by the inverse of the salt concentration (1/H50) at the midpoint of the sigmoidal curve of dependence between the absorbance of hemoglobin and the NaCl concentration. The values of 1/H50 changed from 2.29+/-0.1 to 2.33+/-0.09 after MICE and from 2.30+/-0.08 to 2.23+/-0.12 after HIIE. During MICE mean corpuscular volume increased, probably due to in vivo lysis of older erythrocytes, with preservation of cells that were larger and more resistant to in vitro lysis. The study showed that a single bout of acute exercise affected erythrocyte stability, which increased after MICE and decreased after HIIE. PMID- 25144435 TI - Isolated myocardial bridging and exercise-related cardiac events. AB - Myocardial bridging, which is defined as cardiac muscle overlying a part of a coronary artery, is the most common congenital coronary artery anomaly. Myocardial bridging is usually benign, but has been associated with exercise related cardiac events. Guidelines for athletic participation in these patients are primarily based on reports from the general population with myocardial bridging. We performed a systematic literature search of PubMed, Ovid and Google Scholar for articles addressing exercise-related cardiac events associated with myocardial bridging. We identified 69 cases of which only 35 were well defined. We conclude that there are insufficient data to form definitive guidelines as to how physically active individuals with myocardial bridging should be managed. Prudence suggests that management should be individualized for those with possible symptoms. Beta adrenergic blockade is recommended as initial medical therapy. Surgery should be restricted to those with continued symptoms despite beta blocker therapy. There is no evidence that asymptomatic individuals without clinical evidence of ischemia should be restricted from vigorous activity. PMID- 25144436 TI - Oxygen uptake, muscle activity and ground reaction force during water aerobic exercises. AB - This study aimed to compare the oxygen uptake (VO2), the muscle activity of lower limbs, and the vertical ground reaction force (V-GRF) of women performing water aerobic exercises at different intensities. 12 young women performed the experimental protocol, which consisted of 3 water exercises (stationary running [SR], frontal kick [FK] and cross country skiing [CCS]) at 3 intensities (first and second ventilatory thresholds and maximum effort). A two-way repeated measures ANOVA was used. Regarding VO2, different responses between intensities (p<0.001) were found, and values between exercises were similar. For electromyographic activity (EMG), differences between intensities for all muscles (p<0.001) were found. Greater EMG signals were observed in the FK compared to SR for rectus femoris, semitendinosus, vastus lateralis and biceps femoris muscles (p<0.05). Regarding V-GRF, there was an increase in the V-GRF at greater intensities compared to the first ventilatory threshold (p=0.001). In addition, lower values were found during CCS compared to the SR and FK exercises (p<0.001). Thus, greater cardiorespiratory and neuromuscular responses were observed with increasing intensity. Exercises such as CCS could be used to attenuate the V-GRF; if the purpose is to reduce the muscular activity of lower limbs at a specific intensity, SR could be recommended. PMID- 25144437 TI - Correlation between acute and short-term changes in flexibility using two stretching techniques. AB - This study aimed to determine whether increases in flexibility following a single session predict increases in flexibility after a short-term stretching training program involving static stretching (SS) or proprioceptive neuromuscular facilitation (PNF) techniques. 70 adults (aged 18-30 years) of both sexes were randomly assigned to 2 groups: PNF (2 series of contract-relax stretching) and SS (static stretching for 1 min). Both stretching protocols were performed for 7 consecutive days. Active knee extension was evaluated before and after the first session and one day after the end of the intervention. Two-way ANOVA showed significant flexibility gains for both groups and no difference between them. The changes in flexibility after the first intervention session were strongly correlated with the changes after the training program in both groups (PNF r=0.82, p=0.001; SS: r=0.82, p=0.001). Linear regression showed that the increases in flexibility predicted the gains after both training programs (PNF: r(2)=0.67, p=0.001; SS: r(2)=0.61, p=0.005). In conclusion, the acute changes in flexibility after a single session of PNF and SS predict the gains in flexibility after longer-term training -programs. PMID- 25144438 TI - Effects of partial-body cryotherapy (- 110 degrees C) on muscle recovery between high-intensity exercise bouts. AB - The aim of this study was to evaluate the effects of a single partial-body cryotherapy bout between training sessions on strength recovery. 12 young men (23.9+/-5.9 years) were randomly exposed to 2 different conditions separated by 7 days: 1) Partial-body cryotherapy (subjects were exposed to 3 min of partial-body cryotherapy at - 110 degrees C between 2 high-intensity training sessions); 2) Control (subjects were not exposed to partial-body cryotherapy between 2 high intensity training sessions). Subjects were exposed to partial-body cryotherapy after the first training session. The 2 knee extension high-intensity training sessions were separated by a 40-min rest interval. Knee extension training consisted of 6 sets of 10 repetitions at 60 degrees .s(-1) for concentric actions and 6 sets of 10 at 180.s(-1) for eccentric actions. The decrease in eccentric peak torque and total work was significantly (p<0.05) less after partial-body cryotherapy (5.6 and 2%, respectively) when compared to control (16 and 11.6%, respectively). However, the decrease in concentric peak torque and total work was not different (p>0.05) between partial-body cryotherapy (9.4 and 6.5%, respectively) and control (7.5 and 5.2%, respectively). These results indicate that the use of partial-body cryotherapy between-training sessions can enhance eccentric muscle performance recovery. PMID- 25144439 TI - Effect of birth month on physical fitness of soccer players (Under-15) according to biological maturity. AB - This study aims to clarify the relationship between the birth quarters, biological maturity and physical fitness (PF) in Under-15 youth soccer players. Each participant (n=133) was an Under-15 player from a top-elite soccer academy. The data collection period lasted 8 years (from Under-15 2002/2003 to 2009/2010 season). The athletes' birth dates were recorded and organized by birth quarters (Q1, first; Q2, second; Q3, third; Q4, fourth) and by semesters (S1, first; S2, second). Additionally recorded were each athlete's biological maturity (skeletal age, SA), anthropometric profile (stature; body mass; thigh, calf and upper arm girths), and fitness profile (10-m and 30-m sprint times; SJ; CMJ; shuttles in YYIR Test). Significant differences were found for (1) decimal age and SA by quarters (Q4-Q1, Q2) and semesters; and (2) stature (Q3-Q1, Q2, Q4; S1-S2), body mass (Q1-Q3; S1-S2), thigh girth (S1-S2), SJ (Q1-Q2) and sprint time (Q4-Q1, Q2; S1-S2). When maturity was considered as covariate all PF variables, with exception of SJ (Q1-Q2) and 10-m sprint time (S1-S2), were very similar among the studied groups. These findings suggest that (1) seasonal birth effect may result from the observed biological maturation differences, and (2) athletes may have been chosen due to their PF attributes. PMID- 25144440 TI - Spatially distributed dendritic resonance selectively filters synaptic input. AB - An important task performed by a neuron is the selection of relevant inputs from among thousands of synapses impinging on the dendritic tree. Synaptic plasticity enables this by strenghtening a subset of synapses that are, presumably, functionally relevant to the neuron. A different selection mechanism exploits the resonance of the dendritic membranes to preferentially filter synaptic inputs based on their temporal rates. A widely held view is that a neuron has one resonant frequency and thus can pass through one rate. Here we demonstrate through mathematical analyses and numerical simulations that dendritic resonance is inevitably a spatially distributed property; and therefore the resonance frequency varies along the dendrites, and thus endows neurons with a powerful spatiotemporal selection mechanism that is sensitive both to the dendritic location and the temporal structure of the incoming synaptic inputs. PMID- 25144441 TI - Antioxidants for pain in chronic pancreatitis. AB - BACKGROUND: Reduced intake and absorption of antioxidants due to pain and malabsorption are probable causes of the lower levels of antioxidants observed in patients with chronic pancreatitis (CP). Improving the status of antioxidants might be effective in slowing the disease process and reducing pain in CP. OBJECTIVES: To assess the benefits and harms of antioxidants for the treatment of pain in patients with CP. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Conference Proceedings Citation Index from inception to October 2012. Two review authors performed the selection of trials independently. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) evaluating antioxidants for treatment of pain in CP. All trials were included irrespective of blinding, numbers of participants randomly assigned and language of the article. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. The risk of bias of included trials was assessed. Study authors were asked for additional information in the case of missing data. MAIN RESULTS: Twelve RCTs with a total of 585 participants were included. Six trials were double-blinded, placebo-controlled studies, and the other six trials were of less adequate methodology. Most trials were small and had high rates of dropout. Eleven of the 12 included trials described the effects of antioxidants on chronic abdominal pain in chronic pancreatitis. Pain as measured on a visual analogue scale (VAS, scale range 0 to 10) after one to six months was less in the antioxidant group than in the control group (mean difference (MD) -0.33, 95% confidence interval (CI) -0.64 to -0.02, P value 0.04, moderate-quality evidence). The number of pain-free participants was not statistically significantly different (risk ratio (RR) 1.73, 95% CI 0.95 to 3.15, P value 0.07, low-quality evidence). More adverse events were observed in the antioxidant group, both in the parallel trials (RR 4.43, 95% CI 1.60 to 12.29, P value 0.0004, moderate-quality evidence) and in the cross-over trials (RR 5.80, 95% CI 1.56 to 21.53, P value 0.0009, moderate-quality evidence). Adverse events occurred in 16% of participants and were mostly mild (e.g. headache, gastrointestinal complaints), but were sufficient to make participants stop antioxidant use. Other important outcomes such as use of analgesics, exacerbation of pancreatitis and quality of life were rarely reported. One trial from 1991 evaluated the effects of antioxidants on acute pain during exacerbation of chronic pancreatitis and found that a significantly higher proportion of participants in the antioxidant group experienced pain relief. This trial was conducted more than 25 years ago and has not been reproduced since that time. Therefore, additional trials are needed before reliable conclusions can be drawn. AUTHORS' CONCLUSIONS: Current evidence shows that antioxidants can reduce pain slightly in patients with chronic pancreatitis. The clinical relevance of this small reduction is uncertain, and more evidence is needed. Adverse events in one of six patients may prevent the use of antioxidants. Effects of antioxidants on other outcome measures, such as use of analgesics, exacerbation of pancreatitis and quality of life remain uncertain because reliable data are not available. PMID- 25144443 TI - Toward high-performance digital logic technology with carbon nanotubes. AB - The slow-down in traditional silicon complementary metal-oxide-semiconductor (CMOS) scaling (Moore's law) has created an opportunity for a disruptive innovation to bring the semiconductor industry into a postsilicon era. Due to their ultrathin body and ballistic transport, carbon nanotubes (CNTs) have the intrinsic transport and scaling properties to usher in this new era. The remaining challenges are largely materials-related and include obtaining purity levels suitable for logic technology, placement of CNTs at very tight (~5 nm) pitch to allow for density scaling and source/drain contact scaling. This review examines the potential performance advantages of a CNT-based computing technology, outlines the remaining challenges, and describes the recent progress on these fronts. Although overcoming these issues will be challenging and will require a large, sustained effort from both industry and academia, the recent progress in the field is a cause for optimism that these materials can have an impact on future technologies. PMID- 25144442 TI - Leakage detection of Marcellus Shale natural gas at an Upper Devonian gas monitoring well: a 3-d numerical modeling approach. AB - Potential natural gas leakage into shallow, overlying formations and aquifers from Marcellus Shale gas drilling operations is a public concern. However, before natural gas could reach underground sources of drinking water (USDW), it must pass through several geologic formations. Tracer and pressure monitoring in formations overlying the Marcellus could help detect natural gas leakage at hydraulic fracturing sites before it reaches USDW. In this study, a numerical simulation code (TOUGH 2) was used to investigate the potential for detecting leaking natural gas in such an overlying geologic formation. The modeled zone was based on a gas field in Greene County, Pennsylvania, undergoing production activities. The model assumed, hypothetically, that methane (CH4), the primary component of natural gas, with some tracer, was leaking around an existing well between the Marcellus Shale and the shallower and lower-pressure Bradford Formation. The leaky well was located 170 m away from a monitoring well, in the Bradford Formation. A simulation study was performed to determine how quickly the tracer monitoring could detect a leak of a known size. Using some typical parameters for the Bradford Formation, model results showed that a detectable tracer volume fraction of 2.0 * 10(-15) would be noted at the monitoring well in 9.8 years. The most rapid detection of tracer for the leak rates simulated was 81 days, but this scenario required that the leakage release point was at the same depth as the perforation zone of the monitoring well and the zones above and below the perforation zone had low permeability, which created a preferred tracer migration pathway along the perforation zone. Sensitivity analysis indicated that the time needed to detect CH4 leakage at the monitoring well was very sensitive to changes in the thickness of the high-permeability zone, CH4 leaking rate, and production rate of the monitoring well. PMID- 25144444 TI - Plasma metabonomic profiling of lumbar disc herniation and its traditional Chinese medicine subtypes in patients by using gas chromatography coupled with mass spectrometry. AB - Lumbar disc herniation (LDH) is a commonly occurring disease, threatening human health and life quality. Lack of a gold standard of diagnosis has hindered the efficiency and efficacy of clinical therapy against LDH. Traditional Chinese medicine (TCM) has provided an experience-based but subjective diagnosis system for LDH, demanding objective evidence and explanation. In this study, we adopted a metabonomics approach using gas chromatography-mass spectrometry (GC-MS) to profile metabolic characteristics of LDH and its TCM subtypes. Plasma samples of 41 LDH patients and 25 healthy controls were collected. LDH patients were classified into two main subtypes, the reality syndrome and deficiency syndrome, according to TCM theory. By using multivariate statistical analysis and metabolism network analysis, we found diverse perturbations of metabolites in amino acid metabolism and carbohydrate metabolism, in which the amino acids (glutamic acid, aspartic acid, glycine, etc.) were up-regulated and a key carbohydrate metabolite (glucose 1-phosphate) was down-regulated. Few differences were found between the two TCM subtypes. Our findings reveal the metabolic disorders of LDH for the first time and demonstrate the feasibility of the metabonomics approach for LDH research but not for its TCM subtypes. PMID- 25144445 TI - The invisible issue of organ laundering. AB - Global institutions, although suggesting measures to deter organ trafficking, reiterate the lack of official statistics about this illegal trade. In this article, we explore the reasons why organ trafficking remains unreported. We argue that the complex factors that perpetuate invisibility facilitate trafficked organs being "laundered" in the health care systems of the purchaser's country, hindering accurate estimation of the problem. The factors are as follows: (a) issues of globalization, jurisdiction, and law enforcement; (b) the power of health care professionals; (c) the reimbursement of transplantation costs abroad by insurers; (d) ambivalence of the victim status of the sellers; and (e) the buyers as vulnerable offenders. PMID- 25144446 TI - Functional graphene springs for responsive actuation. AB - A new type of graphene fiber spring (GFS) has been demonstrated to possess a large elongation of up to 480% with a stable elasticity coefficient for 100,000 times of stretch. Remarkably, the GFS performs reversibly stretchable actuation under electrostatic effects, and responds to an applied magnetic field for the development of novel magnetostriction switches and actuators once functionalized with magnetic nanocomponents. PMID- 25144447 TI - On the front line: quantitative virus dynamics in honeybee (Apis mellifera L.) colonies along a new expansion front of the parasite Varroa destructor. AB - Over the past fifty years, annual honeybee (Apis mellifera) colony losses have been steadily increasing worldwide. These losses have occurred in parallel with the global spread of the honeybee parasite Varroa destructor. Indeed, Varroa mite infestations are considered to be a key explanatory factor for the widespread increase in annual honeybee colony mortality. The host-parasite relationship between honeybees and Varroa is complicated by the mite's close association with a range of honeybee viral pathogens. The 10-year history of the expanding front of Varroa infestation in New Zealand offered a rare opportunity to assess the dynamic quantitative and qualitative changes in honeybee viral landscapes in response to the arrival, spread and level of Varroa infestation. We studied the impact of de novo infestation of bee colonies by Varroa on the prevalence and titres of seven well-characterised honeybee viruses in both bees and mites, using a large-scale molecular ecology approach. We also examined the effect of the number of years since Varroa arrival on honeybee and mite viral titres. The dynamic shifts in the viral titres of black queen cell virus and Kashmir bee virus mirrored the patterns of change in Varroa infestation rates along the Varroa expansion front. The deformed wing virus (DWV) titres in bees continued to increase with Varroa infestation history, despite dropping infestation rates, which could be linked to increasing DWV titres in the mites. This suggests that the DWV titres in mites, perhaps boosted by virus replication, may be a major factor in maintaining the DWV epidemic after initial establishment. Both positive and negative associations were identified for several pairs of viruses, in response to the arrival of Varroa. These findings provide important new insights into the role of the parasitic mite Varroa destructor in influencing the viral landscape that affects honeybee colonies. PMID- 25144450 TI - van der Waals radii of noble gases. AB - Consistent van der Waals radii are deduced for Ne-Xe, based on the noble gas...oxygen intermolecular distances found in gas phase structures. The set of radii proposed is shown to provide van der Waals distances for a wide variety of noble gas...element atom pairs that represent properly the distribution of distances both in the gas phase and in the solid state. Moreover, these radii show a smooth periodic trend down the group which is parallel to that shown by the halogens. PMID- 25144448 TI - Pterostilbene simultaneously induced G0/G1-phase arrest and MAPK-mediated mitochondrial-derived apoptosis in human acute myeloid leukemia cell lines. AB - BACKGROUND: Pterostilbene (PTER) is a dimethylated analog of the phenolic phytoalexin, resveratrol, with higher anticancer activity in various tumors. Herein, the molecular mechanisms by which PTER exerts its anticancer effects against acute myeloid leukemia (AML) cells were investigated. METHODOLOGY AND PRINCIPAL FINDINGS: Results showed that PTER suppressed cell proliferation in various AML cell lines. PTER-induced G0/G1-phase arrest occurred when expressions of cyclin D3 and cyclin-dependent kinase (CDK)2/6 were inhibited. PTER-induced cell apoptosis occurred through activation of caspases-8-9/-3, and a mitochondrial membrane permeabilization (MMP)-dependent pathway. Moreover, treatment of HL-60 cells with PTER induced sustained activation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK)1/2, and inhibition of both MAPKs by their specific inhibitors significantly abolished the PTER-induced activation of caspases-8/-9/-3. Of note, PTER-induced cell growth inhibition was only partially reversed by the caspase-3-specific inhibitor, Z DEVE-FMK, suggesting that this compound may also act through a caspase independent pathway. Interestingly, we also found that PTER promoted disruption of lysosomal membrane permeabilization (LMP) and release of activated cathepsin B. CONCLUSION: Taken together, our results suggest that PTER induced HL-60 cell death via MAPKs-mediated mitochondria apoptosis pathway and loss of LMP might be another cause for cell apoptosis induced by PTER. PMID- 25144449 TI - Safety of low-dose aspirin in endovascular treatment for intracranial atherosclerotic stenosis. AB - OBJECTIVES: To evaluate the safety of low-dose aspirin plus clopidogrel versus high-dose aspirin plus clopidogrel in prevention of vascular risk within 90 days of duration of dual antiplatelet therapy in patients treated with intracranial endovascular treatment. METHODS: From January 2012 to December 2013, this prospective and observational study enrolled 370 patients with symptomatic intracranial atherosclerotic stenosis of >=70% with poor collateral undergoing intracranial endovascular treatment. Antiplatelet therapy consists of aspirin, at a low-dose of 100 mg or high-dose of 300 mg daily; clopidogrel, at a dose of 75 mg daily for 5 days before endovascular treatment. The dual antiplatelet therapy continued for 90 days after intervention. The study endpoints include acute thrombosis, subacute thrombosis, stroke or death within 90 days after intervention. RESULTS: Two hundred and seventy three patients received low-dose aspirin plus clopidogrel and 97 patients received high-dose aspirin plus clopidogrel before intracranial endovascular treatment. Within 90 days after intervention, there were 4 patients (1.5%) with acute thrombosis, 5 patients (1.8%) with subacute thrombosis, 17 patients (6.2%) with stroke, and 2 death (0.7%) in low-dose aspirin group, compared with no patient (0%) with acute thrombosis, 2 patient (2.1%) with subacute thrombosis, 6 patients (6.2%) with stroke, and 2 death (2.1%) in high-dose aspirin group, and there were no significant difference in all study endpoints between two groups. CONCLUSION: Low dose aspirin plus clopidogrel is comparative in safety with high-dose aspirin plus clopidogrel within 90 days of duration of dual antiplatelet therapy in patients treated with intracranial endovascular treatment. PMID- 25144451 TI - Microcirculatory changes identified by photoacoustic microscopy in patients with complex regional pain syndrome type I after stellate ganglion blocks. AB - Complex regional pain syndrome (CRPS) is a chronic pain syndrome that causes intractable pain, disability, and poor quality of life for patients. The etiology and pathophysiology of CRPS are still poorly understood. Due to a lack of proper diagnostic tools, the prognosis of CRPS is primarily based on clinical observation. The objective of this work is to evaluate a new imaging modality, photoacoustic microscopy (PAM), for assisting diagnoses and monitoring the progress and treatment outcome of CRPS. Blood vasculature and oxygen saturation (sO2) were imaged by PAM from eight adult patients with CRPS-1. Patients' hands and cuticles were imaged both before and after stellate ganglion block (SGB) for comparison. For all patients, both vascular structure and sO2 could be assessed by PAM. In addition, more vessels and stronger signals were observed after SGB. The results show that PAM can help diagnose and monitor CRPS. PMID- 25144453 TI - Mother-infant HIV transmission: do maternal HIV-specific antibodies protect the infant? PMID- 25144452 TI - Reversibly switchable fluorescence microscopy with enhanced resolution and image contrast. AB - Confocal microscopy with optical sectioning has revolutionized biological studies by providing sharper images than conventional optical microscopy. Here, we introduce a fluorescence imaging method with enhanced resolution and imaging contrast, which can be implemented using a commercial confocal microscope setup. This approach, called the reversibly switchable photo-imprint microscopy (rsPIM), is based on the switching dynamics of reversibly switchable fluorophores. When the fluorophores are switched from the bright (ON) state to the dark (OFF) state, their switching rate carries the information about the local excitation light intensity. In rsPIM, a polynomial function is used to fit the fluorescence signal decay during the transition. The extracted high-order coefficient highlights the signal contribution from the center of the excitation volume, and thus sharpens the resolution in all dimensions. In particular, out-of-focus signals are greatly blocked for large targets, and thus the image contrast is considerably enhanced. Notably, since the fluorophores can be cycled between the ON and OFF states, the whole imaging process can be repeated. RsPIM imaging with enhanced image contrast was demonstrated in both fixed and live cells using a reversibly switchable synthetic dye and a genetically encoded red fluorescent protein. Since rsPIM does not require the modification of commercial microscope systems, it may provide a simple and cost-effective solution for subdiffraction imaging of live cells. PMID- 25144455 TI - A watermarking scheme for High Efficiency Video Coding (HEVC). AB - This paper presents a high payload watermarking scheme for High Efficiency Video Coding (HEVC). HEVC is an emerging video compression standard that provides better compression performance as compared to its predecessor, i.e. H.264/AVC. Considering that HEVC may will be used in a variety of applications in the future, the proposed algorithm has a high potential of utilization in applications involving broadcast and hiding of metadata. The watermark is embedded into the Quantized Transform Coefficients (QTCs) during the encoding process. Later, during the decoding process, the embedded message can be detected and extracted completely. The experimental results show that the proposed algorithm does not significantly affect the video quality, nor does it escalate the bitrate. PMID- 25144454 TI - Infiltration of alternatively activated macrophages in cancer tissue is associated with MDSC and Th2 polarization in patients with esophageal cancer. AB - Myeloid derived suppressor cells (MDSCs) expand in cancer bearing hosts and contribute to tumor immune evasion. M2 macrophages constitute a major cellular component of cancer-related inflammation. However, the correlation between circulating MDSCs and infiltrating M2 macrophages in tumor tissues from patients with esophageal cancer (ECA), and its potential relationship with the polarization of Th2 cells remain unclear. In the present study, we showed the level of MDSCs in PBMC and Arg1 in plasma were significantly elevated in ECA patients, and the increased ratio of MDSC in PBMC was closely related to the expression of CD163 in cancer tissues. In addition, the ECA patients exhibited remarkable increases in the mRNA levels of IL-4 and GATA3, as well as the protein levels of IL-13 and IL-6, but IFN-gamma and IL-12 in peripheral blood were decreased. Our data indicate that the increased Th2 cytokines are associated with MDSCs and M2 macrophages polarization, and foster the infiltration of CD163+M2 macrophages in cancer tissues, which promote the formation of immunosuppressive microenvironment in ECA patients. PMID- 25144456 TI - The orexin system in the enteric nervous system of the bottlenose dolphin (Tursiops truncatus). AB - This study provides a general approach to the presence and possible role of orexins and their receptors in the gut (three gastric chambers and intestine) of confined environment bottlenose dolphin. The expression of prepro-orexin, orexin A and B and orexin 1 and 2 receptors were investigated by single immunostaining and western blot analysis. The co-localization of vasoactive intestinal peptide and orexin 1 receptor in the enteric nervous system was examined by double immunostaining. Also, orexin A concentration were measured in plasma samples to assess the possible diurnal variation of the plasma level of peptide in this species. Our results showed that the orexin system is widely distributed in bottlenose dolphin enteric nervous system of the all gastrointestinal tract examined. They are very peculiar and partially differs from that of terrestrial mammals. Orexin peptides and prepro-orexin were expressed in the main stomach, pyloric stomach and proximal intestine; while orexin receptors were expressed in the all examined tracts, with the exception of main stomach where found no evidence of orexin 2 receptor. Co-localization of vasoactive intestinal peptide and orexin 1 receptor were more evident in the pyloric stomach and proximal intestine. These data could suggest a possible role of orexin system on the contractility of bottlenose dolphin gastrointestinal districts. Finally, in agreement with several reports, bottlenose dolphin orexin A plasma level was higher in the morning during fasting. Our results emphasize some common features between bottlenose dolphin and terrestrial mammals. Certainly, further functional investigations may help to better explain the role of the orexin system in the energy balance of bottlenose dolphin and the complex interaction between feeding and digestive physiology. PMID- 25144457 TI - Two-point magnitude MRI for rapid mapping of brown adipose tissue and its application to the R6/2 mouse model of Huntington disease. AB - The recent discovery of active brown fat in human adults has led to renewed interest in the role of this key metabolic tissue. This is particularly true for neurodegenerative conditions like Huntington disease (HD), an adult-onset heritable disorder with a prominent energy deficit phenotype. Current methods for imaging brown adipose tissue (BAT) are in limited use because they are equipment wise demanding and often prohibitively expensive. This prompted us to explore how a standard MRI set-up can be modified to visualize BAT in situ by taking advantage of its characteristic fat/water content ratio to differentiate it from surrounding white fat. We present a modified MRI protocol for use on an 11.7 T small animal MRI scanner to visualize and quantify BAT in wild-type and disease model laboratory mice. In this application study using the R6/2 transgenic mouse model of HD we demonstrate a significantly reduced BAT volume in HD mice vs. matched controls (n = 5 per group). This finding provides a plausible structural explanation for the previously described temperature phenotype of HD mice and underscores the significance of peripheral tissue pathology for the HD phenotype. On a more general level, the results demonstrate the feasibility of MR-based BAT imaging in rodents and open the path towards transferring this imaging approach to human patients. Future studies are needed to determine if this method can be used to track disease progression in HD and other disease entities associated with BAT abnormalities, including metabolic conditions such as obesity, cachexia, and diabetes. PMID- 25144458 TI - CYP2W1 is highly expressed in adrenal glands and is positively associated with the response to mitotane in adrenocortical carcinoma. AB - BACKGROUND: Adrenocortical tumors comprise frequent adenomas (ACA) and rare carcinomas (ACC). Human cytochrome P450 2W1 (CYP2W1) is highly expressed in some cancers holding the potential to activate certain drugs into tumor cytotoxins. OBJECTIVE: To investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC. MATERIAL AND METHODS: CYP2W1 expression was investigated by qRT-PCR in 13 normal adrenal glands, 32 ACA, 25 ACC, and 9 different non-adrenal normal tissue samples and by immunohistochemistry in 352 specimens (23 normal adrenal glands, 33 ACA, 239 ACC, 67 non-adrenal normal or neoplastic samples). RESULTS: CYP2W1 mRNA expression was absent/low in normal non-adrenal tissues, but high in normal and neoplastic adrenal glands (all P<0.01 vs non-adrenal normal tissues). Accordingly, CYP2W1 immunoreactivity was absent/low (H-score 0-1) in 72% of non-adrenal normal tissues, but high (H-score 2-3) in 44% of non-adrenal cancers, in 65% of normal adrenal glands, in 62% of ACAs and in 50% of ACCs (all P<0.001 vs non-adrenal normal tissues), being significantly increased in steroid-secreting compared to non-secreting tumors. In ACC patients treated with mitotane only, high CYP2W1 immunoreactivity adjusted for ENSAT stage was associated with longer overall survival and time to progression (P<0.05 and P<0.01, respectively), and with a better response to therapy both as palliative (response/stable disease in 42% vs 6%, P<0.01) or adjuvant option (absence of disease recurrence in 69% vs 45%, P<0.01). CONCLUSION: CYP2W1 is highly expressed in both normal and neoplastic adrenal glands making it a promising tool for targeted therapy in ACC. Furthermore, CYP2W1 may represent a new predictive marker for the response to mitotane treatment. PMID- 25144459 TI - The specific cleavage of lactone linkage to open-loop in cyclic lipopeptide during negative ESI tandem mass spectrometry: the hydrogen bond interaction effect of 4-ethyl guaiacol. AB - Mass spectrometry is a valuable tool for the analysis and identification of chemical compounds, particularly proteins and peptides. Lichenysins G, the major cyclic lipopeptide of lichenysin, and the non-covalent complex of lichenysins G and 4-ethylguaiacol were investigated with negative ion ESI tandem mass spectrometry. The different fragmentation mechanisms for these compounds were investigated. Our study shows the 4-ethylguaiacol hydrogen bond with the carbonyl oxygen of the ester group in the loop of lichenysins G. With the help of this hydrogen bond interaction, the ring structure preferentially opens in lactone linkage rather than O-C bond of the ester-group to produce alcohol and ketene. Isothermal titration 1H-NMR analysis verified the hydrogen bond and determined the proportion of subject and ligand in the non-covalent complex to be 1?1. Theoretical calculations also suggest that the addition of the ligand can affect the energy of the transition structures (TS) during loop opening. PMID- 25144460 TI - Comparative metabolite profiling of Solanum tuberosum against six wild Solanum species with Colorado potato beetle resistance. AB - The Colorado potato beetle Leptinotarsa decemlineata (Say) (CPB) is a coleopteran herbivore that feeds on the foliage on Solanum species, in particular, potato. Six resistant wild Solanum species were identified, and two of these species had low levels of glycoalkaloids. Comparative analysis of the untargeted metabolite profiles of the foliage using UPLC-qTOF-MS was done to find metabolites shared between the wild species but not with Solanum tuberosum (L.) to identify resistance-related metabolites. It was found that only S. tuberosum produced the triose glycoalkaloids solanine and chaconine. Instead, the six wild species produced glycoalkaloids that shared in common tetrose sugar side chains. Additionally, there were non-glycoalkaloid metabolites associated with resistance including hydroxycoumarin and a phenylpropanoid, which were produced in all wild species but not in S. tuberosum. PMID- 25144463 TI - Rhodium-catalyzed transannulation of N-sulfonyl-1,2,3-triazoles and epoxides: regioselective synthesis of substituted 3,4-dihydro-2H-1,4-oxazines. AB - Rhodium-catalyzed transannulation of 1,2,3-triazoles and ring-opening reactions of epoxides is described. A number of 3,4-dihydro-2H-1,4-oxazines are obtained in moderate yields probably involving generation of alpha-imino rhodium(II) carbene species. PMID- 25144462 TI - Mycetoma: experience of 482 cases in a single center in Mexico. AB - Mycetoma is a chronic granulomatous disease. It is classified into eumycetoma caused by fungi and actinomycetoma due to filamentous actinomycetes. Mycetoma can be found in geographic areas in close proximity to the Tropic of Cancer. Mexico is one of the countries in which this disease is highly endemic. In this retrospective study we report epidemiologic, clinical and microbiologic data of mycetoma observed in the General Hospital of Mexico in a 33 year-period (1980 to 2013). A total of 482 cases were included which were clinical and microbiology confirmed. Four hundred and forty four cases (92.11%) were actinomycetomas and 38 cases (7.88%) were eumycetomas. Most patients were agricultural workers; there was a male predominance with a sex ratio of 3:1. The mean age was 34.5 years old (most ranged from 21 to 40 years). The main affected localization was lower and upper limbs (70.74% and 14.52% respectively). Most of the patients came from humid tropical areas (Morelos, Guerrero and Hidalgo were the regions commonly reported). The main clinical presentation was as tumor-like soft tissue swelling with draining sinuses (97.1%). Grains were observed in all the cases. The principal causative agents for actinomycetoma were: Nocardia brasiliensis (78.21%) and Actinomadura madurae (8.7%); meanwhile, for eumycetomas: Madurella mycetomatis and Scedosporium boydii (synonym: Pseudallescheria boydii) were identified. This is a single-center, with long-follow up, cross-sectional study that allows determining the prevalence and characteristics of mycetoma in different regions of Mexico. PMID- 25144461 TI - LIN-3/EGF promotes the programmed cell death of specific cells in Caenorhabditis elegans by transcriptional activation of the pro-apoptotic gene egl-1. AB - Programmed cell death (PCD) is the physiological death of a cell mediated by an intracellular suicide program. Although key components of the PCD execution pathway have been identified, how PCD is regulated during development is poorly understood. Here, we report that the epidermal growth factor (EGF)-like ligand LIN-3 acts as an extrinsic signal to promote the death of specific cells in Caenorhabditis elegans. The loss of LIN-3 or its receptor, LET-23, reduced the death of these cells, while excess LIN-3 or LET-23 signaling resulted in an increase in cell deaths. Our molecular and genetic data support the model that the LIN-3 signal is transduced through LET-23 to activate the LET-60/RAS-MPK 1/ERK MAPK pathway and the downstream ETS domain-containing transcription factor LIN-1. LIN-1 binds to, and activates transcription of, the key pro-apoptotic gene egl-1, which leads to the death of specific cells. Our results provide the first evidence that EGF induces PCD at the whole organism level and reveal the molecular basis for the death-promoting function of LIN-3/EGF. In addition, the level of LIN-3/EGF signaling is important for the precise fine-tuning of the life versus-death fate. Our data and the previous cell culture studies that say EGF triggers apoptosis in some cell lines suggest that the EGF-mediated modulation of PCD is likely conserved in C. elegans and humans. PMID- 25144464 TI - Covalent defects restrict supramolecular self-assembly of homopolypeptides: case study of beta2-fibrils of poly-L-glutamic acid. AB - Poly-L-glutamic acid (PLGA) often serves as a model in studies on amyloid fibrils and conformational transitions in proteins, and as a precursor for synthetic biomaterials. Aggregation of PLGA chains and formation of amyloid-like fibrils was shown to continue on higher levels of superstructural self-assembly coinciding with the appearance of so-called beta2-sheet conformation manifesting in dramatic redshift of infrared amide I' band below 1600 cm(-1). This spectral hallmark has been attributed to network of bifurcated hydrogen bonds coupling C = O and N-D (N-H) groups of the main chains to glutamate side chains. However, other authors reported that, under essentially identical conditions, PLGA forms the conventional in terms of infrared characteristics beta1-sheet structure (exciton-split amide I' band with peaks at ca. 1616 and 1683 cm(-1)). Here we attempt to shed light on this discrepancy by studying the effect of increasing concentration of intentionally induced defects in PLGA on the tendency to form beta1/beta2-type aggregates using infrared spectroscopy. We have employed carbodiimide-mediated covalent modification of Glu side chains with n-butylamine (NBA), as well as electrostatics-driven inclusion of polylysine chains, as two different ways to trigger structural defects in PLGA. Our study depicts a clear correlation between concentration of defects in PLGA and increasing tendency to depart from the beta2-structure toward the one less demanding in terms of chemical uniformity of side chains: beta1-structure. The varying predisposition to form beta1- or beta2-type aggregates assessed by infrared absorption was compared with the degree of morphological order observed in electron microscopy images. Our results are discussed in the context of latent covalent defects in homopolypeptides (especially with side chains capable of hydrogen-bonding) that could obscure their actual propensities to adopt different conformations, and limit applications in the field of synthetic biomaterials. PMID- 25144465 TI - Multi-resolution voxel phantom modeling: a high-resolution eye model for computational dosimetry. AB - Voxel models of the human body are commonly used for simulating radiation dose with a Monte Carlo radiation transport code. Due to memory limitations, the voxel resolution of these computational phantoms is typically too large to accurately represent the dimensions of small features such as the eye. Recently reduced recommended dose limits to the lens of the eye, which is a radiosensitive tissue with a significant concern for cataract formation, has lent increased importance to understanding the dose to this tissue. A high-resolution eye model is constructed using physiological data for the dimensions of radiosensitive tissues, and combined with an existing set of whole-body models to form a multi resolution voxel phantom, which is used with the MCNPX code to calculate radiation dose from various exposure types. This phantom provides an accurate representation of the radiation transport through the structures of the eye. Two alternate methods of including a high-resolution eye model within an existing whole-body model are developed. The accuracy and performance of each method is compared against existing computational phantoms. PMID- 25144466 TI - Small RNA sequence analysis of adenovirus VA RNA-derived miRNAs reveals an unexpected serotype-specific difference in structure and abundance. AB - Human adenoviruses (HAds) encode for one or two highly abundant virus-associated RNAs, designated VA RNAI and VA RNAII, which fold into stable hairpin structures resembling miRNA precursors. Here we show that the terminal stem of the VA RNAs originating from Ad4, Ad5, Ad11 and Ad37, all undergo Dicer dependent processing into virus-specific miRNAs (so-called mivaRNAs). We further show that the mivaRNA duplex is subjected to a highly asymmetric RISC loading with the 3'-strand from all VA RNAs being the favored strand, except for the Ad37 VA RNAII, where the 5' mivaRNAII strand was preferentially assembled into RISC. Although the mivaRNA seed sequences are not fully conserved between the HAds a bioinformatics prediction approach suggests that a large fraction of the VA RNAII-, but not the VA RNAI-derived mivaRNAs still are able to target the same cellular genes. Using small RNA deep sequencing we demonstrate that the Dicer processing event in the terminal stem of the VA RNAs is not unique and generates 3'-mivaRNAs with a slight variation of the position of the 5' terminal nucleotide in the RISC loaded guide strand. Also, we show that all analyzed VA RNAs, except Ad37 VA RNAI and Ad5 VA RNAII, utilize an alternative upstream A start site in addition to the classical +1 G start site. Further, the 5'-mivaRNAs with an A start appears to be preferentially incorporated into RISC. Although the majority of mivaRNA research has been done using Ad5 as the model system our analysis demonstrates that the mivaRNAs expressed in Ad11- and Ad37-infected cells are the most abundant mivaRNAs associated with Ago2-containing RISC. Collectively, our results show an unexpected variability in Dicer processing of the VA RNAs and a serotype-specific loading of mivaRNAs into Ago2-based RISC. PMID- 25144468 TI - Inkjet-printed bioassays for direct reading with a multimode DVD/Blu-Ray optical drive. AB - Compact disc-based bioassays have been developed as novel point-of-care (POC) tools for various applications in chemical analysis and biomedical diagnosis. For the fabrication of assay discs, the surface patterning and sample introduction have been restricted to manual delivery that is unfavorable for on-demand high throughput medical screening. Herein, we have adapted a conventional inkjet printer to prepare bioassays on regular DVD-Rs and accomplished quantitative analysis with a multimode DVD/Blu-Ray optical drive in conjunction with free disc diagnostic software. The feasibility and accuracy of this method have been demonstrated by the quantitative analysis of inkjet-printed biotin-streptavidin binding assays on DVD, which serves as a trial system for other complex, medically relevant sandwich-format or competitive immunoassays. PMID- 25144467 TI - Bacterial community composition of size-fractioned aggregates within the phycosphere of cyanobacterial blooms in a eutrophic freshwater lake. AB - Bacterial community composition of different sized aggregates within the Microcystis cyanobacterial phycosphere were determined during summer and fall in Lake Taihu, a eutrophic lake in eastern China. Bloom samples taken in August and September represent healthy bloom biomass, whereas samples from October represent decomposing bloom biomass. To improve our understanding of the complex interior structure in the phycosphere, bloom samples were separated into large (>100 um), medium (10-100 um) and small (0.2-10 um) size aggregates. Species richness and library coverage indicated that pyrosequencing recovered a large bacterial diversity. The community of each size aggregate was highly organized, indicating highly specific conditions within the Microcystis phycosphere. While the communities of medium and small-size aggregates clustered together in August and September samples, large- and medium-size aggregate communities in the October sample were grouped together and distinct from small-size aggregate community. Pronounced changes in the absolute and relative percentages of the dominant genus from the two most important phyla Proteobacteria and Bacteroidetes were observed among the various size aggregates. Bacterial species on large and small-size aggregates likely have the ability to degrade high and low molecular weight compounds, respectively. Thus, there exists a spatial differentiation of bacterial taxa within the phycosphere, possibly operating in sequence and synergy to catalyze the turnover of complex organic matters. PMID- 25144471 TI - New understanding of the difference of photocatalytic activity among anatase, rutile and brookite TiO2. AB - In general, anatase TiO2 exhibits higher photocatalytic activities than rutile TiO2. However, the reasons for the differences in photocatalytic activity between anatase and rutile are still being debated. In this work, the band structure, density of states, and effective mass of photogenerated charge carriers for anatase, rutile and brookite TiO2 are investigated by the first-principle density functional theory calculation. The results indicate that anatase appears to be an indirect band gap semiconductor, while rutile and brookite belong to the direct band gap semiconductor category. Indirect band gap anatase exhibits a longer lifetime of photoexcited electrons and holes than direct band gap rutile and brookite because the direct transitions of photogenerated electrons from the conduction band (CB) to valence band (VB) of anatase TiO2 is impossible. Furthermore, anatase has the lightest average effective mass of photogenerated electrons and holes as compared to rutile and brookite. The lightest effective mass suggests the fastest migration of photogenerated electrons and holes from the interior to surface of anatase TiO2 particle, thus resulting in the lowest recombination rate of photogenerated charge carriers within anatase TiO2. Therefore, it is not surprising that anatase usually shows a higher photocatalytic activity than rutile and brookite. This investigation will provide some new insight into understanding the difference of photocatalytic activity among anatase, rutile and brookite. PMID- 25144469 TI - Effects of YC-1 on learning and memory functions of aged rats. AB - BACKGROUND: The aim of this study was to investigate the effects of a potent nitric oxide-guanylate cyclase activator, 3-(5'-hydroxymethyl-2'-furyl)-1 benzylindazole (YC-1), on learning and memory functions in aged rats. MATERIAL AND METHODS: Rats were divided into 2 groups as 4-month-old and 24-month-old rats. Rats received YC-1 (1 mg/kg/day) for 2 weeks long-term. Morris water maze (MWM) and passive avoidance (PA) tests were used to determine learning and memory functions. RESULTS: In the MWM test, there is a significant increase in the acquisition latency (1-4 days) of 24-month-old rats. There is a significant reduction in the "time spent in the escape platform's quadrant" in 24-month-old rats compared to 4-month-old rats in the probe trial of the MWM test. YC-1 treatment reversed the reduction of the "time spent in the escape platform's quadrant" of 24-month-old rats. In the PA test, there was no significant difference in the 1st-day latency of rats in all groups. On the 2nd day, retention latency significantly decreased in the 24-month-old rats compared to 4 month-olds. YC-1 reversed the diminished retention latency in 24-month-old rats. YC-1 treatment and aging did not affect results of the locomotor activity test or the foot-shock sensitivity test, suggesting our results were not due to a change in motor activity or disability of the animals. CONCLUSIONS: Our findings suggest that activation of the NO-sGC-cGMP pathway plays an important role in spatial and emotional learning and memory functions in aged rats. PMID- 25144472 TI - International glossina genome initiative 2004-2014: a driver for post-genomic era research on the African continent. PMID- 25144473 TI - Central and peripheral cardiovascular changes immediately after waterpipe smoking. AB - BACKGROUND: Tobacco cigarette smoking is a global health problem that kills millions each year. Recently, tobacco smoking using a waterpipe (WP) has become popular worldwide. However, unlike cigarettes, the cardiovascular (CV) risks associated with WP smoking are uncertain. In this study, the immediate effects of WP smoking on central and peripheral CV indices were evaluated in 53 young healthy smokers. MATERIALS AND METHODS: Strain-gauge plethysmography was used to measure forearm blood flow (Bf), vascular resistance (Vr), and venous capacitance (Vc) and outflow (Vf) at rest (R) and after occlusion (Oc), whereas heart rate (HR) and blood pressure (BP) were measured using standard automated auscultatory methods immediately before and after a 30-min WP smoking session. RESULTS: Smoking resulted in HR, diastolic BP, mean arterial BP, rate pressure product and OcVr increases (p < 0.05) 6.6, 3.6, 2.5, 8.0 and 16%, respectively, whereas OcBf and OcVf decreased (p < 0.05) 8.8 and 14.3%, respectively. Additionally, smoking induced changes in the central CV components correlated (p < 0.05) with changes in the periphery. CONCLUSION: These results demonstrated changes in the CV central and peripheral components immediately after WP smoking. The correlations between the changes in these components suggest that the periphery is controlled, at least partially, by the same mechanism(s) affecting the central CV components during WP smoking. PMID- 25144475 TI - Use of novel inhalation kinetic studies to refine physiologically-based pharmacokinetic models for ethanol in non-pregnant and pregnant rats. AB - Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and developmental effects in the rat. Physiologically-based pharmacokinetic (PBPK) models have been used to predict the inhalation exposure concentrations necessary to produce blood EtOH concentrations (BEC) in the range associated with these effects. Previous laboratory reports often lacked sufficient detail to adequately simulate reported exposure scenarios associated with BECs in this range, or lacked data on the time-course of EtOH in target tissues (e.g. brain, liver, eye, fetus). To address these data gaps, inhalation studies were performed at 5000, 10 000, and 21 000 ppm (6 h/d) in non-pregnant female Long-Evans (LE) rats and at 21 000 ppm (6.33 h/d) for 12 d of gestation in pregnant LE rats to evaluate our previously published PBPK models at toxicologically-relevant blood and tissue concentrations. Additionally, nose-only and whole-body plethysmography studies were conducted to refine model descriptions of respiration and uptake within the respiratory tract. The resulting time-course and plethysmography data from these in vivo studies were compared to simulations from our previously published models, after which the models were recalibrated to improve descriptions of tissue dosimetry by accounting for dose-dependencies in pharmacokinetic behavior. Simulations using the recalibrated models reproduced these data from non-pregnant, pregnant, and fetal rats to within a factor of 2 or better across datasets, resulting in a suite of model structures suitable for simulation of a broad range of EtOH exposure scenarios. PMID- 25144474 TI - The acute exposure effects of inhaled nickel nanoparticles on murine endothelial progenitor cells. AB - INTRODUCTION: The discovery of endothelial progenitor cells (EPCs) may help to explain observed cardiovascular effects associated with inhaled nickel nanoparticle exposures, such as increases in vascular inflammation, generation of reactive oxygen species, altered vasomotor tone and potentiated atherosclerosis in murine species. METHODS: Following an acute whole body inhalation exposure to 500 ug/m(3) of nickel nanoparticles for 5 h, bone marrow EPCs from C57BL/6 mice were isolated. EPCs were harvested for their RNA or used in a variety of assays including chemotaxis, tube formation and proliferation. Gene expression was assessed for important receptors involved in EPC mobilization and homing using RT PCR methods. EPCs, circulating endothelial progenitor cells (CEPCs), circulating endothelial cells (CECs) and endothelial microparticles (EMPs) were quantified on a BD FACSCalibur to examine endothelial damage and repair associated with the exposure. RESULTS AND CONCLUSIONS: Acute exposure to inhaled nickel nanoparticles significantly increased both bone marrow EPCs as well as their levels in circulation (CEPCs). CECs were significantly elevated indicating that endothelial damage occurred due to the exposure. There was no significant difference in EMPs between the two groups. Tube formation and chemotaxis, but not proliferation, of bone marrow EPCs was impaired in the nickel nanoparticle exposed group. These results coincided with a decrease in the mRNA of receptors involved in EPC mobilization and homing. These data provide new insight into how an acute nickel nanoparticle exposure to half of the current Occupational Safety & Health Administration (OSHA) permissible exposure limit may adversely affect EPCs and exacerbate cardiovascular disease states. PMID- 25144476 TI - Waterpipe effects on pulmonary function and cardiovascular indices: a comparison to cigarette smoking in real life situation. AB - INTRODUCTION: Smoking is known to have physiological effects on biological systems. The purpose of this study is to evaluate acute and chronic effects on pulmonary functions and cardiovascular indices of waterpipe (WP) smoking in real life circumstances. METHODS: Three groups were included in the study: non-smokers (N = 42), WP smokers (N = 42) and cigarette smokers (N = 48). A questionnaire was completed for each participant, in addition to pulmonary function [forced expiratory volume at 1 s (FEV1), 6 s (FEV6), percentage of FEV1/FEV6], and cardiovascular [diastolic blood pressure (DBP), systolic blood pressure (SBP) and heart rate (HR)] measures, taken before and after smoking. RESULTS: Mean values of FEV1, FEV6, FEV1/FEV6, DBP and SBP in WP and cigarette smokers were very close. However, WP smoking significantly increased HR compared to cigarette smokers (p = 0.007); duration of smoking, age at first WP and quantity of smoking affected pulmonary function and cardiovascular values. In the subgroup of WP smokers, DBP was acutely increased by a larger WP size (p = 0.011), while the FEV6 was acutely increased by a smaller WP size (p = 0.045). CONCLUSION: WP smoking affected the cardiovascular system more than cigarette smoking, while it had similar effects on pulmonary function. PMID- 25144477 TI - Outdoor wood furnaces create significant indoor particulate pollution in neighboring homes. AB - CONTEXT: The use of outdoor wood furnaces (OWFs) is common in many parts of the United States. Little published information exists on the concentrations of outdoor and indoor fine particulates found near OWFs. OBJECTIVE: To compare PM2.5 (cts) and PM0.5 (cts) particle concentrations inside four Connecticut homes located 30.5-259 m from OWFs, and inside six Connecticut control homes located more than 2 km from the nearest OWF. MATERIALS AND METHODS: PM2.5 (cts) and PM0.5 (cts) measurements were made with a Dylos light-scattering particulate counter. RESULTS: Mean PM2.5 (cts) concentrations were 4.21 times as great in the four OWF exposed homes than the six control homes (0.302 * 10(6) counts/m(3) versus 0.0718 counts * 10(6)/m(3) p < 0.001). The mean PM2.5 (cts) concentrations inside the four OWF exposed homes roughly corresponds to a mass PM2.5 of 37 ug/m(3), which is above the US EPA 24-h PM2.5 limit of 35 ug/m(3). Mean PM0.5 (cts) concentrations were 3.44 times as great in the four OWF exposed homes than in the six control homes (0.657 versus 0.191 * 10(6)/m(3) p < 0.001). Mean PM2.5 (cts) and PM0.5 (cts) concentrations were significantly higher in the house 259 m from an OWF as compared with the mean of the six control homes. CONCLUSION: Existing regulations, such as the present Connecticut law requiring a 61 meter distance between an OWF and neighboring homes, are not adequate to protect the health of neighboring residents. PMID- 25144478 TI - Brain suppression of AP-1 by inhaled diesel exhaust and reversal by cerium oxide nanoparticles. AB - One of the uses of cerium oxide nanoparticles (nanoceria, CeO2) is as a diesel fuel additive to improve fuel efficiency. Gene/environment interactions are important determinants in the etiology of age-related disorders. Thus, it is possible that individuals on high-fat diet and genetic predisposition to vascular disease may be more vulnerable to the adverse health effects of particle exposure. The aim of this pilot study was to test the hypothesis that inhalation of diesel exhaust (DE) or diesel exhaust-containing cerium oxide nanoparticles (DCeE) induces stress in the brain of a susceptible animal model. Atherosclerotic prone, apolipoprotein E knockout (ApoE(-/-)) mice fed a high-fat diet, were exposed by inhalation to purified air (control), DE or DCeE. The stress responsive transcription factor, activator protein-1 (AP-1), was significantly decreased in the cortical and subcortical fraction of the brain after DE exposure. The addition of nanoceria to the diesel fuel reversed this effect. The activation of another stress-related transcription factor (NF-kappaB) was not inhibited. AP-1 is composed of complexes of the Jun and/or Fos family of proteins. Exposure to DCeE caused c-Jun activation and this may be a mechanism by which addition of nanoceria to the fuel reversed the effect of DE exposure on AP 1 activation. This pilot study demonstrates that exposure to DE does impact the brain and addition of nanoceria may be protective. However, more extensive studies are necessary to determine how DE induced reduction of AP-1 activity and compensation by nanoceria impacts normal function of the brain. PMID- 25144479 TI - Magnon transistor for all-magnon data processing. AB - An attractive direction in next-generation information processing is the development of systems employing particles or quasiparticles other than electrons -ideally with low dissipation--as information carriers. One such candidate is the magnon: the quasiparticle associated with the eigen-excitations of magnetic materials known as spin waves. The realization of single-chip all-magnon information systems demands the development of circuits in which magnon currents can be manipulated by magnons themselves. Using a magnonic crystal--an artificial magnetic material--to enhance nonlinear magnon-magnon interactions, we have succeeded in the realization of magnon-by-magnon control, and the development of a magnon transistor. We present a proof of concept three-terminal device fabricated from an electrically insulating magnetic material. We demonstrate that the density of magnons flowing from the transistor's source to its drain can be decreased three orders of magnitude by the injection of magnons into the transistor's gate. PMID- 25144480 TI - Responding to violence in pediatric facilities. PMID- 25144481 TI - Academic practice partnership: transitions into practice for new nurses. PMID- 25144482 TI - A new leader's "trust barometer". PMID- 25144483 TI - Demystifying accountability by decreasing employee absences. PMID- 25144484 TI - Innovations that INSPIRE. PMID- 25144485 TI - Is there really safety in numbers? PMID- 25144487 TI - Storming the gates of interprofessional collaboration. AB - This type of collaboration is the way of the future; are you aware of its benefits for leaders? PMID- 25144488 TI - Redefining "charge nurse" within the front line. AB - Don't overlook the importance of charge nurses. Learn how one organization redefined the role and strengthened these leaders, increasing patient and staff satisfaction. PMID- 25144489 TI - Leadership q&a. PMID- 25144492 TI - Change in awareness of gluten-related disorders among chefs and the general public in the UK: a 10-year follow-up study. AB - BACKGROUND AND OBJECTIVES: In view of the increasing popularity of a gluten-free diet, we sought to determine whether there has been a change in awareness of gluten-related disorders (GRD) among the general public and chefs. MATERIALS AND METHODS: A face-to-face questionnaire on coeliac disease (CD) and gluten sensitivity (GS) was performed on the general public and chefs based in Sheffield, UK. The assessment was first carried out in 2003 and repeated in 2013. RESULTS: In total, 513 public members in 2003 (mean age 49.2 years, 62% women) were compared with 575 public members in 2013 (mean age 37.8 years, 57% women). There was a significant increase in the public's awareness of GRD from the years 2003 to 2013, CD [44.2% to 74.4%, adjusted odds ratio (AOR) 3.9; 95% confidence interval (CI) 3.0-5.19] and GS (58.3% to 89%, AOR 7.1; 95% CI 5.0-9.98; P<0.001). Also, 322 chefs in 2003 (mean age 37.6 years, 15% women) were compared with 265 chefs in 2013 (mean age 27.1 years, 38% women). There was a significant increase in chefs' awareness of GRD from the years 2003 to 2013, CD (17.1% to 78.1%, AOR 12.5; 95% CI 7.9-19.6) and GS (9.3% to 87.5%, AOR 65.7; 95% CI 35.4-122; P<0.001). Whereas in 2003 the public were significantly more aware of GRD than chefs, by 2013, this had reached a similar prevalence in both groups. In addition, the correct recognition of the gluten-free symbol was 44% for the public and 40% for chefs (P=0.28). Gluten-free products were sold by 41% of restaurants and 27% of takeaways (P=0.07). CONCLUSION: There has been a marked increase in both the public's and chefs' awareness of GRD. Such findings may ease the social phobia that individuals with GRD have traditionally been accustomed to. PMID- 25144490 TI - Establishment of a rat model of portal vein ligation combined with in situ splitting. AB - BACKGROUND: Portal vein ligation (PVL) combined with in situ splitting (ISS) has been shown to induce remarkable liver regeneration in patients. The purpose of this study was to establish a model of PVL+ISS in rats for exploring the possible mechanisms of liver regeneration using these techniques. MATERIALS AND METHODS: Rats were randomly assigned to three experimental groups: selective PVL, selective PVL+ISS and sham operation. The hepatic regeneration rate (HRR), Ki-67, liver biochemical determinations and histopathology were assessed at 24, 48, and 72 h and 7 days after the operation. The microcirculation of the median lobes before and after ISS was examined by laser speckle contrast imaging. Meanwhile, cytokines such as TNF-alpha, IL-6, HGF and HSP70 in regenerating liver lobes at 24 h was investigated by RT-PCR and ELISA. RESULTS: The HRR of PVL+ISS was much higher than that of the PVL at 72 h and 7 days after surgery (p<0.01). The expression of Ki-67 in hepatocytes in the regenerating liver lobe was stronger in the PVL+ISS group than in the PVL group at 48 and 72 h (p<0.01). There was a significant reduction in microcirculation blood perfusion of the left median lobe before and after ISS. Liver biochemical determinations and histopathology demonstrated more severe hepatocyte injury in the PVL+ISS group. Both the mRNA levels of TNF-alpha and IL-6 and the protein levels of TNF-alpha, IL-6 and HGF in regenerating liver lobes were higher in the PVL+ISS than the PVL alone. CONCLUSIONS: The higher HRR in the PVL+ISS compared with the PVL confirmed that we had successfully established a PVL+ISS model in rats. The possible mechanisms included the reduced microcirculation blood perfusion of the left median lobe and up-regulation of cytokines in the regenerating lobes after ISS. PMID- 25144493 TI - Cost of treating hepatitis C in Germany: a retrospective multicenter analysis. AB - BACKGROUND: Viral hepatitis is major a public health problem affecting millions of people worldwide. Estimates assume 400 000-500 000 people chronically infected with hepatitis C virus (HCV) in Germany. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. The aim of the study was to assess the costs for treating patients with chronic HCV in Germany. METHODS: We conducted a retrospective multicenter observational study. The design was approved by an ethics committee, and patients were asked for their informed consent. Patients were grouped in four different health states. Healthcare utilization data were extracted from doctor files of six medical centers in Germany. RESULTS: Data of 315 patients with chronic HCV were analyzed. The mean age was 49.4 years, 57.5% were male and 67.9% had a genotype 1 infection. The most common routes of transmission were injection drug use (39.0%) and infection through blood products (15.9%). The average total cost was ?19 147 including ambulatory care and diagnostics (?1686), pharmaceuticals (?14 875), inpatient care (?1293), and sick leave (?1293). For patients in stable health states (mild and moderate HCV, compensated cirrhosis), costs did not differ significantly and were mainly influenced by antiviral treatment. For patients with decompensated cirrhosis, inpatient care accounted for the largest part of the costs. CONCLUSION: Treatment of HCV patients involves high costs, mainly associated with the length of antiviral therapy. Viral eradication can prevent severe disease stages, which are associated with high costs. It is necessary to follow current guidelines and monitor patients closely to avoid unnecessary costs. PMID- 25144494 TI - Noninvasive markers in the assessment and management of autoimmune liver diseases. AB - Historically, liver biopsy has been used to determine the etiology of liver disease, the degree of inflammation, the stage of liver fibrosis, and the response to treatments. In the last decade, the advent of noninvasive tests has improved the diagnosis and management of autoimmune liver diseases. For example, serum markers can identify hepatic inflammation, whereas ultrasound and MRI can diagnose liver fibrosis. Physicians now have a much larger repertoire of diagnostic tests to assess the liver parenchyma compared with liver biopsy alone. In some rare cases, noninvasive tests may provide an alternative to liver biopsy. In general, however, these noninvasive tests complement liver biopsy and provide quick, accurate, and reliable adjunctive data. PMID- 25144496 TI - The formic acid-nitric acid complex: microwave spectrum, structure, and proton transfer. AB - Rotational spectra are reported for seven isotopologues of the complex HCOOH-HNO3 in a supersonic jet. The system is planar and bound by a pair of hydrogen bonds, much like the more widely studied carboxylic acid dimers. Double proton exchange interconverts the system between a pair of equivalent structures, as revealed by a splitting of the a-type spectrum that disappears when one of the hydrogen bonding protons is replaced by deuterium. The observation of relative intensities that are consistent with nuclear spin statistics in a symmetric and antisymmetric pair of tunneling states provides additional evidence for such a motion. The observed splittings in the pure rotational spectrum are 1-2 orders of magnitude smaller than those recently reported in the pure rotational spectra of several related carboxylic acid dimers. This is a curious difference, although we note that because the observed spectra do not cross the tunneling doublet, the splittings are a measure of the difference in effective rotational constants for the two states, not the tunneling frequency itself. The observed rotational constants have been used to determine an accurate vibrationally averaged structure for the complex. The two hydrogen bond lengths, 1.686(17) A and 1.813(10) A for the hydrogen bonds involving the HNO3 and HCOOH protons, respectively, differ by 0.127(27) A. Likewise, the associated oxygen-oxygen distances determined for the parent species, 2.631 and 2.794 A, differ by 0.163 A. These results suggest that the double proton transfer is necessarily accompanied by substantial motion of the heavy atom frame, and thus this system, in principle, provides an excellent prototype for multidimensional tunneling processes. Ab initio calculations of the binding energy and the barrier height are presented. Excellent agreement between the calculated equilibrium structure and the experimental, vibrationally averaged structure suggests that the vibrational wave function is not highly delocalized in the region between the equivalent potential wells. (14)N nuclear quadrupole hyperfine structure is interpreted in terms of the degree to which the HNO3 releases its proton in either of the equivalent potential energy minima. PMID- 25144495 TI - Inhibition by acrolein of light-induced stomatal opening through inhibition of inward-rectifying potassium channels in Arabidopsis thaliana. AB - Acrolein is a reactive alpha,beta-unsaturated aldehyde derived from lipid peroxides, which are produced in plants under a variety of stress. We investigated effects of acrolein on light-induced stomatal opening using Arabidopsis thaliana. Acrolein inhibited light-induced stomatal opening in a dose dependent manner. Acrolein at 100 MUM inhibited plasma membrane inward-rectifying potassium (Kin) channels in guard cells. Acrolein at 100 MUM inhibited Kin channel KAT1 expressed in a heterologous system using Xenopus leaves oocytes. These results suggest that acrolein inhibits light-induced stomatal opening through inhibition of Kin channels in guard cells. PMID- 25144497 TI - Temperature-dependent dynamics of dry and hydrated beta-casein studied by quasielastic neutron scattering. AB - beta-Casein is a component of casein micelle with amphillic nature and is recognized as a "natively disordered" protein that lacks secondary structures. In this study, the temperature and hydration effects on the dynamics of beta-casein are explored by quasielastic neutron scattering (QENS). An upturn in the mean square displacement (MSD) of hydrated beta-casein indicates an increase of protein flexibility at a temperature of ~225 K. Another increase in MSD at ~100 K, observed in both dry and hydrated beta-casein, is ascribed to the methyl group rotations, which are not sensitive to hydration. QENS analysis in the energy domain reveals that the fraction of hydrogen atoms participating in motion in a sphere of diffusion is highly hydration dependent and increases with temperature. In the time domain analysis, a logarithmic-like decay is observed in the range of picosecond to nanosecond (beta-relaxation time) in the dynamics of hydrated beta casein. This dynamical behavior has been observed in hydrated globular and oligomeric proteins. Our temperature-dependent QENS experiments provide evidence that lack of a secondary structure in beta-casein results in higher flexibility in its dynamics and easier reversible thermal unfolding compared to other rigid biomolecules. PMID- 25144499 TI - Novel screening method for glaucomatous eyes with myopic tilted discs: the crescent moon sign. AB - IMPORTANCE: To our knowledge, there is no reliable screening method for glaucomatous eyes with myopic tilted discs. OBJECTIVE: To evaluate the diagnostic ability of a novel screening modality, the crescent moon (CM) sign, defined as the discontinuity between the superior or inferior optic rim margin and the temporal optic rim margin, for the detection of glaucomatous eyes with myopic tilted discs. DESIGN, SETTING, AND PARTICIPANTS: The study was cross-sectional and conducted in a hospital setting from November 1, 2011, to November 1, 2013. Seventy eyes of 70 individuals with early open-angle glaucoma (mean deviation greater than -6 dB) and 70 eyes of 70 normal control participants who had myopic tilted discs were recruited. Another independent group consisting of 60 eyes of 60 individuals with early glaucoma and 60 eyes of 60 normal control participants was enrolled. Two masked glaucoma specialists independently assessed the optic disc on stereoscopic disc photography. The diagnostic performance of the CM sign was evaluated in comparison with violation of the ISNT rule (inferior >= superior >= nasal >= temporal order of configuration for disc rim thickness in normal eyes) and the modified ISNT rule (application of the ISNT rule based on the long axis of the disc). MAIN OUTCOMES AND MEASURES: Sensitivity and specificity of the CM sign. RESULTS: The CM sign was more frequently observed in the inferotemporal optic rim margin than in the superotemporal optic rim margin. In a comparative evaluation of the glaucoma diagnostic sensitivity and specificity, the CM sign showed higher sensitivities (90.0%-91.4%) than the ISNT rule (73.3%-75.7%) or the modified ISNT rule (68.6%-70.0%). The CM sign also showed higher specificities (82.9%-83.3%) than the ISNT rule (68.3%-71.4%) or the modified ISNT rule (76.6% 80.0%). Furthermore, the CM sign was shown to be associated with the occurrence of visual field defects in the corresponding hemifield (P < .001). CONCLUSIONS AND RELEVANCE: The CM sign can be a useful screening tool for the detection of early glaucoma with myopic tilted discs. PMID- 25144498 TI - Elevated levels of Dickkopf-1 are associated with beta-catenin accumulation and poor prognosis in patients with chondrosarcoma. AB - BACKGROUND: Dickkopf-1 (DKK1) is an antagonist of Wnt/beta-catenin signaling implicated in tumorigenesis. However, the biological role of DKK1 and beta catenin involved in chondrosarcoma has not been sufficiently investigated. This study was designed to investigate the expression profiles of DKK1 and beta catenin, and to clarify their clinical values in chondrosarcoma. METHODS: The mRNA and protein levels of DKK1 and beta-catenin in fresh chondrosarcoma and the corresponding non-tumor tissues were analyzed by Real-time PCR and Western blot, respectively. The protein expression patterns of DKK1 and beta-catenin were investigated by immunohistochemistry. The associations among DKK1 level, beta catenin accumulation, clinicopathological factors and the overall survival were separately evaluated. RESULTS: Both DKK1 and beta-catenin levels were remarkably elevated in chondrosarcoma compared with the corresponding non-tumor tissues. High DKK1 level and positive beta-catenin accumulation in chondrosarcoma specimens were 58.7% and 53.9%, respectively. Elevated DKK1 level significantly correlated with positive beta-catenin accumulation, and they were remarkably associated with histological grade and Musculoskeletal Tumor Society stage. Furthermore, DKK1 level and beta-catenin accumulation had significant impacts on the prognosis of chondrosarcoma patients. Multivariate analysis revealed that DKK1 level was an independent prognostic factor for overall survival. CONCLUSIONS: Elevated DKK1 levels associated with beta-catenin accumulation play a crucial role in chondrosarcoma. DKK1 can serve as a novel predictor of poor prognosis in patients with chondrosarcoma. PMID- 25144501 TI - Interpretative repertoires that shape low-income African American women's reproductive health care seeking: "don't want to know" and "taking charge of your health". AB - In the context of reproductive and sexual health, African American women have higher incidence of disease and poorer outcomes on key indicators when compared with White women. In this study, we used discourse analysis to identify and examine the workings of two clusters of interpretive resources ("interpretative repertoires") associated with reproductive/sexual health care seeking among low income African American women who participated in semistructured interviews as part of a health promotion initiative. Interpretative repertoires are ways of accounting for engaging in or refraining from engaging in actions, which are shared by people in a community. We labeled the two interpretative repertoires "Don't Want to Know," and "Take Charge of Your Health." Within the "Don't Want to Know" repertoire, that testing would lead to threatening findings was assumed, a chain of devastating consequences was imagined, and a preference for uncertainty over certain knowledge was expressed. Conversely, the "Take Charge of Your Health" repertoire valued certainty over uncertainty, though in both interpretive frameworks, knowledge-based and emotion-based decision-making were intertwined. We conclude that health promotion initiatives--if they are to succeed in encouraging women to obtain valuable preventive health care services--must respond, in their choices of language and outreach strategies, to the expressed dilemma of wishing for reassurance but fearing bad news, to the intertwining of emotional reasoning and technorationality in health decision making, and to the particular relational experiences of African American women. Failure to do so will contribute to the continuation of reproductive and sexual health disparities. PMID- 25144502 TI - Cerebral Glucose Metabolism and Sedation in Brain-injured Patients: A Microdialysis Study. AB - BACKGROUND: Disturbed brain metabolism is a signature of primary damage and/or precipitates secondary injury processes after severe brain injury. Sedatives and analgesics target electrophysiological functioning and are as such well-known modulators of brain energy metabolism. Still unclear, however, is how sedatives impact glucose metabolism and whether they differentially influence brain metabolism in normally active, healthy brain and critically impaired, injured brain. We therefore examined and compared the effects of anesthetic drugs under both critical (<1 mmol/L) and noncritical (>1 mmol/L) extracellular brain glucose levels. METHODS: We performed an explorative, retrospective analysis of anesthetic drug administration and brain glucose concentrations, obtained by bedside microdialysis, in 19 brain-injured patients. RESULT: Our investigations revealed an inverse linear correlation between brain glucose and both the concentration of extracellular glutamate (Pearson r=-0.58, P=0.01) and the lactate/glucose ratio (Pearson r=-0.55, P=0.01). For noncritical brain glucose levels, we observed a positive linear correlation between midazolam dose and brain glucose (P<0.05). For critical brain glucose levels, extracellular brain glucose was unaffected by any type of sedative. CONCLUSIONS: These findings suggest that the use of anesthetic drugs may be of limited value in attempts to influence brain glucose metabolism in injured brain tissue. PMID- 25144503 TI - Clinical research into anesthetic neurotoxicity: does anesthesia cause neurological abnormalities in humans? AB - General anesthetics mitigate distress and exaggerated hemodynamic responses to pain and stressful stimulation, allowing surgery and diagnostic procedures to be performed worldwide in millions of children every year. Emerging studies, mainly carried out in early postnatal laboratory animals, demonstrate widespread neuronal elimination, alteration in neuronal circuitry, and long-term neurological disabilities following exposure to all commonly used sedatives and anesthetics. These findings have raised concerns among parents, anesthesiologists, neuroscientists, and government regulators about the safety of anesthetic drugs in children, especially infants. Accumulating evidence from epidemiological studies suggests an association between surgery with anesthesia in early childhood and subsequent behavioral and cognitive abnormalities. During the Fourth Pediatric Anesthesia NeuroDevelopmental Assessment (PANDA) symposium, a meeting attended by many stakeholders, the most recent findings in the field were presented and discussed. This review summarizes the current state of clinical research into the effects of anesthetic exposure in human brain development, addresses some of the difficulties in examining the phenomenon, and introduces the most recent clinical findings presented at the PANDA symposium. The unanimous consensus among participants was that additional preclinical and clinical research efforts are urgently required to address this important concern for child health. PMID- 25144505 TI - Postoperative cognitive function following general versus regional anesthesia: a systematic review. AB - The effect of anesthetic technique on postoperative outcomes remains in question. This systematic review compares the role of regional versus general anesthesia, with a particular focus on postoperative cognitive function. Potentially relevant articles were identified by searching publicly available computerized databases for this systematic review. Any surgical procedure was accepted with the exception of cardiac, carotid, and neurosurgical procedures. Any regional anesthetic technique was accepted unless combined with a general anesthetic or in conjunction with propofol as a sedative. Any measure of postoperative cognitive function was accepted as long as it was performed no sooner than 7 days postoperatively. Sixteen studies met inclusion criteria and were included in the final analysis. Three studies showed some difference in cognitive function between regional and general anesthesia, whereas the remaining 13 showed no difference between regional and general anesthesia on postoperative cognitive function. PMID- 25144504 TI - Review: effects of anesthetics on brain circuit formation. AB - The results of several retrospective clinical studies suggest that exposure to anesthetic agents early in life is correlated with subsequent learning and behavioral disorders. Although ongoing prospective clinical trials may help to clarify this association, they remain confounded by numerous factors. Thus, some of the most compelling data supporting the hypothesis that a relatively short anesthetic exposure can lead to a long-lasting change in brain function are derived from animal models. The mechanism by which such changes could occur remains incompletely understood. Early studies identified anesthetic-induced neuronal apoptosis as a possible mechanism of injury, and more recent work suggests that anesthetics may interfere with several critical processes in brain development. The function of the mature brain requires the presence of circuits, established during development, which perform the computations underlying learning and cognition. In this review, we examine the mechanisms by which anesthetics could disrupt brain circuit formation, including effects on neuronal survival and neurogenesis, neurite growth and guidance, formation of synapses, and function of supporting cells. There is evidence that anesthetics can disrupt aspects of all of these processes, and further research is required to elucidate which are most relevant to pediatric anesthetic neurotoxicity. PMID- 25144506 TI - Neurodevelopmental outcomes after initial childhood anesthetic exposure between ages 3 and 10 years. AB - INTRODUCTION: Epidemiologic studies examining the association between anesthetic exposure and neurodevelopmental outcomes have primarily focused on exposures occurring under 3 years of age. In this study, we assess outcomes associated with initial anesthetic exposure occurring between 3 and 10 years of age. METHODS: We used data from the Western Australian Pregnancy Cohort (Raine) Study to examine the risk of cognitive deficit at age 10 in children with initial anesthetic exposure between 3 and 5 years and between 5 and 10 years of age compared with children unexposed at those ages. The cohort included 2868 children born from 1989 to 1992 evaluated using a range of neuropsychological tests. A modified multivariable Poisson regression model was used to determine the adjusted association of initial anesthetic exposure in each age group with outcomes. RESULTS: Exposed and unexposed children were found to have similar neuropsychological test results except for the McCarron Assessment of Neuromuscular Development (MAND) motor function scores. Even after adjusting for demographic and comorbidity differences, children exposed to anesthesia had a higher risk of motor deficit after initial exposure between ages 3 and 5 years (adjusted risk ratio, 2.32; 95% confidence interval, 1.42-3.79) and between 5 and 10 years (adjusted risk ratio, 2.33; 95% confidence interval, 1.21-4.48) compared with unexposed children. CONCLUSIONS: Initial exposure to anesthesia after age 3 had no measurable effects on language or cognitive function. Decreased motor function was found in children initially exposed after age 3 even after accounting for comorbid illness and injury history. These results suggest that there may be distinct windows of vulnerability for different neurodevelopmental domains in children. PMID- 25144507 TI - Engaging stakeholders in research related to anesthesia and neurodevelopment in children. AB - The Fourth PANDA symposium on Anesthesia and Neurodevelopment in Children invited 4 leaders in community engagement and federal government collaboration to share their experiences with overcoming challenges in promoting public health issues. There continues to be emerging evidence from laboratory findings in animal models demonstrating neurotoxic effects and neurodevelopmental changes from early exposure to anesthetic and sedative drugs, but studies in humans have been very limited and inconclusive. Although definitive recommendations for clinical care still cannot be made given the limitations in the clinical data, the need for open communication among clinicians, parents, and other stakeholders is clear. A "top-down, bottom-up" engagement strategy including parents, children, clinicians, government agencies, and community organizations may improve communication and collaboration. To reach the goal of "improving quality, safety, efficiency, and effectiveness of health care in children," clinicians and researchers will need to adopt strategies to engage and partner with stakeholders as coinvestigators who actively participate in efforts to increase anesthetic safety in children. Collaborations with government regulatory administration can improve the efficacy and effectiveness of resource utilization to address public health needs. This session provided an opportunity for open dialog between clinicians, researchers, and community leaders to discuss strategies to engage stakeholders to partake in patient-centered outcomes research on anesthetic neurotoxicity. PMID- 25144508 TI - Selective addition of secondary amines to C60: formation of penta- and hexaamino[60]fullerenes. AB - Secondary amines are well-known to add to [60]fullerene to form the tetraamino epoxy adduct C60(O)(NR1R2)4 under both photolysis and thermal conditions in the presence of oxygen. We have now found that pentaamino hydroxyl adduct C60(OH)(NR1R2)5 and hexaamino adduct C60(NR1R2)6 can be formed as the major products in the dark in the presence of oxygen. Key steps of the reaction mechanism probably involve repeated oxygen oxidation of the radical ion pair between fullerene and amines. PMID- 25144510 TI - Hydrotropy: monomer-micelle equilibrium and minimum hydrotrope concentration. AB - Drug molecules with low aqueous solubility can be solubilized by a class of cosolvents, known as hydrotropes. Their action has often been explained by an analogy with micelle formation, which exhibits critical micelle concentration (CMC). Indeed, hydrotropes also exhibit "minimum hydrotrope concentration" (MHC), a threshold concentration for solubilization. However, MHC is observed even for nonaggregating monomeric hydrotropes (such as urea); this raises questions over the validity of this analogy. Here we clarify the effect of micellization on hydrotropy, as well as the origin of MHC when micellization is not accompanied. On the basis of the rigorous Kirkwood-Buff (KB) theory of solutions, we show that (i) micellar hydrotropy is explained also from preferential drug-hydrotrope interaction; (ii) yet micelle formation reduces solubilization effeciency per hydrotrope molecule; (iii) MHC is caused by hydrotrope-hydrotrope self association induced by the solute (drug) molecule; and (iv) MHC is prevented by hydrotrope self-aggregation in the bulk solution. We thus need a departure from the traditional view; the structure of hydrotrope-water mixture around the drug molecule, not the structure of the aqueous hydrotrope solutions in the bulk phase, is the true key toward understanding the origin of MHC. PMID- 25144513 TI - Plasma exchange in antineutrophil cytoplasm antibody-associated vasculitis. AB - PURPOSE OF REVIEW: This article reviews the use of plasma exchange for the treatment of antineutrophil cytoplasm antibody-associated vasculitis (AAV) with a focus on current controversies and knowledge gaps. RECENT FINDINGS: Experimental evidence suggesting that antineutrophil cytoplasm antibodies are pathogenic continues to evolve and support the theory that rapid removal of antineutrophil cytoplasm antibody with plasma exchange may be beneficial. Although early, small trials of plasma exchange in rapidly progressive glomerulonephritis and vasculitis suggested that plasma exchange may improve a patient's potential for renal recovery, more recent analyses have called the net benefit of plasma exchange into question. Furthermore, there is uncertainty as to whether plasma exchange is beneficial to patients with particular organ manifestations of their AAV (e.g., lung hemorrhage). SUMMARY: Whether plasma exchange should be used routinely in antineutrophil cytoplasm antibody-associated vasculitis, in patients with certain manifestations or severity of disease only, or not at all, remains unclear. Given that plasma exchange is expensive and invasive, further research to resolve these uncertainties is required. PMID- 25144511 TI - Methodologies for the development of the management of cough: CHEST guideline and expert panel report. AB - BACKGROUND: This series of guidance documents on cough, which will be published over time, is a hybrid of two processes: (1) evidence-based guidelines and (2) trustworthy consensus statements based on a robust and transparent process. METHODS: The CHEST Guidelines Oversight Committee selected a nonconflicted Panel Chair and jointly assembled an international panel of experts in each clinical area with few, if any, conflicts of interest. PICO (population, intervention, comparator, outcome)-based key questions and parameters of eligibility were developed for each clinical topic to inform the comprehensive literature search. Existing guidelines, systematic reviews, and primary studies were assessed for relevance and quality. Data elements were extracted into evidence tables and synthesized to provide summary statistics. These, in turn, are presented to support the evidence-based graded recommendations. A highly structured consensus based Delphi approach was used to provide expert advice on all guidance statements. Transparency of process was documented. RESULTS: Evidence-based guideline recommendations and consensus-based suggestions were carefully crafted to provide direction to health-care providers and investigators who treat and/or study patients with cough. Manuscripts and tables summarize the evidence in each clinical area supporting the recommendations and suggestions. CONCLUSIONS: The resulting guidance statements are based on a rigorous methodology and transparency of process. Unless otherwise stated, the recommendations and suggestions meet the guidelines for trustworthiness developed by the Institute of Medicine and can be applied with confidence by physicians, nurses, other health care providers, investigators, and patients. PMID- 25144514 TI - Tea component, epigallocatechin gallate, potentiates anticataleptic and locomotor sensitizing effects of caffeine in mice. AB - Tea is the most popular beverage worldwide. Caffeine, the psychoactive principle of tea, pharmacologically interacts with several drugs and bioactive molecules. Epigallocatechin gallate (EGCG) is a major component of tea and its known interactions with caffeine make it worthwhile to further study them by investigating the influence of EGCG on the anticataleptic and locomotor sensitizing effects of caffeine. In the present investigation, we observed that (a) administration of caffeine or EGCG alone inhibited haloperidol-induced catalepsy, a widely used animal model to study parkinsonism, and (b) a combination of caffeine and EGCG produced greater inhibition of haloperidol induced catalepsy. Furthermore, after repeated administration of caffeine and EGCG, either alone or in combination, we observed that (c) caffeine and EGCG contrasted the sensitization of catalepsy observed after repeated haloperidol administration by significantly reducing the duration of catalepsy. Furthermore, as haloperidol-induced catalepsy was also associated with increased lipid peroxidation, we observed that (d) EGCG administration reduced striatal lipid peroxide levels in a dose-dependent manner and that (e) the combination of caffeine with EGCG was most effective in reducing haloperidol-increased striatal lipid peroxide. Finally, we observed that (f) chronic caffeine and EGCG significantly elicited locomotor sensitization and that (g) their combination resulted in significantly greater effects. In conclusion, EGCG potentiated the effects of caffeine on haloperidol-induced catalepsy and of caffeine-elicited locomotor sensitization. Overall, these observations indicate critical interactions between caffeine and EGCG in an animal model of parkinsonism and locomotor activity and suggest that tea consumption might reduce antipsychotic induced side effects. PMID- 25144516 TI - Research in prehospital and disaster health and medicine: developing a research objective statement. AB - A concise, well-designed research objective statement for proposed research is important for directing and coordinating a study.While often only a single or a few sentences in a manuscript, the research objective statement is usually the single most important element in the design and conduct of a research study. PMID- 25144515 TI - Fiction or not? Fifty Shades is associated with health risks in adolescent and young adult females. AB - BACKGROUND: No prior study has empirically characterized the association between health risks and reading popular fiction depicting violence against women. Fifty Shades--a blockbuster fiction series--depicts pervasive violence against women, perpetuating a broader social narrative that normalizes these types of risks and behaviors in women's lives. The present study characterized the association between health risks in women who read and did not read Fifty Shades; while our cross-sectional study design precluded causal determinations, an empirical representation of the health risks in women consuming the problematic messages in Fifty Shades is made. METHODS: Females ages 18 to 24 (n=715), who were enrolled in a large Midwestern university, completed a cross-sectional online survey about their health behaviors and Fifty Shades' readership. The analysis included 655 females (219 who read at least the first Fifty Shades novel and 436 who did not read any part of Fifty Shades). Age- and race-adjusted multivariable models characterized Fifty Shades' readers and nonreaders on intimate partner violence victimization (experiencing physical, sexual and psychological abuse, including cyber-abuse, at some point during their lifetime); binge drinking (consuming five or more alcoholic beverages on six or more days in the last month); sexual practices (having five or more intercourse partners and/or one or more anal sex partner during their lifetime); and using diet aids or fasting for 24 or more hours at some point during their lifetime. RESULTS: One-third of subjects read Fifty Shades (18.6%, or 122/655, read all three novels, and 14.8%, or 97/655, read at least the first novel but not all three). In age- and race-adjusted models, compared with nonreaders, females who read at least the first novel (but not all three) were more likely than nonreaders to have had, during their lifetime, a partner who shouted, yelled, or swore at them (relative risk [RR]=1.25) and who delivered unwanted calls/text messages (RR=1.34); they were also more likely to report fasting (RR=1.80) and using diet aids (RR=1.77) at some point during their lifetime. Compared with nonreaders, females who read all three novels were more likely to report binge drinking in the last month (RR=1.65) and to report using diet aids (RR=1.65) and having five or more intercourse partners during their lifetime (RR=1.63). CONCLUSIONS: Problematic depictions of violence against women in popular culture-such as in film, novels, music, or pornography-create a broader social narrative that normalizes these risks and behaviors in women's lives. Our study showed strong correlations between health risks in women's lives-including violence victimization-and consumption of Fifty Shades, a fiction series that portrays violence against women. While our cross-sectional study cannot determine temporality, the order of the relationship may be inconsequential; for example, if women experienced adverse health behaviors first (e.g., disordered eating), reading Fifty Shades might reaffirm those experiences and potentially aggravate related trauma. Likewise, if women read Fifty Shades before experiencing the health behaviors assessed in our study, it is possible that the book influenced the onset of these behaviors by creating an underlying context for the behaviors. PMID- 25144509 TI - Evacuation of the ICU: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: Despite the high risk for patient harm during unanticipated ICU evacuations, critical care providers receive little to no training on how to perform safe and effective ICU evacuations. We reviewed the pertinent published literature and offer suggestions for the critical care provider regarding ICU evacuation. The suggestions in this article are important for all who are involved in pandemics or disasters with multiple critically ill or injured patients, including front-line clinicians, hospital administrators, and public health or government officials. METHODS: The Evacuation and Mobilization topic panel used the American College of Chest Physicians (CHEST) Guidelines Oversight Committee's methodology to develop seven key questions for which specific literature searches were conducted to identify studies upon which evidence-based recommendations could be made. No studies of sufficient quality were identified. Therefore, the panel developed expert opinion-based suggestions using a modified Delphi process. RESULTS: Based on current best evidence, we provide 13 suggestions outlining a systematic approach to prepare for and execute an effective ICU evacuation during a disaster. Interhospital and intrahospital collaboration and functional ICU communication are critical for success. Pre event planning and preparation are required for a no-notice evacuation. A Critical Care Team Leader must be designated within the Hospital Incident Command System. A three-stage ICU Evacuation Timeline, including (1) no immediate threat, (2) evacuation threat, and (3) evacuation implementation, should be used. Detailed suggestions on ICU evacuation, including regional planning, evacuation drills, patient transport preparation and equipment, patient prioritization and distribution for evacuation, patient information and tracking, and federal and international evacuation assistance systems, are also provided. CONCLUSIONS: Successful ICU evacuation during a disaster requires active preparation, participation, communication, and leadership by critical care providers. Critical care providers have a professional obligation to become better educated, prepared, and engaged with the processes of ICU evacuation to provide a safe continuum of critical care during a disaster. PMID- 25144519 TI - [Acceptance of Tinnitus: Validation of the 'Akzeptanzfragebogen bei chronischem Tinnitus' (AFCT).] PMID- 25144520 TI - Risk factors associated with self-injurious behavior among a national sample of undergraduate college students. AB - OBJECTIVE: Nonsuicidal self-injury (NSSI) and suicidality among undergraduates represent important public health issues. This analysis identified risk factors that distinguished 3 groups, those who reported no history of self-harm; self injury, but no suicide attempts (NSSI only); and self-injury and a suicide attempt (NSSI + SA) in the past year. METHODS: Data came from 16,044 undergraduates who completed the Fall 2010 National College Health Assessment. RESULTS: Over 3% of students reported NSSI, and one third of these individuals also attempted suicide. Factors that distinguished the NSSI only and NSSI + SA groups from the no self-harm group included current depressive symptoms, nonheterosexual orientation, an eating disorder/extreme weight control behavior, and diagnosis of an internalizing disorder. Factors that distinguished the NSSI + SA group from the NSSI only group were current depressive symptoms and diagnosis of an internalizing disorder. CONCLUSIONS: Students experiencing mental health problems demonstrate increased risk for NSSI and/or suicidal behavior. PMID- 25144521 TI - Experimental observation of the ion-ion correlation effects on charge inversion and strong adhesion between mica surfaces in aqueous electrolyte solutions. AB - Direct force measurements between two mica surfaces in aqueous electrolyte solutions over broad ranges of LaCl3 concentrations and pH values were carried out with a surface forces apparatus. Charge inversion on mica surfaces is detected once the LaCl3 concentration reaches a critical value. With the continual increase of LaCl3 concentrations, the mica surface will be overscreened by the counterions. It is demonstrated that the two mica surfaces may experience the jump-in contact even at high LaCl3 concentrations, which is seldom seen in monovalent salt solutions. The strong adhesion cannot be attributed to the van der Waals force alone, but should include the ion-ion correlation forces. Through adjusting the pH values in LaCl3 solutions, the ion-ion correlation force can be evaluated quantitatively. These results provide important insight into the fundamental understanding in the role of ion-ion correlations in ion screening mechanism and interactions between charged objects. PMID- 25144523 TI - New Kagome metal Sc3Mn3Al7Si5 and its gallium-doped analogues: synthesis, crystal structure, and physical properties. AB - We report the synthesis, crystal structure, and basic properties of the new intermetallic compound Sc3Mn3Al7Si5. The structure of the compound was established by single-crystal X-ray diffraction, and it crystallizes with a hexagonal structure (Sc3Ni11Si4 type) with Mn atoms forming the Kagome nets. The dc magnetic susceptibility measurements reveal a Curie-Weiss moment of ~0.51 MU(B)/Mn; however, no magnetic order is found for temperatures as low as 1.8 K. Electrical resistivity and heat capacity measurements show that this compound is definitively metallic, with a relatively large specific heat Sommerfeld coefficient, indicating strong electronic correlations. Intriguingly, these features have revealed Sc3Mn3Al7Si5 as a possible quantum spin liquid. With chemical and lattice disorder introduced by doping, a spin liquid to spin glass transition is observed in the highest Ga-doped compounds. The roles of the geometrically frustrated structure and Mn-ligand hybridization in the magnetism of the title compounds are also discussed. PMID- 25144522 TI - Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis regulation in Alzheimer's disease. AB - Oxidative stress resulting from metal-ion misregulation plays a role in the development of Alzheimer's disease (AD). This process includes the production of tissue-damaging reactive oxygen species and amyloid aggregates. Herein we describe the synthesis, characterization and protective capacity of the small molecule, lipoic cyclen, which has been designed to target molecular features of AD. This construct utilizes the biologically compatible and naturally occurring lipoic acid as a foundation for engendering low cellular toxicity in multiple cell lines, radical scavenging capacity, tuning the metal affinity of the parent cyclen, and results in an unexpected affinity for amyloid without inducing aggregation. The hybrid construct thereby shows protection against cell death induced by amyloid aggregates and copper ions. These results provide evidence for the rational design methods used to produce this fused molecule as a potential strategy for the development of lead compounds for the treatment of neurodegenerative disorders. PMID- 25144524 TI - Characterization of two distinct modes of drug binding to human intestinal fatty acid binding protein. AB - The aqueous cytoplasm of cells poses a potentially significant barrier for many lipophilic drugs to reach their sites of action. Fatty acid binding proteins (FABPs) bind to poorly water-soluble fatty acids (FAs) and lipophilic compounds and facilitate their intracellular transport. Several structures of FA in complex with FABPs have been described, but data describing the binding sites of other lipophilic ligands including drugs are limited. Here the environmentally sensitive fluorophores, 1-anilinonapthalene 8-sulfonic acid (ANS), and 11 dansylamino undecanoic acid (DAUDA) were used to investigate drug binding to human intestinal FABP (hIFABP). Most drugs that bound hIFABP were able to displace both ANS and DAUDA. A notable exception was ketorolac, a non-steroidal anti-inflammatory drug that bound to hIFABP and displaced DAUDA but failed to displace ANS. Isothermal titration calorimetry revealed that for the majority of ligands including FA, ANS, and DAUDA, binding to hIFABP was exothermic. In contrast, ketorolac binding to hIFABP was endothermic and entropy-driven. The X ray crystal structure of DAUDA-hIFABP revealed a FA-like binding mode where the carboxylate of DAUDA formed a network of hydrogen bonds with residues at the bottom of the binding cavity and the dansyl group interacted with residues in the portal region. In contrast, NMR chemical shift perturbation (CSP) data suggested that ANS bound only toward the bottom of the hIFABP cavity, whereas ketorolac occupied only the portal region. The CSP data further suggested that ANS and ketorolac were able to bind simultaneously to hIFABP, consistent with the lack of displacement of ANS observed by fluorescence and supported by a model of the ternary complex. The NMR solution structure of the ketorolac-hIFABP complex therefore describes a newly characterized, hydrophobic ligand binding site in the portal region of hIFABP. PMID- 25144528 TI - Incorporation of monovalent cations in sulfate green rust. AB - Green rust is a naturally occurring layered mixed-valent ferrous-ferric hydroxide, which can react with a range of redox-active compounds. Sulfate bearing green rust is generally thought to have interlayers composed of sulfate and water. Here, we provide evidence that the interlayers also contain monovalent cations, using X-ray photoelectron spectroscopy and synchrotron X-ray scattering. For material synthesized with Na(+), K(+), Rb(+), or Cs(+), interlayer thickness derived from basal plane spacings correlates with the radius of the monovalent cation. In addition, sequential washing of the materials with water showed that Na(+) and K(+) were structurally fixed in the interlayer, whereas Rb(+) and Cs(+) could be removed, resulting in a decrease in the basal layer spacing. The incorporation of cations in the interlayer opens up new possibilities for the use of sulfate green rust for exchange reactions with both anions and cations: e.g., radioactive Cs. PMID- 25144525 TI - Specificity and affinity quantification of flexible recognition from underlying energy landscape topography. AB - Flexibility in biomolecular recognition is essential and critical for many cellular activities. Flexible recognition often leads to moderate affinity but high specificity, in contradiction with the conventional wisdom that high affinity and high specificity are coupled. Furthermore, quantitative understanding of the role of flexibility in biomolecular recognition is still challenging. Here, we meet the challenge by quantifying the intrinsic biomolecular recognition energy landscapes with and without flexibility through the underlying density of states. We quantified the thermodynamic intrinsic specificity by the topography of the intrinsic binding energy landscape and the kinetic specificity by association rate. We found that the thermodynamic and kinetic specificity are strongly correlated. Furthermore, we found that flexibility decreases binding affinity on one hand, but increases binding specificity on the other hand, and the decreasing or increasing proportion of affinity and specificity are strongly correlated with the degree of flexibility. This shows more (less) flexibility leads to weaker (stronger) coupling between affinity and specificity. Our work provides a theoretical foundation and quantitative explanation of the previous qualitative studies on the relationship among flexibility, affinity and specificity. In addition, we found that the folding energy landscapes are more funneled with binding, indicating that binding helps folding during the recognition. Finally, we demonstrated that the whole binding-folding energy landscapes can be integrated by the rigid binding and isolated folding energy landscapes under weak flexibility. Our results provide a novel way to quantify the affinity and specificity in flexible biomolecular recognition. PMID- 25144529 TI - RC1339/APRc from Rickettsia conorii is a novel aspartic protease with properties of retropepsin-like enzymes. AB - Members of the species Rickettsia are obligate intracellular, gram-negative, arthropod-borne pathogens of humans and other mammals. The life-threatening character of diseases caused by many Rickettsia species and the lack of reliable protective vaccine against rickettsioses strengthens the importance of identifying new protein factors for the potential development of innovative therapeutic tools. Herein, we report the identification and characterization of a novel membrane-embedded retropepsin-like homologue, highly conserved in 55 Rickettsia genomes. Using R. conorii gene homologue RC1339 as our working model, we demonstrate that, despite the low overall sequence similarity to retropepsins, the gene product of rc1339 APRc (for Aspartic Protease from Rickettsia conorii) is an active enzyme with features highly reminiscent of this family of aspartic proteases, such as autolytic activity impaired by mutation of the catalytic aspartate, accumulation in the dimeric form, optimal activity at pH 6, and inhibition by specific HIV-1 protease inhibitors. Moreover, specificity preferences determined by a high-throughput profiling approach confirmed common preferences between this novel rickettsial enzyme and other aspartic proteases, both retropepsins and pepsin-like. This is the first report on a retropepsin-like protease in gram-negative intracellular bacteria such as Rickettsia, contributing to the analysis of the evolutionary relationships between the two types of aspartic proteases. Additionally, we have also shown that APRc is transcribed and translated in R. conorii and R. rickettsii and is integrated into the outer membrane of both species. Finally, we demonstrated that APRc is sufficient to catalyze the in vitro processing of two conserved high molecular weight autotransporter adhesin/invasion proteins, Sca5/OmpB and Sca0/OmpA, thereby suggesting the participation of this enzyme in a relevant proteolytic pathway in rickettsial life-cycle. As a novel bona fide member of the retropepsin family of aspartic proteases, APRc emerges as an intriguing target for therapeutic intervention against fatal rickettsioses. PMID- 25144530 TI - A survey of overlooked viral infections in biological experiment systems. AB - It is commonly accepted that there are many unknown viruses on the planet. For the known viruses, do we know their prevalence, even in our experimental systems? Here we report a virus survey using recently published small (s)RNA sequencing datasets. The sRNA reads were assembled and contigs were screened for virus homologues against the NCBI nucleotide (nt) database using the BLASTn program. To our surprise, approximately 30% (28 out of 94) of publications had highly scored viral sequences in their datasets. Among them, only two publications reported virus infections. Though viral vectors were used in some of the publications, virus sequences without any identifiable source appeared in more than 20 publications. By determining the distributions of viral reads and the antiviral RNA interference (RNAi) pathways using the sRNA profiles, we showed evidence that many of the viruses identified were indeed infecting and generated host RNAi responses. As virus infections affect many aspects of host molecular biology and metabolism, the presence and impact of viruses needs to be actively investigated in experimental systems. PMID- 25144532 TI - Dietary fermented soybean suppresses UVB-induced skin inflammation in hairless mice via regulation of the MAPK signaling pathway. AB - Soybean may be a promising ingredient for regulating UVB-induced inflammatory damage to the skin. We investigated the anti-inflammatory effects of diets supplemented with fermented soybean on UVB-induced skin photodamage and the effectiveness of soybean (S) and fermented soybean (FS) dietary supplementation. To investigate the effects of two major isoflavones-daidzein and genistein-from FS, we used cocultures with keratinocytes and fibroblasts. Genistein treatment strongly inhibited the production of IL-6 and MAPK signaling. Forty hairless male mice divided into four groups were fed with a control diet (group N: normal, group C; +UVB) or diets with 2.5% S+UVB or 2.5% FS+UVB (group S, group FS) for 8 weeks. Macrophage infiltration to the dermis was reduced more in groups S and FS than in group C. The expression levels of iNOS and COX-2 were significantly decreased in group FS (by 7.7% +/- 0.4% and 21.2% +/- 0.3%, respectively [p < 0.05]). PMID- 25144531 TI - Deciphering combinations of PI3K/AKT/mTOR pathway drugs augmenting anti angiogenic efficacy in vivo. AB - Ocular neovascularization is a common pathology associated with human eye diseases e.g. age-related macular degeneration and proliferative diabetic retinopathy. Blindness represents one of the most feared disabilities and remains a major burden to health-care systems. Current approaches to treat ocular neovascularisation include laser photocoagulation, photodynamic therapy and anti VEGF therapies: Ranibizumab (Lucentis) and Aflibercept (Eylea). However, high clinical costs, frequent intraocular injections, and increased risk of infections are challenges related with these standards of care. Thus, there is a clinical need to develop more effective drugs that overcome these challenges. Here, we focus on an alternative approach by quantifying the in vivo anti-angiogenic efficacy of combinations of phosphatidylinositol-3-kinase (PI3K) pathway inhibitors. The PI3K/AKT/mTOR pathway is a complex signalling pathway involved in crucial cellular functions such as cell proliferation, migration and angiogenesis. RT-PCR confirms the expression of PI3K target genes (pik3ca, pik3r1, mtor and akt1) in zebrafish trunks from 6 hours post fertilisation (hpf) and in eyes from 2 days post fertilisation (dpf). Using both the zebrafish intersegmental vessel and hyaloid vessel assays to measure the in vivo anti angiogenic efficacy of PI3K/Akt/mTOR pathway inhibitors, we identified 5 uM combinations of i) NVP-BEZ235 (dual PI3K-mTOR inhibitor) + PI-103 (dual PI3K-mTOR inhibitor); or ii) LY-294002 (pan-PI3K inhibitor) + NVP-BEZ235; or iii) NVP BEZ235 + rapamycin (mTOR inhibitor); or iv) LY-294002 + rapamycin as the most anti-angiogenic. Treatment of developing larvae from 2-5 dpf with 5 uM NVP-BEZ235 plus PI-103 resulted in an essentially intact ocular morphology and visual behaviour, whereas other combinations severely disrupted the developing retinal morphology and visual function. In human ARPE19 retinal pigment epithelium cells, however, no significant difference in cell number was observed following treatment with the inhibitor combinations. Collectively, these results highlight the potential of combinations of PI3K/AKT/mTOR pathway inhibitors to safely and effectively treat ocular neovascularization. PMID- 25144533 TI - Asymmetric sulfa-Michael addition to alpha-substituted vinyl ketones catalyzed by chiral primary amine. AB - The first effective example of asymmetric conjugate addition-protonation reactions of thiols to alpha-substituted vinyl ketones by chiral primary amine catalysis is reported. A simple chiral primary-tertiary diamine catalyst derived from l-phenylalanine was found to promote the sulfa-Michael addition-protonation reactions with good to excellent enantioselectivity. PMID- 25144535 TI - Development of posture-specific computational phantoms using motion capture technology and application to radiation dose-reconstruction for the 1999 Tokai Mura nuclear criticality accident. AB - The majority of existing computational phantoms are designed to represent workers in typical standing anatomical postures with fixed arm and leg positions. However, workers found in accident-related scenarios often assume varied postures. This paper describes the development and application of two phantoms with adjusted postures specified by data acquired from a motion capture system to simulate unique human postures found in a 1999 criticality accident that took place at a JCO facility in Tokai-Mura, Japan. In the course of this accident, two workers were fatally exposed to extremely high levels of radiation. Implementation of the emergent techniques discussed produced more accurate and more detailed dose estimates for the two workers than were reported in previous studies. A total-body dose of 6.43 and 26.38 Gy was estimated for the two workers, who assumed a crouching and a standing posture, respectively. Additionally, organ-specific dose estimates were determined, including a 7.93 Gy dose to the thyroid and 6.11 Gy dose to the stomach for the crouching worker and a 41.71 Gy dose to the liver and a 37.26 Gy dose to the stomach for the standing worker. Implications for the medical prognosis of the workers are discussed, and the results of this study were found to correlate better with the patient outcome than previous estimates, suggesting potential future applications of such methods for improved epidemiological studies involving next-generation computational phantom tools. PMID- 25144536 TI - Asymmetric wavefront aberrations and pupillary shapes induced by electrical stimulation of ciliary nerve in cats measured with compact wavefront aberrometer. AB - To investigate the changes in the wavefront aberrations and pupillary shape in response to electrical stimulation of the branches of the ciliary nerves in cats. Seven eyes of seven cats were studied under general anesthesia. Trains of monophasic pulses (current, 0.1 to 1.0 mA; duration, 0.5 ms/phase; frequency, 5 to 40 Hz) were applied to the lateral or medial branch of the short ciliary nerve near the posterior pole of the eye. A pair of electrodes was hooked onto one or both branch of the short ciliary nerve. The electrodes were placed about 5 mm from the scleral surface. The wavefront aberrations were recorded continuously for 2 seconds before, 8 seconds during, and for 20 seconds after the electrical stimulation. The pupillary images were simultaneously recorded during the stimulation period. Both the wavefront aberrations and the pupillary images were obtained 10 times/sec with a custom-built wavefront aberrometer. The maximum accommodative amplitude was 1.19 diopters (D) produced by electrical stimulation of the short ciliary nerves. The latency of the accommodative changes was very short, and the accommodative level gradually increased up to 4 seconds and reached a plateau. When only one branch of the ciliary nerve was stimulated, the pupil dilated asymmetrically, and the oblique astigmatism and one of the asymmetrical wavefront terms was also altered. Our results showed that the wavefront aberrations and pupillary dilations can be measured simultaneously and serially with a compact wavefront aberrometer. The asymmetric pupil dilation and asymmetric changes of the wavefront aberrations suggest that each branch of the ciliary nerve innervates specific segments of the ciliary muscle and dilator muscle of the pupil. PMID- 25144534 TI - Cryptococcus gattii VGIII isolates causing infections in HIV/AIDS patients in Southern California: identification of the local environmental source as arboreal. AB - Ongoing Cryptococcus gattii outbreaks in the Western United States and Canada illustrate the impact of environmental reservoirs and both clonal and recombining propagation in driving emergence and expansion of microbial pathogens. C. gattii comprises four distinct molecular types: VGI, VGII, VGIII, and VGIV, with no evidence of nuclear genetic exchange, indicating these represent distinct species. C. gattii VGII isolates are causing the Pacific Northwest outbreak, whereas VGIII isolates frequently infect HIV/AIDS patients in Southern California. VGI, VGII, and VGIII have been isolated from patients and animals in the Western US, suggesting these molecular types occur in the environment. However, only two environmental isolates of C. gattii have ever been reported from California: CBS7750 (VGII) and WM161 (VGIII). The incongruence of frequent clinical presence and uncommon environmental isolation suggests an unknown C. gattii reservoir in California. Here we report frequent isolation of C. gattii VGIII MATalpha and MATa isolates and infrequent isolation of VGI MATalpha from environmental sources in Southern California. VGIII isolates were obtained from soil debris associated with tree species not previously reported as hosts from sites near residences of infected patients. These isolates are fertile under laboratory conditions, produce abundant spores, and are part of both locally and more distantly recombining populations. MLST and whole genome sequence analysis provide compelling evidence that these environmental isolates are the source of human infections. Isolates displayed wide-ranging virulence in macrophage and animal models. When clinical and environmental isolates with indistinguishable MLST profiles were compared, environmental isolates were less virulent. Taken together, our studies reveal an environmental source and risk of C. gattii to HIV/AIDS patients with implications for the >1,000,000 cryptococcal infections occurring annually for which the causative isolate is rarely assigned species status. Thus, the C. gattii global health burden could be more substantial than currently appreciated. PMID- 25144537 TI - Choice of reference sequence and assembler for alignment of Listeria monocytogenes short-read sequence data greatly influences rates of error in SNP analyses. AB - The wide availability of whole-genome sequencing (WGS) and an abundance of open source software have made detection of single-nucleotide polymorphisms (SNPs) in bacterial genomes an increasingly accessible and effective tool for comparative analyses. Thus, ensuring that real nucleotide differences between genomes (i.e., true SNPs) are detected at high rates and that the influences of errors (such as false positive SNPs, ambiguously called sites, and gaps) are mitigated is of utmost importance. The choices researchers make regarding the generation and analysis of WGS data can greatly influence the accuracy of short-read sequence alignments and, therefore, the efficacy of such experiments. We studied the effects of some of these choices, including: i) depth of sequencing coverage, ii) choice of reference-guided short-read sequence assembler, iii) choice of reference genome, and iv) whether to perform read-quality filtering and trimming, on our ability to detect true SNPs and on the frequencies of errors. We performed benchmarking experiments, during which we assembled simulated and real Listeria monocytogenes strain 08-5578 short-read sequence datasets of varying quality with four commonly used assemblers (BWA, MOSAIK, Novoalign, and SMALT), using reference genomes of varying genetic distances, and with or without read pre processing (i.e., quality filtering and trimming). We found that assemblies of at least 50-fold coverage provided the most accurate results. In addition, MOSAIK yielded the fewest errors when reads were aligned to a nearly identical reference genome, while using SMALT to align reads against a reference sequence that is ~0.82% distant from 08-5578 at the nucleotide level resulted in the detection of the greatest numbers of true SNPs and the fewest errors. Finally, we show that whether read pre-processing improves SNP detection depends upon the choice of reference sequence and assembler. In total, this study demonstrates that researchers should test a variety of conditions to achieve optimal results. PMID- 25144538 TI - Non-lethal control of the cariogenic potential of an agent-based model for dental plaque. AB - Dental caries or tooth decay is a prevalent global disease whose causative agent is the oral biofilm known as plaque. According to the ecological plaque hypothesis, this biofilm becomes pathogenic when external challenges drive it towards a state with a high proportion of acid-producing bacteria. Determining which factors control biofilm composition is therefore desirable when developing novel clinical treatments to combat caries, but is also challenging due to the system complexity and the existence of multiple bacterial species performing similar functions. Here we employ agent-based mathematical modelling to simulate a biofilm consisting of two competing, distinct types of bacterial populations, each parameterised by their nutrient uptake and aciduricity, periodically subjected to an acid challenge resulting from the metabolism of dietary carbohydrates. It was found that one population was progressively eliminated from the system to give either a benign or a pathogenic biofilm, with a tipping point between these two fates depending on a multiplicity of factors relating to microbial physiology and biofilm geometry. Parameter sensitivity was quantified by individually varying the model parameters against putative experimental measures, suggesting non-lethal interventions that can favourably modulate biofilm composition. We discuss how the same parameter sensitivity data can be used to guide the design of validation experiments, and argue for the benefits of in silico modelling in providing an additional predictive capability upstream from in vitro experiments. PMID- 25144541 TI - Fingerprinting oils in water via their dissolved VOC pattern using mid-infrared sensors. AB - An infrared attenuated total reflection (IR-ATR) method for detecting, differentiating, and quantifying hydrocarbons dissolved in water relevant for oil spills by evaluating the "fingerprint" of the volatile organic compounds (VOCs) associated with individual oil types in the mid-infrared spectral range (i.e., 800-600 cm(-1)) is presented. In this spectral regime, these hydrocarbons provide distinctive absorption features, which may be used to identify specific hydrocarbon patterns that are characteristic for different crude and refined oils. For analyzing the "VOC fingerprint" resulting from various oil samples, aqueous solutions containing the dissolved hydrocarbons from different crude oils (i.e., types "Barrow", "Goodwyn", and "Saladin") and refined oils (i.e., "Petrol" and "Diesel") were analyzed using a ZnSe ATR waveguide as the optical sensing element. To minimize interferences from the surrounding water matrix and for amplifying the VOC signatures by enrichment, a thin layer of poly(ethylene-co propylene) was coated onto the ATR waveguide surface, thereby enabling the establishment of suitable calibration functions for the quantification of characteristic concentration patterns of the detected VOCs. Multivariate data analysis was then used for a prelininary classification of various oil-types via their VOC patterns. PMID- 25144539 TI - Personal trust increases cooperation beyond general trust. AB - In this paper we present a new methodology which, while allowing for anonymous interaction, it also makes possible to compare decisions of cooperating or defecting when playing games within a group, according to whether or not players personally trust each other. The design thus goes beyond standard approaches to the role of trust in fostering cooperation, which is restricted to general trust. It also allows considering the role of the topology of the social network involved may play in the level of cooperation found. The results of this work support the idea that personal trust promotes cooperation beyond the level of general trust. We also found that this effect carries over to the whole group, making it more cohesive, but that higher levels of cohesion rely on a particular topology. As a conclusion, we hypothesize that personal trust is a psychological mechanism evolved to make human social life possible in the small groups our ancestors lived in, and that this mechanism persists and plays a role in sustaining cooperation and social cohesion. PMID- 25144542 TI - Vaccine-associated paralytic poliomyelitis and BCG-osis in an immigrant child with severe combined immunodeficiency syndrome - Texas, 2013. AB - Poliovirus transmission has been eliminated in most of the world through the use of inactivated poliovirus vaccine (IPV) and live, attenuated oral poliovirus vaccine (OPV). In the United States, use of OPV was discontinued by the year 2000 because of the potential for vaccine-associated paralytic polio (VAPP); an average of eight cases were reported each year in the United States during 1980 2000. Polio eradication efforts in other parts of the world continue to rely on OPV to take advantage of transmission of poliovirus vaccine strains to unvaccinated persons in the population, lower cost, and ease of administration. In 2013, an infant aged 7 months who recently immigrated to the United States from India was referred to a hospital in San Antonio, Texas. The infant had fever, an enlarging skin lesion in the deltoid region with axillary lymphadenopathy, decreased activity, and inability to bear weight on the left leg, progressing to paralysis of the left leg over a 6-week period. Recognition of lymphopenia on complete blood count led to immune evaluation, which revealed the presence of severe combined immunodeficiency syndrome (SCIDS), an inherited disorder. A history of OPV and bacille Calmette-Guerin (BCG) vaccination in India led to the diagnoses of VAPP and BCG-osis, which were confirmed microbiologically. This report demonstrates the importance of obtaining a comprehensive clinical history in a child who has recently immigrated to the United States, with recognition that differing vaccine practices in other countries might require additional consideration of potential etiologies. PMID- 25144543 TI - Racial disparities in access to maternity care practices that support breastfeeding - United States, 2011. AB - Despite the well documented health benefits of breastfeeding, initiation of breastfeeding and breastfeeding duration rates among black infants in the United States are approximately 16% lower than among whites. Although many factors play a role in a woman's ability to breastfeed, experiences during the childbirth hospitalization are critical for establishing breastfeeding. To analyze whether the implementation by maternity facilities of practices that support breastfeeding varied depending on the racial composition of the area surrounding the facility, CDC linked data from its 2011 Maternity Practices in Infant Nutrition and Care (mPINC) survey to U.S. Census data on the percentage of blacks living within the zip code area of each facility. The results of that analysis indicated that facilities in zip code areas where the percentage of black residents was >12.2% (the national average during 2007-2011) were less likely than facilities in zip code areas where the percentage was <=12.2% to meet five of 10 mPINC indicators for recommended practices supportive of breastfeeding and more likely to implement one practice; differences for the other four practices were not statistically significant. Comparing facilities in areas with >12.2% black residents with facilities in areas with <=12.2% black residents, the largest differences were in the percentage of facilities that implemented recommended practices related to early initiation of breastfeeding (46.0% compared with 59.9%), limited use of breastfeeding supplements (13.1% compared with 25.8%), and rooming-in (27.7% compared with 39.4%). These findings suggest there are racial disparities in access to maternity care practices known to support breastfeeding. PMID- 25144544 TI - Update on recommendations for use of herpes zoster vaccine. AB - Herpes zoster vaccine (Zostavax [Merck & Co., Inc.]) was licensed in 2006 and recommended by the Advisory Committee on Immunization Practices (ACIP) in 2008 for prevention of herpes zoster (shingles) and its complications among adults aged >=60 years. The Food and Drug Administration (FDA) approved the use of Zostavax in 2011 for adults aged 50 through 59 years based on a large study of safety and efficacy in this age group. ACIP initially considered the use of herpes zoster vaccine among adults aged 50 through 59 years in June 2011, but declined to recommend the vaccine in this age group, citing shortages of Zostavax and limited data on long-term protection afforded by herpes zoster vaccine. In October 2013, ACIP reviewed the epidemiology of herpes zoster and its complications, herpes zoster vaccine supply, short-term vaccine efficacy in adults aged 50 through 59 years, short- and long- term vaccine efficacy and effectiveness in adults aged >=60 years, an updated cost-effectiveness analysis, and deliberations of the ACIP herpes zoster work group, all of which are summarized in this report. No vote was taken, and ACIP maintained its current recommendation that herpes zoster vaccine be routinely recommended for adults aged >=60 years. Meeting minutes are available at http://www.cdc.gov/vaccines/acip/meetings/meetings-info.html. PMID- 25144545 TI - Closure of varicella-zoster virus-containing vaccines pregnancy registry - United States, 2013. AB - Vaccines that contain live attenuated varicella-zoster virus (VZV) (Varivax, ProQuad, and Zostavax [all products of Merck & Co., Inc.]) are contraindicated during pregnancy. To monitor the pregnancy outcomes of women inadvertently vaccinated with VZV-containing vaccines immediately before or during pregnancy, Merck and CDC established the Merck/CDC Pregnancy Registry for VZV-Containing Vaccines in 1995. This report updates previously published summaries of registry data, provides the rationale for the closure of the registry, and describes plans for continued monitoring of the safety of these vaccines when inadvertently administered to pregnant women or immediately before pregnancy. From inception of the registry in 1995 through March 2012, no cases of congenital varicella syndrome and no increased prevalence of other birth defects have been detected among women vaccinated within 3 months before or during pregnancy. Although a small risk for congenital varicella syndrome cannot be ruled out, the number of exposures being registered each year (approximately two varicella-susceptible women exposed during the high-risk period for congenital varicella syndrome) is now too low to improve on the current estimate of the risk. PMID- 25144546 TI - Notes from the field: atypical pneumonia in three members of an extended family - South Carolina and north Carolina, july-august 2013. AB - On August 5, 2013, the South Carolina Department of Health and Environmental Control was notified of a case of acute respiratory failure in a previously healthy woman. A family interview revealed the patient's uncle and cousin had also been hospitalized with similar symptoms in North Carolina. The South Carolina Department of Health and Environmental Control and the North Carolina Division of Public Health collaborated to identify the cause of the respiratory illness cluster and to prevent additional illnesses. PMID- 25144548 TI - Highly efficient Pd-based core-shell nanowire catalysts for O2 dissociation. AB - The adsorption and dissociation of O2 on the core-shell M@Pd nanowires (M = 3d, 4d, 5d transition metals) are studied using the first-principles density functional method. Suitable core atoms are determined based on the stability of the core-shell NWs and their efficiency for O2 dissociation. With the consideration of the stability and cost, we found that Fe, Co, Ni, Cu, Ru, Ir atoms have lower price than Pd and favor at the core even with O adatom at the surface. The formed M@Pd core-shell nanowires are active for O2 dissociation with activation barriers no larger than 0.25 eV. The results may serve as a guide for the design of efficient Pd-based nanocatalysts for O2 dissociation. PMID- 25144547 TI - Arsenic trioxide and resveratrol show synergistic anti-leukemia activity and neutralized cardiotoxicity. AB - Cardiotoxicity is an aggravating side effect of many clinical antineoplastic agents such as arsenic trioxide (As2O3), which is the first-line treatment for acute promyelocytic leukemia (APL). Clinically, drug combination strategies are widely applied for complex disease management. Here, an optimized, cardiac friendly therapeutic strategy for APL was investigated using a combination of As2O3 and genistein or resveratrol. Potential combinations were explored with respect to their effects on mitochondrial membrane potential, reactive oxygen species, superoxide dismutase activity, autophagy, and apoptosis in both NB4 cells and neonatal rat left ventricular myocytes. All experiments consistently suggested that 5 uM resveratrol remarkably alleviates As2O3-induced cardiotoxicity. To achieve an equivalent effect, a 10-fold dosage of genistein was required, thus highlighting the dose advantage of resveratrol, as poor bioavailability is a common concern for its clinical application. Co administration of resveratrol substantially amplified the anticancer effect of As2O3 in NB4 cells. Furthermore, resveratrol exacerbated oxidative stress, mitochondrial damage, and apoptosis, thereby reflecting its full range of synergism with As2O3. Addition of 5 uM resveratrol to the single drug formula of As2O3 also further increased the expression of LC3, a marker of cellular autophagy activity, indicating an involvement of autophagy-mediated tumor cell death in the synergistic action. Our results suggest a possible application of an As2O3 and resveratrol combination to treat APL in order to achieve superior therapeutics effects and prevent cardiotoxicity. PMID- 25144549 TI - A malaria diagnostic tool based on computer vision screening and visualization of Plasmodium falciparum candidate areas in digitized blood smears. AB - INTRODUCTION: Microscopy is the gold standard for diagnosis of malaria, however, manual evaluation of blood films is highly dependent on skilled personnel in a time-consuming, error-prone and repetitive process. In this study we propose a method using computer vision detection and visualization of only the diagnostically most relevant sample regions in digitized blood smears. METHODS: Giemsa-stained thin blood films with P. falciparum ring-stage trophozoites (n = 27) and uninfected controls (n = 20) were digitally scanned with an oil immersion objective (0.1 um/pixel) to capture approximately 50,000 erythrocytes per sample. Parasite candidate regions were identified based on color and object size, followed by extraction of image features (local binary patterns, local contrast and Scale-invariant feature transform descriptors) used as input to a support vector machine classifier. The classifier was trained on digital slides from ten patients and validated on six samples. RESULTS: The diagnostic accuracy was tested on 31 samples (19 infected and 12 controls). From each digitized area of a blood smear, a panel with the 128 most probable parasite candidate regions was generated. Two expert microscopists were asked to visually inspect the panel on a tablet computer and to judge whether the patient was infected with P. falciparum. The method achieved a diagnostic sensitivity and specificity of 95% and 100% as well as 90% and 100% for the two readers respectively using the diagnostic tool. Parasitemia was separately calculated by the automated system and the correlation coefficient between manual and automated parasitemia counts was 0.97. CONCLUSION: We developed a decision support system for detecting malaria parasites using a computer vision algorithm combined with visualization of sample areas with the highest probability of malaria infection. The system provides a novel method for blood smear screening with a significantly reduced need for visual examination and has a potential to increase the throughput in malaria diagnostics. PMID- 25144550 TI - Incentive spirometry combined with expiratory positive airway pressure improves asthma control and quality of life in asthma: a randomised controlled trial. AB - OBJECTIVES: The use of the incentive spirometer (IS) and expiratory positive airway pressure (EPAP) provides several benefits in patients with respiratory disorders. However, the effects of the use of these devices coupled (IS + EPAP) are still unknown in asthmatic patients. The aim of this study was to evaluate the effect of IS associated with EPAP on exercise tolerance (six-minute walk test - 6MWT), lung function (by spirometry), asthma control (Asthma Control Questionnaire - ACQ) and quality of life (Asthma Quality of Life Questionnaire - AQLQ) in patients with severe asthma. METHODS: Patients were randomised into two groups: IS + EPAP (n = 8) and control (n = 6). The IS + EPAP group performed breathing exercises at home, twice daily for 20 min, over a period of 5 weeks. RESULTS: There was no significant difference in spirometric variables and in the distance walked in the 6MWT in both groups. However, the IS + EPAP group showed an improvement in asthma control (p = 0.002) and quality of life (p = 0.02). CONCLUSIONS: These findings demonstrate that the IS + EPAP protocol, when performed at home, provides an improvement in asthma control and quality of life for patients with severe asthma when evaluated by ACQ and AQLQ, respectively. PMID- 25144551 TI - Assessing asthma control and associated risk factors among persons with current asthma - findings from the child and adult Asthma Call-back Survey. AB - INTRODUCTION: Monitoring the level of asthma control is important in determining the effectiveness of current treatment which may decrease the frequency and intensity of symptoms and functional limitations. Uncontrolled asthma has been associated with decreased quality of life and increased health care use. The objectives of this study were to assess the level of asthma control and identify related risk factors among persons with current asthma. METHODS: Using the 2006 to 2010 BRFSS child and adult Asthma Call-back Survey, asthma control was classified as well-controlled or uncontrolled (not-well-controlled or very-poorly controlled) using three impairment measures: daytime symptoms, night-time symptoms, and taking short-acting beta2-agonists for symptom control. Multivariate logistic regression identified predictors of asthma control. RESULTS: Fifty percent of adults and 38.4% of children with current asthma had uncontrolled asthma. About 63% of children and 53% of adults with uncontrolled asthma were on long-term asthma control medications. Among children, uncontrolled asthma was significantly associated with being younger than 5 years, having annual household income <$15,000, and reporting cost as barriers to medical care. Among adults, it was significantly associated with being 45 years or older, having annual household income of <$25,000, being "other" race, having less than a 4-year college degree, being a current or former smoker, reporting cost as barriers, being obese, and having chronic obstructive pulmonary disease or depression. CONCLUSION: Identifying and targeting modifiable predictors of uncontrolled asthma (low educational attainment, low income, cigarette smoking, and co-morbid conditions including obesity and depression) could improve asthma control. PMID- 25144553 TI - Caregiver depression and perceptions of primary care predict clinic attendance in head start children with asthma. AB - OBJECTIVE: The purpose of this study is to evaluate the mediating role of perceptions of primary care (PC) on the association between depression and PC clinic attendance among caregivers of children with asthma. In adults, depression is associated with lower PC clinic attendance and ~25% of mothers presenting to a pediatric PC clinic will screen positive for depression. Adults' perceptions about their medical care mediate the depression-clinic attendance relation, but this has not been tested in children or in an asthma population. METHODS: This is a secondary prospective data analysis of 141 caregivers of Head Start children diagnosed with asthma, offered an intervention to reduce barriers to PC. Caregivers rated their depressive symptoms and perceptions of PC (access, provider contextual knowledge, and continuity of care) at baseline. PC clinic attendance was tracked prospectively for 6-months. RESULTS: At baseline, 26% of caregivers screened positive for depression. Within 6-months, 66% of children attended a PC appointment. A positive depression screen was not associated with PC attendance (p = 0.07) or continuity of care (p = 0.98) but was inversely associated with perceptions of both access (p = 0.03) and provider contextual knowledge (p = 0.02). Though the total indirect effect was not significant, the specific indirect effect of depression on PC attendance through access was significant (95% CI: 0.01, 0.68). CONCLUSIONS: Providing tangible resources to reduce barriers to PC without addressing perceptions of access may not sufficiently improve PC clinic attendance in pediatric asthma. Screening caregivers for depression may identify families requiring targeted interventions to improve their perceptions of access. PMID- 25144552 TI - Reliability and predictors of resistive load detection in children with persistent asthma: a multivariate approach. AB - OBJECTIVE: Resistive load detection tasks enable analysis of individual differences in psychophysical outcomes. The purpose of this study was to determine both the reliability and predictors of resistive load detection in children with persistent asthma who completed multiple testing sessions. METHODS: Both University of North Carolina (UNC) Charlotte and Ohio University institutional review boards approved the research protocol. The detection of inspiratory resistive loads was evaluated in 75 children with asthma between 8 and 15 years of age. Each child participated in four experimental sessions that occurred approximately once every 2 weeks. Multivariate analyses were used to delineate predictors of task performance. RESULTS: Reliability of resistive load detection was determined for each child, and predictors of load detection outcomes were investigated in two groups of children: those who performed reliably in all four sessions (n = 31) and those who performed reliably in three or fewer sessions (n = 44). Three factors (development, symptoms, and compliance) accounted for 66.3% of the variance among variables that predicted 38.7% of the variance in load detection outcomes (Multiple R = 0.62, p = 0.004) and correctly classified performance as reliable or less reliable in 80.6% of the children, chi(2)(12) = 28.88, p = 0.004. CONCLUSIONS: Cognitive and physical development, appraisal of symptom experiences, and adherence-related behaviors (1) account for a significant proportion of the interrelationships among variables that affect perception of airflow obstruction in children with asthma and (2) differentiate between children who perform more or less reliably in a resistive load detection task. PMID- 25144554 TI - Reduced motivation in the BACHD rat model of Huntington disease is dependent on the choice of food deprivation strategy. AB - Huntington disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free feeding body weight, but not when deprivation levels were adjusted in order to match the rats' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models. PMID- 25144555 TI - Isolation and characterization of two novel plasmids from pathogenic Leptospira interrogans serogroup Canicola Serovar Canicola strain Gui44. AB - BACKGROUND: Previous genomic analysis of pathogenic Leptospira has identified two circular chromosomes but no plasmid. This study aims to investigate potential extrachromosomal elements of L.interrogans serovar Canicola strain Gui44. METHODOLOGY: Two novel plasmids, pGui1 and pGui2, were isolated from the pathogenic strain Gui44, using a modified alkaline lysis method. Southern blotting was performed to determine the presence and size of them. Then, 454 and Hiseq sequencing were applied to obtain and analyze the complete sequences of the two plasmids. Furthermore, real-time quantitative PCR and next-generation sequencing were used to compare relative copy numbers of the two plasmids with that of the chromosomes. Finally, after serial passages in vitro for more than 2 years, the strain Gui44 was subsequently re-sequenced to estimate stability of the two plasmids. PRINCIPAL FINDINGS: The larger plasmid, pGui1, 74,981 base pairs (bp) in length with GC content of 34.63%, possesses 62 open reading frames (ORFs). The smaller plasmid, pGui2, is 66,851 bp in length with GC content of 33.33%, and contains 63 ORFs. The replication initiation proteins encoded by pGui1 and pGui2 demonstrate significant sequence similarity with LA1839 (86% and 88%), a well-known replication protein in another pathogenic L.interrogans serovar Lai strain Lai, suggesting the ability for autonomous plasmid replication. Quantitative PCR and next-generation sequencing confirms a single copy of both plasmids and their stable presence in the strain Gui44 with in vitro serial passages after more than 2 years. Interestingly, the two plasmids both contain a significant number of novel genes (35 in pGui1 and 52 in pGui2). CONCLUSIONS: This report confirms the presence of two separate circular plasmids in serovar Canicola strain Gui44 and provides a new understanding of genomic organization, adaptation, evolution and pathogenesis of Leptospira, which will aid in the development of in vivo genetic manipulation systems in pathogenic Leptospira species. PMID- 25144558 TI - Synthesis of 1-(2,3-dihydrobenzofuran-3-yl)-methanesulfonohydrazides through insertion of sulfur dioxide. AB - A three-component reaction of 2-(allyloxy)anilines, sulfur dioxide and hydrazines under mild conditions is developed, which gives rise to 1-(2,3-dihydrobenzofuran 3-yl)-methanesulfonohydrazides in good yields. This radical process involves an intramolecular 5-exo-cyclization and insertion of sulfur dioxide. PMID- 25144556 TI - Autophagic degradation of the inhibitory p53 isoform Delta133p53alpha as a regulatory mechanism for p53-mediated senescence. AB - Delta133p53alpha, a p53 isoform that can inhibit full-length p53, is downregulated at replicative senescence in a manner independent of mRNA regulation and proteasome-mediated degradation. Here we demonstrate that, unlike full-length p53, Delta133p53alpha is degraded by autophagy during replicative senescence. Pharmacological inhibition of autophagy restores Delta133p53alpha expression levels in replicatively senescent fibroblasts, without affecting full length p53. The siRNA-mediated knockdown of pro-autophagic proteins (ATG5, ATG7 and Beclin-1) also restores Delta133p53alpha expression. The chaperone-associated E3 ubiquitin ligase STUB1, which is known to regulate autophagy, interacts with Delta133p53alpha and is downregulated at replicative senescence. The siRNA knockdown of STUB1 in proliferating, early-passage fibroblasts induces the autophagic degradation of Delta133p53alpha and thereby induces senescence. Upon replicative senescence or STUB1 knockdown, Delta133p53alpha is recruited to autophagosomes, consistent with its autophagic degradation. This study reveals that STUB1 is an endogenous regulator of Delta133p53alpha degradation and senescence, and identifies a p53 isoform-specific protein turnover mechanism that orchestrates p53-mediated senescence. PMID- 25144557 TI - Functional specialization among members of Knickkopf family of proteins in insect cuticle organization. AB - Our recent study on the functional analysis of the Knickkopf protein from T. castaneum (TcKnk), indicated a novel role for this protein in protection of chitin from degradation by chitinases. Knk is also required for the laminar organization of chitin in the procuticle. During a bioinformatics search using this protein sequence as the query, we discovered the existence of a small family of three Knk-like genes (including the prototypical TcKnk) in the T. castaneum genome as well as in all insects with completed genome assemblies. The two additional Knk-like genes have been named TcKnk2 and TcKnk3. Further complexity arises as a result of alternative splicing and alternative polyadenylation of transcripts of TcKnk3, leading to the production of three transcripts (and by inference, three proteins) from this gene. These transcripts are named TcKnk3 Full Length (TcKnk3-FL), TcKnk3-5' and TcKnk3-3'. All three Knk-family genes appear to have essential and non-redundant functions. RNAi for TcKnk led to developmental arrest at every molt, while down-regulation of either TcKnk2 or one of the three TcKnk3 transcripts (TcKnk3-3') resulted in specific molting arrest only at the pharate adult stage. All three Knk genes appear to influence the total chitin content at the pharate adult stage, but to variable extents. While TcKnk contributes mostly to the stability and laminar organization of chitin in the elytral and body wall procuticles, proteins encoded by TcKnk2 and TcKnk3-3' transcripts appear to be required for the integrity of the body wall denticles and tracheal taenidia, but not the elytral and body wall procuticles. Thus, the three members of the Knk-family of proteins perform different essential functions in cuticle formation at different developmental stages and in different parts of the insect anatomy. PMID- 25144560 TI - Improving radiopharmaceutical supply chain safety by implementing bar code technology. AB - The aim of this study was to describe and evaluate an approach for improving radiopharmaceutical supply chain safety by implementing bar code technology. We first evaluated the current situation of our radiopharmaceutical supply chain and, by means of the ALARM protocol, analysed two dispensing errors that occurred in our department. Thereafter, we implemented a bar code system to secure selected key stages of the radiopharmaceutical supply chain. Finally, we evaluated the cost of this implementation, from overtime, to overheads, to additional radiation exposure to workers. An analysis of the events that occurred revealed a lack of identification of prepared or dispensed drugs. Moreover, the evaluation of the current radiopharmaceutical supply chain showed that the dispensation and injection steps needed to be further secured. The bar code system was used to reinforce product identification at three selected key stages: at usable stock entry; at preparation-dispensation; and during administration, allowing to check conformity between the labelling of the delivered product (identity and activity) and the prescription. The extra time needed for all these steps had no impact on the number and successful conduct of examinations. The investment cost was reduced (2600 euros for new material and 30 euros a year for additional supplies) because of pre-existing computing equipment. With regard to the radiation exposure to workers there was an insignificant overexposure for hands with this new organization because of the labelling and scanning processes of radiolabelled preparation vials. Implementation of bar code technology is now an essential part of a global securing approach towards optimum patient management. PMID- 25144559 TI - Comparison of LVEF assessed by 2D echocardiography, gated blood pool SPECT, 99mTc tetrofosmin gated SPECT, and 18F-FDG gated PET with ERNV in patients with CAD and severe LV dysfunction. AB - INTRODUCTION: Left ventricular ejection fraction (LVEF) is the single most important predictor of prognosis in patients with coronary artery disease (CAD) and left ventricular (LV) dysfunction. Equilibrium radionuclide ventriculography (ERNV) is considered the most reliable technique for assessing LVEF. Most of these patients undergo two dimensional (2D) echocardiography and myocardial viability study using gated myocardial perfusion imaging (MPI) or gated F fluorodeoxyglucose (F-FDG) PET. However, the accuracy of LVEF assessed by these methods is not clear. This study has been designed to assess the correlation and agreement between the LVEF measured by 2D echocardiography, gated blood pool single photon emission computed tomography (SPECT), Tc tetrofosmin gated SPECT, and F-FDG gated PET with ERNV in CAD patients with severe LV dysfunction. PATIENTS AND METHODS: Patients with CAD and severe LV dysfunction [ejection fraction (EF) <35 assessed by 2D echocardiography] were prospectively included in the study. These patients underwent ERNV along with gated blood pool SPECT, Tc tetrofosmin gated SPECT, and F-FDG gated PET as per the standard protocol for myocardial viability assessment and LVEF calculation. Spearman's coefficient of correlation (r) was calculated for the different sets of values with significance level kept at a P-value less than 0.05. Bland-Altman plots were inspected to visually assess the between-agreement measurements from different methods. RESULTS: Forty-one patients were prospectively included. LVEF calculated by various radionuclide methods showed good correlation with ERNV as follows: gated blood pool SPECT, r=0.92; MPI gated SPECT, r=0.85; and F-FDG gated PET, r=0.76. However, the correlation between 2D echocardiography and ERNV was poor (r=0.520). The Bland-Altman plot for LVEF measured by all radionuclide methods showed good agreement with ERNV. However, agreement between 2D echocardiography and ERNV is poor, as most of the values in this plot gave a negative difference for low EF and a positive difference for high EF. The mean difference between various techniques [2D echocardiography (a), gated blood pool SPECT (b), MPI gated SPECT (c), F-FDG gated PET (d)] and ERNV (e) was as follows: (a)-(e), 3.3; (b)-(e), 5; (c)-(e), 1.1; and (d)-(e), 2.9. The best possible correlation and agreement was found between MPI gated SPECT and ERNV. CONCLUSION: This study showed good correlation and agreement between MPI gated SPECT and F-FDG gated PET with ERNV for LVEF calculation in CAD patients with severe LV dysfunction. Thus, subjecting patients who undergo viability assessment by MPI gated SPECT or F-FDG gated PET to a separate procedure like ERNV for LVEF assessment may not be warranted. As the gated blood pool SPECT also showed good correlation and agreement with ERNV for LVEF assessment in CAD patients with severe LV dysfunction, with better characteristics than ERNV, it can be routinely used whenever accurate LVEF assessment is needed. PMID- 25144561 TI - Superiority of delayed risk stratification in differentiated thyroid cancer after total thyroidectomy and radioactive iodine ablation. AB - AIM: The aim of this study was to validate the effectiveness of delayed risk stratification (DRS) in predicting structural progression and compare the predictive value of American Thyroid Association (ATA) risk stratification with that of DRS in patients with differentiated thyroid cancer (DTC). METHODS: A total of 398 patients with DTC who underwent surgery followed by radioactive iodine ablation were enrolled. Patients were categorized as having excellent response, acceptable response, biochemical incomplete response, or structural incomplete response at 8-15 months' evaluation after radioactive iodine ablation for DRS. Effectiveness of DRS was evaluated according to structural progression free survival (PFS; median follow-up, 10.7 years). RESULTS: A total of 229 patients (57.5%) were classified as having excellent response, 78 (19.6%) as having acceptable response, 62 (15.6%) as having biochemical incomplete response, and 29 patients (7.3%) as having structural incomplete response. After DRS, 60.2% of intermediate-risk patients and 20.5% of high-risk patients were shifted to the excellent response category. Sixty-nine patients (17.3%) showed structural progression. DRS showed statistical difference in PFS (hazard ratio, 4.268; 95% confidence interval, 3.258-5.477; P<0.001). In multivariate analysis of ATA risk stratification and DRS, DRS was significantly associated with PFS (hazard ratio, 4.383; 95% confidence interval, 3.250-5.912; P<0.001), but ATA risk stratification was not. There was no significant difference in deviances between the use of DRS alone and the use of both DRS and ATA risk stratification (chi=0.103, d.f.=1, P=0.748). CONCLUSION: DRS is superior to ATA risk stratification in predicting structural disease progression for DTC patients. PMID- 25144562 TI - Usefulness of 18F-FDG PET/CT in the detection of neurolymphomatosis. AB - PURPOSE: Neurolymphomatosis (NL) is an uncommon complication of lymphoma and leukemia. Few data have been reported regarding the utilization of fluorine-18 fluorodeoxyglucose PET/computed tomography (F-FDG PET/CT) in this disease. The aim of this study was to assess the role of F-FDG PET/CT in the diagnosis of NL. PATIENTS AND METHODS: Eight patients who suffered from NL due to lymphoma or leukemia were studied. The diagnosis of NL lesions was established according to ;the combination of neurologic symptoms, and imaging techniques including MRI and PET/CT, and/or analysis of cerebrospinal fluid, pathology, and clinical follow up. RESULTS: Eight patients with lymphoma or leukemia were diagnosed with NL during or after treatment. F-FDG PET/CT was positive in all eight patients. A total of 19 NL lesions were detected by F-FDG PET/CT. Morphological abnormality was seen in seven of 19 lesions on the syn-modality CT. However, all lesions were F-FDG avid with a maximum standardized uptake value of 6.42 +/- 3.02, and presented with linear and nodular hypermetabolic patterns. There was a significant difference in the detection of NL lesions between PET and syn modality CT [100% (19/19) vs. 36.8% (7/19), chi=14.74, P<0.001]. The NL lesions were located predominantly in the nerve root of the thoracic and lumbar segments (63.2%). In four patients, PET/CT was performed after treatment and was useful for assessing the treatment response. CONCLUSION: F-FDG PET/CT is a sensitive imaging modality for the detection of NL lesions. Further research involving more patients is needed to confirm our findings. PMID- 25144563 TI - beta-Radiation exposure to fingertips after using a trained routine application method during radiosynovectomy. AB - There are few, but worrisome, data available on fingertip radiation exposure of medical personnel during radiosynovectomy (RSV). To reduce radiation exposure, we performed a dedicated application procedure. This report summarizes the acquired skin equivalent dose [Hp(0.07)] of the personnel involved in the preparation and administration of the three RSV beta-emitters Y, Re and Er. Over a period of 3 years, 547 joints in 368 patients were treated with 52421 MBq of the aforementioned three radionuclides. The Hp(0.07) was recorded with thermoluminescence dosimeters worn on the dominant index fingertip and was analysed monthly. Eight staff members were exposed to an Hp(0.07) of 492 mSv. The cumulative dose was less than 10 MUSv/MBq. The dose per person was 1.1 MUSv/MBq in physicians and up to 4.5 MUSv/MBq in technicians. The accumulated personal Hp(0.07) during RSV was far below the regulatory limit and published data. PMID- 25144564 TI - Measuring glomerular filtration rate using 51Cr-EDTA: body surface area normalization before or after Brochner-Mortensen correction? AB - BACKGROUND: Guidelines for measuring glomerular filtration rate (GFR) using Cr EDTA require normalizing of GFR for body surface area (BSA) before applying the Brochner-Mortensen (BM) correction. The guideline explicitly mentions the importance of performing BSA normalization before BM correction and that this is particularly important in children in whom the effects of BSA normalization are largest. MATERIALS AND METHODS: We theoretically showed that the order of applying BM correction and BSA indexing is indeed important for patient populations having a low BSA and a high slow GFR. We then compared the exact GFR, obtained from the double-exponential concentration-time curve in Duchenne muscular dystrophy (DMD) patients, with the GFR obtained from the slow compartment method using the BM correction. RESULTS: The median GFR for the 20 DMD patients obtained from the BSA-BM order deviates 5.40% from the exact GFR (P=0.0006), whereas the median GFR obtained from the BM-BSA order deviates only 0.05% (P>0.05) from the exact GFR, resulting in a median of differences of 5.50% between the two methods (P<0.0001). CONCLUSION: The correct order of application in this DMD population should be BM correction first, followed by BSA indexing, and not vice versa. In general, the order of applying the BM correction and BSA normalization becomes more important with increasing slow GFR and extreme low BSA. The order of application is of less importance for people with normal BSA and/or normal GFR. PMID- 25144565 TI - UK audit of glomerular filtration rate measurement from plasma sampling in 2013. AB - INTRODUCTION: An audit was carried out into UK glomerular filtration rate (GFR) calculation. The results were compared with an identical 2001 audit. METHODS: Participants used their routine method to calculate GFR for 20 data sets (four plasma samples) in millilitres per minute and also the GFR normalized for body surface area. Some unsound data sets were included to analyse the applied quality control (QC) methods. Variability between centres was assessed for each data set, compared with the national median and a reference value calculated using the method recommended in the British Nuclear Medicine Society guidelines. The influence of the number of samples on variability was studied. Supplementary data were requested on workload and methodology. RESULTS: The 59 returns showed widespread standardization. The applied early exponential clearance correction was the main contributor to the observed variability. These corrections were applied by 97% of centres (50% - 2001) with 80% using the recommended averaged Brochner-Mortenson correction. Approximately 75% applied the recommended Haycock body surface area formula for adults (78% for children). The effect of the number of samples used was not significant. There was wide variability in the applied QC techniques, especially in terms of the use of the volume of distribution. CONCLUSION: The widespread adoption of the guidelines has harmonized national GFR calculation compared with the previous audit. Further standardization could further reduce variability. This audit has highlighted the need to address the national standardization of QC methods. Radionuclide techniques are confirmed as the preferred method for GFR measurement when an unequivocal result is required. PMID- 25144568 TI - Anion dependent self-assembly of 56-metal Cd-Ln nanoclusters with enhanced near infrared luminescence properties. AB - Two series of Cd-Ln clusters: nano-drum [Ln8Cd24L12(OAc)48] and nano-double-drum [Ln12Cd44L20Cl30(OAc)54] (Ln = Nd and Yb) were prepared using a flexible Schiff base ligand bearing two aryl-Br groups. Chloride (Cl(-)) ions, together with the interactions of Br with other electronegative atoms, play a key role in the formation of the nano-double-drums. The structures were studied by TEM and photophysical properties were determined. PMID- 25144567 TI - Methyl donor-deficient diet during development can affect fear and anxiety in adulthood in C57BL/6J mice. AB - DNA methylation is one of the essential factors in the control of gene expression. Folic acid, methionine and choline (methyl donors)--all nutrients related to one-carbon metabolism--are known as important mediators of DNA methylation. A previous study has shown that long-term administration of a diet lacking in methyl donors caused global DNA hypermethylation in the brain (Pogribny et al., 2008). However, no study has investigated the effects of a diet lacking in methyl donors during the developmental period on emotional behaviors such as fear and anxiety-like behavior in association with gene expressions in the brain. In addition, it has not been elucidated whether a diet supplemented with methyl donors later in life can reverse these changes. Therefore, we examined the effects of methyl donor deficiency during the developmental period on fear memory acquisition/extinction and anxiety-like behavior, and the relevant gene expressions in the hippocampus in juvenile (6-wk) and adult (12-wk) mice. We found that juvenile mice fed a methyl-donor-deficient diet had impaired fear memory acquisition along with decreases in the gene expressions of Dnmt3a and Dnmt3b. In addition, reduced anxiety-like behavior with decreased gene expressions of Grin2b and Gabar2 was observed in both the methyl-donor-deficient group and the body-weight-matched food-restriction group. After being fed a diet supplemented with methyl donors ad libitum, adult mice reversed the alteration of gene expression of Dnmt3a, Dnmt3b, Grin2b and Gabar2, but anxiety-like behavior became elevated. In addition, impaired fear-memory formation was observed in the adult mice fed the methyl-donor-deficient diet during the developmental period. Our study suggested that developmental alterations in the one-carbon metabolic pathway in the brain could have effects on emotional behavior and memory formation that last into adulthood. PMID- 25144566 TI - Genetic variation in iron metabolism is associated with neuropathic pain and pain severity in HIV-infected patients on antiretroviral therapy. AB - HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p<0.05) and 5 variants in 4 genes (p<0.01) were nominally associated with DNP: polymorphisms in TF, TFRC, BMP6, ACO1, SLC11A2, and FXN conferred reduced risk (adjusted odds ratios [ORs] ranging from 0.2 to 0.7, all p<0.05); other variants in TF, CP, ACO1, BMP6, and B2M conferred increased risk (ORs ranging from 1.3 to 3.1, all p<0.05). Risks associated with some variants were statistically significant either in black or white subgroups but were consistent in direction. ACO1 rs2026739 remained significantly associated with DNP in whites (permutation p<0.0001) after correction for multiple tests. Several of the same iron-regulatory-gene polymorphisms, including ACO1 rs2026739, were also associated with severity of DNP (all p<0.05). Common polymorphisms in iron-management genes are associated with DNP and with DNP severity in HIV-infected persons receiving cART. Consistent risk estimates across population subgroups and persistence of the ACO1 rs2026739 association after adjustment for multiple testing suggest that genetic variation in iron-regulation and transport modulates susceptibility to DNP. PMID- 25144569 TI - Distance mapping in proteins using fluorescence spectroscopy: tyrosine, like tryptophan, quenches bimane fluorescence in a distance-dependent manner. AB - Tryptophan-induced quenching of fluorophores (TrIQ) uses intramolecular fluorescence quenching to assess distances in proteins too small (<15 A) to be easily probed by traditional Forster resonance energy transfer methods. A powerful aspect of TrIQ is its ability to obtain an ultrafast snapshot of a protein conformation, by identifying "static quenching" (contact between the Trp and probe at the moment of light excitation). Here we report new advances in this site-directed fluorescence labeling (SDFL) approach, gleaned from recent studies of T4 lysozyme (T4L). First, we show that like TrIQ, tyrosine-induced quenching (TyrIQ) occurs for the fluorophore bimane in a distance-dependent fashion, although with some key differences. The Tyr "sphere of quenching" for bimane (<=10 A) is smaller than for Trp (<=15 A, Calpha-Calpha distance), and the size difference between the quenching residue (Tyr) and control (Phe) differs by only a hydroxyl group. Second, we show how TrIQ and TyrIQ can be used together to assess the magnitude and energetics of a protein movement. In these studies, we placed a bimane (probe) and Trp or Tyr (quencher) on opposite ends of a "hinge" in T4L and conducted TrIQ and TyrIQ measurements. Our results are consistent with an ~5 A change in Calpha-Calpha distances between these sites upon substrate binding, in agreement with the crystal structures. Subsequent Arrhenius analysis suggests the activation energy barrier (Ea) to this movement is relatively low (~1.5-2.5 kcal/mol). Together, these results demonstrate that TyrIQ, used together with TrIQ, significantly expands the power of quenching-based distance mapping SDFL studies. PMID- 25144571 TI - Experimental colitis is exacerbated by concomitant infection with Mycobacterium avium ssp. paratuberculosis. AB - BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disorder of the human gastrointestinal tract. Although genetic, immunological, environmental, and bacterial factors have been implicated, the pathogenesis is incompletely understood. The histopathological appearance of CD strikingly resembles Johne's disease, a ruminant inflammatory bowel disease, caused by Mycobacterium avium ssp. paratuberculosis (MAP), but a causative role of MAP in CD has not been established. In this work, we hypothesized that MAP might exacerbate an already existing intestinal disease. METHODS: We combined dextran sulfate sodium (DSS) induced colitis with MAP infection in mice and monitored the immune response and bacterial count in different organs. RESULTS: An increased size of liver and spleen was observed in DSS-treated and MAP-infected animals (DSS + MAP) as compared with DSS-treated uninfected (DSS + PBS) mice. Similarly, DSS treatment increased the number and size of MAP-induced liver granulomas and enhanced the MAP counts in enteric tissue. MAP infection in turn delayed the mucosal healing of DSS-induced tissue damage. Finally, high numbers of MAP were found in mesenteric fat tissue causing large granuloma and necrotic regions. CONCLUSIONS: Taken together, we present an in vivo model to study the role of MAP infection in CD. Our results confirm the hypothesis that MAP is able to exacerbate existing intestinal inflammation. PMID- 25144570 TI - Two-stage genome-wide methylation profiling in childhood-onset Crohn's Disease implicates epigenetic alterations at the VMP1/MIR21 and HLA loci. AB - BACKGROUND: As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease. METHODS: The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. Data were corrected for differential leukocyte proportions. Targeted replication was performed in adults using pyrosequencing. Methylation changes were correlated with gene expression in blood and intestinal mucosa. RESULTS: We identified 65 individual CpG sites with methylation alterations achieving epigenome-wide significance after Bonferroni correction (P < 1.1 * 10(-7)), and 19 differently methylated regions displaying unidirectional methylation change. There was a highly significant enrichment of methylation changes around GWAS single nucleotide polymorphisms (P = 3.7 * 10( 7)), notably the HLA region and MIR21. Two-locus discriminant analysis in the discovery cohort predicted disease in the pediatric replication cohort with high accuracy (area under the curve, 0.98). The findings strongly implicate the transcriptional start site of MIR21 as a region of extended epigenetic alteration, containing the most significant individual probes (P = 1.97 * 10( 15)) within a GWAS risk locus. In extension studies, we confirmed hypomethylation of MIR21 in adults (P = 6.6 * 10(-5), n = 172) and show increased mRNA expression in leukocytes (P < 0.005, n = 66) and in the inflamed intestine (P = 1.4 * 10( 6), n = 99). CONCLUSIONS: We demonstrate highly significant and replicable differences in DNA methylation in CD, defining the disease-associated epigenome. The data strongly implicate known GWAS loci, with compelling evidence implicating MIR21 and the HLA region. PMID- 25144572 TI - Supplementation with eicosapentaenoic acid-rich fish oil improves exercise economy and reduces perceived exertion during submaximal steady-state exercise in normal healthy untrained men. AB - Based on the effects of n-3 polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on reduction of blood viscosity, we theorized that PUFA could improve aerobic performance by increasing oxygen supply to tissues. Twenty male subjects were randomly divided into two groups (n = 10): a fish oil group (FG) and a control (CG). Maximal oxygen uptake and oxygen uptake during submaximal exercise were measured using a cycle ergometer. For 8 weeks, the FG then ingested capsules containing 3.6 g/day of EPA rich fish oil, while the CG took 3.6 g/day of a medium-chain triglyceride. After supplementation, erythrocyte EPA and DHA in the FG were significantly increased. In the FG, a negative linear correlation was detected in the change between erythrocyte EPA and whole oxygen uptake during submaximal exercise pre- and post supplementation. The present study showed that EPA-rich fish oil supplementation improves exercise economy in humans. PMID- 25144574 TI - Properties of complexes formed by Na(+), Mg(2+), and Fe(2+) binding with benzene molecules. AB - A theoretical investigation was performed to study cation-pi interactions in complexes of benzene (Bz) with cations, that is, M(z+)(Bz)n for M(z+) = Na(+), Mg(2+), Fe(2+) and n = 1-3, using MP2 theory with the 6-31+G* and 6-311++G** basis sets and the DFT/(B3LYP and B3LYP-D)/6-311++G** methods. Binding energies and structures of the complexes are reported. The splitting between the quintet and single states of the Fe(2+) complexes was found to depend on the number of benzene molecules in the complex and the complex's structure. All of the M(z+)(Bz) complexes prefer a half-sandwich geometry. A geometry with the cation sandwiched between the two benzene rings was found for the M(z+)(Bz)2 complexes, with the benzene rings either in an eclipsed or staggered conformation. An approximate cyclic structure, with the cation at its center, was found for three benzene molecules interacting with the cation. The cation-benzene binding energy is substantial and equal to 22, 108, and 151 kcal/mol for the Na(+)(Bz), Mg(2+)(Bz), and Fe(2+)(Bz) complexes, respectively. The strength of the interaction of the cation with an individual benzene molecule decreases as the number of benzene molecules bound to the cation increases; for example, it is 108 kcal/mol for Mg(2+)(Bz), but only 71 kcal/mol for Mg(2+)(Bz)3. There is a range of values for the M(z+)(Bz)n intermolecular vibrational frequencies; for example, they are ~230-360 and ~10-330 cm(-1) for the Mg(2+)(Bz) and Mg(2+)(Bz)3 complexes, respectively. Binding of the cation to benzene both red and blue shifts the benzene vibrational frequencies. This shifting is larger for the Mg(2+) and Fe(2+) complexes, as compared to those for Na(+), as a result of the former's stronger cation-benzene binding. The present study is an initial step to understand the possible importance of cation-pi interactions for polycyclic aromatic hydrocarbon aggregation processes during soot formation. PMID- 25144575 TI - Spin-one Ising model for ice VII-plastic ice phase transitions. AB - We propose a spin model compatible with ice VII-plastic ice phase transitions and critical phenomena discovered recently by computer simulations. The Blume-Capel spin-1 Ising model is extended in order to describe the entropic stabilization effect in the plastic ice phase. The model shares the same set of tricritical exponents with simulation, indicating that they are of the same universality class. PMID- 25144573 TI - A panel of Trypanosoma brucei strains tagged with blue and red-shifted luciferases for bioluminescent imaging in murine infection models. AB - BACKGROUND: Genetic engineering with luciferase reporter genes allows monitoring Trypanosoma brucei (T.b.) infections in mice by in vivo bioluminescence imaging (BLI). Until recently, luminescent T.b. models were based on Renilla luciferase (RLuc) activity. Our study aimed at evaluating red-shifted luciferases for in vivo BLI in a set of diverse T.b. strains of all three subspecies, including some recently isolated from human patients. METHODOLOGY/PRINCIPAL FINDINGS: We transfected T.b. brucei, T.b. rhodesiense and T.b. gambiense strains with either RLuc, click beetle red (CBR) or Photinus pyralis RE9 (PpyRE9) luciferase and characterised their in vitro luciferase activity, growth profile and drug sensitivity, and their potential for in vivo BLI. Compared to RLuc, the red shifted luciferases, CBR and PpyRE9, allow tracking of T.b. brucei AnTaR 1 trypanosomes with higher details on tissue distribution, and PpyRE9 allows detection of the parasites with a sensitivity of at least one order of magnitude higher than CBR luciferase. With CBR-tagged T.b. gambiense LiTaR1, T.b. rhodesiense RUMPHI and T.b. gambiense 348 BT in an acute, subacute and chronic infection model respectively, we observed differences in parasite tropism for murine tissues during in vivo BLI. Ex vivo BLI on the brain confirmed central nervous system infection by all luminescent strains of T.b. brucei AnTaR 1, T.b. rhodesiense RUMPHI and T.b. gambiense 348 BT. CONCLUSIONS/SIGNIFICANCE: We established a genetically and phenotypically diverse collection of bioluminescent T.b. brucei, T.b. gambiense and T.b. rhodesiense strains, including drug resistant strains. For in vivo BLI monitoring of murine infections, we recommend trypanosome strains transfected with red-shifted luciferase reporter genes, such as CBR and PpyRE9. Red-shifted luciferases can be detected with a higher sensitivity in vivo and at the same time they improve the spatial resolution of the parasites in the entire body due to the better kinetics of their substrate D luciferin. PMID- 25144578 TI - "The uncertainty is what is driving me crazy": the tripartite model of uncertainty in the adolescent and young adult cancer context. AB - Building on scholarship indicating that uncertainty is a fundamental component of the cancer experience, this study focuses on an understudied population: adolescents and young adults (AYAs) with cancer. Because AYAs' health outcomes lag behind those of older and younger people with cancer, scholars have recommended that the subjective experiences of AYAs be better understood. Using the tripartite model of uncertainty sources as a guiding framework, we analyzed naturally occurring messages from an online discussion forum for AYA cancer survivors. The majority of messages communicating uncertainty expressed medical uncertainty regarding the complexities of understanding treatment options and sequelae. Results indicated that several overarching areas of AYA uncertainty correspond to themes reported by other cancer populations, but that some distinctive concerns arise amid the normative complexities of late adolescence and young adulthood. PMID- 25144576 TI - Corneal cell adhesion to contact lens hydrogel materials enhanced via tear film protein deposition. AB - Tear film protein deposition on contact lens hydrogels has been well characterized from the perspective of bacterial adhesion and viability. However, the effect of protein deposition on lens interactions with the corneal epithelium remains largely unexplored. The current study employs a live cell rheometer to quantify human corneal epithelial cell adhesion to soft contact lenses fouled with the tear film protein lysozyme. PureVision balafilcon A and AirOptix lotrafilcon B lenses were soaked for five days in either phosphate buffered saline (PBS), borate buffered saline (BBS), or Sensitive Eyes Plus Saline Solution (Sensitive Eyes), either pure or in the presence of lysozyme. Treated contact lenses were then contacted to a live monolayer of corneal epithelial cells for two hours, after which the contact lens was sheared laterally. The apparent cell monolayer relaxation modulus was then used to quantify the extent of cell adhesion to the contact lens surface. For both lens types, lysozyme increased corneal cell adhesion to the contact lens, with the apparent cell monolayer relaxation modulus increasing up to an order of magnitude in the presence of protein. The magnitude of this increase depended on the identity of the soaking solution: lenses soaked in borate-buffered solutions (BBS, Sensitive Eyes) exhibited a much greater increase in cell attachment upon protein addition than those soaked in PBS. Significantly, all measurements were conducted while subjecting the cells to moderate surface pressures and shear rates, similar to those experienced by corneal cells in vivo. PMID- 25144579 TI - Longitudinal relationships among visual acuity, daily functional status, and mortality: the Salisbury Eye Evaluation Study. AB - IMPORTANCE: Determination of the mechanisms by which visual loss increases mortality risk is important for developing interventional strategies. OBJECTIVE: To evaluate the direct and indirect effects of loss of visual acuity (VA) on mortality risk through functional status changes among aging adults. DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal study of a population-based sample of 2520 noninstitutionalized adults aged 65 to 84 years from September 16, 1993, through July 26, 2003, in the greater Salisbury area of Maryland. Participants underwent reassessment 2, 6, and 8 years after baseline. Mortality status was ascertained from linkage with the National Death Index through 2009. EXPOSURES: Results of VA testing and self-reported functional status based on activities of daily living (ADL) and instrumental ADL (IADL). MAIN OUTCOMES AND MEASURE: Mortality. RESULTS: Worse VA levels at baseline were associated with an increased the risk for mortality (hazard ratio [HR], 1.16 [95% CI, 1.04-1.28]; P < .01) through their effect on lower IADL levels at baseline. Declines in VA over time were associated with increased mortality risk (HR, 1.78 [95% CI, 1.27-2.51]; P < .001) by way of decreasing IADL levels over time. Participants experiencing the mean linear decline in VA of 1 letter on the Early Treatment Diabetic Retinopathy Study acuity chart per year are expected to have a 16% increase in mortality risk during the 8-year study exclusively through associated declines in IADL levels. CONCLUSIONS AND RELEVANCE: In this longitudinal study of older adults, VA loss adversely affected IADL levels, which subsequently increased the risk for mortality. Prevention of disabling ocular conditions, treatment of correctable visual impairment, and interventions designed to prevent the effect of visual impairment on IADL declines may all reduce mortality risk in aging adults. PMID- 25144580 TI - Kaleidoscopes, forensic nursing, and change. PMID- 25144581 TI - Why we do what we do: a theoretical evaluation of the integrated practice model for forensic nursing science. AB - An evaluation of the Integrated Practice Model for Forensic Nursing Science () is presented utilizing methods outlined by . A brief review of nursing theory basics and evaluation methods by Meleis is provided to enhance understanding of the ensuing theoretical evaluation and critique. The Integrated Practice Model for Forensic Nursing Science, created by forensic nursing pioneer Virginia Lynch, captures the theories, assumptions, concepts, and propositions inherent in forensic nursing practice and science. The historical background of the theory is explored as Lynch's model launched the role development of forensic nursing practice as both a nursing and forensic science specialty. It is derived from a combination of nursing, sociological, and philosophical theories to reflect the grounding of forensic nursing in the nursing, legal, psychological, and scientific communities. As Lynch's model is the first inception of forensic nursing theory, it is representative of a conceptual framework although the title implies a practice theory. The clarity and consistency displayed in the theory's structural components of assumptions, concepts, and propositions are analyzed. The model is described and evaluated. A summary of the strengths and limitations of the model is compiled followed by application to practice, education, and research with suggestions for ongoing theory development. PMID- 25144582 TI - Enrichment of theory through critique, restructuring, and application. PMID- 25144583 TI - Client satisfaction with nursing-led sexual assault and domestic violence services in Ontario. AB - INTRODUCTION: There is still little known about survivors' experiences of and satisfaction with comprehensive nursing-led hospital-based sexual assault and domestic violence treatment programs. METHOD: To address this gap, we surveyed and collected information from clients/guardians presenting to 30 of 35 of Ontario's Sexual Assault/Domestic Violence Treatment Centres across seven domains: presentation characteristics, client characteristics, assailant characteristics, assault characteristics, health consequences, service use, and satisfaction with services. RESULTS: One thousand four hundred eighty-four clients participated in the study, 96% of whom were women/girls. Most were White (75.3%), 12-44 years old (87.8%), and living with family (69.6%); 97.9% of clients used at least one service. The most commonly used service was assessment and/or documentation of injury (84.8%), followed by on-site follow-up care (73.6%). Almost all clients/guardians reported that they received the care needed (98.6%), rated the overall care as excellent or good (98.8%), and stated that the care had been provided in a sensitive manner (95.4%). Concerns and recommendations to improve care expressed by a small proportion of clients/guardians focused on long wait times, negative emergency department staff attitudes, issues of privacy and confidentiality, and difficulty with accessing services. DISCUSSION: The high uptake and positive evaluation of services provided by Ontario's Sexual Assault/Domestic Violence Treatment Centre programs confirms the value of nursing-led, hospital-based care in the aftermath of sexual assault and domestic violence. Ongoing evaluation of such services will ensure the best care possible for this patient population. PMID- 25144584 TI - Women's center staff perceptions of the campus climate on sexual violence. AB - BACKGROUND: Sexual assault is a major public health problem disproportionately affecting women on college and university campuses. As sexual assault is often unreported, survivors may not have the access to resources and services that are helpful in healing. Campus-based women's centers provide a comfortable place and resource to address women's issues on campus. Individuals who work in these centers have open communication channels with students and a role in the administrative structure that may provide a unique understanding of survivors, the student environment, and the institutional context regarding sexual assault. OBJECTIVE: The purpose of this study was to understand the perceptions of campus based women's center staff on college and university campuses, specifically regarding campus-based responses to sexual assault. METHODS: Participants responded electronically to six open-ended survey questions. Data were analyzed using a qualitative content analysis approach to identify key themes present within the data. RESULTS: Key concepts identified included respect, trust, confidentiality, trained professionals, and comprehensive and consistent response. CONCLUSIONS: The findings provide an early description of the perceptions of staff in campus-based women's centers related to prevention, reporting, and response to sexual violence on campuses and can be used to inform campus policies and practices as well as forensic and college-based nursing practice. PMID- 25144585 TI - The emergence of forensic nursing and advanced nursing practice in Switzerland: an innovative case study consultation. AB - BACKGROUND AND METHODS: The objectives of this article were to systematically describe and examine the novel roles and responsibilities assumed by nurses in a forensic consultation for victims of violence at a University Hospital in French speaking Switzerland. Utilizing a case study methodology, information was collected from two main sources: (a) discussion groups with nurses and forensic pathologists and (b) a review of procedures and protocols. Following a critical content analysis, the roles and responsibilities of the forensic nurses were described and compared with the seven core competencies of advanced nursing practice as outlined by Hamric, Spross, and Hanson (2009). RESULTS: Advanced nursing practice competencies noted in the analysis included "direct clinical practice," "coaching and guidance," and "collaboration." The role of the nurse in terms of "consultation," "leadership," "ethics," and "research" was less evident in the analysis. DISCUSSION AND CONCLUSION: New forms of nursing are indeed practiced in the forensic clinical setting, and our findings suggest that nursing practice in this domain is following the footprints of an advanced nursing practice model. Further reflections are required to determine whether the role of the forensic nurse in Switzerland should be developed as a clinical nurse specialist or that of a nurse practitioner. PMID- 25144586 TI - Victimization and perpetration of sexual violence in college-aged men and women. AB - OBJECTIVE: Sexual violence is a significant public health issue on college campuses. Much of the research to date has focused on sexual violence victimization with less data on perpetration of sexual violence. This analysis describes sexual violence victimization and perpetration experiences in a sample of college students. METHODS: We sought to recruit college students attending three universities in the United States. A cross-sectional survey design was used to contact students through e-mail or voluntary gatherings. Each participant completed a questionnaire focused on experiences of sexual violence. RESULTS: A total of 1,978 students consented to participate in the study with 1,829 completing the questions related to victimization experiences and 1,479 completing the questions related to perpetration experiences. Thirty-eight percent (n = 700) of the sample (men and women) reported sexual violence victimization. Victimization among women and men was 42.6% and 28.7%, respectively. Almost 6% (n = 100) of the sample reported sexual violence perpetration. Men reported a higher rate of perpetration, 14.5% (n = 60), compared to women, 3.8% (n = 40). CONCLUSION: This study provides data on both victimization and perpetration experiences of college students. Both college men and women reported experiences of being victimized as well as perpetrating sexual violence. Understanding victimization and perpetration on college campuses will increase awareness, thus piercing the silence, of unwanted sexual experiences and help move college campuses toward a response. PMID- 25144587 TI - Children in foster care: what forensic nurses need to know. AB - Children living in foster care are a unique population with specialized healthcare needs. This article will assist forensic nurses and advanced practice forensic nurses, particularly those working in pediatrics, in understanding the needs of children in foster care and implementing a practice plan to better meet their healthcare needs. To that end, a basic understanding of the foster care system is crucial and involves an appreciation of the interface between the legal system and the child welfare system. Most important to providing care to children in foster care is a true understanding of trauma exposure and its potential effects on the lives of children: physically, developmentally, emotionally, and psychologically. This article will assist forensic nurses working with pediatric populations to more fully understand the needs of children in foster care and to develop innovative interventions to appropriately meet their unique needs. PMID- 25144588 TI - A Danish adaptation of the quality in psychiatric care-forensic in-patient questionnaire: psychometric properties and factor structure. AB - OBJECTIVE: The aims of this study were to adapt and evaluate the psychometric properties and factor structure of the Danish version of the Quality in Psychiatric Care-Forensic In-Patient (QPC-FIP) questionnaire. METHODS: A sample of 139 inpatients from 25 wards in Denmark who received care during 5 weeks in March and April 2012 participated in the study by completing the QPC-FIP instrument. RESULTS: Confirmatory factor analysis revealed that the factor structure of the Danish version was equivalent to that of the original Swedish QPC-FIP. The results indicate that the concept of quality of care expressed in the QPC-FIP is equivalent among forensic inpatients in nationally different healthcare systems and cultural contexts. CONCLUSION: The Danish version of QPC FIP is a reliable and valid measurement instrument recommended for use in evaluating quality of care in forensic inpatient care. PMID- 25144589 TI - Examining sexual assault survival of adult women: responses, mediators, and current theories. AB - The purpose of this article is to examine the state of the science of sexual assault research to direct future research in three key areas: responses, mediators, and current theory with a religious or spiritual focus addressing recovery. Three research questions guided the investigation of literature and the formation of this article: (a) What are common survivor responses to, and long term effects of, sexual assault?; (b) What are mediators for recovery after sexual assault?; and (c) What theory with a religious or spiritual focus exists to address recovery from sexual assault? This research identifies significant gaps in the literature underscoring the importance of future research that examines responses to and long-term effects of sexual assault, need for mediators during recovery, and need to develop theory using religious and spiritual tenets aiding in recovery from sexual assault. Further research is necessary to develop this science, expand understanding, and support sexual assault survivors on their recovery journey. PMID- 25144592 TI - C-H functionalization in the synthesis of amino acids and peptides. PMID- 25144593 TI - The effect of point-of-care ultrasonography on imaging studies in the medical ICU: a comparative study. AB - BACKGROUND: Point-of-care ultrasonography performed by frontline intensivists offers the possibility of reducing the use of traditional imaging in the medical ICU (MICU). We compared the use of traditional radiographic studies between two MICUs: one where point-of-care ultrasonography is used as a primary imaging modality, the other where it is used only for procedure guidance. METHODS: This study was a retrospective 3-month chart review comparing the use of chest radiographs, CT scans (chest and abdomen/pelvis), transthoracic echocardiography performed by the cardiology service, and DVT ultrasonography studies performed by the radiology service between two MICUs of similar size and acuity and staffing levels. RESULTS: Total number of admissions, patient demographics, and disease acuity were similar between MICUs. Comparing the non-point-of-care ultrasonography MICU with the point-of-care ultrasonography MICU, there were 3.75 +/- 4.6 vs 0.82 +/- 1.85 (P < .0001) chest radiographs per patient, 0.10 +/- 0.31 vs 0.04 +/- 0.20 (P = .0007) chest CT scans per patient, 0.17 +/- 0.44 vs 0.05 +/ 0.24 (P < .0001) abdomen/pelvis CT scans per patient, 0.20 +/- 0.47 vs 0.02 +/- 0.14 (P < .0001) radiology service-performed DVT studies per patient, and 0.18 +/ 0.40 vs 0.07 +/- 0.26 (P < .0001) cardiology service-performed transthoracic echocardiography studies per patient, respectively. CONCLUSIONS: The use of point of-care ultrasonography in an MICU is associated with a significant reduction in the number of imaging studies performed by the radiology and cardiology services. PMID- 25144591 TI - Triage: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: Pandemics and disasters can result in large numbers of critically ill or injured patients who may overwhelm available resources despite implementing surge-response strategies. If this occurs, critical care triage, which includes both prioritizing patients for care and rationing scarce resources, will be required. The suggestions in this chapter are important for all who are involved in large-scale pandemics or disasters with multiple critically ill or injured patients, including front-line clinicians, hospital administrators, and public health or government officials. METHODS: The Triage topic panel reviewed previous task force suggestions and the literature to identify 17 key questions for which specific literature searches were then conducted to identify studies upon which evidence-based recommendations could be made. No studies of sufficient quality were identified. Therefore, the panel developed expert opinion-based suggestions using a modified Delphi process. Suggestions from the previous task force that were not being updated were also included for validation by the expert panel. RESULTS: The suggestions from the task force outline the key principles upon which critical care triage should be based as well as a path for the development of the plans, processes, and infrastructure required. This article provides 11 suggestions regarding the principles upon which critical care triage should be based and policies to guide critical care triage. CONCLUSIONS: Ethical and efficient critical care triage is a complex process that requires significant planning and preparation. At present, the prognostic tools required to produce an effective decision support system (triage protocol) as well as the infrastructure, processes, legal protections, and training are largely lacking in most jurisdictions. Therefore, critical care triage should be a last resort after mass critical care surge strategies. PMID- 25144595 TI - Bone densitometry in children and adolescents. AB - PURPOSE OF REVIEW: Abnormalities in bone health are increasingly recognized in the pediatric population. Although the methodologies for assessing bone mineral density were originally developed for adults, great strides have been made in recent years, improving their applicability to children. Understanding these technologies, their interpretation, utility, and limitations is critical when assessing a child or adolescent with a suspected abnormality in bone mineral density. RECENT FINDINGS: Improved normative databases that address some of the confounding variables in the growing and maturing child have solidified dual energy X-ray absorptiometry as the preferred method for the assessment of bone mineral density in children. Consensus statements by expert panels now provide specific guidance to clinicians seeking to evaluate children with fractures or at risk for fractures. Although still primarily a research tool, continued development of quantitative computed tomography applications in pediatrics suggests there may be a complementary role for clinical use in the future. SUMMARY: In the child or adolescent with a significant fracture history or a potential for fractures because of an underlying cause, clinicians now have guidelines and normative data to better focus their evaluation. Likewise, researchers can use this information to improve clinical trial design and interpretation of results. PMID- 25144596 TI - Precocious puberty. AB - PURPOSE OF REVIEW: Precocious puberty continues to elicit great interest and concern among medical practitioners, as well as the public. RECENT FINDINGS: Studies have elucidated neural regulation of puberty by kisspeptin, neurokinin B, and other factors. Cohort studies from the North America and Europe suggest that the age of thelarche may be earlier than determined 2 decades ago, and menarche may be slightly earlier, but the causes are unclear. Long-term outcomes of gonadotropin-releasing hormone analog therapy demonstrate increases in final height in the youngest treated patients, with no apparent adverse bone or reproductive consequences. SUMMARY: Although the appropriate threshold age of onset of central puberty remains uncertain, gonadotropin-releasing hormone analog therapy is well tolerated and effective in suppressing luteinizing hormone pulses and ovarian activity. PMID- 25144594 TI - Histone deacetylase 3 promotes RCAN1 stability and nuclear translocation. AB - Regulator of calcineurin 1 (RCAN1; also referred as DSCR1 or MCIP1) is located in close proximity to a Down syndrome critical region of human chromosome 21. Although RCAN1 is an endogenous inhibitor of calcineurin signaling that controls lymphocyte activation, apoptosis, heart development, skeletal muscle differentiation, and cardiac function, it is not yet clear whether RCAN1 might be involved in other cellular activities. In this study, we explored the extra functional roles of RCAN1 by searching for novel RCAN1-binding partners. Using a yeast two-hybrid assay, we found that RCAN1 (RCAN1-1S) interacts with histone deacetylase 3 (HDAC3) in mammalian cells. We also demonstrate that HDAC3 deacetylates RCAN1. In addition, HDAC3 increases RCAN1 protein stability by inhibiting its poly-ubiquitination. Furthermore, HDAC3 promotes RCAN1 nuclear translocation. These data suggest that HDAC3, a new binding regulator of RCAN1, affects the protein stability and intracellular localization of RCAN1. PMID- 25144597 TI - Alterations in neuromuscular control at the knee in individuals with chronic ankle instability. AB - CONTEXT: Few authors have assessed neuromuscular knee-stabilization strategies in individuals with chronic ankle instability (CAI) during functional activities. OBJECTIVE: To investigate the influence of CAI on neuromuscular characteristics around the knee during a stop-jump task. DESIGN: Case-control study. SETTING: Research laboratory. Participants or Other Participants: A total of 19 participants with self-reported unilateral CAI and 19 healthy control participants volunteered for this study. INTERVENTION(S): Participants performed double-legged, vertical stop-jump tasks onto a force plate, and we measured muscle activation around the knee of each limb. MAIN OUTCOME MEASURE(S): We calculated the integrated electromyography for the vastus medialis oblique, vastus lateralis, medial hamstrings, and lateral hamstrings muscles during the 100 ms before and after initial foot contacts with the force plate and normalized by the ensemble peak electromyographic value. Knee sagittal-plane kinematics were also analyzed during a stop-jump task. RESULTS: Compared with control participants, the CAI group demonstrated greater prelanding integrated electromyographic activity of the vastus medialis oblique (CAI = 52.28 +/- 11.25%.ms, control = 43.90 +/- 10.13%.ms, t36 = 2.41, P = .021, effect size = 0.78, 95% confidence interval = 0.11, 1.43) and less knee-flexion angle at the point of initial foot contact (CAI = 7.81 degrees +/- 8.27 degrees , control = 14.09 degrees +/- 8.7 degrees , t36 = -2.28, P = .029, effect size = -0.74, 95% confidence interval = -1.38, -0.07) and at 100 ms post-initial foot contact (CAI = 51.36 degrees +/- 5.29 degrees , control = 58.66 degrees +/- 7.66 degrees , t36 = -3.42, P = .002, effect size = -1.11, 95% confidence interval = -1.77, 0.40). No significant results were noted for the other electromyographic measures. CONCLUSIONS: We found altered feed-forward patterns of the vastus medialis oblique and altered postlanding knee sagittal-plane kinematics in the CAI group. These observations may provide insight regarding sensorimotor characteristics that may be associated with CAI. PMID- 25144598 TI - Importance of airflow for physiologic and ergogenic effects of precooling. AB - CONTEXT: Cooling the body before exercise (precooling) has been studied as an ergogenic aid for many thermal conditions; however, airflow accompanying exercise is seldom reported. OBJECTIVE: To determine whether the physiologic and ergogenic benefits of precooling before endurance exercise may be negated with semirealistic airflow in hot conditions. DESIGN: Crossover study. SETTING: Climate-controlled chamber in a research laboratory. PATIENTS OR OTHER PARTICIPANTS: Ten fit, healthy cyclists. INTERVENTION(S): After a familiarization trial, participants completed 4 randomized, counterbalanced sessions consisting of no precooling versus precooling and no fan airflow versus airflow (~4.8 m/s) during exercise. Precooling was via chest-deep immersion (~24 degrees C) for 1 hour or until core temperature dropped 0.5 degrees C. Participants then cycled at 95% ventilatory threshold in a hot environment (temperature = 30 degrees C, relative humidity = 50%) until volitional exhaustion, core temperature reached >39.5 degrees C, or heart rate reached >95% of maximum. MAIN OUTCOME MEASURE(S): Thermal strain was assessed via core temperature (esophageal and rectal thermistors) and mean skin temperature (thermistors at 10 sites) and cardiovascular strain via heart rate and ratings of perceived exertion. RESULTS: Endurance time (28 +/- 12 minutes without precooling or airflow) increased by 30 +/- 23 minutes with airflow (~109%; 95% confidence interval = 12, 45 minutes; P < .001) and by 16 +/- 15 minutes with precooling (~61%; 95% confidence interval = 4, 25 minutes; P = .013), but it was not further extended when the strategies were combined (29 +/- 21 minutes longer than control). During cycling without precooling or airflow, mean core and skin temperatures were higher than in all other trials. Precooling reduced heart rate by 7-11 beats/min during the first 5 minutes of exercise, but this attenuation ended by 15 minutes. CONCLUSIONS: Most laboratory-based precooling studies have (inadvertently) overestimated the extent of the physiologic and ergogenic benefits for typical athlete-endurance situations. Precooling increases work capacity effectively when airflow is restricted but may have little or no benefit when airflow is present. PMID- 25144600 TI - Calibration of blood pressure data after replacement of the standard mercury sphygmomanometer by an oscillometric device and concurrent change of cuffs. AB - Oscillometric blood pressure (BP) measurement devices are increasingly replacing standard mercury sphygmomanometers and generalizability of validation studies to other environments, for example, national survey environments, is assumed. We compared BP measurements according to two highly standardized German national survey BP protocols: a standard mercury sphygmomanometer and an oscillometric device, Datascope Accutorr Plus, each with specific manufacturer-provided cuffs and cuff-selection rules. A sample of 105 adults were subjected to alternate same arm BP measurements according to the principles of the International Protocol revision 2010 for the validation of BP-measuring devices in adults of the European Society of Hypertension. In all, 315 BP measurement pairs were obtained. The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were higher by the standard mercury old protocol and increased with BP, age, and pulse pressure, and were associated with the ratios of the cuff width to the arm circumference. The mean systolic difference (datascope new protocol-standard mercury old protocol) in participants with old protocol: for SBP<120 was -3.5 +/- 4.9 mmHg (n=162), for SBP 120-139 (n=108) was -6.4 +/- 5.8 mmHg, and for SBP >= 140 (n=45) was -11.9 +/- 7.2 mmHg. For DBP<80/80-89/>= 90 in 230/67/18 participants, the differences were -1.9 +/- 5.0/-6.8 +/- 5.9/-7.6 +/- 5.2 mmHg. A calibration formula for SBP derived from linear regression modeling includes SBP, sex, age, pulse pressure, and the difference in the cuff-width to arm circumference ratios for the two devices (for DBP without age). Our study suggests that even in a highly standardized national survey environment, reported agreement from validation studies may not be replicable and comparisons in the specific clinical or research setting can be useful before replacing the mercury device completely. PMID- 25144599 TI - Altered knee and ankle kinematics during squatting in those with limited weight bearing-lunge ankle-dorsiflexion range of motion. AB - CONTEXT: Ankle-dorsiflexion (DF) range of motion (ROM) may influence movement variables that are known to affect anterior cruciate ligament loading, such as knee valgus and knee flexion. To our knowledge, researchers have not studied individuals with limited or normal ankle DF-ROM to investigate the relationship between those factors and the lower extremity movement patterns associated with anterior cruciate ligament injury. OBJECTIVE: To determine, using 2 different measurement techniques, whether knee- and ankle-joint kinematics differ between participants with limited and normal ankle DF-ROM. DESIGN: Cross-sectional study. SETTING: Sports medicine research laboratory. PATIENTS OR OTHER PARTICIPANTS: Forty physically active adults (20 with limited ankle DF-ROM, 20 with normal ankle DF-ROM). MAIN OUTCOME MEASURE(S): Ankle DF-ROM was assessed using 2 techniques: (1) nonweight-bearing ankle DF-ROM with the knee straight, and (2) weight-bearing lunge (WBL). Knee flexion, knee valgus-varus, knee internal external rotation, and ankle DF displacements were assessed during the overhead squat, single-legged squat, and jump-landing tasks. Separate 1-way analyses of variance were performed to determine whether differences in knee- and ankle-joint kinematics existed between the normal and limited groups for each assessment. RESULTS: We observed no differences between the normal and limited groups when classifying groups based on nonweight-bearing passive-ankle DF-ROM. However, individuals with greater ankle DF-ROM during the WBL displayed greater knee flexion and ankle-DF displacement and peak knee flexion during the overhead-squat and single-legged squat tasks. In addition, those individuals also demonstrated greater knee-varus displacement during the single-legged squat. CONCLUSIONS: Greater ankle DF-ROM assessed during the WBL was associated with greater knee flexion and ankle-DF displacement during both squatting tasks as well as greater knee-varus displacement during the single-legged squat. Assessment of ankle DF ROM using the WBL provided important insight into compensatory movement patterns during squatting, whereas nonweight-bearing passive ankle DF-ROM did not. Improving ankle DF-ROM during the WBL may be an important intervention for altering high-risk movement patterns commonly associated with noncontact anterior cruciate ligament injury. PMID- 25144601 TI - Binding to semiflexible polymers: a novel method to control the structures of small numbers of building blocks. AB - Through the molecular dynamics simulation method, we demonstrate that long semi flexible polymer chains can serve as an effective soft elastic medium for manipulating the ordered structures of small numbers of building blocks, which can be easily controlled by the chain bending stiffness. For two spherical particles in a polymer-particle mixture, three types of local organization are identified: monomer level tight particle bridging, direct contact aggregation, and dispersion. For small numbers of spherical particles in a polymer-particle mixture, the ordered structures of particles, such as spherical and linear particle aggregations, depend mainly on chain bending stiffness. For non spherical building blocks, the relative orientations of neighboring building blocks are also strongly affected by chain bending stiffness. These results can help us to understand the complexity of the self-assembly of small numbers of building blocks in polymer-particle mixtures and the gene activity in living cells, as well as to construct novel materials in the nanotechnology field. PMID- 25144602 TI - Non-covalent double functionalization of carbon nanotubes with a NADH oxidation Ru(II)-based molecular catalyst and a NAD-dependent glucose dehydrogenase. AB - We report the double functionalization of multiwalled carbon nanotube electrodes by two functional pyrene molecules. In combination, an immobilized Ru(II)-based NADH oxidation catalyst and glucose dehydrogenase achieve highly efficient glucose oxidation with low overpotential of -0.10 V and high current densities of 6 mA cm(-2). PMID- 25144603 TI - Factors determining success of awake and asleep magnetic resonance imaging scans in nonsedated children. AB - Effective techniques that allow children to complete magnetic resonance imaging (MRI) scans without sedation are high priority for the imaging community. We used behavioral approaches to scan 64 sleeping infants and toddlers younger than 4 years, and 156 awake children aged 2.5 to 18 years, for a neuroimaging research protocol. Infants and their families participated in a desensitization protocol for several days, then scanning was performed at the child's bedtime during natural sleep. For awake young children, a behavioral protocol was used that included tangible reinforcers, exploration of the scanner environment and a brief practice session. Two scan sessions were targeted for awake children. Success rates by participant were quantified in terms of the proportion of requisite scans in each session that were successfully acquired. The average success rate in sleeping infants and toddlers was 0.461. For awake children aged 2.5 to 6 years, success rates for each session were 0.739 and 0.847. For children aged 7 years and older, success rates were over 0.900 for both the sessions. Overall, though success was lower later in a scan session for both sleeping infants and awake young children, our results demonstrate that it is feasible to collect high quality imaging data using standard imaging sequences in infants and children without sedation. PMID- 25144605 TI - Thermographic characterization of masticatory muscle regions in volunteers with and without myogenous temporomandibular disorder: preliminary results. AB - OBJECTIVES: This study aims to conduct a non-invasive measurement of the cutaneous temperature of selected masticatory muscle regions of volunteers with and without myogenous temporomandibular disorder (TMD), using infrared thermography. METHODS: 23 females (10 myogenous TMD volunteers and 13 controls) were recruited and studied. The temperature at the surface of the facial area over the anterior temporalis and masseter muscles was assessed by medical thermography, using regional lateral views and clinical examination. RESULTS: The temperature levels measured at the masseter and anterior temporalis muscle regions in myogenous TMD volunteers (32.85 +/- 0.85 and 34.37 +/- 0.64 oC, respectively) were significantly lower (p < 0.05) than those measured in controls (33.49 +/- 0.92 and 34.78 +/- 0.44 oC, respectively). Medical infrared imaging indicated a mean difference of 1.4 oC between the masseter and anterior temporalis regions. Analysis of the comparison between the absolute and normalized mean temperatures was performed using the pairwise comparison of receiver operating characteristic curves, and no statistically significant difference was observed (p > 0.05). The sensitivity and specificity of the thermographic assessment for the masseter region was of 70% and 73%, respectively and for the anterior temporalis region was of 80% and 62%, respectively. CONCLUSIONS: This method of evaluating masticatory muscle regions of this preliminary study seems to indicate that it can be used as an aid in complimentary diagnosing of TMDs. PMID- 25144604 TI - Molecular epidemiology of reemergent rabies in Yunnan Province, southwestern China. AB - Yunnan Province in China borders 3 countries (Vietnam, Laos, and Myanmar) in Southeast Asia. In the 1980s, a large-scale rabies epidemic occurred in this province, which subsided by the late 1990s. However, 3 human cases of rabies in 2000 indicated reemergence of the disease in 1 county. In 2012, rabies was detected in 77 counties; 663 persons died of rabies during this new epidemic. Fifty two rabies virus strains obtained during 2008-2012 were identified and analyzed phylogenetically by sequencing the nucleoprotein gene. Of the 4 clades identified, clades YN-A and YN-C were closely related to strains from neighboring provinces, and clade YN-B was closely related to strains from Southeast Asia, but formed a distinct branch. Rabies virus diversity might be attributed to dog movements among counties, provinces, and neighboring countries. These findings suggest that Yunnan Province is a focal point for spread of rabies between Southeast Asia and China. PMID- 25144607 TI - Nutrient metal elements in plants. AB - Plants need many different metal elements for growth, development and reproduction, which must be mobilized from the soil matrix and absorbed by the roots as metal ions. Once taken up by the roots, metal ions are allocated to different parts of the plant by the vascular tissues. Metals are naturally present in the soil, but human activities, ranging from mining and agriculture to sewage processing and heavy industry, have increased the amount of metal pollution in the environment. Plants are challenged by environmental metal ion concentrations that fluctuate from low to high toxic levels, and have therefore evolved mechanisms to cope with such phenomena. In this review, we focus on recent data that provide insight into the molecular mechanisms of metal absorption and transport by plants, also considering the effect of metal deficiency and toxicity. We also highlight the positive effects of some non essential metals on plant fitness. PMID- 25144608 TI - The effect of pi contacts between metal ions and fluorophores on the fluorescence of PET sensors: implications for sensor design for cations and anions. AB - The idea that M...C pi contacts between diamagnetic heavy metal ions such as Pb(II), Ag(I), Pd(II), or Hg(II) and the anthracenyl fluorophore of adpa ((N-(9 anthracenylmethyl)-N-(2-pyridinylmethyl)-2-pyridinemethanamine) are responsible for quenching the fluorescence of the complexes of these metal ions with adpa is explored crystallographically. The structures of [Pb(adpa)(NO3)2] (1), [Ag(adpa)NO3] (2), [Pd(adpa)NO3]NO3 (3), [Zn(adpa)(NO3)2] (4), and [Cd(adpa)Br2] (5) are reported. The pi contacts with the fluorophore are for 1 are a Pb...C pi contact of 3.178 A; for 2, an Ag...C pi contact of 3.016 A; and for 3, a Pd...C pi contact of 2.954 A on the axial site of the Pd(II) ion. The Zn(II) ion in 4 has no Zn...C pi contact, with the anthracenyl fluorophore rotated completely away from the Zn(II) ion. These structures confirm that in the Pb(II), Ag(I), and Pd(II) complexes of adpa, which experience strong quenching of fluorescence, there are strong M...C pi contacts, as expected if it is the pi contacts that quench fluorescence. In contrast, for the Zn(II) adpa complex, which forms no pi contact, there is a strong increase in fluorescence intensity. The structure of 5 shows a long Cd...C pi contact at 3.369 A, in contrast to a previously reported structure with two coordinated nitrates where the Cd...C pi contact is 3.097 A. The long Cd...C pi contact in [Cd(adpa)Br2] suggests how coordination of Br(-), as well as other more covalently bound ligands such as Cl(-), SCN(-), and S2O3(2 ), cause an increase in fluorescence intensity, reported for the Cd(II)adpa complex in 50% CH3OH/H2O. Coordination of covalently bound ligands to the Cd(II) weakens the Cd...C pi contact and so enhances fluorescence, whereas more ionically bound ligands such as SO4(2-), NO3(-), or H2O produce a strong Cd...C pi contact and weakened fluorescence. Complexes of the Cd(II)/adpa type may form the basis for a new type of anion/small molecule sensor. The tendency of metal ions to form pi contacts with aromatic groups is analyzed in terms of the frequency of occurrence of pi contacted structures in the literature, as well as by DFT calculations on the adpa complexes. PMID- 25144606 TI - Mechanisms of carbon nanotube aggregation and the reversion of carbon nanotube aggregates in aqueous medium. AB - Single-walled carbon nanotubes (SWCNTs) dispersed in aqueous medium have many potential applications in chemistry, biology, and medicine. Reversible aggregation of SWCNTs dispersed in water has been frequently reported, but the mechanisms behind are not well understood. Here we show that SWCNTs dispersed into aqueous medium assisted by various charged molecules can be reversibly aggregated by a variety of electrolytes with two distinct mechanisms. Direct binding of counterions to SWCNTs leads to aggregation when the surface charge is neutralized from 74 to 86%. This aggregation is driven by electrostatic instead of van der Waals interactions, thus showing similarity to that of DNA condensation induced by multivalent cations. Sequestration of counterions by chelating reagents leads to the redispersion of SWCNT aggregates. In contrast to various metal ions, polyelectrolytes have the unique ability to induce SWCNT aggregation by bridging between individual SWCNTs. Aggregation through the latter mechanism can be engineered to be reversible by exploiting various mechanisms of chain breaking, including reduction of disulfide bond in the polymer chain, and the cleavage action of proteolytic enzymes. These findings clarify the mechanisms of SWCNT aggregation, and have broad implications in various applications of SWCNTs in water. PMID- 25144610 TI - The use of many-body expansions and geometry optimizations in fragment-based methods. AB - Conspectus Chemists routinely work with complex molecular systems: solutions, biochemical molecules, and amorphous and composite materials provide some typical examples. The questions one often asks are what are the driving forces for a chemical phenomenon? How reasonable are our views of chemical systems in terms of subunits, such as functional groups and individual molecules? How can one quantify the difference in physicochemical properties of functional units found in a different chemical environment? Are various effects on functional units in molecular systems additive? Can they be represented by pairwise potentials? Are there effects that cannot be represented in a simple picture of pairwise interactions? How can we obtain quantitative values for these effects? Many of these questions can be formulated in the language of many-body effects. They quantify the properties of subunits (fragments), referred to as one-body properties, pairwise interactions (two-body properties), couplings of two-body interactions described by three-body properties, and so on. By introducing the notion of fragments in the framework of quantum chemistry, one obtains two immense benefits: (a) chemists can finally relate to quantum chemistry, which now speaks their language, by discussing chemically interesting subunits and their interactions and (b) calculations become much faster due to a reduced computational scaling. For instance, the somewhat academic sounding question of the importance of three-body effects in water clusters is actually another way of asking how two hydrogen bonds affect each other, when they involve three water molecules. One aspect of this is the many-body charge transfer (CT), because the charge transfers in the two hydrogen bonds are coupled to each other (not independent). In this work, we provide a generalized view on the use of many-body expansions in fragment-based methods, focusing on the general aspects of the property expansion and a contraction of a many-body expansion in a formally two body series, as exemplified in the development of the fragment molecular orbital (FMO) method. Fragment-based methods have been very successful in delivering the properties of fragments, as well as the fragment interactions, providing insights into complex chemical processes in large molecular systems. We briefly review geometry optimizations performed with fragment-based methods and present an efficient geometry optimization method based on the combination of FMO with molecular mechanics (MM), applied to the complex of a subunit of protein kinase 2 (CK2) with a ligand. FMO results are discussed in comparison with experimental and MM-optimized structures. PMID- 25144611 TI - Metformin and gynecologic cancers. AB - IMPORTANCE: The obese population in the United States is reaching epic proportions, and obesity is linked to an increased risk for several cancers including gynecologic cancers. Obesity is not only a risk factor but also a marker of poor prognosis. It is crucial to develop novel treatment strategies to target this population. Metformin is a biguanide drug, typically used for diabetes treatment, currently being studied to evaluate its role in the treatment and prevention of gynecologic cancers. OBJECTIVE: The aim of this study was to review the underlying biologic mechanisms of metformin's antitumorigenic effects. We assessed the epidemiologic and preclinical data that support the use of metformin in patients with endometrial and ovarian cancer. Finally, we reviewed current clinical trials that incorporate metformin as a prevention or treatment strategy for gynecologic cancers. EVIDENCE ACQUISITION: A thorough search of PubMed for all current literature was performed. All preclinical, clinical, and epidemiologic reviews were evaluated across all cancers, with a focus on gynecologic cancer. RESULTS: The preclinical, epidemiologic, and clinical data evaluated in this review are strongly supportive of the use of metformin for the prevention and treatment of gynecologic cancer. On the basis of these data, centers are currently enrolling for clinical trials using metformin in patients diagnosed with gynecologic malignancies. CONCLUSIONS AND RELEVANCE: The data supporting the use of metformin in the prevention and treatment of cancers are building, including that of endometrial and ovarian cancer. The association between obesity, insulin resistance, as well as increased risk and poor outcomes in endometrial and ovarian cancer patients makes metformin an attractive agent for the prevention and treatment of these diseases. PMID- 25144609 TI - Commensal-pathogen interactions in the intestinal tract: lactobacilli promote infection with, and are promoted by, helminth parasites. AB - The intestinal microbiota are pivotal in determining the developmental, metabolic and immunological status of the mammalian host. However, the intestinal tract may also accommodate pathogenic organisms, including helminth parasites which are highly prevalent in most tropical countries. Both microbes and helminths must evade or manipulate the host immune system to reside in the intestinal environment, yet whether they influence each other's persistence in the host remains unknown. We now show that abundance of Lactobacillus bacteria correlates positively with infection with the mouse intestinal nematode parasite, Heligmosomoides polygyrus, as well as with heightened regulatory T cell (Treg) and Th17 responses. Moreover, H. polygyrus raises Lactobacillus species abundance in the duodenum of C57BL/6 mice, which are highly susceptible to H. polygyrus infection, but not in BALB/c mice, which are relatively resistant. Sequencing of samples at the bacterial gyrB locus identified the principal Lactobacillus species as L. taiwanensis, a previously characterized rodent commensal. Experimental administration of L. taiwanensis to BALB/c mice elevates regulatory T cell frequencies and results in greater helminth establishment, demonstrating a causal relationship in which commensal bacteria promote infection with an intestinal parasite and implicating a bacterially-induced expansion of Tregs as a mechanism of greater helminth susceptibility. The discovery of this tripartite interaction between host, bacteria and parasite has important implications for both antibiotic and anthelmintic use in endemic human populations. PMID- 25144612 TI - More than interpreters needed: the specialized care of the immigrant pregnant patient. AB - The immigrant pregnant woman faces unique challenges. This article provides an overview of these challenges and interventions to maximize health outcomes for the immigrant pregnant woman. A patient's immigrant status may impact her social stability and access to health care. Lack of familiarity with western health care, health financing, and the English language can create significant barriers. In addition, providers must remember to evaluate the immigrant pregnant woman for underlying health conditions that may be present including infectious diseases endemic to their country of origin and chronic diseases or cervical center as yet unidentified because of lack of previous health care screening. Female genital modification found in some immigrant populations can be associated with poorer obstetric outcomes and should be documented and addressed. Finally, some immigrant populations have a high incidence of past severe trauma and need additional psychiatric evaluation and support. PMID- 25144613 TI - Surgical site infections in gynecology. AB - IMPORTANCE: Surgical site infections (SSIs) are preventable, yet nearly 2% of all surgical cases are complicated by an SSI. Each SSI increases the cost of a postoperative hospital stay by more than $10,000. Thus, SSI prevention has become the focus of health care systems and hospitals because it is a reducible health care cost. OBJECTIVE: The objective of this review was to better understand the guidelines and recommendations related to the prevention, diagnosis, and management of SSIs. EVIDENCE ACQUISITION: This study is a thorough review of the most up-to-date peer-reviewed articles and review articles as well as guidelines and recommendations of various professional organizations including the US Centers for Disease Control and Prevention and the American College of Obstetrics and Gynecology. RESULTS: A review of the literature has identified several evidence-based recommendations that physicians should adhere to in an effort to decrease the incidence of SSIs. CONCLUSIONS AND RELEVANCE: By adhering to clinical recommendations and evidence, we can correctly prevent, diagnose, and treat SSIs. In turn, this will improve health outcomes and decrease health care related costs, thus increasing the value of health care that we provide to patients. Furthermore, we can gain improvements in the quality measures used by hospitals and insurers. PMID- 25144614 TI - Metallodithiolates as ligands to dinitrosyl iron complexes: toward the understanding of structures, equilibria, and spin coupling. AB - Metallodithiolate ligands are used to design heterobimetallic complexes by adduct formation through S-based reactivity. Such adducts of dinitrosyl iron were synthesized with two metalloligands, namely, Ni(bme-daco) and V=O(bme-daco) (bme daco = bismercaptoethane diazacyclooctane), and, for comparison, an N heterocyclic carbene, namely, 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (Imes), by cleavage of the (MU-I)2[Fe(NO)2]2 dimer of electronic configuration {Fe(NO)2}(9) (Enemark-Feltham notation). With Fe(NO)2I as Lewis acid acceptor, 1:1 adducts resulted for both the IMes.Fe(NO)2I, complex 2, and V=O(bme daco).Fe(NO)2I, complex 4. The NiN2S2 demonstrated binding capability at both thiolates, with two Fe(NO)2I addenda positioned transoid across the NiN2S2 square plane, Ni(bme-daco).2(Fe(NO)2I), complex 3. Enhanced binding ability was realized for the dianionic vanadyl dithiolate complex, [Et4N]2[V=O(ema)], (ema = N,N' ethylenebis(2-mercaptoacetamide)), which, unlike the neutral (V=O)N2S2, demonstrated reactivity with the labile tungsten carbonyl complex, cis W(CO)4(pip)2, (pip = piperidine), yielding [Et4N]2[V=O(ema)W(CO)4], complex 1, whose nu(CO) IR values indicated the dianionic vanadyl metalloligand to be of similar donor ability to the neutral NiN2S2 ligands. The solid-state molecular structures of 1-4 were determined by X-ray diffraction analyses. Electron paramagnetic resonance (EPR) measurements characterize the {Fe(NO)2}(9) complexes in solution, illustrating superhyperfine coupling via the (127)I to the unpaired electron on iron for complex 2. The EPR characterizations of 3 [Ni(bme daco).2(Fe(NO)2I)] and 4 [V=O(bme-daco).Fe(NO)2I] indicate these complexes are EPR silent, likely due to strong coupling between paramagnetic centers. Within samples of complex 4, individual paramagnetic centers with localized superhyperfine coupling from the (51)V and (127)I are observed in a 3:1 ratio, respectively. However, spin quantitation reveals that these species represent a minor fraction (<10%) of the total complex and thus likely represent disassociated paramagnetic sites. Computational studies corroborated the EPR assignments as well as the experimentally observed stability/instability of the heterobimetallic DNIC complexes. PMID- 25144615 TI - Development of a new generation of high-resolution anatomical models for medical device evaluation: the Virtual Population 3.0. AB - The Virtual Family computational whole-body anatomical human models were originally developed for electromagnetic (EM) exposure evaluations, in particular to study how absorption of radiofrequency radiation from external sources depends on anatomy. However, the models immediately garnered much broader interest and are now applied by over 300 research groups, many from medical applications research fields. In a first step, the Virtual Family was expanded to the Virtual Population to provide considerably broader population coverage with the inclusion of models of both sexes ranging in age from 5 to 84 years old. Although these models have proven to be invaluable for EM dosimetry, it became evident that significantly enhanced models are needed for reliable effectiveness and safety evaluations of diagnostic and therapeutic applications, including medical implants safety. This paper describes the research and development performed to obtain anatomical models that meet the requirements necessary for medical implant safety assessment applications. These include implementation of quality control procedures, re-segmentation at higher resolution, more-consistent tissue assignments, enhanced surface processing and numerous anatomical refinements. Several tools were developed to enhance the functionality of the models, including discretization tools, posing tools to expand the posture space covered, and multiple morphing tools, e.g., to develop pathological models or variations of existing ones. A comprehensive tissue properties database was compiled to complement the library of models. The results are a set of anatomically independent, accurate, and detailed models with smooth, yet feature-rich and topologically conforming surfaces. The models are therefore suited for the creation of unstructured meshes, and the possible applications of the models are extended to a wider range of solvers and physics. The impact of these improvements is shown for the MRI exposure of an adult woman with an orthopedic spinal implant. Future developments include the functionalization of the models for specific physical and physiological modeling tasks. PMID- 25144617 TI - Determination of methyl isocyanate in outdoor residential air near metam-sodium soil fumigations. AB - The soil fumigant metam-sodium (CH3NHCS2Na) produces the bioactive respiratory irritant methyl isothiocyanate (MITC). Recent laboratory gas-phase oxidative studies indicate that MITC rapidly transforms to the more toxic methyl isocyanate (MIC) in the lower atmosphere. Inhalation exposure risks from MITC plus MIC may therefore be an occupational worker and/or bystander health concern. To address this concern, MIC was monitored, along with MITC, in outdoor residential air in Washington state during the peak fall metam fumigation season. XAD-7 cartridges, coated with 1-(2-pyridyl)piperazine, were developed to retain MIC as its stable substituted urea derivative. Of the 68 residential air measurements of MIC, 15 (22%) were observed to be above the California Environmental Protection Agency's chronic inhalation reference level of 1 MUg/m(3), with an observed maximum MIC air concentration of 4.4 MUg/m(3). This study indicates MIC air concentrations can be anticipated along with MITC in residential air where seasonal metam soil fumigant applications occur. PMID- 25144616 TI - Defining the estimated core genome of bacterial populations using a Bayesian decision model. AB - The bacterial core genome is of intense interest and the volume of whole genome sequence data in the public domain available to investigate it has increased dramatically. The aim of our study was to develop a model to estimate the bacterial core genome from next-generation whole genome sequencing data and use this model to identify novel genes associated with important biological functions. Five bacterial datasets were analysed, comprising 2096 genomes in total. We developed a Bayesian decision model to estimate the number of core genes, calculated pairwise evolutionary distances (p-distances) based on nucleotide sequence diversity, and plotted the median p-distance for each core gene relative to its genome location. We designed visually-informative genome diagrams to depict areas of interest in genomes. Case studies demonstrated how the model could identify areas for further study, e.g. 25% of the core genes with higher sequence diversity in the Campylobacter jejuni and Neisseria meningitidis genomes encoded hypothetical proteins. The core gene with the highest p-distance value in C. jejuni was annotated in the reference genome as a putative hydrolase, but further work revealed that it shared sequence homology with beta lactamase/metallo-beta-lactamases (enzymes that provide resistance to a range of broad-spectrum antibiotics) and thioredoxin reductase genes (which reduce oxidative stress and are essential for DNA replication) in other C. jejuni genomes. Our Bayesian model of estimating the core genome is principled, easy to use and can be applied to large genome datasets. This study also highlighted the lack of knowledge currently available for many core genes in bacterial genomes of significant global public health importance. PMID- 25144619 TI - Antimicrobial activity of Antrodia camphorata extracts against oral bacteria. AB - Antrodia camphorata (A. camphorata) is a unique, endemic and extremely rare mushroom species native to Taiwan, and both crude extracts of and purified chemical compounds from A. camphorata have been reported to have a variety of significant beneficial effects, such as anti-tumor and anti-inflammatory activity. However, reports on the effects of A. camphorata against dental pathogens have been limited. Oral health is now recognized as important for overall general health, including conditions such as dental caries, periodontal disease and rheumatoid arthritis. Streptococcus mutans (S. mutans) and Porphyromonas gingivalis (P. gingivalis) are the most common bacteria associated with dental plaque and periodontopathic diseases, respectively. Thus, our study examined the ability of five various crude extracts of A. camphorata to inhibit the growth of dental bacteria and anti-adherence in vitro. Among the extracts, the ethanol, ethyl acetate and chloroform extracts exhibited the lowest MICs against P. gingivalis and S. mutans (MIC = 4~16 ug/mL). The MIC of the aqueous extract was greater than 2048 ug/mL against both P. gingivalis and S. mutans. In vitro adherence of S. mutans was significantly inhibited by the addition of either the ethyl acetate extract or chloroform extract (MIC = 16~24 ug/mL), while the ethanol extract (MIC = 32~64 ug/mL) exhibited moderate inhibitory activity. Based on the result of this study, the ethyl acetate and chloroform extracts of A. camphorata may be good candidates for oral hygiene agents to control dental caries and periodontopathic conditions. PMID- 25144618 TI - FTO is a relevant factor for the development of the metabolic syndrome in mice. AB - The metabolic syndrome is a worldwide problem mainly caused by obesity. FTO was found to be a obesity-risk gene in humans and FTO deficiency in mice led to reduction in adipose tissue. Thus, FTO is an important factor for the development of obesity. Leptin-deficient mice are a well characterized model for analysing the metabolic syndrome. To determine the relevance of FTO for the development of the metabolic syndrome we analysed different parameters in combined homozygous deficient mice (Lep(ob/ob);Fto(-/-)). Lep(ob/ob);Fto(-/-) mice showed an improvement in analysed hallmarks of the metabolic syndrome in comparison to leptin-deficient mice wild type or heterozygous for Fto. Lep(ob/ob);Fto(-/-) mice did not develop hyperglycaemia and showed an improved glucose tolerance. Furthermore, extension of beta-cell mass was prevented in Lep(ob/ob);Fto(-/-)mice and accumulation of ectopic fat in the liver was reduced. In conclusion this study demonstrates that FTO deficiency has a protective effect not only on the development of obesity but also on the metabolic syndrome. Thus, FTO plays an important role in the development of metabolic disorders and is an interesting target for therapeutic agents. PMID- 25144620 TI - Cinchona alkaloid squaramide/AgOAc cooperatively catalyzed diastereo- and enantioselective Mannich/cyclization cascade reaction of isocyanoacetates and cyclic trifluoromethyl ketimines. AB - An efficient diastereo- and enantioselective Mannich-type/cyclization cascade reaction of alpha-substituted isocyanoacetates and cyclic trifluoromethyl ketimines cooperatively catalyzed by cinchona alkaloid-derived multi-hydrogen bonding donor squaramide and AgOAc has been investigated, affording the optically active trifluoromethyl-substituted tetrahydroimidazo[1,5-c]quinazoline derivatives in excellent yields (up to 99%) and good to excellent stereoselectivities (up to >15:1 dr, up to 98% ee) under mild conditions. PMID- 25144622 TI - Synthetic gene involving azobenzene-tethered T7 promoter for the photocontrol of gene expression by visible light. AB - In the present study, we demonstrate photoregulation of gene expression in a cell free translation system from a T7 promoter containing two azobenzene derivatives at specific positions. As photoswitches, we prepared azobenzene-4'-carboxlyic acid (Azo) and 2,6-dimethylazobenzene-4'-carboxylic acid (DM-Azo), which were isomerized from trans to cis upon irradiation with UV light (lambda < 370 nm), and 4-methylthioazobenzene-4'-carboxylic acid (S-Azo) and 2,6-dimethyl-4 (methylthio)azobenzene-4'-carobxylic acid (S-DM-Azo), which were cis-isomerized by irradiation with 400 nm visible light. Expression of green fluorescent protein from a promoter modified with S-Azo or S-DM-Azo could be induced by harmless visible light whereas that from a promoter modified with Azo or DM-Azo was induced only by UV light (340-360 nm). Thus, efficient photoregulation of green fluorescent protein production was achieved in a cell-free translation system with visible light without photodamage. PMID- 25144623 TI - Tuning electronic and magnetic properties of silicene with magnetic superhalogens. AB - Due to its compatibility with the well-developed Si-based semiconductor industry, silicene has attracted considerable attention. Using density functional theory we show for the first time that the recently synthesized superhalogen MnCl3 can be used to tune the electronic and magnetic properties of silicene, from semi metallic to semiconducting with a wide range of band gaps, as well as from nonmagnetic to ferromagnetic (or antiferromagnetic) by changing the coverage of the superhalogen molecules. The electronic properties can be further modulated when a superhalogen and a halogen are used synergistically. The present study indicates that because of the large electron affinity and rich structural diversity superhalogen molecules have advantages over the conventional halogen atoms in modulating the material properties of silicene. PMID- 25144624 TI - Methylated Glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer. AB - BACKGROUND: Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). METHODS: Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay. RESULTS: The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007). CONCLUSIONS: We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted. PMID- 25144625 TI - Subgroup effects in a randomised trial of different types and doses of exercise during breast cancer chemotherapy. AB - BACKGROUND: The Combined Aerobic and Resistance Exercise Trial tested different types and doses of exercise in breast cancer patients receiving chemotherapy. Here, we explore potential moderators of the exercise training responses. METHODS: Breast cancer patients initiating chemotherapy (N=301) were randomly assigned to three times a week, supervised exercise of a standard dose of 25-30 min of aerobic exercise, a higher dose of 50-60 min of aerobic exercise, or a higher dose of 50-60 min of combined aerobic and resistance exercise. Outcomes were patient-reported symptoms and health-related fitness. Moderators were baseline demographic, exercise/fitness, and cancer variables. RESULTS: Body mass index moderated the effects of the exercise interventions on bodily pain (P for interaction=0.038), endocrine symptoms (P for interaction=0.029), taxane/neuropathy symptoms (P for interaction=0.013), aerobic fitness (P for interaction=0.041), muscular strength (P for interaction=0.007), and fat mass (P for interaction=0.005). In general, healthy weight patients responded better to the higher-dose exercise interventions than overweight/obese patients. Menopausal status, age, and baseline fitness moderated the effects on patient-reported symptoms. Premenopausal, younger, and fitter patients achieved greater benefits from the higher-dose exercise interventions. CONCLUSIONS: Healthy weight, fitter, and premenopausal/younger breast cancer patients receiving chemotherapy are more likely to benefit from higher-dose exercise interventions. PMID- 25144626 TI - Eph receptors as therapeutic targets in glioblastoma. AB - The dismal outlook for patients with the most aggressive and common form of adult brain cancer, glioblastoma (GBM), motivates a search for new therapeutic strategies and targets for this aggressive disease. Here we review the findings to date on the role of Eph family receptor tyrosine kinases and their ephrin ligands in brain cancer. Expression of the Eph family of cell surface proteins is generally downregulated to very low levels in normal adult tissues making them particularly attractive for directed therapeutic targeting. Recent Eph targeting studies in pre-clinical models of GBM have been very encouraging and may provide an avenue to treat these highly refractory aggressive tumours. PMID- 25144627 TI - A metabolic view on menopause and ageing. AB - The ageing of the global population calls for a better understanding of age related metabolic consequences. Here we report the effects of age, sex and menopause on serum metabolites in 26,065 individuals of Northern European ancestry. Age-specific metabolic fingerprints differ significantly by gender and, in females, a substantial atherogenic shift overlapping the time of menopausal transition is observed. In meta-analysis of 10,083 women, menopause status associates with amino acids glutamine, tyrosine and isoleucine, along with serum cholesterol measures and atherogenic lipoproteins. Among 3,204 women aged 40-55 years, menopause status associates additionally with glycine and total, monounsaturated, and omega-7 and -9 fatty acids. Our findings suggest that, in addition to lipid alterations, menopause may contribute to future metabolic and cardiovascular risk via influencing amino-acid concentrations, adding to the growing evidence of the importance of amino acids in metabolic disease progression. These observations shed light on the metabolic consequences of ageing, gender and menopause at the population level. PMID- 25144628 TI - Remission after potassium iodide therapy in patients with Graves' hyperthyroidism exhibiting thionamide-associated side effects. AB - CONTEXT: Thionamides have various side effects. OBJECTIVE: The effectiveness of potassium iodide (KI) was evaluated in hyperthyroid patients who experienced side effects to thionamides. DESIGN AND SETTING: An observational study was conducted at an academic medical center. PATIENTS: Among 1388 patients with Graves' hyperthyroidism treated with thionamides, 204 (14.7%) exhibited side effects, and 44 were treated with KI and followed for 17.6 (median; range, 8.6-28.4) years. MAIN OUTCOME MEASURES: The primary endpoint was the initial response to KI, and the secondary endpoint was the long-term prognosis. RESULTS: The conditions of 29 (65.9%) of the 44 patients were well controlled with KI alone (10-400 mg/d) (A group), and 17 (38.6%) patients went into remission after 7.4 (1.9-23.0) years. The conditions of 15 (34.1%) patients were not controlled with KI alone (B group), even at a high dose (100-750 mg/d), but seven patients (15.9%) were controlled with a combination of KI and low-dose thionamides, resulting in remission after 7.2 (2.8-10.8) years. The initial parameters did not predict the response to KI or long-term prognosis. However, remission occurred in 70.8% of the patients treated with less than 200 mg of KI, compared with 35.0% of the patients who required 200 mg or more of KI (P < .05). CONCLUSIONS: Among hyperthyroid patients with thionamide-associated side effects, KI therapy was effective in two-thirds of cases, and about 40% of the patients experienced remission after KI therapy alone. The chance of remission was small among the patients refractory to KI. PMID- 25144630 TI - The changes of serum glypican4 in obese patients with different glucose metabolism status. AB - CONTEXT AND OBJECTIVE: Glypican 4 (Gpc4) was identified as a novel adipokine capable of intensifying insulin signaling and regulating adipocyte differentiation. This study was performed to investigate the changes of serum Gpc4 levels in obese patients with different glucose metabolism status and its association with metabolic-related parameters. DESIGN AND PARTICIPANTS: A total of 170 obese patients with different glucose metabolism status and 38 normal controls were recruited, and obese patients were divided into 4 groups: OB1, obese patients with normal glucose tolerance (NGT) and normal insulin levels; OB2, obese patients with normal glucose tolerance and hyperinsulinemia; OB3, obese patients with impaired glucose tolerance; and OB4, obese patients with type 2 diabetes mellitus. Serum Gpc4 was determined by commercially available ELISA kits. RESULTS: Serum Gpc4 levels in the OB2, -3, and -4 groups were significantly increased in comparison with that in the OB1 group (3.5 [2.0-5.3] ng/mL, 3.0 [1.5 6.1] ng/mL, and 3.4 [1.8-5.4] ng/mL vs 1.9 [1.3-4.3] ng/mL, P < .05). The levels were positively correlated with body mass index (BMI), systolic blood pressure (SBP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting insulin (FINS), and homeostasis model assessment of insulin resistance (HOMA-IR) in all subjects. Multiple linear regression showed that SBP, AST, HOMA-IR, and FINS were independent contributors to circulating Gpc4 levels after adjusting for age, gender, and BMI in all subjects (P < .05). Additionally, serum Gpc4 levels in males of the normal group and the OB3 group were higher than those in females (2.9 [2.1-4.9] ng/mL vs 1.6 [1.2-3.1] ng/mL; 4.8 [2.5-6.3] ng/mL vs 2.7 [1.1-4.4] ng/mL, P < .05). CONCLUSIONS: Serum Gpc4 levels were significantly elevated in obese patients with insulin resistance and positively correlated with BMI, SBP, ALT, AST, FINS, and HOMA-IR, suggesting Gpc4 is a novel adipokine associated with obesity and insulin resistance-related metabolic disorders. PMID- 25144631 TI - Characterization of GAB1 expression over the menstrual cycle in women with and without polycystic ovarian syndrome provides a new insight into its pathophysiology. AB - CONTEXT: In a previous microarray analysis, GRB2-associated binding protein 1 (GAB1), a docking protein closely related to the insulin receptor substrate, was down-regulated in endometrium of women with polycystic ovary syndrome (PCOS). OBJECTIVE: The objective of the study was to characterize the cyclic expression of endometrial GAB1 in vivo in normal women and those with PCOS as well as investigate the possible mechanisms of endometrial regulation of GAB1 expression and action in vitro. DESIGN: This was an experimental and case-control study. SETTING: The study was conducted at a tertiary university hospital. PATIENTS: Normal proven fertile women (controls; n = 31) and women with PCOS (cases; n = 26) participated in the study. INTERVENTIONS: INTERVENTIONS included timed endometrial biopsies at different phases of the menstrual cycle. Ishikawa cells were cultured with beta-estradiol (E2), medroxyprogesterone acetate, and E2 + medroxyprogesterone acetate. Transfection of small interfering RNA for GAB1 in Ishikawa cells incubated with or without insulin. MAIN OUTCOME MEASURES: GAB1 mRNA expression in Ishikawa cells and in endometrium of cases and controls was measured. Protein expression of phosphorylated MAPK by Western blot was also measured. Immunohistochemical localization and expression of phosphorylated GAB1 in endometrium was also measured, using a digital histological score. RESULTS: In endometrial tissue, GAB1 mRNA was reduced in the proliferative phase of PCOS women, compared with controls (P = .003; ANOVA). When all the phases of the menstrual cycle were grouped, GAB1 protein expression was reduced in endometrium of PCOS women (P < .0001; Student t test). E2 increases GAB1 mRNA expression in Ishikawa cells (P = .001; ANOVA). Phosphorylated MAPK is reduced in cells transfected with small interfering RNA for GAB1 (P = .008; ANOVA) and incubated with insulin. CONCLUSIONS: GAB1 mRNA expression is positively modulated by E2. Endometrial GAB1 protein and mRNA expression are reduced in women with PCOS, suggesting that the endometrium of PCOS women have a defect in insulin signaling due to GAB1 down-regulation. PMID- 25144629 TI - Circulating sclerostin associated with vertebral bone marrow fat in older men but not women. AB - CONTEXT: Osteocyte activity is crucial to the maintenance of bone quality. Sclerostin, an osteocyte product, inhibits bone formation, yet higher circulating sclerostin is associated with higher bone density. Bone marrow fat (MF) is associated with osteoporosis, but little is known about the relationship between osteocyte activity and MF. OBJECTIVE: Our objective was to assess the relationships between circulating sclerostin, vertebral MF, volumetric bone mineral density (vBMD), and other fat depots in older adults. DESIGN, SETTING, AND PARTICIPANTS: We conducted a cross-sectional study in the Age Gene/Environment Susceptibility-Reykjavik cohort. MAIN OUTCOME MEASURES: Outcome measures included vertebral MF (L1-L4) measured with magnetic resonance spectroscopy and vBMD (spine and hip) and abdominal fat measured with quantitative computed tomography. RESULTS: After excluding subjects with bone active medication use (n = 50), inadequate serum (n = 2), or inadequate magnetic resonance spectroscopy (n = 1), analyses included 115 men and 134 women (mean age 79 y, mean body mass index 27.7 kg/m(2)). In men, but not women, vertebral MF was greater in those with higher serum sclerostin levels. MF was 52.2 % in the lowest tertile of serum sclerostin and 56.3% in the highest tertile in men (P for trend <.01) in models adjusted for age, body mass index, and diabetes. Sclerostin was positively associated with cortical and trabecular total hip vBMD, weight in men and women, and total fat mass in men but was not associated with total lean mass or abdominal fat depots. CONCLUSION: Circulating sclerostin levels are associated with higher vertebral marrow fat in men, suggesting a relationship between osteocyte function and marrow adipogenesis. PMID- 25144633 TI - Calcitonin nasal spray and increased cancer risk: a population-based nested case control study. AB - CONTEXT: The concern regarding cancer risk has resulted in the recommendation to pull calcitonin nasal spray (CNS) from the market. OBJECTIVE: We conducted a nested case-control study to evaluate the association between CNS use in osteoporosis patients in Taiwan and their subsequent risk of cancer. DESIGN: This was a population-based nested case-control study. SETTING: Data were obtained from the Taiwan National Health Insurance Research Database. PATIENTS OR OTHER PARTICIPANTS: The study cohort consisted of 28 222 patients diagnosed with osteoporosis between January 1, 2000, and December 31, 2011. We identified 1925 cancer patients as the study group and 2 noncancer patients frequency matched according to age at index date, sex, comorbidity, index-year, and osteoporosis year as the control group. MAIN OUTCOME MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression analysis. RESULTS: Use of CNS in women with osteoporosis significantly increased the risk of liver cancer (OR = 1.94, 95% CI = 1.23-3.05) but decreased the risk of breast cancer (OR = 0.35, 95% CI = 0.15-0.80). Further analysis of monthly CNS dosages showed that the association between CNS and liver cancer is limited to higher dose users. CONCLUSION: The findings of this population-based nested case-control study suggest that CNS use might increase the risk of liver cancer in female osteoporosis patients but decrease the risk of breast cancer. Our data do not completely support the decision to discontinue use of CNS in osteoporosis patients. PMID- 25144632 TI - Combination of peptide YY3-36 with GLP-1(7-36) amide causes an increase in first phase insulin secretion after IV glucose. AB - CONTEXT: The combination of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) has been proposed as a potential treatment for diabetes and obesity. However, the combined effects of these hormones, PYY(3-36) and GLP-1(7-36 amide), on glucose homeostasis are unknown. OBJECTIVE: This study sought to investigate the acute effects of PYY(3-36) and GLP-1(7-36) amide, individually and in combination, on insulin secretion and sensitivity. SETTING AND DESIGN: Using a frequently sampled iv glucose tolerance test (FSIVGTT) and minimal modeling, this study measured the effects of PYY(3-36) alone, GLP-1(7-36) amide alone, and a combination of PYY(3 36) and GLP-1(7-36) amide on acute insulin response to glucose (AIRg) and insulin sensitivity index (SI) in 14 overweight human volunteers, studied in a clinical research facility. RESULTS: PYY(3-36) alone caused a small but nonsignificant increase in AIRg. GLP-1(7-36) amide alone and the combination of PYY(3-36) and GLP-1(7-36) amide did increase AIRg significantly. No significant differences in SI were observed with any intervention. CONCLUSIONS: PYY(3-36) lacks any significant acute effects on first-phase insulin secretion or SI when tested using an FSIVGTT. Both GLP-1(7-36) amide alone and the combination of PYY3-36 and GLP-1(7-36) amide increase first-phase insulin secretion. There does not seem to be any additive or synergistic effect between PYY(3-36) and GLP-1(7-36) amide on first-phase insulin secretion. Neither hormone alone nor the combination had any significant effects on SI. PMID- 25144634 TI - Endothelial progenitor cells are reduced in acromegalic patients and can be restored by treatment with somatostatin analogs. AB - CONTEXT: Acromegaly increases cardiovascular risk, possibly due to the high prevalence of classical risk factors. However, in vitro studies show a protective role of GH/IGF-1 on the endothelium. OBJECTIVE: The objective of the study was to investigate circulating endothelial progenitor cells (EPCs), a marker of vascular regeneration, in acromegalic patients and how they are affected by acromegaly treatment. DESIGN: This was a cross-sectional case-control and observational study. SETTING: The study was conducted at a tertiary ambulatory referral endocrinology center. PATIENTS: Forty-three acromegalic patients (26 active; 17 inactive) and 43 control subjects matched by age, gender, and degree of glucose tolerance participated in the study. INTERVENTION: Circulating EPCs were quantified by flow cytometry based on the expression of CD34, CD133, and kinase insert domain-containing receptor (KDR). Nine patients with active acromegaly were reevaluated after 24 weeks of treatment with somatostatin analogs (SSAs). MAIN OUTCOME MEASURE: Differences in EPC levels between patients and controls were measured. RESULTS: Acromegalic patients showed a significant reduction of the total CD34(+)KDR(+) EPC population compared with controls, which was more evident in patients without diabetes or hypertension. More definite CD34(+)CD133(+)KDR(+) EPCs were reduced in patients with active compared with those with inactive acromegaly and compared with controls. The number of CD34(+)CD133(+)KDR(+) EPCs correlated with IGF-1 levels (r = -0.45; P < .001), fasting plasma glucose (r = -0.40; P = .004), and the homeostasis model assessment index of insulin resistance (r = -0.32; P = .026). CD34(+)CD133(+)KDR(+) EPCs increased 2-fold after SSA treatment. CONCLUSIONS: Acromegalic patients have a reduced endothelial regenerative capacity, possibly due to activation of the GH/IGF-1, rather than concomitant risk factors. Treatment with SSAs can restore immature EPCs to normal levels. PMID- 25144635 TI - Glucose-dependent insulinotropic polypeptide inhibits bone resorption in humans. AB - BACKGROUND: In humans, the pronounced postprandial reduction in bone resorption (decreasing bone resorption markers by around 50%) has been suggested to be caused by gut hormones. Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone secreted postprandially from the small intestine. The hormone is known as an incretin hormone, but preclinical studies have suggested that it may also influence bone metabolism, showing both antiresorptive and anabolic effects as reflected by changes in biomechanical measures, microarchitecture, and activity of the bone cells in response to GIP stimulation. Its role in human bone homeostasis, however, is unknown. OBJECTIVE: To examine the effect of GIP administration on bone resorption in humans. MATERIALS AND METHODS: Plasma samples were obtained from 10 healthy subjects during four conditions: euglycemic (5 mmol/L) and hyperglycemic (12 mmol/L) 90-minute glucose clamps with co infusion of GIP (4 pmol/kg/min for 15 min, followed by 2 pmol/kg/min for 45 min) or placebo. The samples were analyzed for concentrations of degradation products of C-terminal telopeptide of type I collagen (CTX), a bone resorption marker. RESULTS regarding effects on pancreatic hormone secretion have been published. RESULTS: During euglycemia, the decremental area under the curve in CTX was significantly (P < .001) higher during GIP infusion (2084 +/- 686 % * min) compared to saline infusion (656 +/- 295 % * min). During hyperglycemia, GIP infusion significantly (P < .001) augmented the decremental area under the curve to 2785 +/- 446 % * minutes, compared to 1308 +/- 448 % * minutes during saline infusion, with CTX values corresponding to 49% of basal values. CONCLUSIONS: We conclude that GIP reduces bone resorption in humans, interacting with a possible effect of hyperglycemia. PMID- 25144636 TI - Azvudine, a novel nucleoside reverse transcriptase inhibitor showed good drug combination features and better inhibition on drug-resistant strains than lamivudine in vitro. AB - Azvudine is a novel nucleoside reverse transcriptase inhibitor with antiviral activity on human immunodeficiency virus, hepatitis B virus and hepatitis C virus. Here we reported the in vitro activity of azvudine against HIV-1 and HIV-2 when used alone or in combination with other antiretroviral drugs and its drug resistance features. Azvudine exerted highly potent inhibition on HIV-1 (EC(50)s ranging from 0.03 to 6.92 nM) and HIV-2 (EC(50)s ranging from 0.018 to 0.025 nM). It also showed synergism in combination with six approved anti-HIV drugs on both C8166 and PBMC. In combination assay, the concentrations of azvudine used were 1000 or 500 fold lower than other drugs. Azvudine also showed potent inhibition on NRTI-resistant strains (L74V and T69N). Although M184V caused 250 fold reduction in susceptibility, azvudine remained active at nanomolar range. In in vitro induced resistant assay, the frequency of M184I mutation increased with induction time which suggests M184I as the key mutation in azvudine treatment. As control, lamivudine treatment resulted in a higher frequency of M184I/V given the same induction time and higher occurrence of M184V was found. Molecular modeling analysis suggests that steric hindrance is more pronounced in mutant M184I than M184V due to the azido group of azvudine. The present data demonstrates the potential of azvudine as a complementary drug to current anti-HIV drugs. M184I should be the key mutation, however, azvudine still remains active on HIV-1LAI M184V at nanomolar range. PMID- 25144637 TI - Characterization of an insecticidal toxin and pathogenicity of Pseudomonas taiwanensis against insects. AB - Pseudomonas taiwanensis is a broad-host-range entomopathogenic bacterium that exhibits insecticidal activity toward agricultural pests Plutella xylostella, Spodoptera exigua, Spodoptera litura, Trichoplusia ni and Drosophila melanogaster. Oral infection with different concentrations (OD = 0.5 to 2) of wild-type P. taiwanensis resulted in insect mortality rates that were not significantly different (92.7%, 96.4% and 94.5%). The TccC protein, a component of the toxin complex (Tc), plays an essential role in the insecticidal activity of P. taiwanensis. The DeltatccC mutant strain of P. taiwanensis, which has a knockout mutation in the tccC gene, only induced 42.2% mortality in P. xylostella, even at a high bacterial dose (OD = 2.0). TccC protein was cleaved into two fragments, an N-terminal fragment containing an Rhs-like domain and a C terminal fragment containing a Glt symporter domain and a TraT domain, which might contribute to antioxidative stress activity and defense against macrophagosis, respectively. Interestingly, the primary structure of the C terminal region of TccC in P. taiwanensis is unique among pathogens. Membrane localization of the C-terminal fragment of TccC was proven by flow cytometry. Sonicated pellets of P. taiwanensis DeltatccC strain had lower toxicity against the Sf9 insect cell line and P. xylostella larvae than the wild type. We also found that infection of Sf9 and LD652Y-5d cell lines with P. taiwanensis induced apoptotic cell death. Further, natural oral infection by P. taiwanensis triggered expression of host programmed cell death-related genes JNK-2 and caspase-3. PMID- 25144638 TI - Meibomian gland dysfunction determines the severity of the dry eye conditions in visual display terminal workers. AB - OBJECTIVE: To explore meibomian gland dysfunction (MGD) may determine the severity of dry eye conditions in visual display terminal (VDT) workers. METHODOLOGY: Prospective, case-control study carried out in China.106 eyes of 53 patients (VDT work time >4 hour per day) were recruited as the Long time VDT group; 80 eyes of 40 control subjects (VDT work time <= 4 hour per day) served as the Short time VDT group. A questionnaire of Ocular Surface Disease Index (OSDI) and multiple tests were performed. Three dry eye tests: tear film breakup time (BUT), corneal fluorescein staining, Schirmer I test; and three MGD parameters: lid margin abnormality score, meibum expression assessment (meibum score), and meibomian gland dropout degree (meiboscore) using Keratograph 5 M. PRINCIPAL FINDINGS: OSDI and corneal fluorescein score were significantly higher while BUT was dramatically shorter in the long time VDT group than the short time VDT group. However, the average of Schirmer tear volumes was in normal ranges in both groups. Interestingly, the three MGD parameters were significantly higher in the long time VDT group than the short time one (P<0.0001). When 52 eyes with Schirmer <10 mm and 54 eyes with Schirmer >= 10 mm were separated from the long time VDT workers, no significant differences were found between the two subgroups in OSDI, fluorescein staining and BUT, as well as the three MGD parameters. All three MGD parameters were positively correlated with VDT working time (P<0.0001) and fluorescein scores (P<0.0001), inversely correlated with BUT (P<0.05), but not correlated with Schirmer tear volumes in the VDT workers. CONCLUSIONS: Our findings suggest that a malfunction of meibomian glands is associated with dry eye patients in long term VDT workers with higher OSDI scores whereas some of those patients presenting a normal tear volume. PMID- 25144640 TI - Preliminary studies on membrane filtration for the production of potable water: a case of Tshaanda rural village in South Africa. AB - Ultrafiltration (UF) systems have been used globally for treating water from resources including rivers, reservoirs, and lakes for the production of potable water in the past decade. UF membranes with a pore size of between 0.1 and 0.01 micrometres provide an effective barrier for bacteria, viruses, suspended particles, and colloids. The use of UF membrane technology in treating groundwater for the supply of potable water in the impoverished and rural village, Tshaanda (i.e., the study area) is demonstrated. The technical and administrative processes that are critical for the successful installation of the pilot plant were developed. Given the rural nature of Tshaanda, the cultural and traditional protocols were observed. Preliminary results of the water quality of untreated water and the permeate are presented. Escherichia coli in the untreated water during the dry season (i.e., June and July) was 2 cfu/100 ml and was <1 cfu/100 ml (undetected) following UF, which complied with the WHO and South African National Standards and Guidelines of <1 cfu/100 ml. During the wet/rainy season (February) total coliform was unacceptably high (>2419.2 cfu/100 ml) before UF. Following UF, it dramatically reduced to acceptable level (7 cfu/100 ml) which is within the WHO recommended level of <10 cfu/100 ml. Additionally, during the wet/rainy season E. coli and enterococci were unacceptably high (40.4 cfu/100 ml and 73.3 cfu/100 ml, respectively) before UF but were completely removed following UF, which are within the WHO and SANS recommended limit. The values for electrical conductivity (EC) and turbidity were constantly within the WHO recommended limits of 300 uS/cm corrected at 25 degrees C and <5 NTU, respectively, before and after UF, during dry season and wet season. This suggests that there is no need for pre-treatment of the water for suspended particles and colloids. Considering these data, it can be concluded that the water is suitable for human consumption, following UF. PMID- 25144639 TI - Identification of urinary peptide biomarkers associated with rheumatoid arthritis. AB - Early diagnosis and treatment of rheumatoid arthritis are associated with improved outcomes but current diagnostic tools such as rheumatoid factor or anti citrullinated protein antibodies have shown limited sensitivity. In this pilot study we set out to establish a panel of urinary biomarkers associated with rheumatoid arthritis using capillary electrophoresis coupled to mass spectrometry. We compared the urinary proteome of 33 participants of the Scottish Early Rheumatoid Arthritis inception cohort study with 30 healthy controls and identified 292 potential rheumatoid arthritis-specific peptides. Amongst them, 39 were used to create a classifier model using support vector machine algorithms. Specific peptidic fragments were differentially excreted between groups; fragments of protein S100-A9 and gelsolin were less abundant in rheumatoid arthritis while fragments of uromodulin, complement C3 and fibrinogen were all increasingly excreted. The model generated was subsequently tested in an independent test-set of 31 samples. The classifier demonstrated a sensitivity of 88% and a specificity of 93% in diagnosing the condition, with an area under the receiver operating characteristic curve of 0.93 (p<0.0001). These preliminary results suggest that urinary biomarkers could be useful in the early diagnosis of rheumatoid arthritis. Further studies are currently being undertaken in larger cohorts of patients with rheumatoid arthritis and other athridities to assess the potential of the urinary peptide based classifier in the early detection of rheumatoid arthritis. PMID- 25144642 TI - A simple algorithm for treating horizontal benign paroxysmal positional vertigo. AB - OBJECTIVE: Horizontal benign paroxysmal positional vertigo (H-BPPV) is more difficult to successfully treat than posterior benign paroxysmal positional vertigo (P-BPPV) because of the diverse mechanisms required. We developed a simple, rapid, and effective treatment algorithm for treating all subtypes of H BPPV in an ear, nose, and throat (ENT) outpatient department. MATERIALS AND METHODS: Four hundred ninety patients with BPPV receiving outpatient treatment at Mackay Memorial Hospital were investigated. Among the 490 patients, 86 (17.6%; 86/490) were diagnosed as having H-BPPV variants using the McClure-Pagnini test. Fifty-four patients were female, and 32 were male; they ranged in age from 18 to 92 years (mean age, 56.2 yr). RESULTS: Among the 86 H-BPPV patients, 74.4% (64/86) were hypothesized to have canalithiasis, 20.9% (18/86) were hypothesized to have cupulolithiasis-utricle type (Cup-U), and 4.7% (4/86) were hypothesized to have the cupulolithiasis-cupula type (Cup-C). The primary treatment maneuver was the forced prolonged position (FPP). For 3 patients exhibiting refractory symptoms, we introduced the Gufoni maneuver. The total average success rate of treatment was 96%. CONCLUSION: We concluded that for H-BPPV patients with initial geotropic nystagmus, the FPP alone yielded an excellent treatment-control rate, and the barbecue-rotation maneuver was unnecessary. However, observing the nystagmus transformation of apogeotropic patients was necessary before administering treatment. For cupulolithiasis patients with the apogeotropic variant who did not respond to FPP treatment alone, we determined that the Gufoni maneuver was necessary as well. PMID- 25144641 TI - Knowledge, practices, and perceived barriers regarding cancer pain management among physicians and nurses in Korea: a nationwide multicenter survey. AB - PURPOSE: Medical professionals' practices and knowledge regarding cancer pain management have often been cited as inadequate. This study aimed to evaluate knowledge, practices and perceived barriers regarding cancer pain management among physicians and nurses in Korea. METHODS: A nationwide questionnaire survey was administered to physicians and nurses involved in the care of cancer patients. Questionnaire items covered pain assessment and documentation practices, knowledge regarding cancer pain management, the perceived barriers to cancer pain control, and processes perceived as the major causes of delay in opioid administration. RESULTS: A total of 333 questionnaires (149 physicians and 284 nurses) were analyzed. Nurses performed pain assessment and documentation more regularly than physicians did. Although physicians had better knowledge of pain management than did nurses, both groups lacked knowledge regarding the side effects and pharmacology of opioids. Physicians working in the palliative care ward and nurses who had received pain management education obtained higher scores on knowledge. Physicians perceived patients' reluctance to take opioids as a barrier to pain control, more so than did nurses, while nurses perceived patients' tendency to under-report of pain as a barrier, more so than did physicians. Physicians and nurses held different perceptions regarding major cause of delay during opioid administration. CONCLUSIONS: There were differences between physicians and nurses in knowledge and practices for cancer pain management. An effective educational strategy for cancer pain management is needed in order to improve medical professionals' knowledge and clinical practices. PMID- 25144643 TI - Utility of psychological screening for the diagnosis of pediatric episodic vertigo. AB - BACKGROUND/OBJECTIVES: Childhood episodic vertigo has been reported to be associated with migraine or childhood periodic syndromes such as benign paroxysmal vertigo of childhood. There is discrete evidence that unexpected recurrent vertigo is associated with a high level of depression and anxiety in adults. However, only a few studies describe the frequency and characteristics of psychiatric comorbidity in vertiginous children. The aim of this study is to evaluate the incidence and characteristics of emotional and behavioral problems using outpatient-based psychological screening tools in children with episodic vertigo attacks. METHODS: A total of 105 patients and 138 controls, aged 4 to 17 years, were enrolled. All were identified with a primary complaint of recurrent episodic vertigo. All patients received a complete battery of audiological and vestibular tests. Psychological assessment was performed using standardized questionnaires, including Strength and Difficulties Questionnaire (SDQ), Children's Depression Inventory (CDI), and Screen for Child Anxiety Related Emotional Disorders (SCARED). RESULTS: Compared with community controls, children presenting vertigo attacks had significantly higher mean scores on almost all scales of SDQ, CDI, and SCARED, except two parameters, namely, prosocial behavior and separation anxiety. About half of the patients, compared to 10 to 11% of the controls, had significant levels of distress that could adversely impact treatment outcomes and might need psychiatric consultation. Significant distress or impairment in social interactions was more prominent in older ages. CONCLUSION: Our findings suggest that children/adolescents with recurrent episodic vertigo should be screened for possible associated psychological symptoms. PMID- 25144644 TI - Diameter of long process of incus for stapes prosthesis. PMID- 25144645 TI - Impact of ECG findings and process-of-care characteristics on the likelihood of not receiving reperfusion therapy in patients with ST-elevation myocardial infarction: results of a field evaluation. AB - BACKGROUND: Many patients with ST-elevation myocardial infarction (STEMI) do not receive reperfusion therapy and are known to have poorer outcomes. We aimed to perform the first population-level, integrated analysis of clinical, ECG and hospital characteristics associated with non-receipt of reperfusion therapy in patients with STEMI. METHODS AND RESULTS: This systematic evaluation of STEMI care in 82 hospitals in Quebec included all patients with a discharge diagnosis of myocardial infarction, presenting with characteristic symptoms and an ECG showing STEMI as attested by at least one of two study cardiologists or left bundle branch block (LBBB). Excluding LBBB, an ECG was considered a definite STEMI diagnosis if both cardiologists scored 'certain STEMI' and ambiguous if one scored 'uncertain' or 'not STEMI'. Centers were classified according to accessibility to primary percutaneous coronary intervention (PPCI): 1) on-site PPCI; 2) routine transfer for PPCI; 3) varying mix of PPCI transfer and on-site fibrinolysis; and 4) routine on-site fibrinolysis. Of 3730 STEMI/LBBB patients, 812 (21.8%) did not receive reperfusion therapy. In multivariate analysis, likelihood of no reperfusion therapy was a function of PPCI accessibility (odds ratio [OR] for fibrinolysis versus PPCI centers = 3.1; 95% CI: 2.2-4.4), presence of LBBB (OR = 24.1; 95% CI: 17.8-32.9) and an ECG ambiguous for STEMI (OR = 4.1; 95% CI: 3.3-5.1). When the ECG was ambiguous, likelihood of no reperfusion therapy was highest in hospitals most distant from PPCI centers. CONCLUSIONS: ECG diagnostic ambiguity, LBBB and PPCI accessibility are important predictors of not receiving reperfusion therapy, suggesting opportunities for improving outcomes. PMID- 25144647 TI - In situ monitoring of electric field distribution in mouse tumor during electroporation. AB - PURPOSE: To investigate the feasibility of magnetic resonance (MR) electric impedance tomography ( EIT electric impedance tomography ) technique for in situ monitoring of electric field distribution during in vivo electroporation of mouse tumors to predict reversibly electroporated tumor areas. MATERIALS AND METHODS: All experiments received institutional animal care and use committee approval. Group 1 consisted of eight tumors that were used for determination of predicted area of reversibly electroporated tumor cells with MR EIT electric impedance tomography by using a 2.35-T MR imager. In addition, T1-weighted images of tumors were acquired to determine entrapment of contrast agent within the reversibly electroporated area. A correlation between predicted reversible electroporated tumor areas as determined with MR EIT electric impedance tomography and areas of entrapped MR contrast agent was evaluated to verify the accuracy of the prediction. Group 2 consisted of seven tumors that were used for validation of radiologic imaging with histopathologic staining. Histologic analysis results were then compared with predicted reversible electroporated tumor areas from group 1. Results were analyzed with Pearson correlation analysis and one-way analysis of variance. RESULTS: Mean coverage +/- standard deviation of tumors with electric field that leads to reversible electroporation of tumor cells obtained with MR EIT electric impedance tomography (38% +/- 9) and mean fraction of tumors with entrapped MR contrast agent (41% +/- 13) were correlated (Pearson analysis, r = 0.956, P = .005) and were not statistically different (analysis of variance, P = .11) from mean fraction of tumors from group 2 with entrapped fluorescent dye (39% +/- 12). CONCLUSION: MR EIT electric impedance tomography can be used for determining electric field distribution in situ during electroporation of tissue. Implementation of MR EIT electric impedance tomography in electroporation-based applications, such as electrochemotherapy and irreversible electroporation tissue ablation, would enable corrective interventions before the end of the procedure and would additionally improve the treatment outcome. PMID- 25144646 TI - Regional ventilation changes in severe asthma after bronchial thermoplasty with (3)He MR imaging and CT. AB - PURPOSE: To quantify regional lung ventilation in healthy volunteers and patients with severe asthma (both before and after thermoplasty) by using a combination of helium 3 ((3)He) magnetic resonance (MR) imaging and computed tomography (CT), with the intention of developing more effective image-guided treatments for obstructive lung diseases. MATERIALS AND METHODS: With approval of the local institutional review board, informed consent, and an Investigational New Drug Exemption, six healthy volunteers and 10 patients with severe asthma were imaged in compliance with HIPAA regulations by using both multidetector CT and (3)He MR imaging. Individual bronchopulmonary segments were labeled voxel by voxel from the CT images and then registered to the (3)He MR images by using custom software. The (3)He signal intensity was then analyzed by evaluating the volume weighted fraction of total-lung signal intensity present in each segment (segmental ventilation percentage [ SVP segmental ventilation percentage ]) and by identifying the whole-lung defect percentage and the segmental defect percentage. Of the 10 patients with asthma, seven received treatment with bronchial thermoplasty and were imaged with (3)He MR a second time. Changes in segmental defect percentages and whole-lung defect percentages are presented. RESULTS: Ventilation measures for healthy volunteers yielded smaller segment-to segment variation (mean SVP segmental ventilation percentage , 100% +/- 18 [standard deviation]) than did the measures for patients with severe asthma (mean SVP segmental ventilation percentage , 97% +/- 23). Patients with asthma also demonstrated larger segmental defect percentages (median, 13.5%; interquartile range, 8.9%-17.8%) than healthy volunteers (median, 6%; interquartile range, 5.6% 6.3%). These quantitative results confirm what is visually observed on the (3)He images. A Spearman correlation of r = -0.82 was found between the change in whole lung defect percentage and the number of days between final treatment and second (3)He imaging. CONCLUSION: Regional quantification of lung ventilation is indeed feasible and may be a useful technique for image-guided treatment of obstructive lung diseases, such as bronchial thermoplasty for severe asthma. In these patients, ventilation defects decreased as a function of time after treatment. PMID- 25144648 TI - Characterization of digestive involvement in patients with chronic T. cruzi infection in Barcelona, Spain. AB - BACKGROUND: Digestive damage due to Chagas disease (CD) occurs in 15-20% of patients diagnosed as a result of peristaltic dysfunction in some endemic areas. The symptoms of chronic digestive CD are non-specific, and there are numerous confounders. Diagnosis of CD may easily be missed if symptoms are not evaluated by a well trained physician. Regular tests, as barium contrast examinations, probably lack the necessary sensitivity to detect early digestive damage. METHODS: 71 individuals with T. cruzi infection (G1) and 18 without (G2) coming from Latin American countries were analyzed. They were asked for clinical and epidemiological data, changes in dietary habits, and history targeting digestive and cardiac CD symptoms. Serological tests for T. cruzi, barium swallow, barium enema, an urea breath test, and esophageal manometry were requested for all patients. PRINCIPAL FINDINGS: G1 and G2 patients did not show differences in lifestyle and past history. Fifteen (21.1%) of G1 had digestive involvement. Following Rezende criteria, esophagopathy was observed in 8 patients in G1 (11.3%) and in none of those in G2. Manometry disorders were recorded in 34 G1 patients and in six in G2. Isolated hypotensive lower esophageal sphincter (LES) was found in sixteen G1 patients (23.9%) and four G2 patients (28.8%). Achalasia was observed in two G1 patients. Among G1 patients, ineffective esophageal motility was seen in six (five with symptoms), diffuse esophageal spasm in two (one with dysphagia and regurgitation), and nutcracker esophagus in three (all with symptoms). There were six patients with hypertonic upper esophageal sphincter (UES) among G1. Following Ximenes criteria, megacolon was found in ten G1 patients (13.9%), and in none of the G2 patients. CONCLUSIONS: The prevalence of digestive chronic CD in our series was 21.1%. Dysphagia is a non-pathognomonic symptom of CD, but a good marker of early esophageal involvement. Manometry could be a useful diagnostic test in selected cases, mainly in patients with T. cruzi infection and dysphagia in whose situation barium swallow does not evidence alterations. Constipation is a common but non-specific symptom that can be easily managed. Testing for CD is mandatory in a patient from Latin America with constipation or dysphagia, and if diagnosis is confirmed, megacolon and esophageal involvement should be investigated. PMID- 25144651 TI - 207Pb and 119Sn solid-state NMR and relativistic density functional theory studies of the historic pigment lead-tin yellow type I and its reactivity in oil paintings. AB - Lead soaps (lead carboxylates) have been detected in traditional oil paintings in layers containing the pigment lead-tin yellow type I (LTY-I). LTY-I has been used by artists from at least the second quarter of the 15th century until the first half of the 18th century. Soap formation can lead to protrusions in paint layers and increased transparency, causing the paint support to become visible. We have characterized LTY-I by (119)Sn and (207)Pb solid-state NMR (ssNMR) spectroscopy. Using a combination of NMR techniques and DFT molecular cluster calculations, we identify the individual species in LTY-I and determine their (119)Sn and (207)Pb chemical-shift tensors. The presence of starting materials from the synthesis, minium, and tin(IV) oxide was also verified. Knowledge of the chemical-shift tensor components and the impurities in LTY-I is important for examining the chemistry of degradation processes and soap formation. We demonstrate that ssNMR can be used to detect reaction between Pb2SnO4 and added palmitic acid in a model paint sample containing LTY-I. PMID- 25144650 TI - A diferrous-dinitrosyl intermediate in the N2O-generating pathway of a deflavinated flavo-diiron protein. AB - Flavo-diiron proteins (FDPs) function as anaerobic nitric oxide scavengers in some microorganisms, catalyzing reduction of nitric to nitrous oxide. The FDP from Thermotoga maritima can be prepared in a deflavinated form with an intact diferric site (deflavo-FDP). Hayashi et al. [(2010) Biochemistry 49, 7040-7049] reported that reaction of NO with reduced deflavo-FDP produced substoichiometric N2O. Here we report a multispectroscopic approach to identify the iron species in the reactions of deflavo-FDP with NO. Mossbauer spectroscopy identified two distinct ferrous species after reduction of the antiferromagnetically coupled diferric site. Approximately 60% of the total ferrous iron was assigned to a diferrous species associated with the N2O-generating pathway. This pathway proceeds through successive diferrous-mononitrosyl (S = (1)/2 Fe(II){FeNO}(7)) and diferrous-dinitrosyl (S = 0 [{FeNO}(7)]2) species that form within ~100 ms of mixing of the reduced protein with NO. The diferrous-dinitrosyl intermediate converted to an antiferromagnetically coupled diferric species that was spectroscopically indistinguishable from that in the starting deflavinated protein. These diiron species closely resembled those reported for the flavinated FDP [Caranto et al. (2014) J. Am. Chem. Soc. 136, 7981-7992], and the time scales of their formation and decay were consistent with the steady state turnover of the flavinated protein. The remaining ~40% of ferrous iron was inactive in N2O generation but reversibly bound NO to give an S = (3)/2 {FeNO}(7) species. The results demonstrate that N2O formation in FDPs can occur via conversion of S = 0 [{FeNO}(7)]2 to a diferric form without participation of the flavin cofactor. PMID- 25144649 TI - Intralipid decreases apolipoprotein M levels and insulin sensitivity in rats. AB - BACKGROUND: Apolipoprotein M (ApoM) is a constituent of high-density lipoproteins (HDL). It plays a crucial role in HDL-mediated reverse cholesterol transport. Insulin resistance is associated with decreased ApoM levels. AIMS: To assess the effects of increased free fatty acids (FFAs) levels after short-term Intralipid infusion on insulin sensitivity and hepatic ApoM gene expression. METHODS: Adult male Sprague-Dawley (SD) rats infused with 20% Intralipid solution for 6 h. Glucose infusion rates (GIR) were determined by hyperinsulinemic-euglycemic clamp during Intralipid infusion and plasma FFA levels were measured by colorimetry. Rats were sacrificed after Intralipid treatment and livers were sampled. Human embryonic kidney 293T cells were transfected with a lentivirus mediated human apoM overexpression system. Goto-Kakizaki (GK) rats were injected with the lentiviral vector and insulin tolerance was assessed. Gene expression was assessed by real-time RT-PCR and PCR array. RESULTS: Intralipid increased FFAs by 17.6 folds and GIR was decreased by 27.1% compared to the control group. ApoM gene expression was decreased by 40.4% after Intralipid infusion. PPARbeta/delta expression was not changed by Intralipid. Whereas the mRNA levels of Acaca, Acox1, Akt1, V-raf murine sarcoma 3611 viral oncogene homolog, G6pc, Irs2, Ldlr, Map2k1, pyruvate kinase and RBC were significantly increased in rat liver after Intralipid infusion. The Mitogen-activated protein kinase 8 (MAPK8) was significantly down-regulated in 293T cells overexpressing ApoM. Overexpression of human ApoM in GK rats could enhance the glucose-lowering effect of exogenous insulin. CONCLUSION: These results suggest that Intralipid could decrease hepatic ApoM levels. ApoM overexpression may have a potential role in improving insulin resistance in vivo and modulating apoM expression might be a future therapeutic strategy against insulin resistance in type 2 diabetes. PMID- 25144652 TI - Asymmetric environmental effects on the structure and vibrations of cis [Pt(NH3)2Cl2] in condensed phases. AB - We report the structural and vibrational properties of anticancer drug cisplatin (cis-[Pt(NH3)2Cl2]) in gas phase, in solid phase, and in aqueous solution using density functional theory (DFT) calculations, quantum mechanical/molecular mechanical (QM/MM) molecular dynamics, and effective normal modes analysis. In contrast with the gas-phase case, asymmetric hydrogen bonding environments are found in both solid phase and aqueous solution. It is shown that the discrepancy of the molecular geometry between previous gas phase calculations and the X-ray crystal structure can be resolved by considering intermolecular hydrogen bonds in the calculations of solid phase. In addition, our simulations in solid phase and aqueous solution reveal that asymmetric environmental effects lead to several spectral features observed in experiments, such as the blue-shift in the N-H stretching region and the frequency splitting of NH3 symmetric deformation modes. Furthermore, a similar decoupling and localization of several vibrational modes of cisplatin is found in solid phase and aqueous solution, in comparison to those of O-H stretching modes of water molecules in liquid water [ J. Phys. Chem. Lett. 2013 , 4 ( 19 ), 3245 - 3250 ]. PMID- 25144654 TI - Advanced training in trauma life support for ambulance crews. AB - BACKGROUND: There is an increasing global burden of injury especially in low- and middle-income countries (LMICs). To address this, models of trauma care initially developed in high income countries are being adopted in LMIC settings. In particular, ambulance crews with advanced life support (ALS) training are being promoted in LMICs as a strategy for improving outcomes for victims of trauma. However, there is controversy as to the effectiveness of this health service intervention and the evidence has yet to be rigorously appraised. OBJECTIVES: To quantify the impact of ALS-trained ambulance crews versus crews without ALS training on reducing mortality and morbidity in trauma patients. SEARCH METHODS: The search for studies was run on the 16th May 2014. We searched the Cochrane Injuries Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (Ovid), ISI WOS (SCI-EXPANDED, SSCI, CPCI-S & CPSI-SSH), CINAHL Plus (EBSCO), PubMed and screened reference lists. SELECTION CRITERIA: Randomised controlled trials, controlled trials and non randomised studies, including before-and-after studies and interrupted time series studies, comparing the impact of ALS-trained ambulance crews versus crews without ALS training on the reduction of mortality and morbidity in trauma patients. DATA COLLECTION AND ANALYSIS: Two review authors assessed study reports against the inclusion criteria, and extracted data. MAIN RESULTS: We found one controlled before-and-after trial, one uncontrolled before-and-after study, and one randomised controlled trial that met the inclusion criteria. None demonstrated evidence to support ALS training for pre-hospital personnel. In the uncontrolled before-and-after study, 'a priori' sub-group analysis showed an increase in mortality among patients who had a Glasgow Coma Scale score of less than nine and received care from ALS trained ambulance crews. Additionally, when the pre-hospital trauma score was taken into account in logistic regression analysis, mortality in the patients receiving care from ALS trained crews increased significantly. AUTHORS' CONCLUSIONS: At this time, the evidence indicates that there is no benefit of advanced life support training for ambulance crews on patient outcomes. PMID- 25144655 TI - Bilateral symmetry detection on the basis of Scale Invariant Feature Transform. AB - The automatic detection of bilateral symmetry is a challenging task in computer vision and pattern recognition. This paper presents an approach for the detection of bilateral symmetry in digital single object images. Our method relies on the extraction of Scale Invariant Feature Transform (SIFT) based feature points, which serves as the basis for the ascertainment of the centroid of the object; the latter being the origin under the Cartesian coordinate system to be converted to the polar coordinate system in order to facilitate the selection symmetric coordinate pairs. This is followed by comparing the gradient magnitude and orientation of the corresponding points to evaluate the amount of symmetry exhibited by each pair of points. The experimental results show that our approach draw the symmetry line accurately, provided that the observed centroid point is true. PMID- 25144653 TI - EF-P dependent pauses integrate proximal and distal signals during translation. AB - Elongation factor P (EF-P) is required for the efficient synthesis of proteins with stretches of consecutive prolines and other motifs that would otherwise lead to ribosome pausing. However, previous reports also demonstrated that levels of most diprolyl-containing proteins are not altered by the deletion of efp. To define the particular sequences that trigger ribosome stalling at diprolyl (PPX) motifs, we used ribosome profiling to monitor global ribosome occupancy in Escherichia coli strains lacking EF-P. Only 2.8% of PPX motifs caused significant ribosomal pausing in the Deltaefp strain, with up to a 45-fold increase in ribosome density observed at the pausing site. The unexpectedly low fraction of PPX motifs that produce a pause in translation led us to investigate the possible role of sequences upstream of PPX. Our data indicate that EF-P dependent pauses are strongly affected by sequences upstream of the PPX pattern. We found that residues as far as 3 codons upstream of the ribosomal peptidyl-tRNA site had a dramatic effect on whether or not a particular PPX motif triggered a ribosomal pause, while internal Shine Dalgarno sequences upstream of the motif had no effect on EF-P dependent translation efficiency. Increased ribosome occupancy at particular stall sites did not reliably correlate with a decrease in total protein levels, suggesting that in many cases other factors compensate for the potentially deleterious effects of stalling on protein synthesis. These findings indicate that the ability of a given PPX motif to initiate an EF-P-alleviated stall is strongly influenced by its local context, and that other indirect post transcriptional effects determine the influence of such stalls on protein levels within the cell. PMID- 25144657 TI - Probing bacterial-fungal interactions at the single cell level. AB - Interactions between fungi and prokaryotes are abundant in many ecological systems. A wide variety of biomolecules regulate such interactions and many of them have found medicinal or biotechnological applications. However, studying a fungal-bacterial system at a cellular level is technically challenging. New microfluidic devices provided a platform for microscopic studies and for long term, time-lapse experiments. Application of these novel tools revealed insights into the dynamic interactions between the basidiomycete Coprinopsis cinerea and the bacterium Bacillus subtilis. Direct contact was mediated by polar attachment of bacteria to only a subset of fungal hyphae suggesting a differential competence of fungal hyphae and thus differentiation of hyphae within a mycelium. The fungicidal activity of B. subtilis was monitored at a cellular level and showed a novel mode of action on fungal hyphae. PMID- 25144656 TI - Diffusion tensor and volumetric magnetic resonance measures as biomarkers of brain damage in a small animal model of HIV. AB - BACKGROUND: There are currently no widely accepted neuro-HIV small animal models. We wanted to validate the HIV-1 Transgenic rat (Tg) as an appropriate neuro-HIV model and then establish in vivo imaging biomarkers of neuropathology, within this model, using MR structural and diffusion tensor imaging (DTI). METHODS: Young and middle-aged Tg and control rats were imaged using MRI. A subset of middle-aged animals underwent longitudinal repeat imaging six months later. Total brain volume (TBV), ventricular volume (VV) and parenchymal volume (PV = TBV-VV) were measured. Fractional anisotropy (FA) and mean diffusivity (MD) values of the corpus callosum (CC) were calculated from DTI data. RESULTS: TBV and PV were smaller in Tg compared to control rats in young and middle-aged cohorts (p<0.0001). VV increased significantly (p = 0.005) over time in the longitudinal Tg cohort. There were lower FA (p<0.002) and higher MD (p<0.003) values in the CC of middle-aged Tg rats compared to age-matched controls. Longitudinally, MD significantly decreased over time in Tg rats (p<0.03) while it did not change significantly in the control cohort over the same period of time (p>0.05). CONCLUSIONS: We detected brain volume loss in the Tg rat, probably due to astrocytic dysfunction/loss, loss of structural/axonal matrix and striatal neuronal loss as suggested by immunofluorescence. Increased MD and decreased FA in the CC probably reflect microstructural differences between the Tg and Control rats which could include increased extracellular space between white matter tracts, demyelination and axonal degeneration, among other pathologies. We believe that the Tg rat is an adequate model of neuropathology in HIV and that volumetric MR and DTI measures can be potentially used as biomarkers of disease progression. PMID- 25144658 TI - Burgers or tofu? Eating between two worlds: risk information seeking and processing during dietary acculturation. AB - This study attempted to examine what factors might motivate Chinese international students, the fastest growing ethnic student group in the United States, to seek and process information about potential health risks from eating American-style food. This goal was accomplished by applying the Risk Information Seeking and Processing (RISP) model to this study. An online 2 (severity: high vs. low) * 2 (coping strategies: present vs. absent) between-subjects experiment was conducted via Qualtrics to evaluate the effects of the manipulated variables on the dependent variables of interest as well as various relationships proposed in the RISP model. A convenience sample of 635 participants was recruited online. Data were analyzed primarily using structural equation modeling (SEM) in AMOS 21.0 with maximum likelihood estimation. The final conceptual model has a good model fit to the data given the sample size. The results showed that although the experimentally manipulated variables failed to cause any significant differences in individuals' perceived severity and self-efficacy, this study largely supported the RISP model's propositions about the sociopsychological factors that explain individual variations in information seeking and processing. More specifically, the findings indicated a prominent role of informational subjective norms and affective responses (both negative and positive emotions) in predicting individuals' information seeking and processing. Future implications and limitations are also discussed. PMID- 25144659 TI - Immature teratoma of the maxillary sinus: a rare pediatric tumor. AB - IMPORTANCE: Noncongenital immature teratomas in the head and neck are extremely rare, and to our knowledge have not previously been reported in the maxillary sinus of a pediatric patient. OBSERVATIONS: Teratomas are neoplasms that contain tissue from more than 1 embryonic cell layer that is foreign to the location where they arise and are most commonly found in the sacrococcygeal and gonadal regions in children. We present an unusual case of an immature teratoma in the maxillary sinus of a 10-year-old boy and discuss the diagnostic workup, management, and clinical course. CONCLUSIONS AND RELEVANCE: Immature teratomas represent a subset of benign teratomas with immature elements that may carry a worse prognosis. PMID- 25144660 TI - Hepatoma-selective imaging of heavy metal ions using a 'clicked' galactosylrhodamine probe. AB - This study depicts the 'click' construction of a water-soluble galactosyl rhodamine that can selectively probe mercury ions internalized by hepatoma cells over other cancer cells. PMID- 25144663 TI - Organocatalytic carbon-sulfur bond-forming reactions. PMID- 25144662 TI - Epidemiology of intestinal polyparasitism among Orang Asli school children in rural Malaysia. AB - BACKGROUND: This cross-sectional study aimed to investigate the current prevalence and risk factors associated with intestinal polyparasitism (the concurrent infection with multiple intestinal parasite species) among Orang Asli school children in the Lipis district of Pahang state, Malaysia. METHODS/PRINCIPAL FINDINGS: Fecal samples were collected from 498 school children (50.6% boys and 49.4% girls), and examined by using direct smear, formalin-ether sedimentation, trichrome stain, modified Ziehl Neelsen stain, Kato-Katz, and Harada Mori techniques. Demographic, socioeconomic, environmental, and personal hygiene information were collected by using a pre-tested questionnaire. Overall, 98.4% of the children were found to be infected by at least one parasite species. Of these, 71.4% had polyparasitism. The overall prevalence of Trichuris trichiura, Ascaris lumbricoides, hookworm, Giardia duodenalis, Entamoeba spp., and Cryptosporidium spp. infections were 95.6%, 47.8%, 28.3%, 28.3%, 14.1% and 5.2%, respectively. Univariate and multivariate analyses showed that using an unsafe water supply as a source for drinking water, presence of other family members infected with intestinal parasitic infections (IPI), not washing vegetables before consumption, absence of a toilet in the house, not wearing shoes when outside, not cutting nails periodically, and not washing hands before eating were significant risk factors associated with intestinal polyparasitism among these children. CONCLUSIONS/SIGNIFICANCE: Intestinal polyparasitism is highly prevalent among children in the peninsular Malaysian Aboriginal communities. Hence, effective and sustainable control measures, including school based periodic chemotherapy, providing adequate health education focused on good personal hygiene practices and proper sanitation, as well as safe drinking water supply should be implemented to reduce the prevalence and consequences of these infections in this population. PMID- 25144661 TI - Special populations: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: Past disasters have highlighted the need to prepare for subsets of critically ill, medically fragile patients. These special patient populations require focused disaster planning that will address their medical needs throughout the event to prevent clinical deterioration. The suggestions in this article are important for all who are involved in large-scale disasters or pandemics with multiple critically ill or injured patients, including frontline clinicians, hospital administrators, and public health or government officials. METHODS: Key questions regarding the care of critically ill or injured special populations during disasters or pandemics were identified, and a systematic literature review (1985-2013) was performed. No studies of sufficient quality were identified. Therefore, the panel developed expert opinion-based suggestions using a modified Delphi process. The panel did not include pediatrics as a separate special population because pediatrics issues are embedded in each consensus document. RESULTS: Fourteen suggestions were formulated regarding the care of critically ill and injured patients from special populations during pandemics and disasters. The suggestions cover the following areas: defining special populations for mass critical care, special population planning, planning for access to regionalized service for special populations, triage and resource allocation of special populations, therapeutic considerations, and crisis standards of care for special populations. CONCLUSIONS: Chronically ill, technologically dependent, and complex critically ill patients present a unique challenge to preparing and implementing mass critical care. There are, however, unique opportunities to engage patients, primary physicians, advocacy groups, and professional organizations to lessen the impact of disaster on these special populations. PMID- 25144664 TI - Efficient femtosecond energy transfer from carotenoid to retinal in gloeobacter rhodopsin-salinixanthin complex. AB - The retinal proton pump xanthorhodopsin (XR) was recently found to function with an attached carotenoid light harvesting antenna, salinixanthin (SX). It is intriguing to discover if this departure from single chromophore architecture is singular or if it has been adopted by other microbial rhodopsins. In search of other cases, retinal protein encoding genes in numerous bacteria have been identified containing sequences corresponding to carotenoid binding sites like that in XR. Gloeobacter rhodopsin (GR), exhibiting particularly close homology to XR, has been shown to attach SX, and fluorescence measurements suggest SX can function as a light harvesting (LH) antenna in GR as well. In this study, we test this suggestion in real time using ultrafast transient absorption. Results show that energy transfer indeed occurs from S2 of SX to retinal in the GR-SX composite with an efficiency of ~40%, even higher than that in XR. This validates the earlier fluorescence study, and supports the notion that many microbial retinal proteins use carotenoid antennae to harvest light. PMID- 25144665 TI - Soil bacterial community response to differences in agricultural management along with seasonal changes in a Mediterranean region. AB - Land-use change is considered likely to be one of main drivers of biodiversity changes in grassland ecosystems. To gain insight into the impact of land use on the underlying soil bacterial communities, we aimed at determining the effects of agricultural management, along with seasonal variations, on soil bacterial community in a Mediterranean ecosystem where different land-use and plant cover types led to the creation of a soil and vegetation gradient. A set of soils subjected to different anthropogenic impact in a typical Mediterranean landscape, dominated by Quercus suber L., was examined in spring and autumn: a natural cork oak forest, a pasture, a managed meadow, and two vineyards (ploughed and grass covered). Land uses affected the chemical and structural composition of the most stabilised fractions of soil organic matter and reduced soil C stocks and labile organic matter at both sampling season. A significant effect of land uses on bacterial community structure as well as an interaction effect between land uses and season was revealed by the EP index. Cluster analysis of culture-dependent DGGE patterns showed a different seasonal distribution of soil bacterial populations with subgroups associated to different land uses, in agreement with culture-independent T-RFLP results. Soils subjected to low human inputs (cork-oak forest and pasture) showed a more stable bacterial community than those with high human input (vineyards and managed meadow). Phylogenetic analysis revealed the predominance of Proteobacteria, Actinobacteria, Bacteroidetes, and Firmicutes phyla with differences in class composition across the site, suggesting that the microbial composition changes in response to land uses. Taken altogether, our data suggest that soil bacterial communities were seasonally distinct and exhibited compositional shifts that tracked with changes in land use and soil management. These findings may contribute to future searches for bacterial bio indicators of soil health and sustainable productivity. PMID- 25144667 TI - The challenge of allograft vasculopathy in cardiac transplantation. AB - PURPOSE OF REVIEW: Cardiac allograft vasculopathy (CAV) is a unique form of accelerated atherosclerosis occurring in heart transplant recipients and this complication has a major negative impact on long-term survival. An understanding of recent advances in the understanding of CAV pathogenesis, accurate diagnosis and effective treatment is important given the increasing number of heart transplant procedures being performed annually. RECENT FINDINGS: This review article will discuss the complex immunological and nonimmunological processes that are likely to contribute to endothelial activation and the chronic inflammatory response causing intimal hyperplasia that is characteristic of CAV. Accurate diagnosis of CAV is essential, and both current and emerging imaging modalities will be reviewed. Finally, current treatment of CAV, together with future therapeutic strategies, will be discussed. SUMMARY: CAV is an important complication-limiting survival after heart transplant, and a clear understanding of the underlying pathophysiological processes is important. The diagnosis of CAV can be difficult, but it is possible with the appropriate imaging modalities. Effective treatment of CAV remains an important clinical challenge, and current immunosuppressive therapy has limited efficacy. However, newer immunosuppressive agents have demonstrated promising results in clinical trials, and this will hopefully allow more effective disease management in the near future. PMID- 25144666 TI - Diagnosis of ventilator-associated pneumonia: a pilot, exploratory analysis of a new score based on procalcitonin and chest echography. AB - BACKGROUND: To facilitate the clinical diagnosis of ventilator-associated pneumonia (VAP) in the ICU, the Clinical Pulmonary Infection Score (CPIS) has been proposed but has shown a low diagnostic performance in subsequent studies. We propose a new score based on procalcitonin level and chest echography with the aim of improving VAP diagnosis: the Chest Echography and Procalcitonin Pulmonary Infection Score (CEPPIS). METHODS: This retrospective pilot study recruited patients admitted to the Intensive Care Unit of the Emergency Department, Careggi University Hospital (Florence, Italy), from January 2009 to December 2011. Patients were retrospectively divided into a microbiologically confirmed VAP group or a control group based on diagnosis of VAP and positive tracheal aspirate culture. RESULTS: A total of 221 patients were included, with 113 in the microbiologically confirmed VAP group and 108 in the control group. A CEPPIS > 5 retrospectively fixed was significantly better in predicting VAP (OR, 23.78; sensitivity, 80.5%; specificity, 85.2%) than a CPIS > 6 (OR, 3.309; sensitivity, 39.8%; specificity, 83.3%). The receiver operating characteristic area under the curve analysis also showed a significantly higher diagnostic value for CEPPIS > 5 than CPIS > 6 (0.829 vs 0.616, respectively; P < .0001). CONCLUSIONS: In this pilot, exploratory analysis, CEPPIS is effective in predicting VAP. Prospective validation is needed to confirm the potential value of this score to facilitate VAP diagnosis. PMID- 25144668 TI - Bronchial artery revascularization in lung transplantation: revival of an abandoned operation. AB - PURPOSE OF REVIEW: Current results of lung transplantation still lag behind those of other solid-organ transplants. Although bronchial dehiscence was the main cause of early mortality in the past, modern-day operative techniques and immunosuppression regiments have decreased, but not eliminated, this complication. Current barriers to long-term survival are chronic lung allograft dysfunction and infection. Bronchial artery revascularization was effective in decreasing bronchial anastomotic complications, but it was largely abandoned because of technical challenges. RECENT FINDINGS: Long-term follow-up in patients with bronchial artery revascularization has shown a survival advantage compared with the standard lung transplant technique. Recent data also show decreased infection, decreased early rejection and decreased bronchiolitis obliterans syndrome, in addition to confirming the known advantages in bronchial healing. Modifications of the technique have also made bronchial artery revascularization feasible in the pediatric population. SUMMARY: Bronchial artery revascularization, although initially designed for bronchial healing, has clinical advantages that extend long term, including survival, infection and decreased graft dysfunction. Its usage in lung transplantation needs to be revisited. PMID- 25144669 TI - Impact of female sex on long-term acute coronary syndrome outcomes. AB - OBJECTIVES: Recent literature shows a greater risk for adverse clinical outcomes following acute coronary syndrome (ACS) events in women undergoing a percutaneous coronary intervention (PCI), especially in young and diabetic patients. We aimed to assess the impact of sex on clinical results following ACS. METHODS: From our database of all-comer PCI patients, between 1 April 2004 and 31 December 2011, the procedural and angiographic results and clinical outcomes up to 5 years of 5819 patients with ACS undergoing emergent PCI were analyzed and compared according to sex. RESULTS: A total of 1425 (24.5%) of the patients were women. They presented at an older age (72.7+/-11.3 vs. 65.2+/-12.3 years, P<0.001), and more had diabetes mellitus (46.7 vs. 40.0%, P<0.001) and previous heart failure (12.1 vs. 7.26%, P=0.001). Mortality (21.63 vs. 13.22% at 5 years, P<0.001) and combined endpoints of death, myocardial infarction, and target-vessel revascularization (30.72 vs. 24.65% at 5 years, P<0.001) were higher in women. In a multivariate analysis using age, previous diabetes, heart failure, coronary artery bypass graft surgery, baseline glomerular filtration rate, presentation with ST-elevation myocardial infarction, and proximal left anterior descending artery disease, female sex was no longer an independent predictor of outcomes. No sex differences in mortality or major adverse cardiac events were observed in young or diabetic patients. CONCLUSION: Our results show no sex differences in clinical endpoints among ACS patients undergoing PCI after correction for advanced age and comorbidities. Importantly, no differences were found in patients with diabetes mellitus or those younger than 60 years of age. This may reflect the importance of the administration of evidence-based therapeutics in women. PMID- 25144670 TI - Thrombomodulin -33G/A and Ala455Val polymorphisms are associated with the risk of coronary artery disease: a meta-analysis including 12 584 patients. AB - BACKGROUND: Thrombomodulin (TM) -33G/A and Ala455Val polymorphisms have been indicated to be correlated with the risk of coronary artery disease (CAD), but study results are still inclusive. Thus, a meta-analysis was carried out. MATERIALS AND METHODS: Databases including PubMed, Embase, CNKI, and Web of Science (ISI) were searched. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Thirteen case control studies on the relationship between TM -33G/A and Ala455Val polymorphisms and the risk of CAD were included in this meta-analysis. The association between the TM -33G/A polymorphism and the risk of CAD was significant (OR=1.65; 95% CI, 1.35-2.02; P<0.01; I(2)=15%). This result remained statistically significant when the adjusted ORs were combined (OR=1.50; 95% CI, 1.23-1.84; P<0.01; I(2)=0%). The association between the TM Ala455Val polymorphism and the risk of CAD was also significant (OR=1.14; 95% CI, 1.05-1.24; P<0.01; I(2)=0%). This result remained statistically significant when the adjusted ORs were combined (OR=1.57; 95% CI, 1.05-2.34; P=0.03; I(2)=32%). CONCLUSION: This meta-analysis suggested that TM 33G/A and Ala455Val polymorphisms were risk factors for CAD. PMID- 25144671 TI - Relationship between bone mineral density and a 10-year risk for coronary artery disease in a healthy Korean population: the Korea National Health and Nutrition Examination Survey 2008-2010. AB - INTRODUCTION: Bone mineral density (BMD) is associated with atherosclerosis and vascular calcification. If BMD is related independently to the risk of coronary heart disease (CHD), BMD could play an important role in CHD risk prediction. We assessed the hypothesis that BMD is related independently to the risk of CHD. MATERIALS AND METHODS: We used data from the fourth and fifth Korea National Health and Nutrition Examination Surveys. The study sample included men and women aged 20-79 years, who did not have myocardial infarction, angina pectoris, stroke, or diabetes mellitus. We evaluated the relationship between BMD and the Framingham risk score for each sex. RESULTS: In the male population, femur neck BMD [coefficient=-2.167, 95% confidence interval (CI) -3.385 to -0.950, P=0.001] and lumbar spine BMD (coefficient=-1.539, 95% CI -2.546 to -0.532, P=0.003) showed an inverse correlation with the Framingham risk score after adjusting for covariates. In the female population, the relationship between BMD parameters and the Framingham risk score was not significant after adjusting for covariates. In the male population, those with femur neck BMD values in the first quartile had greater odds of a 10-year risk greater than or equal to 10% for CHD compared with those in the fourth quartile (odds ratio=1.942, 95% CI 1.315-2.869, P<0.001). CONCLUSION: BMD was correlated inversely with the 10-year risk for CHD in the healthy male population. This result suggests that in the male population, measurement of BMD could be useful for prediction of the risk of CHD. PMID- 25144672 TI - Microvascular function and incident erectile dysfunction: a new perspective for their relationship. PMID- 25144673 TI - Decellularized Lymph Nodes as Scaffolds for Tissue Engineered Lymph Nodes. AB - BACKGROUND: The lymphatic system is commonly injured during cancer treatment. However, despite the morbidity of these injuries, there are currently no options for replacing damaged lymphatics. The purpose of this study was to optimize methods for decellularization of murine lymph nodes (LN) and to determine if these scaffolds can be used to tissue engineer lymph node-like structures. METHODS AND RESULTS: LNs were harvested from adult mice and subjected to various decellularization protocols. The degree of decellularization and removal of nuclear material was analyzed histologically and quantitatively using DNA isolation. In addition, we analyzed histological architecture by staining for matrix proteins. After the optimal method of decellularization was identified, decellularized constructs were implanted in the renal capsule of syngeneic or allogeneic recipient mice and analyzed for antigenicity. Finally, to determine if decellularized constructs could deliver lymphocytes to recipient animals, the matrices were repopulated with splenocytes, implanted in submuscular pockets, and harvested 14 days later. Decellularization was best accomplished with the detergent sodium dodecyl sulfate (SDS), resulting in negligible residual cellular material but maintenance of LN architecture. Implantation of decellularized LNs into syngeneic or allogeneic mice did not elicit a significant antigenic response. In addition, repopulation of decellularized LNs with splenocytes resulted in successful in vivo cellular delivery. CONCLUSIONS: We show, for the first time, that LNs can be successfully decellularized and that these matrices have preserved extracellular matrix architecture and the potential to deliver leukocytes in vivo. Future studies are needed to determine if tissue engineered lymph nodes maintain immunologic function. PMID- 25144674 TI - A sulfated cyanobacterial polysaccharide proven as a strong inhibitor of human complement activity in an in vitro assay. AB - Cyanobacterial exopolysaccharides are a rich source of, so far, widely unexplored polysaccharides. One of these exopolysaccharides is a highly sulfated, linear polysaccharide from Synechocystis aquatilis containing the amino sugar N-acetyl fucosamine. Some sulfated polysaccharides and glycosaminoglycans are known to be inhibitors of the human complement system, which is an important part of the innate immune system. Defects in this system or misregulation can cause serious diseases. Therefore, new compounds with complement inhibiting activity and simple test assays are of great interest. Exopolysaccharides from S. aquatilis (arabinofucans) were compared to those from Synechocystis pevalekii (complex heteropolysaccharides) and the well-known complement inhibitor heparin. Investigations were performed with a modified ELISA test system based on a commercially available test kit quantifying the membrane attack complex. Hereby the testing becomes more stable, robust, reproducible, easier to handle and, for the first time, the effect of exopolysaccharides and heparin on the lectin pathway could be tested. The exopolysaccharides from S. aquatilis could be shown to be a 30 times stronger inhibitor of the classical pathway of the complement system compared to heparin (IC50 = 0.3 ug/mL vs. 9.2 ug/mL). These exopolysaccharides are also inhibitors of the lectin pathway (IC50 = 10.8 ug/mL) in which, however, heparin is more potent (IC50 = 2.0 ug/mL). Interestingly, these exopolysaccharides do not inhibit the alternative pathway. The exopolysaccharides from S. pevalekii are inactive in all pathways. Furthermore, partially hydrolyzed and desulfated exopolysaccharides from S. aquatilis were tested showing that a minimum molecular size and degree of sulfation are important for the inhibitory effects, whereas unspecific influences by complex formation of exopolysaccharides with calcium could be excluded. PMID- 25144675 TI - Feature selection for the identification of antitumor compounds in the alcohol total extracts of Curcuma longa. AB - Antitumor activity has been reported for turmeric, the dried rhizome of Curcuma longa. This study proposes a new feature selection method for the identification of the antitumor compounds in turmeric total extracts. The chemical composition of turmeric total extracts was analyzed by gas chromatography-mass spectrometry (21 ingredients) and high-performance liquid chromatography-mass spectrometry (22 ingredients), and their cytotoxicity was detected through an 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay against HeLa cells. A support vector machine for regression and a generalized regression neural network were used to research the composition-activity relationship and were later combined with the mean impact value to identify the antitumor compounds. The results showed that six volatile constituents (three terpenes and three ketones) and seven nonvolatile constituents (five curcuminoids and two unknown ingredients) with high absolute mean impact values exhibited a significant correlation with the cytotoxicity against HeLa cells. With the exception of the two unknown ingredients, the identified 11 constituents have been reported to exhibit cytotoxicity. This finding indicates that the feature selection method may be a supplementary tool for the identification of active compounds from herbs. PMID- 25144676 TI - Rural-urban differences in objective and subjective measures of physical activity: findings from the National Health and Nutrition Examination Survey (NHANES) 2003-2006. AB - INTRODUCTION: Lower levels of physical activity among rural relative to urban residents have been suggested as an important contributor to rural-urban health disparity; however, empirical evidence is sparse. METHODS: We examined rural urban differences in 4 objective physical activity measures (2 intensity thresholds by 2 bout lengths) and 4 subjective measures (total, leisure, household, and transportation) in a nationally representative sample of participants in the National Health and Nutrition Examination Survey (NHANES) 2003-2006. The sample comprised 5,056 adults aged 20 to 75 years. Rural-Urban Commuting Area (RUCA) codes were matched with NHANES subjects to identify urban status and 2 types of rural status. Rural-urban and within-rural differences in physical activity were estimated without and with controls for demographic and socioeconomic variables. RESULTS: Rural residents were less active than urban residents in high-intensity long bout (2,020 counts per minute threshold and 10 miniutes or longer bout length) accelerometer-measured physical activity (42.5 +/ 6.2 min/wk vs 55.9 +/- 2.8 min/wk) but the difference disappeared with a lower intensity threshold (760 counts per minute). Rural residents reported more total physical activity than urban residents (438.3 +/- 35.3min/wk vs 371.2 +/- 12.5 min/wk), with differences primarily attributable to household physical activity. Within rural areas, micropolitan residents were less active than residents in smaller rural areas. Controlling for other variables reduced the size of the differences. CONCLUSION: The direction and significance of rural-urban difference in physical activity varied by the method of physical activity measurement, likely related to rural residents spending more time in low-intensity household physical activity but less time in high-intensity physical activity. Micropolitan residents were substantially less active than residents in smaller rural areas, indicating that physical activity did not vary unidirectionally with degree of urbanization. PMID- 25144678 TI - Lessons learned from a healthful vending pilot program in Delaware state agency buildings, 2011-2012. AB - INTRODUCTION: Changes in food availability in worksites can result in changes in eating behavior and weight status. Nemours Health and Prevention Services, in conjunction with partners in Delaware, conducted a 6-month pilot program to assess the feasibility and impact of requiring that 75% of the items in vending machines in 3 state agency buildings have healthful items. METHODS: We collected process evaluation data from October 2011 through April 2012 by taking weekly photographs of all machines to record the number of healthful items available. Outcomes were measured through sales reports designed to enumerate changes in number and type of items sold and overall profit from each building. RESULTS: We found challenges in fully implementing the 75% goal. In one of the 3 buildings, all machines were compliant within 7 weeks; in another, full compliance did not occur until week 19. Despite these challenges, the number of items sold in each machine was comparable to numbers from the previous year. Total profits from each building varied across the 3 sites and during the pilot. One building had a 51% increase in profits in January 2012 compared with profits averaged for January 2011 and January 2010. In contrast, monthly profit at another building fluctuated from an increase of 6% to a loss of 30%. CONCLUSION: Overall, our results suggest that collaborative efforts can result in a feasible intervention with little negative influence on profits. PMID- 25144677 TI - Adaptation and evaluation of the WillTry tool among children in Guam. AB - INTRODUCTION: Fruit and vegetable consumption may reduce risk for chronic disease and obesity. Children's fruit and vegetable intake is mediated by a preference or willingness to try them. This study's primary objective was to adapt the previously validated WillTry tool and to evaluate the adapted version among children in Guam. METHODS: Adaptations to the WillTry tool included both novel fruits and vegetables unique to Guam and common ones. Children aged 3 to 11 years who attended 2 community-based summer day camps in 2013 were shown images matching 14 food questions in an initial interview and in a second interview conducted 3 to 72 hours later. Responses were "no," "maybe," or "yes" and were coded as 1, 2, or 3, respectively. A higher score indicated more willingness to try fruits and vegetables. Factor analyses determined components of willingness. Psychometric properties and reliability were analyzed. RESULTS: Sixty-five children completed the first interview, and 64 completed the second. Factor analyses revealed 3 components (scales):1) local novel (guava, breadfruit, eggplant, sweet sop, star apple, taro leaves), 2) local common (carrot, papaya, long beans, salad greens), and 3) imported (apple, canned peaches, canned corn). All but the imported scale had sufficient internal consistency (Cronbach's alpha > 0.69). Each scale had substantial reliability (ICC > 0.76). We found no significant differences by age, sex, or type of camp for any scale. Mean scores were 2.1 (local novel), 2.4 (local common), and 2.7 (imported), and all were significantly different. CONCLUSION: The adapted WillTry was culturally relevant and had psychometric properties similar to those of the original. An unexpected finding was the tool's potential for documenting the nutrition transition. PMID- 25144679 TI - Use of sunscreen and indoor tanning devices among a nationally representative sample of high school students, 2001-2011. AB - Adolescents are particularly vulnerable to engaging in poor skin-protection behaviors. The objective of this study was to examine use of sunscreen and indoor tanning devices among a nationally representative sample of high school students during a 10-year period (2001-2011) using data from the Youth Risk Behavior Surveillance System. The percentage of youth who reported using sunscreen declined from 67.7% in 2001 to 56.1% in 2011. The prevalence of using indoor tanning devices was highest among white females: 37.4% in 2009 and 29.3% in 2011. These findings indicate the need for prevention efforts aimed at adolescents to reduce risks for skin cancer. PMID- 25144680 TI - Facial expression training optimises viewing strategy in children and adults. AB - This study investigated whether training-related improvements in facial expression categorization are facilitated by spontaneous changes in gaze behaviour in adults and nine-year old children. Four sessions of a self-paced, free-viewing training task required participants to categorize happy, sad and fear expressions with varying intensities. No instructions about eye movements were given. Eye-movements were recorded in the first and fourth training session. New faces were introduced in session four to establish transfer-effects of learning. Adults focused most on the eyes in all sessions and increased expression categorization accuracy after training coincided with a strengthening of this eye-bias in gaze allocation. In children, training-related behavioural improvements coincided with an overall shift in gaze-focus towards the eyes (resulting in more adult-like gaze-distributions) and towards the mouth for happy faces in the second fixation. Gaze-distributions were not influenced by the expression intensity or by the introduction of new faces. It was proposed that training enhanced the use of a uniform, predominantly eyes-biased, gaze strategy in children in order to optimise extraction of relevant cues for discrimination between subtle facial expressions. PMID- 25144682 TI - LnV3Te3O15(OH)3.nH2O (Ln = Ce, Pr, Nd, Sm, Eu, Gd; n = 1-2): a new series of semiconductors with mixed-valent tellurium (IV,VI) oxoanions. AB - Six new lanthanide tellurium vanadates with the general formula LnV3Te3O15(OH)3.nH2O (LnVTeO) (Ln = Ce, Pr, Nd, Sm, Eu, and Gd; n = 2 for Ce and Pr; n = 1 for Nd, Sm, Eu, and Gd) have been prepared hydrothermally via the reactions of lanthanide nitrates, TeO2, and V2O5 at 230 degrees C. LnVTeO adopts a three-dimensional (3D) channel structure with a space group of P63/mmc. Surprisingly, two types of oxoanions: Te(IV)O3(2-) trigonal pyramids and Te(VI)O6(6-) octahedra, coexist in these compounds. Solid-state UV-vis-NIR absorption spectra for LnVTeO show approximate band gaps on the order of 1.9 eV, suggesting the wide band gap semiconducting nature of these materials. No magnetic phase transition was observed in any of the analogues, but a clear increase in the strength of short-range antiferromagnetic correlations was found with the shortening of distances between magnetically coupled Ln(3+) ions in LnVTeO. PMID- 25144681 TI - Amelioration of DSS-induced murine colitis by VSL#3 supplementation is primarily associated with changes in ileal microbiota composition. AB - Inflammatory bowel diseases encompass gastrointestinal illnesses typified by chronic inflammation, loss of epithelial integrity and gastrointestinal microbiota dysbiosis. In an effort to counteract these characteristic perturbations, we used stem cells and/or a probiotic therapy in a murine model of Dextran Sodium Sulfate induced colitis to examine both their efficacy in ameliorating disease and impact on niche-specific microbial communities of the lower GI tract. Colitis was induced in C57BL/6 mice by administering 3% DSS in drinking water for 10 days prior to administering one of three treatment plans: daily probiotic (VSL#3) supplementation for 3 days, a single tail vein injection of 1x10 (6) murine mesenchymal stem cells, or both. Ileal, cecal and colonic sections were collected for microbiota and histological analyses. Microbiota profiling revealed distinct bacterial community compositions in the ileum, cecum and colon of control untreated animals, all of which were predicted in silico to be enriched for a number of discrete KEGG pathways, indicating compositional and functional niche specificity in healthy animals. DSS-treatment perturbed community composition in all three niches with ileal communities exhibiting the greatest change relative to control animals. Each treatment group exhibited treatment-specific alterations in microbiota composition in the lower GI tract, though disease scores were only improved in VSL#3-treated animals. The ileal microbiota were most profoundly altered in composition in this group of animals and characterized by significant Enterobacteriaceae enrichment compared with colitic mice (P<0.05). PMID- 25144683 TI - Ten simple rules of live tweeting at scientific conferences. PMID- 25144684 TI - Silver and gold nanoparticles exposure to in vitro cultured retina--studies on nanoparticle internalization, apoptosis, oxidative stress, glial- and microglial activity. AB - The complex network of neuronal cells in the retina makes it a potential target of neuronal toxicity--a risk factor for visual loss. With growing use of nanoparticles (NPs) in commercial and medical applications, including ophthalmology, there is a need for reliable models for early prediction of NP toxicity in the eye and retina. Metal NPs, such as gold and silver, gain much of attention in the ophthalmology community due to their potential to cross the barriers of the eye. Here, NP uptake and signs of toxicity were investigated after exposure to 20 and 80 nm Ag- and AuNPs, using an in vitro tissue culture model of the mouse retina. The model offers long-term preservation of retinal cell types, numbers and morphology and is a controlled system for delivery of NPs, using serum-free defined culture medium. AgNO3-treatment was used as control for toxicity caused by silver ions. These end-points were studied; gross morphological organization, glial activity, microglial activity, level of apoptosis and oxidative stress, which are all well described as signs of insult to neural tissue. TEM analysis demonstrated cellular- and nuclear uptake of all NP types in all neuronal layers of the retina. Htx-eosin staining showed morphological disruption of the normal complex layered retinal structure, vacuole formation and pyknotic cells after exposure to all Ag- and AuNPs. Significantly higher numbers of apoptotic cells as well as an increased number of oxidative stressed cells demonstrated NP-related neuronal toxicity. NPs also caused increased glial staining and microglial cell activation, typical hallmarks of neural tissue insult. This study demonstrates that low concentrations of 20 and 80 nm sized Ag- and AuNPs have adverse effects on the retina, using an organotypic retina culture model. Our results motivate careful assessment of candidate NP, metallic or-non-metallic, to be used in neural systems for therapeutic approaches. PMID- 25144685 TI - Negative interference by rheumatoid factor of plasma B-type natriuretic peptide in chemiluminescent microparticle immunoassays. AB - BACKGROUND: The chemiluminescent microparticle immunoassay (CMIA) is widely used for the quantitative determination of B-type natriuretic peptide (BNP) in human ethylenediaminetetraacetic acid plasma. Rheumatoid factor (RF) is usually thought to result in a positive interference in immunoassays, but it is not clear whether its presence in plasma can lead to interferences in the CMIA of BNP. METHODS: The estimation of BNP recovery was carried out by diluting high-concentration BNP samples with RF-positive or RF-negative plasma at a ratio of 1:9. The diluted samples were then tested using the ARCHITECT i2000 System and ARCHITECT BNP Reagent Kits and the recovery was then calculated. RESULTS: When the RF level ranged from 48 to 1420 IU/mL, the average recovery of BNP was 79.29% and 91.61% in the RF-positive and RF-negative plasma samples, respectively, and was thus significantly lower in the group of RF-positive plasma samples than in the group of RF-negative plasma samples. At a dilution of 1:16, the measured BNP level increased by >36% in six of the seven RF-positive plasma samples. The recovery of BNP increased significantly in the RF-positive plasma samples after pretreatment with IgG-sensitive latex particles. In addition, The BNP recovery was not significantly related to the plasma RF at concentrations ranging from 48 to 2720 IU/mL. CONCLUSIONS: Measurement of BNP by CMIA is susceptible to interference from RF leading to predominantly (but not exclusively) lower results. Pretreatment of samples with blocking reagents is advisable prior to the initiation of denying patient's necessary treatment. PMID- 25144686 TI - Sedentary behavior and health outcomes: an overview of systematic reviews. AB - OBJECTIVE: 1) To synthesize the current observational evidence for the association between sedentary behavior and health outcomes using information from systematic reviews. 2) To assess the methodological quality of the systematic reviews found. METHODOLOGY/PRINCIPAL FINDINGS: Medline; Excerpta Medica (Embase); PsycINFO; and Web of Science were searched for reviews published up to September 2013. Additional publications were provided by Sedentary Behaviour Research Network members. The methodological quality of the systematic reviews was evaluated using recommended standard criteria from AMSTAR. For each review, improper use of causal language in the description of their main results/conclusion was evaluated. Altogether, 1,044 review titles were identified, 144 were read in their entirety, and 27 were included. Based on the systematic reviews with the best methodological quality, we found in children and adolescents, strong evidence of a relationship between time spent in sedentary behavior and obesity. Moreover, moderate evidence was observed for blood pressure and total cholesterol, self-esteem, social behavior problems, physical fitness and academic achievement. In adults, we found strong evidence of a relationship between sedentary behavior and all-cause mortality, fatal and non-fatal cardiovascular disease, type 2 diabetes and metabolic syndrome. In addition, there is moderate evidence for incidence rates of ovarian, colon and endometrial cancers. CONCLUSIONS: This overview based on the best available systematics reviews, shows that sedentary behavior may be an important determinant of health, independently of physical activity. However, the relationship is complex because it depends on the type of sedentary behavior and the age group studied. The relationship between sedentary behavior and many health outcomes remains uncertain; thus, further studies are warranted. PMID- 25144687 TI - Production of an attenuated phenol-soluble modulin variant unique to the MRSA clonal complex 30 increases severity of bloodstream infection. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and death. Phenol-soluble modulins (PSMs) are recently-discovered toxins with a key impact on the development of Staphylococcus aureus infections. Allelic variants of PSMs and their potential impact on pathogen success during infection have not yet been described. Here we show that the clonal complex (CC) 30 lineage, a major cause of hospital-associated sepsis and hematogenous complications, expresses an allelic variant of the PSMalpha3 peptide. We found that this variant, PSMalpha3N22Y, is characteristic of CC30 strains and has significantly reduced cytolytic and pro-inflammatory potential. Notably, CC30 strains showed reduced cytolytic and chemotactic potential toward human neutrophils, and increased hematogenous seeding in a bacteremia model, compared to strains in which the genome was altered to express non-CC30 PSMalpha3. Our findings describe a molecular mechanism contributing to attenuated pro inflammatory potential in a main MRSA lineage. They suggest that reduced pathogen recognition via PSMs allows the bacteria to evade elimination by innate host defenses during bloodstream infections. Furthermore, they underscore the role of point mutations in key S. aureus toxin genes in that adaptation and the pivotal importance PSMs have in defining key S. aureus immune evasion and virulence mechanisms. PMID- 25144689 TI - Is Matang Mangrove Forest in Malaysia sustainably rejuvenating after more than a century of conservation and harvesting management? AB - Matang Mangrove Forest Reserve (MMFR) in Peninsular Malaysia is under systematic management since 1902 and still considered as the best managed mangrove forest in the world. The present study on silvimetrics assessed the ongoing MMFR forest management, which includes a first thinning after 15 years, a second thinning after 20 years and clear-felling of 30-year old forest blocks, for its efficiency and productivity in comparison to natural mangroves. The estimated tree structural parameters (e.g. density, frequency) from three different-aged mangrove blocks of fifteen (MF15), twenty (MF20), and thirty (MF30) years old indicated that Bruguiera and Excoecaria spp. did not constitute a significant proportion of the vegetation (<5%), and hence the results focused majorly on Rhizophora apiculata. The density of R. apiculata at MF15, MF20 and MF30 was 4,331, 2,753 and 1,767 stems ha(-1), respectively. In relation to ongoing practices of the artificial thinnings at MMFR, the present study suggests that the first thinning could be made earlier to limit the loss of exploitable wood due to natural thinning. In fact, the initial density at MF15 was expected to drop down from 6,726 to 1,858 trees ha(-1) before the first thinning. Therefore the trees likely to qualify for natural thinning, though having a smaller stem diameter, should be exploited for domestic/commercial purposes at an earlier stage. The clear-felling block (MF30) with a maximum stem diameter of 30 cm was estimated to yield 372 t ha(-1) of the above-ground biomass and suggests that the mangrove management based on a 30-year rotation is appropriate for the MMFR. Since Matang is the only iconic site that practicing sustainable wood production, it could be an exemplary to other mangrove locations for their improved management. PMID- 25144688 TI - Quantitative analysis of vasodilatory action of quercetin on intramural coronary resistance arteries of the rat in vitro. AB - BACKGROUND: Dietary quercetin improves cardiovascular health, relaxes some vascular smooth muscle and has been demonstrated to serve as a substrate for the cyclooxygenase enzyme. AIMS: 1. To test quantitatively a potential direct vasodilatory effect on intramural coronary resistance artery segments, in different concentrations. 2. To scale vasorelaxation at different intraluminal pressure loads on such vessels of different size. 3. To test the potential role of prostanoids in vasodilatation induced by quercetin. METHODS: Coronary arterioles (70-240 um) were prepared from 24 rats and pressurized in PSS, using a pressure microangiometer. RESULTS: The spontaneous tone that developed at 50 mmHg was relaxed by quercetin in the 10(-9) moles/lit concentration (p<0.05), while 10(-5) moles/lit caused full relaxation. Significant relaxation was observed at all pressure levels (10-100 mmHg) at 10(-7) moles/lit concentration of quercetin. The cyclooxygenase blocker indomethacin (10(-5) moles/lit) induced no relaxation but contraction when physiological concentrations of quercetin were present in the tissue bath (p<0.02 with Anova), this contraction being more prominent in smaller vessels and in the higher pressure range (p<0.05, Pearson correlation). A further 2-8% contraction could be elicited by the NO blocker L-NAME (10(-4) moles/lit). CONCLUSION: These results demonstrate that circulating levels of quercetin (10(-7) moles/lit) exhibit a substantial coronary vasodilatory effect. The extent of it is commeasurable with that of several other physiological mechanisms of coronary blood flow control. At least part of this relaxation is the result of an altered balance toward the production of endogenous vasodilatory prostanoids in the coronary arteriole wall. PMID- 25144691 TI - Study of exciton transfer in dense quantum dot nanocomposites. AB - Nanocomposites of colloidal quantum dots (QDs) integrated into conjugated polymers (CPs) are key to hybrid optoelectronics, where engineering the excitonic interactions at the nanoscale is crucial. For such excitonic operation, it was believed that exciton diffusion is essential to realize nonradiative energy transfer from CPs to QDs. In this study, contrary to the previous literature, efficient exciton transfer is demonstrated in the nanocomposites of dense QDs, where exciton transfer can be as efficient as 80% without requiring the assistance of exciton diffusion. This is enabled by uniform dispersion of QDs at high density (up to ~70 wt%) in the nanocomposite while avoiding phase segregation. Theoretical modeling supports the experimental observation of weakly temperature dependent nonradiative energy transfer dynamics. This new finding provides the ability to design hybrid light-emitting diodes that show an order of magnitude enhanced external quantum efficiencies. PMID- 25144692 TI - Band gap engineering of ZnO using core/shell morphology with environmentally benign Ag2S sensitizer for efficient light harvesting and enhanced visible-light photocatalysis. AB - Band gap engineering offers tunable optical and electronic properties of semiconductors in the development of efficient photovoltaic cells and photocatalysts. Our study demonstrates the band gap engineering of ZnO nanorods to develop a highly efficient visible-light photocatalyst. We engineered the band gap of ZnO nanorods by introducing the core/shell geometry with Ag2S sensitizer as the shell. Introduction of the core/shell geometry evinces great promise for expanding the light-harvesting range and substantial suppression of charge carrier recombination, which are of supreme importance in the realm of photocatalysis. To unveil the superiority of Ag2S as a sensitizer in engineering the band gap of ZnO in comparison to the Cd-based sensitizers, we also designed ZnO/CdS core/shell nanostructures having the same shell thickness. The photocatalytic performance of the resultant core/shell nanostructures toward methylene blue (MB) dye degradation has been studied. The results imply that the ZnO/Ag2S core/shell nanostructures reveal 40- and 2-fold enhancement in degradation constant in comparison to the pure ZnO and ZnO/CdS core/shell nanostructures, respectively. This high efficiency is elucidated in terms of (i) efficient light harvesting owing to the incorporation of Ag2S and (ii) smaller conduction band offset between ZnO and Ag2S, promoting more efficient charge separation at the core/shell interface. A credible photodegradation mechanism for the MB dye deploying ZnO/Ag2S core/shell nanostructures is proposed from the analysis of involved active species such as hydroxyl radicals (OH(*)), electrons (e(-)(CB)), holes (h(+)(VB)), and superoxide radical anions (O2(*-)) in the photodegradation process utilizing various active species scavengers and EPR spectroscopy. The findings show that the MB oxidation is directed mainly by the assistance of hydroxyl radicals (OH(*)). The results presented here provide new insights for developing band gap engineered semiconductor nanostructures for energy-harvesting applications and demonstrate Ag2S to be a potential sensitizer to supersede Cd-based sensitizers for eco-friendly applications. PMID- 25144690 TI - Sympathetic denervation-induced MSC mobilization in distraction osteogenesis associates with inhibition of MSC migration and osteogenesis by norepinephrine/adrb3. AB - The sympathetic nervous system regulates bone formation and resorption under physiological conditions. However, it is still unclear how the sympathetic nerves affect stem cell migration and differentiation in bone regeneration. Distraction osteogenesis is an ideal model of bone regeneration due to its special nature as a self-engineering tissue. In this study, a rat model of mandibular distraction osteogenesis with transection of cervical sympathetic trunk was used to demonstrate that sympathetic denervation can deplete norepinephrine (NE) in distraction-induced bone callus, down-regulate beta3-adrenergic receptor (adrb3) in bone marrow mesenchymal stem cells (MSCs), and promote MSC migration from perivascular regions to bone-forming units. An in vitro Transwell assay was here used to demonstrate that NE can inhibit stroma-derived factor-1 (SDF-1)-induced MSC migration and expression of the migration-related gene matrix metalloproteinase-2 (MMP-2) and downregulate that of the anti-migration gene tissue inhibitor of metalloproteinase-3 (TIMP-3). Knockdown of adrb3 using siRNA abolishes inhibition of MSC migration. An in vitro osteogenic assay was used to show that NE can inhibit the formation of MSC bone nodules and expression of the osteogenic marker genes alkaline phosphatase (ALP), osteocalcin (OCN), and runt related transcription factor-2 (RUNX2), but knockdown of adrb3 by siRNA can abolish such inhibition of the osteogenic differentiation of MSCs. It is here concluded that sympathetic denervation-induced MSC mobilization in rat mandibular distraction osteogenesis is associated with inhibition of MSC migration and osteogenic differentiation by NE/adrb3 in vitro. These findings may facilitate understanding of the relationship of MSC mobilization and sympathetic nervous system across a wide spectrum of tissue regeneration processes. PMID- 25144693 TI - Termination of parental rights for parents with substance use disorder: for whom and then what? AB - The purpose of this study is to investigate the correlates of termination of parental rights (TPR) for parents with substance use disorder (SUD) and to determine what happens with regard to permanency once a TPR decision is made. Bivariate techniques and hierarchical nonlinear modeling are used. Parents of older youth, boys, and Hispanics were less likely, whereas parents who failed to make progress in substance use treatment and parenting skills are more likely to experience TPR. At follow up, 85% of the children were adopted, 7% remained in a substitute care settings, and 7% were reunified with their parents. Concerns remain for children without a permanent home setting. PMID- 25144695 TI - Factors associated with perceived health among Korean adolescents. AB - This study examined the influences of personal, social, and environmental structural factors on the perceived health of Korean adolescents. Using a two stage generalized hierarchical logistic linear multilevel model, this study found that general high school enrollment, younger age, normal weight, and frequent exercise increased the likelihood of a positive self-perception of health. Higher levels of parental concern and quality of school life also contributed to the likelihood of students perceiving themselves as healthy. In contrast, psychological symptoms and negative self-esteem decreased the likelihood that students perceived themselves as healthy. The results provide implications for disease prevention and health promotion programs. PMID- 25144696 TI - Alcohol use during pregnancy: considerations for Australian policy. AB - Although there is an extensive recorded history of concerns related to alcohol exposed pregnancies and possible outcomes of fetal alcohol spectrum disorder in recent scientific literature, Australia has only recently begun to accurately or systematically diagnose and record these conditions, or to provide comprehensive, coordinated, policy-guided funding, prevention, and treatment. This article discusses some considerations that can guide policy development within the Australian context including the social context and determinates of alcohol consumption during pregnancy and the need to consider the issue as one that goes beyond the decision making of individual women. The article also identifies the contribution of research to guide evidence-based policy development, including emerging evidence of epigenetics, and systematic reviews for prevention. Other policy considerations include costs, and the possibility of the prevention paradox applying to this field, with its associated impact on costs and focus of prevention. PMID- 25144697 TI - A pilot randomized study of skills training for African American cancer survivors. AB - This study tested the efficacy of a psychosocial group intervention for African American breast cancer survivors based on the Cancer Survival Toolbox with the specific aim of decreasing distress and improving aspects of psychosocial functioning and quality of life. This pilot study utilized a randomized, repeated measures, experimental design. The study sample (N = 71) consisted of an intervention group (n = 23) of cancer survival skills training for 6 weeks and a control group (n = 48). The study could not confirm that cancer skills training in a psychoeducational group setting had a positive effect on decreasing stress or improving aspects of psychosocial functioning and quality of life. PMID- 25144698 TI - Culturally competent health care from the immigrant lens: a qualitative interpretive meta-synthesis (QIMS). AB - Immigrant groups comprise a large segment of ethnic minorities in the United States. Although the literature is rich with strategies to deliver culturally and linguistically appropriate services to eliminate health inequities, studies addressing cultural competence from the immigrant's perspective are limited. Further research is needed to build knowledge of the predictors and needs of this population, and to influence health care policy and practice. Using qualitative interpretive meta-synthesis, this study describes the lived experience of immigrants accessing health care to understand the essence of cultural competence in health care through their lens. Findings provide insight on expanding the definition of culturally competent health care beyond language, behaviors, attitudes, and policies. PMID- 25144694 TI - Current approaches to support the psychosocial care of African American adults with diabetes: a brief review. AB - African Americans are disproportionately affected by Type 2 diabetes and experience significantly higher age-adjusted prevalence of the disease. Psychosocial support, material resources, and education can have a significant impact on successful diabetes management, particularly among populations with diabetes-related psychological distress such as African Americans. This brief review of the literature identifies and synthesizes current evidence on faith based, community-based, empowerment-based, strength-based, and culturally competent strategies that may be particularly relevant for social work practitioners supporting African American adults at risk for or diagnosed with Type 2 diabetes. Discussion focuses on multiple influences on the self determination of clients working to manage their condition. PMID- 25144700 TI - The impact of family and parental education on adolescents' substance use: a study of U.S. high school seniors. AB - This study explores the impact of family structure and parental education on adolescents' substance use using a racially diverse sample of 14,268, 12th-grade high school adolescents. Findings reveal that family structure affects adolescents' substance use. In addition, racial differences are noted. African American adolescents report a relatively lower rate of substance use compared to White and Hispanic adolescents, yet they are gravely affected by substance use outcomes. The study lends further support that family structure and parental education variables may buffer adolescents from substance abuse influences. Implications for practice and policy are discussed. PMID- 25144701 TI - An evaluation of the public health paradigm: a view of social work. AB - This article engages in a critical review of the public health paradigm to determine the compatibility with social work's guiding value of social justice. This critical examination explores the history, epistemology, and view of health underlying the public health paradigm. Implications of the public health paradigm's view of health on social work practice and discourse is examined. PMID- 25144699 TI - Peer navigators and integrated care to address ethnic health disparities of people with serious mental illness. AB - People of color with serious mental illnesses experience high rates of morbidity and mortality. Patient navigators, developed for cancer care, may help this group benefit from integrated care. This review examined patient navigators' key ingredients for cancer care for relevance to patients of color for application of peer services to psychiatric goals. Among cancer patients, navigators lead to greater treatment engagement and improved health outcomes for ethnic minority groups. Research also suggests peers can improve integrated care by providing effective psychiatric services to individuals with mental illness. Ongoing research examines peer navigators' impact on integrated care for patients of color. PMID- 25144702 TI - Disaggregating race and ethnicity in chronic health conditions: implications for public health social work. AB - This study examines the ethnic subgroup variation in chronic health by comparing self-reports of chronic conditions across diverse ethnic subgroups of Asian American (Vietnamese, Filipino, Chinese), Latino American (Cuban, Portuguese, Mexican), and African Caribbean (Haitian, Jamaican, Trinidadian/Tobagonian) respondents. This analysis utilizes linked data from the Collaborative Psychiatric Epidemiology Surveys (CPES). Logistic regression revealed significant subgroup differences in reports of chronic respiratory, cardiovascular, and pain conditions across nine ethnic subgroups masked by racial categorization. Findings suggest that precautions must be taken by public health social workers as there may be far more ethnic heterogeneity than is apparent among broad racial categories. PMID- 25144703 TI - Nonemergency medical transportation and health care visits among chronically ill urban and rural medicaid beneficiaries. AB - Inaccessibility to health care services due to lack of transportation affects the most vulnerable segments of the society. The effect of Medicaid-provided nonemergency medical transportation (NEMT) in Oklahoma on health care visits for the management of chronic illnesses is examined. Analyses of claims data show that African Americans are the highest users of NEMT. Medicaid beneficiaries who use NEMT services are significantly more likely to make the recommended number of annual visits for the management of chronic conditions than those who do not use NEMT. Increased use of NEMT by making the services more accommodating and convenient for beneficiaries is proposed. PMID- 25144704 TI - Schistosoma japonicum soluble egg antigens facilitate hepatic stellate cell apoptosis by downregulating Akt expression and upregulating p53 and DR5 expression. AB - BACKGROUND: The induction of hepatic stellate cell (HSC) apoptosis has potential as a potent strategy to diminish the progression of liver fibrosis. Previous studies have demonstrated the ability of soluble egg antigens (SEA) from schistosomes to inhibit HSC activation and to induce apoptosis in vitro. In this study, we aimed to explore the mechanism of SEA-induced apoptosis in HSCs. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we found that SEA could upregulate p53 and DR5 and downregulate the p-Akt. The apoptosis of HSCs induced by SEA could be reduced in HSCs that were treated with p53-specific siRNA and in HSCs that were treated with DR5-specific shRNA. In addition, GW501516, which enhances the expression of Akt, could also decrease the SEA-induced HSC apoptosis. We also found that the increased expression of p53 and DR5 induced by SEA through Mdm2 were reduced by GW501516. CONCLUSIONS/SIGNIFICANCE: Our data suggest that SEA can induce HSC apoptosis by downregulating Akt expression and upregulating p53 dependent DR5 expression. PMID- 25144705 TI - Recognition of double-stranded DNA using energetically activated duplexes with interstrand zippers of 1-, 2- or 4-pyrenyl-functionalized O2'-alkylated RNA monomers. AB - Despite advances with triplex-forming oligonucleotides, peptide nucleic acids, polyamides and--more recently--engineered proteins, there remains an urgent need for synthetic ligands that enable specific recognition of double-stranded (ds) DNA to accelerate studies aiming at detecting, regulating and modifying genes. Invaders, i.e., energetically activated DNA duplexes with interstrand zipper arrangements of intercalator-functionalized nucleotides, are emerging as an attractive approach toward this goal. Here, we characterize and compare Invaders based on 1-, 2- and 4-pyrenyl-functionalized O2'-alkylated uridine monomers X-Z by means of thermal denaturation experiments, optical spectroscopy, force-field simulations and recognition experiments using DNA hairpins as model targets. We demonstrate that Invaders with +1 interstrand zippers of X or Y monomers efficiently recognize mixed-sequence DNA hairpins with single nucleotide fidelity. Intercalator-mediated unwinding and activation of the double-stranded probe, coupled with extraordinary stabilization of probe-target duplexes (DeltaT(m)/modification up to +14.0 degrees C), provides the driving force for dsDNA recognition. In contrast, Z-modified Invaders show much lower dsDNA recognition efficiency. Thus, even very conservative changes in the chemical makeup of the intercalator-functionalized nucleotides used to activate Invader duplexes, affects dsDNA-recognition efficiency of the probes, which highlights the importance of systematic structure-property studies. The insight from this study will guide future design of Invaders for applications in molecular biology and nucleic acid diagnostics. PMID- 25144706 TI - A model-based approach for identifying signatures of ancient balancing selection in genetic data. AB - While much effort has focused on detecting positive and negative directional selection in the human genome, relatively little work has been devoted to balancing selection. This lack of attention is likely due to the paucity of sophisticated methods for identifying sites under balancing selection. Here we develop two composite likelihood ratio tests for detecting balancing selection. Using simulations, we show that these methods outperform competing methods under a variety of assumptions and demographic models. We apply the new methods to whole-genome human data, and find a number of previously-identified loci with strong evidence of balancing selection, including several HLA genes. Additionally, we find evidence for many novel candidates, the strongest of which is FANK1, an imprinted gene that suppresses apoptosis, is expressed during meiosis in males, and displays marginal signs of segregation distortion. We hypothesize that balancing selection acts on this locus to stabilize the segregation distortion and negative fitness effects of the distorter allele. Thus, our methods are able to reproduce many previously-hypothesized signals of balancing selection, as well as discover novel interesting candidates. PMID- 25144707 TI - Indocyanine green video angiography predicts outcome of extravasation injuries. AB - BACKGROUND: Extravasation of cytotoxic drugs is a serious complication of systemic cancer treatment. Still, a reliable method for early assessment of tissue damage and outcome prediction is missing. Here, we demonstrate that the evaluation of blood flow by indocyanine green (ICG) angiography in the extravasation area predicts for the need of surgical intervention. METHODS: Twenty-nine patients were evaluated by ICG angiography after extravasation of vesicant or highly irritant cytotoxic drugs administered by peripheral i.v. infusion. Tissue perfusion as assessed by this standardized method was correlated with clinical outcome. RESULTS: The perfusion index at the site of extravasation differed significantly between patients with reversible tissue damage and thus healing under conservative management (N = 22) versus those who needed surgical intervention due to the development of necrosis (N = 7; P = 0.0001). Furthermore, in patients benefiting from conservative management, the perfusion index was significantly higher in the central extravasation area denoting hyperemia, when compared with the peripheral area (P = 0.0001). CONCLUSIONS: In this patient cohort, ICG angiography as indicator of local perfusion within the extravasation area was of prognostic value for tissue damage. ICG angiography could thus be used for the early identification of patients at risk for irreversible tissue damage after extravasation of cytotoxic drugs. PMID- 25144708 TI - Linear associations between clinically assessed upper motor neuron disease and diffusion tensor imaging metrics in amyotrophic lateral sclerosis. AB - OBJECTIVE: To assess the relationship between clinically assessed Upper Motor Neuron (UMN) disease in Amyotrophic Lateral Sclerosis (ALS) and local diffusion alterations measured in the brain corticospinal tract (CST) by a tractography driven template-space region-of-interest (ROI) analysis of Diffusion Tensor Imaging (DTI). METHODS: This cross-sectional study included 34 patients with ALS, on whom DTI was performed. Clinical measures were separately obtained including the Penn UMN Score, a summary metric based upon standard clinical methods. After normalizing all DTI data to a population-specific template, tractography was performed to determine a region-of-interest (ROI) outlining the CST, in which average Mean Diffusivity (MD) and Fractional Anisotropy (FA) were estimated. Linear regression analyses were used to investigate associations of DTI metrics (MD, FA) with clinical measures (Penn UMN Score, ALSFRS-R, duration-of-disease), along with age, sex, handedness, and El Escorial category as covariates. RESULTS: For MD, the regression model was significant (p = 0.02), and the only significant predictors were the Penn UMN Score (p = 0.005) and age (p = 0.03). The FA regression model was also significant (p = 0.02); the only significant predictor was the Penn UMN Score (p = 0.003). CONCLUSIONS: Measured by the template-space ROI method, both MD and FA were linearly associated with the Penn UMN Score, supporting the hypothesis that DTI alterations reflect UMN pathology as assessed by the clinical examination. PMID- 25144709 TI - A novel insulin receptor-binding protein from Momordica charantia enhances glucose uptake and glucose clearance in vitro and in vivo through triggering insulin receptor signaling pathway. AB - Diabetes, a common metabolic disorder, is characterized by hyperglycemia. Insulin is the principal mediator of glucose homeostasis. In a previous study, we identified a trypsin inhibitor, named Momordica charantia insulin receptor (IR) binding protein (mcIRBP) in this study, that might interact with IR. The physical and functional interactions between mcIRBP and IR were clearly analyzed in the present study. Photo-cross-linking coupled with mass spectrometry showed that three regions (17-21, 34-40, and 59-66 residues) located on mcIRBP physically interacted with leucine-rich repeat domain and cysteine-rich region of IR. IR binding assay showed that the binding behavior of mcIRBP and insulin displayed a cooperative manner. After binding to IR, mcIRBP activated the kinase activity of IR by (5.87 +/- 0.45)-fold, increased the amount of phospho-IR protein by (1.31 +/- 0.03)-fold, affected phosphoinositide-3-kinase/Akt pathways, and consequently stimulated the uptake of glucose in 3T3-L1 cells by (1.36 +/- 0.12)-fold. Intraperitoneal injection of 2.5 nmol/kg mcIRBP significantly decreased the blood glucose levels by 20.9 +/- 3.2% and 10.8 +/- 3.6% in normal and diabetic mice, respectively. Microarray analysis showed that mcIRBP affected genes involved in insulin signaling transduction pathway in mice. In conclusion, our findings suggest that mcIRBP is a novel IRBP that binds to sites different from the insulin-binding sites on IR and stimulates both the glucose uptake in cells and the glucose clearance in mice. PMID- 25144712 TI - Closely related NDM-1-encoding plasmids from Escherichia coli and Klebsiella pneumoniae in Taiwan. AB - OBJECTIVE: Two plasmids carrying blaNDM-1 isolated from carbapenem-resistant Klebsiella pneumoniae (CR-KP) and carbapenem-resistant Escherichia coli (CR-EC) were sequenced. CR-KP and CR-EC were isolated from two Taiwanese patients without travel histories. METHODS: Complete sequencing of the plasmids (pLK75 and pLK78) was conducted using a shotgun approach. Annotation of the contigs was performed using the RAST Server, followed by manual inspection and correction. RESULTS: These similar plasmids were obtained from two patients with overlapping stays at the same hospital. The pLK75 and pLK78 plasmids were 56,489-bp and 56,072-bp in length, respectively. Plasmid annotation revealed a common backbone similar to the IncN plasmid pR46. The regions flanking the blaNDM-1 genes in these plasmids were very similar to plasmid pNDM-HU01 in Japan, which contains a complex class 1 integron located next to an ISCR1 element. The ISCR1 element has been suggested to provide a powerful mechanism for mobilising antibiotic resistance genes. CONCLUSION: Two indigenous NDM-1-producing Enterobacteriaceae cases were identified for the first time in Taiwan, highlighting the alarming introduction of NDM-1-producing Enterobacteriaceae in this region. PMID- 25144710 TI - The Par-PrkC polarity complex is required for cilia growth in zebrafish photoreceptors. AB - Specification and development of the apical membrane in epithelial cells requires the function of polarity proteins, including Pard3 and an atypical protein kinase C (PrkC). Many epithelial cells possess microtubule-based organelles, known as cilia, that project from their apical surface and the membrane surrounding the cilium is contiguous with the apical cell membrane. Although cilia formation in cultured cells required Pard3, the in vivo requirement for Pard3 in cilia development remains unknown. The vertebrate photoreceptor outer segment represents a highly specialized cilia structure in which to identify factors necessary for apical and ciliary membrane formation. Pard3 and PrkC localized to distinct domains within vertebrate photoreceptors. Using partial morpholino knockdown, photo-morpholinos, and pharmacological approaches, the function of Pard3 and PrkC were found to be required for the formation of both the apical and ciliary membrane of vertebrate photoreceptors. Inhibition of Pard3 or PrkC activity significantly reduced the size of photoreceptor outer segments and resulted in mislocalization of rhodopsin. Suppression of Pard3 or PrkC also led to a reduction in cilia size and cilia number in Kupffer's Vesicle, which resulted in left-right asymmetry defects. Thus, the Par-PrkC complex functions in cilia formation in vivo and this likely reflects a general role in specifying non ciliary and ciliary compartments of the apical domain. PMID- 25144711 TI - Association of CVD candidate gene polymorphisms with ischemic stroke and cerebral hemorrhage in Chinese individuals. AB - BACKGROUND: Contribution of cardiovascular disease related genetic risk factors for stroke are not clearly defined. We performed a genetic association study to assess the association of 56 previously characterized gene variants in 34 candidate genes from cardiovascular disease related biological pathways with ischemic stroke and cerebral hemorrhage in a Chinese population. METHODS: There were 1280 stroke patients (1101 with ischemic stroke and 179 with cerebral hemorrhage) and 1380 controls in the study. The genotypes for 56 polymorphisms of 34 candidate genes were determined by the immobilized probe approach and the associations of gene polymorphisms with ischemic stroke and cerebral hemorrhage were performed by logistic regression under an allelic model. RESULTS: After adjusting for age, sex, BMI and hypertension status by logistic regression analysis, we found that NPPA rs5063 was significantly associated with both ischemic stroke (odds ratio [OR] 0.69; 95% confidence interval [CI], 0.52 to 0.90; P = 0.006) and cerebral hemorrhage(OR = 0.39; 95%CI, 0.19 to 0.78; P = 0.007). In addition, MTHFR rs1801133 also was associated with cerebral hemorrhage (OR = 1.48; 95%CI, 1.16 to 1.89; P = 0.001) but not with ischemic stroke (OR = 1.08; 95%CI, 0.96 to 1.22; P = 0.210). After false discovery rate (FDR) correction, the association of NPPA rs5063 and MTHFR rs1801133 with cerebral hemorrhage remained significant. CONCLUSIONS: The NPPA rs5063 is associated with reduced risk for cerebral hemorrhage and MTHFR rs1801133 is associated with increased risk of cerebral hemorrhage in a Chinese population. PMID- 25144714 TI - Sertoli cells maintain Leydig cell number and peritubular myoid cell activity in the adult mouse testis. AB - The Sertoli cells are critical regulators of testis differentiation and development. In the adult, however, their known function is restricted largely to maintenance of spermatogenesis. To determine whether the Sertoli cells regulate other aspects of adult testis biology we have used a novel transgenic mouse model in which Amh-Cre induces expression of the receptor for Diphtheria toxin (iDTR) specifically within Sertoli cells. This causes controlled, cell-specific and acute ablation of the Sertoli cell population in the adult animal following Diphtheria toxin injection. Results show that Sertoli cell ablation leads to rapid loss of all germ cell populations. In addition, adult Leydig cell numbers decline by 75% with the remaining cells concentrated around the rete and in the sub-capsular region. In the absence of Sertoli cells, peritubular myoid cell activity is reduced but the cells retain an ability to exclude immune cells from the seminiferous tubules. These data demonstrate that, in addition to support of spermatogenesis, Sertoli cells are required in the adult testis both for retention of the normal adult Leydig cell population and for support of normal peritubular myoid cell function. This has implications for our understanding of male reproductive disorders and wider androgen-related conditions affecting male health. PMID- 25144713 TI - System-level planning, coordination, and communication: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: System-level planning involves uniting hospitals and health systems, local/regional government agencies, emergency medical services, and other health care entities involved in coordinating and enabling care in a major disaster. We reviewed the literature and sought expert opinions concerning system-level planning and engagement for mass critical care due to disasters or pandemics and offer suggestions for system-planning, coordination, communication, and response. The suggestions in this chapter are important for all of those involved in a pandemic or disaster with multiple critically ill or injured patients, including front-line clinicians, hospital administrators, and public health or government officials. METHODS: The American College of Chest Physicians (CHEST) consensus statement development process was followed in developing suggestions. Task Force members met in person to develop nine key questions believed to be most relevant for system-planning, coordination, and communication. A systematic literature review was then performed for relevant articles and documents, reports, and other publications reported since 1993. No studies of sufficient quality were identified upon which to make evidence-based recommendations. Therefore, the panel developed expert opinion-based suggestions using a modified Delphi process. RESULTS: Suggestions were developed and grouped according to the following thematic elements: (1) national government support of health-care coalitions/regional health authorities (HC/RHAs), (2) teamwork within HC/RHAs, (3) system-level communication, (4) system-level surge capacity and capability, (5) pediatric patients and special populations, (6) HC/RHAs and networks, (7) models of advanced regional care systems, and (8) the use of simulation for preparedness and planning. CONCLUSIONS: System-level planning is essential to provide care for large numbers of critically ill patients because of disaster or pandemic. It also entails a departure from the routine, independent system and involves all levels from health-care institutions to regional health authorities. National government support is critical, as are robust communication systems and advanced planning supported by realistic exercises. PMID- 25144715 TI - Inhibitory effect of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H benzo(b)pyran (K-1) on human primary endometrial hyperplasial cells mediated via combined suppression of Wnt/beta-catenin signaling and PI3K/Akt survival pathway. AB - Endometrial hyperplasia is a precursor to the most common gynecologic cancer diagnosed in women. Apart from estrogenic induction, aberrant activation of the Wnt/beta-catenin signal is well known to correlate with endometrial hyperplasia and its carcinoma. The benzopyran compound 2-(piperidinoethoxyphenyl)-3-(4 hydroxyphenyl)-2H-benzo (b) pyran(K-1), a potent antiestrogenic agent, has been shown to have apoptosis-inducing activity in rat uterine hyperplasia. The current study was undertaken to explore the effect of the benzopyran compound K-1 on growth and Wnt signaling in human endometrial hyperplasial cells. Primary culture of atypical endometrial hyperplasial cells was characterized by the epithelial cell marker cytokeratin-7. Results revealed that compound K-1 reduced the viability of primary endometrial hyperplasial cells and expression of ERalpha, PR, PCNA, Wnt7a, FZD6, pGsk3beta and beta-catenin without affecting the growth of the primary culture of normal endometrial cells. The beta-catenin target genes CyclinD1 and c-myc were also found to be reduced, whereas the expression of axin2 and Wnt/beta-catenin signaling inhibitor Dkk-1 was found to be upregulated, which caused the reduced interaction of Wnt7a and FZD6. Nuclear accumulation of beta catenin was found to be decreased by compound K-1. K-1 also suppressed the pPI3K/pAkt survival pathway and induced the cleavage of caspases and PARP, thus subsequently causing the apoptosis of endometrial hyperplasial cells. In conclusion, compound K-1 suppressed the growth of human primary endometrial hyperplasial cells through discontinued Wnt/beta-catenin signaling and induced apoptosis via inhibiting the PI3K/Akt survival pathway. PMID- 25144716 TI - Sialidase NEU4 is involved in glioblastoma stem cell survival. AB - The human sialidase, NEU4, has emerged as a possible regulator of neuronal differentiation and its overexpression has been demonstrated to promote the acquisition of a stem cell-like phenotype in neuroblastoma cells. In this paper, we demonstrated that glioblastoma stem cells (GSCs) isolated from glioblastoma multiforme (GBM) cell lines and patients' specimens as neurospheres are specifically marked by the upregulation of NEU4; in contrast, the expression of NEU4 is very low in non-neurosphere-differentiated GBM cells. We showed that NEU4 silencing by miRNA or a chemical inhibitor of its catalytic activity triggered key events in GSCs, including (a) the activation of the glycogen synthase kinase 3beta, with the consequent inhibition of Sonic Hedgehog and Wnt/beta-catenin signalling pathways; (b) the decrease of the stem cell-like gene expression and marker signatures, evidenced by the reduction of NANOG, OCT-4, SOX-2, CD133 expression, ganglioside GD3 synthesis, and an altered protein glycosylation profile; and (c) a significant decrease in GSCs survival. Consistent with this finding, increased NEU4 activity and expression induced in the more differentiated GBM cells by the NEU4 agonist thymoquinone increased the expression of OCT-4 and GLI-1. Thus, NEU4 expression and activity appeared to help to determine the molecular signature of GSCs and to be closely connected with their survival properties. Given the pivotal role played by GSCs in GBM lethality, our results strongly suggest that NEU4 inhibition could significantly improve current therapies against this tumour. PMID- 25144717 TI - Amyloid-beta induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease. AB - Increasing evidence has shown the aberrant expression of inflammasome-related proteins in Alzheimer's disease (AD) brain; these proteins, including NLRP1 inflammasome, are implicated in the execution of inflammatory response and pyroptotic death. Although current data are associated NLRP1 genetic variants with AD, the involvement of NLRP1 inflammasome in AD pathogenesis is still unknown. Using APPswe/PS1dE9 transgenic mice, we found that cerebral NLRP1 levels were upregulated. Our in vitro studies further showed that increased NLRP1 mediated caspase-1-dependent 'pyroptosis' in cultured cortical neurons in response to amyloid-beta. Moreover, we employed direct in vivo infusion of non viral small-interfering RNA to knockdown NLRP1 or caspase-1 in APPswe/PS1dE9 brain, and discovered that these NLRP1 or caspase-1 deficiency mice resulted in significantly reduced neuronal pyroptosis and reversed cognitive impairments. Taken together, our findings indicate an important role for NLRP1/caspase-1 signaling in AD progression, and point to the modulation of NLRP1 inflammasome as a promising strategy for AD therapy. PMID- 25144718 TI - An unexpected role for caspase-2 in neuroblastoma. AB - Caspase-2 has been implicated in various cellular functions, including cell death by apoptosis, oxidative stress response, maintenance of genomic stability and tumor suppression. The loss of the caspase-2 gene (Casp2) enhances oncogene mediated tumorigenesis induced by E1A/Ras in athymic nude mice, and also in the EMU-Myc lymphoma and MMTV/c-neu mammary tumor mouse models. To further investigate the function of caspase-2 in oncogene-mediated tumorigenesis, we extended our studies in the TH-MYCN transgenic mouse model of neuroblastoma. Surprisingly, we found that loss of caspase-2 delayed tumorigenesis in the TH MYCN neuroblastoma model. In addition, tumors from TH-MYCN/Casp2(-/-) mice were predominantly thoracic paraspinal tumors and were less vascularized compared with tumors from their TH-MYCN/Casp2(+/+) counterparts. We did not detect any differences in the expression of neuroblastoma-associated genes in TH-MYCN/Casp2( /-) tumors, or in the activation of Ras/MAPK signaling pathway that is involved in neuroblastoma progression. Analysis of expression array data from human neuroblastoma samples showed a correlation between low caspase-2 levels and increased survival. However, caspase-2 levels correlated with clinical outcome only in the subset of MYCN-non-amplified human neuroblastoma. These observations indicate that caspase-2 is not a suppressor in MYCN-induced neuroblastoma and suggest a tissue and context-specific role for caspase-2 in tumorigenesis. PMID- 25144719 TI - RIP3 is downregulated in human myeloid leukemia cells and modulates apoptosis and caspase-mediated p65/RelA cleavage. AB - The receptor-interacting protein kinase 3 (RIP3) associates with RIP1 in a necrosome complex that can induce necroptosis, apoptosis, or cell proliferation. We analyzed the expression of RIP1 and RIP3 in CD34+ leukemia cells from a cohort of patients with acute myeloid leukemia (AML) and CD34+ cells from healthy donors. RIP3 expression was significantly reduced in most AML samples, whereas the expression of RIP1 did not differ significantly. When re-expressed in the mouse DA1-3b leukemia cell line, RIP3 induced apoptosis and necroptosis in the presence of caspase inhibitors. Transfection of RIP3 in the WEHI-3b leukemia cell line or in the mouse embryonic fibroblasts also resulted in increased cell death. Surprisingly, re-expression of a RIP3 mutant with an inactive kinase domain (RIP3 kinase dead (RIP3-KD)) induced significantly more and earlier apoptosis than wild type RIP3 (RIP3-WT), indicating that the RIP3 kinase domain is an essential regulator of apoptosis/necroptosis in leukemia cells. The induced in vivo expression of RIP3-KD but not RIP3-WT prolonged the survival of mice injected with leukemia cells. The expression of RIP3-KD induced p65/RelA nuclear factor kappaB (NF-kappaB) subunit caspase-dependent cleavage, and a non-cleavable p65/RelA D361E mutant rescued these cells from apoptosis. p65/RelA cleavage appears to be at least partially mediated by caspase-6. These data indicate that RIP3 silencing in leukemia cells results in suppression of the complex regulation of the apoptosis/necroptosis switch and NF-kappaB activity. PMID- 25144721 TI - Effects of acute versus post-acute systemic delivery of neural progenitor cells on neurological recovery and brain remodeling after focal cerebral ischemia in mice. AB - Intravenous transplantation of neural progenitor cells (NPCs) induces functional recovery after stroke, albeit grafted cells are not integrated into residing neural networks. However, a systematic analysis of intravenous NPC delivery at acute and post-acute time points and their long-term consequences does not exist. Male C57BL6 mice were exposed to cerebral ischemia, and NPCs were intravenously grafted on day 0, on day 1 or on day 28. Animals were allowed to survive for up to 84 days. Mice and tissues were used for immunohistochemical analysis, flow cytometry, ELISA and behavioral tests. Density of grafted NPCs within the ischemic hemisphere was increased when cells were transplanted on day 28 as compared with transplantation on days 0 or 1. Likewise, transplantation on day 28 yielded enhanced neuronal differentiation rates of grafted cells. Post-ischemic brain injury, however, was only reduced when NPCs were grafted at acute time points. On the contrary, reduced post-ischemic functional deficits due to NPC delivery were independent of transplantation paradigms. NPC-induced neuroprotection after acute cell delivery was due to stabilization of the blood brain barrier (BBB), reduction in microglial activation and modulation of both peripheral and central immune responses. On the other hand, post-acute NPC transplantation stimulated post-ischemic regeneration via enhanced angioneurogenesis and increased axonal plasticity. Acute NPC delivery yields long term neuroprotection via enhanced BBB integrity and modulation of post-ischemic immune responses, whereas post-acute NPC delivery increases post-ischemic angioneurogenesis and axonal plasticity. Post-ischemic functional recovery, however, is independent of NPC delivery timing, which offers a broad therapeutic time window for stroke treatment. PMID- 25144720 TI - MicroRNA-302 induces proliferation and inhibits oxidant-induced cell death in human adipose tissue-derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are a heterogeneous population of cells that proliferate in vitro as plastic-adherent cells, have a fibroblast-like morphology, form colonies in vitro and can differentiate into bone, cartilage and fat cells. The abundance, ease and repeatable access to subcutaneous adipose tissue and the simple isolation procedures provide clear advantages for the use of human adipose tissue-derived mesenchymal stem cells (hASDCs) in clinical applications. We screened microRNAs (miRNAs) that affected the proliferation and survival of hADSCs. Transfection of miR-302d mimic increased cell proliferation and protected cells from oxidant-induced cell death in hADSCs, which was supported by flow-cytometric analysis. miR-302d did not affect the expression of Bcl-2 family members or anti-oxidant molecules. The Nrf2-Keap1 system, which is one of the major mechanisms for the cellular defense against oxidative stress, was not altered by transfection of miR-302d mimic. To identify the target of the miR-302d actions on proliferation and survival of hADSCs, a microarray analysis was performed using miR-302d-overexpressing hADSCs. Real-time PCR analysis showed that transfection of miR-302d mimic inhibited the CDKN1A and CCL5 expression. Downregulation of CDKN1A with a specific siRNA mimicked the effect of miR-302d on hADSCs proliferation, but did not affect miR-302d-induced cell survival. Downregulation of CCL5 protected oxidant-induced cell death as miR-302d, inhibited oxidant-induced reactive oxygen species (ROS) generation and the addition of recombinant CCL5 inhibited the protective action of miR-302d on oxidant-induced cell death. This study indicates that miR-302 controls proliferation and cell survival of hADSCs through different targets and that this miRNA can be used to enhance the therapeutic efficacy of hADSCs transplantation in vivo. PMID- 25144722 TI - Mir-509-5p joins the Mdm2/p53 feedback loop and regulates cancer cell growth. AB - Although the Mdm2/p53 interaction has been well documented, it is not clear whether there are new microRNAs participating in this regulatory network. Here, we provide evidence that miR-509-5p, which is downregulated in a subset of newly diagnosed cervical cancer and hepatocellular carcinoma tissues compared with the adjacent nontumor tissue, can be activated by p53 through binding the promoter of miR-509-5p and it suppresses the growth and invasion/migration of cervical cancer and hepatoma cells by regulating apoptosis and the G1/S-phase transition of cell cycle. Furthermore, Mdm2 was identified to be a target of miR-509-5p by targeting its 3'-UTR. Restoration of Mdm2 abrogated the cell phenotypes induced by miR-509 5p. Moreover, ectopic expression of miR-509-5p in HeLa and QGY-7703 cells repressed the expression of Mdm2, subsequently enhancing its p53-activating effects. These results suggest that miR-509-5p is a new regulator of Mdm2/p53 pathway and may play a key role in cancer development. PMID- 25144723 TI - Spherical nucleic acids as a divergent platform for synthesizing RNA-nanoparticle conjugates through enzymatic ligation. AB - Herein, we describe a rapid, divergent method for using spherical nucleic acids (SNAs) as a universal platform for attaching RNA to DNA-modified nanoparticles using enzyme-mediated techniques. This approach provides a sequence-specific method for the covalent attachment of one or more in vitro transcribed RNAs to a universal SNA scaffold, regardless of RNA sequence. The RNA-nanoparticle constructs are shown to effectively knock down two different gene targets using a single, dual-ligated nanoparticle construct. PMID- 25144724 TI - Circulating mucosal associated invariant T cells are activated in Vibrio cholerae O1 infection and associated with lipopolysaccharide antibody responses. AB - BACKGROUND: Mucosal Associated Invariant T (MAIT) cells are innate-like T cells found in abundance in the intestinal mucosa, and are thought to play a role in bridging the innate-adaptive interface. METHODS: We measured MAIT cell frequencies and antibody responses in blood from patients presenting with culture confirmed severe cholera to a hospital in Dhaka, Bangladesh at days 2, 7, 30, and 90 of illness. RESULTS: We found that MAIT (CD3+CD4-CD161hiValpha7.2+) cells were maximally activated at day 7 after onset of cholera. In adult patients, MAIT frequencies did not change over time, whereas in child patients, MAITs were significantly decreased at day 7, and this decrease persisted to day 90. Fold changes in MAIT frequency correlated with increases in LPS IgA and IgG, but not LPS IgM nor antibody responses to cholera toxin B subunit. CONCLUSIONS: In the acute phase of cholera, MAIT cells are activated, depleted from the periphery, and as part of the innate response against V. cholerae infection, are possibly involved in mechanisms underlying class switching of antibody responses to T cell independent antigens. PMID- 25144725 TI - A new model for pore formation by cholesterol-dependent cytolysins. AB - Cholesterol Dependent Cytolysins (CDCs) are important bacterial virulence factors that form large (200-300 A) membrane embedded pores in target cells. Currently, insights from X-ray crystallography, biophysical and single particle cryo Electron Microscopy (cryo-EM) experiments suggest that soluble monomers first interact with the membrane surface via a C-terminal Immunoglobulin-like domain (Ig; Domain 4). Membrane bound oligomers then assemble into a prepore oligomeric form, following which the prepore assembly collapses towards the membrane surface, with concomitant release and insertion of the membrane spanning subunits. During this rearrangement it is proposed that Domain 2, a region comprising three beta-strands that links the pore forming region (Domains 1 and 3) and the Ig domain, must undergo a significant yet currently undetermined, conformational change. Here we address this problem through a systematic molecular modeling and structural bioinformatics approach. Our work shows that simple rigid body rotations may account for the observed collapse of the prepore towards the membrane surface. Support for this idea comes from analysis of published cryo-EM maps of the pneumolysin pore, available crystal structures and molecular dynamics simulations. The latter data in particular reveal that Domains 1, 2 and 4 are able to undergo significant rotational movements with respect to each other. Together, our data provide new and testable insights into the mechanism of pore formation by CDCs. PMID- 25144727 TI - Does current behaviour predict the course of children's physical fitness? AB - The secular trend of reduced physical fitness (PF) leads to increased health risks. The aim of the present paper is to analyse various current factors that affect health behaviour with respect to the course of PF over 2 years. A path analysis combined with a latent growth curve analysis was based on a study that was conducted between June 2008 and June 2010 with 145 primary German school children (52.1% male, average age at baseline 7.95 years +/- 0.95). PF was tested with the German Motor Test 6-18. For the mean PF and the course of PF, direct and indirect influences were shown over three levels, including migration background on the first level and physical activity (PA) on the second level. Body mass index (BMI) impacted the mean PF but not the course of PF. The influence of sedentary behaviour on the mean PF was diminished (compared to bivariate analysis) due to its common variance mainly with BMI. PA affected not only current PF in children but also the course of PF (a(intercept) = .28, P = .001; a(slope) = .27, P = .21). Consequently, preventive measures should focus on early adoption and maintenance of PA. PMID- 25144726 TI - Evaluation of up-converting phosphor technology-based lateral flow strips for rapid detection of Bacillus anthracis Spore, Brucella spp., and Yersinia pestis. AB - Bacillus anthracis, Brucella spp., and Yersinia pestis are zoonotic pathogens and biowarfare- or bioterrorism-associated agents that must be detected rapidly on site from various samples (e.g., viscera and powders). An up-converting phosphor technology-based lateral flow (UPT-LF) strip was developed as a point-of-care testing (POCT) to satisfy the requirements of first-level emergency response. We developed UPT-LF POCT to quantitatively detect the three pathogens within 15 min. Sample and operation-error tolerances of the assay were comprehensively evaluated. The sensitivity of UPT-LF assay to bacterial detection reached 10(4) cfu . mL(-1) (100 cfu/test), with a linear quantitative range of 4 to 6 orders of magnitude. Results revealed that the UPT-LF assay exhibited a high specificity with the absence of false-positive results even at 10(9) cfu . mL(-1) of non specific bacterial contamination. The assay could tolerate samples with a wide pH range (2 to 12), high ion strengths (>= 4 mol . L(-1) of NaCl), high viscosities (<= 25 mg . mL(-1) of PEG20000 or >= 20% of glycerol), and high concentrations of bio-macromolecule (<= 200 mg . mL(-1) of bovine serum albumin or >= 80 mg . mL( 1) of casein). The influence of various types of powders and viscera (fresh and decomposed) on the performance of UPT-LF assay was determined. The operational error of liquid measurement exhibited few effects on sensitivity and specificity. The developed UPT-LF POCT assay is applicable under field conditions with excellent tolerance to sample complexity and operational error. PMID- 25144728 TI - Parenteral nutrition in the intensive care unit: cautious use improves outcome. AB - Critical illness is characterised by nutritional and metabolic disorders, resulting in increased muscle catabolism, fat-free mass loss, and hyperglycaemia. The objective of the nutritional support is to limit fat-free mass loss, which has negative consequences on clinical outcome and recovery. Early enteral nutrition is recommended by current guidelines as the first choice feeding route in ICU patients. However, enteral nutrition alone is frequently associated with insufficient coverage of the energy requirements, and subsequently energy deficit is correlated to worsened clinical outcome. Controlled trials have demonstrated that, in case of failure or contraindications to full enteral nutrition, parenteral nutrition administration on top of insufficient enteral nutrition within the first four days after admission could improve the clinical outcome, and may attenuate fat-free mass loss. Parenteral nutrition is cautious if all-in one solutions are used, glycaemia controlled, and overnutrition avoided. Conversely, the systematic use of parenteral nutrition in the ICU patients without clear indication is not recommended during the first 48 hours. Specific methods, such as thigh ultra-sound imaging, 3rd lumbar vertebra-targeted computerised tomography and bioimpedance electrical analysis, may be helpful in the future to monitor fat-free mass during the ICU stay. Clinical studies are warranted to demonstrate whether an optimal nutritional management during the ICU stay promotes muscle mass and function, the recovery after critical illness and reduces the overall costs. PMID- 25144729 TI - Synthesis of polysubstituted phenanthridines via ligand-free copper-catalyzed annulation. AB - A novel procedure for the cascade reaction of the addition of a Grignard reagent to a nitrile with a copper-catalyzed C-N bond coupling was developed, which afforded various polysubstituted phenanthridines in moderate to good yields with tolerance for a wide variety of substrates. Experimental data demonstrated that the reaction proceeded more likely through a Cu(I/III) catalytic cycle. PMID- 25144731 TI - The evolution of extreme polyandry in social insects: insights from army ants. AB - The unique nomadic life-history pattern of army ants (army ant adaptive syndrome), including obligate colony fission and strongly male-biased sex-ratios, makes army ants prone to heavily reduced effective population sizes (Ne). Excessive multiple mating by queens (polyandry) has been suggested to compensate these negative effects by increasing genetic variance in colonies and populations. However, the combined effects and evolutionary consequences of polyandry and army ant life history on genetic colony and population structure have only been studied in a few selected species. Here we provide new genetic data on paternity frequencies, colony structure and paternity skew for the five Neotropical army ants Eciton mexicanum, E. vagans, Labidus coecus, L. praedator and Nomamyrmex esenbeckii; and compare those data among a total of nine army ant species (including literature data). The number of effective matings per queen ranged from about 6 up to 25 in our tested species, and we show that such extreme polyandry is in two ways highly adaptive. First, given the detected low intracolonial relatedness and population differentiation extreme polyandry may counteract inbreeding and low Ne. Second, as indicated by a negative correlation of paternity frequency and paternity skew, queens maximize intracolonial genotypic variance by increasingly equalizing paternity shares with higher numbers of sires. Thus, extreme polyandry is not only an integral part of the army ant syndrome, but generally adaptive in social insects by improving genetic variance, even at the high end spectrum of mating frequencies. PMID- 25144732 TI - Rational design of a fusion protein to exhibit disulfide-mediated logic gate behavior. AB - Synthetic cellular logic gates are primarily built from gene circuits owing to their inherent modularity. Single proteins can also possess logic gate functions and offer the potential to be simpler, quicker, and less dependent on cellular resources than gene circuits. However, the design of protein logic gates that are modular and integrate with other cellular components is a considerable challenge. As a step toward addressing this challenge, we describe the design, construction, and characterization of AND, ORN, and YES logic gates built by introducing disulfide bonds into RG13, a fusion of maltose binding protein and TEM-1 beta lactamase for which maltose is an allosteric activator of enzyme activity. We rationally designed these disulfide bonds to manipulate RG13's allosteric regulation mechanism such that the gating had maltose and reducing agents as input signals, and the gates could be toggled between different gating functions using redox agents, although some gates performed suboptimally. PMID- 25144734 TI - Identification of a novel hypocholesterolemic protein, major royal jelly protein 1, derived from royal jelly. AB - Royal jelly (RJ) intake lowers serum cholesterol levels in animals and humans, but the active component in RJ that lowers serum cholesterol level and its molecular mechanism are unclear. In this study, we set out to identify the bile acid-binding protein contained in RJ, because dietary bile acid-binding proteins including soybean protein and its peptide are effective in ameliorating hypercholesterolemia. Using a cholic acid-conjugated column, we separated some bile acid-binding proteins from RJ and identified the major RJ protein 1 (MRJP1), MRJP2, and MRJP3 as novel bile acid-binding proteins from RJ, based on matrix assisted laser desorption ionization time-of-flight mass spectrometry. Purified MRJP1, which is the most abundant protein of the bile acid-binding proteins in RJ, exhibited taurocholate-binding activity in vitro. The micellar solubility of cholesterol was significantly decreased in the presence of MRJP1 compared with casein in vitro. Liver bile acids levels were significantly increased, and cholesterol 7alpha-hydroxylase (CYP7A1) mRNA and protein tended to increase by MRJP1 feeding compared with the control. CYP7A1 mRNA and protein levels were significantly increased by MRJP1 tryptic hydrolysate treatment compared with that of casein tryptic hydrolysate in hepatocytes. MRJP1 hypocholesterolemic effect has been investigated in rats. The cholesterol-lowering action induced by MRJP1 occurs because MRJP1 interacts with bile acids induces a significant increase in fecal bile acids excretion and a tendency to increase in fecal cholesterol excretion and also enhances the hepatic cholesterol catabolism. We have identified, for the first time, a novel hypocholesterolemic protein, MRJP1, in RJ. Interestingly, MRJP1 exhibits greater hypocholesterolemic activity than the medicine beta-sitosterol in rats. PMID- 25144730 TI - An exponential growth of computational phantom research in radiation protection, imaging, and radiotherapy: a review of the fifty-year history. AB - Radiation dose calculation using models of the human anatomy has been a subject of great interest to radiation protection, medical imaging, and radiotherapy. However, early pioneers of this field did not foresee the exponential growth of research activity as observed today. This review article walks the reader through the history of the research and development in this field of study which started some 50 years ago. This review identifies a clear progression of computational phantom complexity which can be denoted by three distinct generations. The first generation of stylized phantoms, representing a grouping of less than dozen models, was initially developed in the 1960s at Oak Ridge National Laboratory to calculate internal doses from nuclear medicine procedures. Despite their anatomical simplicity, these computational phantoms were the best tools available at the time for internal/external dosimetry, image evaluation, and treatment dose evaluations. A second generation of a large number of voxelized phantoms arose rapidly in the late 1980s as a result of the increased availability of tomographic medical imaging and computers. Surprisingly, the last decade saw the emergence of the third generation of phantoms which are based on advanced geometries called boundary representation (BREP) in the form of Non-Uniform Rational B-Splines (NURBS) or polygonal meshes. This new class of phantoms now consists of over 287 models including those used for non-ionizing radiation applications. This review article aims to provide the reader with a general understanding of how the field of computational phantoms came about and the technical challenges it faced at different times. This goal is achieved by defining basic geometry modeling techniques and by analyzing selected phantoms in terms of geometrical features and dosimetric problems to be solved. The rich historical information is summarized in four tables that are aided by highlights in the text on how some of the most well-known phantoms were developed and used in practice. Some of the information covered in this review has not been previously reported, for example, the CAM and CAF phantoms developed in 1970s for space radiation applications. The author also clarifies confusion about 'population-average' prospective dosimetry needed for radiological protection under the current ICRP radiation protection system and 'individualized' retrospective dosimetry often performed for medical physics studies. To illustrate the impact of computational phantoms, a section of this article is devoted to examples from the author's own research group. Finally the author explains an unexpected finding during the course of preparing for this article that the phantoms from the past 50 years followed a pattern of exponential growth. The review ends on a brief discussion of future research needs (a supplementary file '3DPhantoms.pdf' to figure 15 is available for download that will allow a reader to interactively visualize the phantoms in 3D). PMID- 25144735 TI - Optogenetic modulation and multi-electrode analysis of cerebellar networks in vivo. AB - The firing patterns of cerebellar Purkinje cells (PCs), as the sole output of the cerebellar cortex, determine and tune motor behavior. PC firing is modulated by various inputs from different brain regions and by cell-types including granule cells (GCs), climbing fibers and inhibitory interneurons. To understand how signal integration in PCs occurs and how subtle changes in the modulation of PC firing lead to adjustment of motor behaviors, it is important to precisely record PC firing in vivo and to control modulatory pathways in a spatio-temporal manner. Combining optogenetic and multi-electrode approaches, we established a new method to integrate light-guides into a multi-electrode system. With this method we are able to variably position the light-guide in defined regions relative to the recording electrode with micrometer precision. We show that PC firing can be precisely monitored and modulated by light-activation of channelrhodopsin-2 (ChR2) expressed in PCs, GCs and interneurons. Thus, this method is ideally suited to investigate the spatio/temporal modulation of PCs in anesthetized and in behaving mice. PMID- 25144736 TI - Monitoring the initiation and kinetics of human dendritic cell-induced polarization of autologous naive CD4+ T cells. AB - A crucial step in generating de novo immune responses is the polarization of naive cognate CD4+ T cells by pathogen-triggered dendritic cells (DC). In the human setting, standardized DC-dependent systems are lacking to study molecular events during the initiation of a naive CD4+ T cell response. We developed a TCR restricted assay to compare different pathogen-triggered human DC for their capacities to instruct functional differentiation of autologous, naive CD4+ T cells. We demonstrated that this methodology can be applied to compare differently matured DC in terms of kinetics, direction, and magnitude of the naive CD4+ T cell response. Furthermore, we showed the applicability of this assay to study the T cell polarizing capacity of low-frequency blood-derived DC populations directly isolated ex vivo. This methodology for addressing APC dependent instruction of naive CD4+ T cells in a human autologous setting will provide researchers with a valuable tool to gain more insight into molecular mechanisms occurring in the early phase of T cell polarization. In addition, it may also allow the study of pharmacological agents on DC-dependent T cell polarization in the human system. PMID- 25144738 TI - Neuroantigen-specific autoregulatory CD8+ T cells inhibit autoimmune demyelination through modulation of dendritic cell function. AB - Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model of multiple sclerosis, an immune-mediated demyelinating disorder of the central nervous system (CNS). We have previously shown that CNS-specific CD8+ T cells (CNS-CD8+) ameliorate EAE, at least in part through modulation of CNS specific CD4+ T cell responses. In this study, we show that CNS-CD8+ also modulate the function of CD11c+ dendritic cells (DC), but not other APCs such as CD11b+ monocytes or B220+ B cells. DC from mice receiving either myelin oligodendrocyte glycoprotein-specific CD8+ (MOG-CD8+) or proteolipid protein specific CD8+ (PLP-CD8+) T cells were rendered inefficient in priming T cell responses from naive CD4+ T cells (OT-II) or supporting recall responses from CNS specific CD4+ T cells. CNS-CD8+ did not alter DC subset distribution or MHC class II and CD86 expression, suggesting that DC maturation was not affected. However, the cytokine profile of DC from CNS-CD8+ recipients showed lower IL-12 and higher IL-10 production. These functions were not modulated in the absence of immunization with CD8-cognate antigen, suggesting an antigen-specific mechanism likely requiring CNS-CD8-DC interaction. Interestingly, blockade of IL-10 in vitro rescued CD4+ proliferation and in vivo expression of IL-10 was necessary for the suppression of EAE by MOG-CD8+. These studies demonstrate a complex interplay between CNS-specific CD8+ T cells, DC and pathogenic CD4+ T cells, with important implications for therapeutic interventions in this disease. PMID- 25144737 TI - The RNA helicases AtMTR4 and HEN2 target specific subsets of nuclear transcripts for degradation by the nuclear exosome in Arabidopsis thaliana. AB - The RNA exosome is the major 3'-5' RNA degradation machine of eukaryotic cells and participates in processing, surveillance and turnover of both nuclear and cytoplasmic RNA. In both yeast and human, all nuclear functions of the exosome require the RNA helicase MTR4. We show that the Arabidopsis core exosome can associate with two related RNA helicases, AtMTR4 and HEN2. Reciprocal co immunoprecipitation shows that each of the RNA helicases co-purifies with the exosome core complex and with distinct sets of specific proteins. While AtMTR4 is a predominantly nucleolar protein, HEN2 is located in the nucleoplasm and appears to be excluded from nucleoli. We have previously shown that the major role of AtMTR4 is the degradation of rRNA precursors and rRNA maturation by-products. Here, we demonstrate that HEN2 is involved in the degradation of a large number of polyadenylated nuclear exosome substrates such as snoRNA and miRNA precursors, incompletely spliced mRNAs, and spurious transcripts produced from pseudogenes and intergenic regions. Only a weak accumulation of these exosome substrate targets is observed in mtr4 mutants, suggesting that MTR4 can contribute, but plays rather a minor role for the degradation of non-ribosomal RNAs and cryptic transcripts in Arabidopsis. Consistently, transgene post-transcriptional gene silencing (PTGS) is marginally affected in mtr4 mutants, but increased in hen2 mutants, suggesting that it is mostly the nucleoplasmic exosome that degrades aberrant transgene RNAs to limit their entry in the PTGS pathway. Interestingly, HEN2 is conserved throughout green algae, mosses and land plants but absent from metazoans and other eukaryotic lineages. Our data indicate that, in contrast to human and yeast, plants have two functionally specialized RNA helicases that assist the exosome in the degradation of specific nucleolar and nucleoplasmic RNA populations, respectively. PMID- 25144739 TI - Socioeconomic deprivation and the incidence of 12 cardiovascular diseases in 1.9 million women and men: implications for risk prediction and prevention. AB - BACKGROUND: Recent experimental evidence suggests that socioeconomic characteristics of neighbourhoods influence cardiovascular health, but observational studies which examine deprivation across a wide range of cardiovascular diseases (CVDs) are lacking. METHODS: Record-linkage cohort study of 1.93 million people to examine the association between small-area socioeconomic deprivation and 12 CVDs. Health records covered primary care, hospital admissions, a myocardial infarction registry and cause-specific mortality in England (CALIBER). Patients were aged >=30 years and were initially free of CVD. Cox proportional hazard models stratified by general practice were used. FINDINGS: During a median follow-up of 5.5 years 114,859 people had one of 12 initial CVD presentations. In women the hazards of all CVDs except abdominal aortic aneurysm increased linearly with higher small-area socioeconomic deprivation (adjusted HR for most vs. least deprived ranged from 1.05, 95%CI 0.83 1.32 for abdominal aortic aneurysm to 1.55, 95%CI 1.42-1.70 for heart failure; I2 = 81.9%, tau2 = 0.01). In men heterogeneity was higher (HR ranged from 0.89, 95%CI 0.75-1.06 for cardiac arrest to 1.85, 95%CI 1.67-2.04 for peripheral arterial disease; I2 = 96.0%, tau2 = 0.06) and no association was observed with stable angina, sudden cardiac death, subarachnoid haemorrhage, transient ischaemic attack and abdominal aortic aneurysm. Lifetime risk difference between least and most deprived quintiles was most marked for peripheral arterial disease in women (4.3% least deprived, 5.8% most deprived) and men (4.6% least deprived, 7.8% in most deprived); but it was small or negligible for sudden cardiac death, transient ischaemic attack, abdominal aortic aneurysm and ischaemic and intracerebral haemorrhage, in both women and men. CONCLUSIONS: Associations of small-area socioeconomic deprivation with 12 types of CVDs were heterogeneous, and in men absent for several diseases. Findings suggest that policies to reduce deprivation may impact more strongly on heart failure and peripheral arterial disease, and might be more effective in women. PMID- 25144741 TI - Direct observation of the photodegradation of anthracene and pyrene adsorbed onto mangrove leaves. AB - An established synchronous fluorimetry method was used for in situ investigation of the photodegradation of pyrene (PYR) and anthracene (ANT) adsorbed onto fresh leaves of the seedlings of two mangrove species, Aegiceras corniculatum (L.) Blanco (Ac) and Kandelia obovata (Ko) in multicomponent mixtures (mixture of the ANT and PYR). Experimental results indicated that photodegradation was the main transformation pathway for both ANT and PYR in multicomponent mixtures. The amount of the PAHs volatilizing from the leaf surfaces and entering the inner leaf tissues was negligible. Over a certain period of irradiation time, the photodegradation of both PYR and ANT adsorbed onto the leaves of Ac and Ko followed first-order kinetics, with faster rates being observed on Ac leaves. In addition, the photodegradation rate of PYR on the leaves of the mangrove species in multicomponent mixtures was much slower than that of adsorbed ANT. Compared with the PAHs adsorbed as single component, the photodegradation rate of ANT adsorbed in multicomponent mixtures was slower, while that of PYR was faster. Moreover, the photodegradation of PYR and ANT dissolved in water in multicomponent mixtures was investigated for comparison. The photodegradation rate on leaves was much slower than in water. Therefore, the physical-chemical properties of the substrate may strongly influence the photodegradation rate of adsorbed PAHs. PMID- 25144740 TI - SH3BP2 gain-of-function mutation exacerbates inflammation and bone loss in a murine collagen-induced arthritis model. AB - OBJECTIVE: SH3BP2 is a signaling adapter protein which regulates immune and skeletal systems. Gain-of-function mutations in SH3BP2 cause cherubism, characterized by jawbone destruction. This study was aimed to examine the role of SH3BP2 in inflammatory bone loss using a collagen-induced arthritis (CIA) model. METHODS: CIA was induced in wild-type (Sh3bp2(+/+)) and heterozygous P416R SH3BP2 cherubism mutant knock-in (Sh3bp2(KI/+)) mice, an SH3BP2 gain-of-function model. Severity of the arthritis was determined by assessing the paw swelling and histological analyses of the joints. Micro-CT analysis was used to determine the levels of bone loss. Inflammation and osteoclastogenesis in the joints were evaluated by quantitating the gene expression of inflammatory cytokines and osteoclast markers. Furthermore, involvement of the T- and B-cell responses was determined by draining lymph node cell culture and measurement of the serum anti mouse type II collagen antibody levels, respectively. Finally, roles of the SH3BP2 mutation in macrophage activation and osteoclastogenesis were determined by evaluating the TNF-alpha production levels and osteoclast formation in bone marrow-derived M-CSF-dependent macrophage (BMM) cultures. RESULTS: Sh3bp2(KI/+) mice exhibited more severe inflammation and bone loss, accompanying an increased number of osteoclasts. The mRNA levels for TNF-alpha and osteoclast marker genes were higher in the joints of Sh3bp2(KI/+) mice. Lymph node cell culture showed that lymphocyte proliferation and IFN-gamma and IL-17 production were comparable between Sh3bp2(+/+) and Sh3bp2(KI/+) cells. Serum anti-type II collagen antibody levels were comparable between Sh3bp2(+/+) and Sh3bp2(KI/+) mice. In vitro experiments showed that TNF-alpha production in Sh3bp2(KI/+) BMMs is elevated compared with Sh3bp2(+/+) BMMs and that RANKL-induced osteoclastogenesis is enhanced in Sh3bp2(KI/+) BMMs associated with increased NFATc1 nuclear localization. CONCLUSION: Gain-of-function of SH3BP2 augments inflammation and bone loss in the CIA model through increased macrophage activation and osteoclast formation. Therefore, modulation of the SH3BP2 expression may have therapeutic potential for the treatment of rheumatoid arthritis. PMID- 25144742 TI - Innate-like and conventional T cell populations from hemodialyzed and kidney transplanted patients are equally compromised. AB - Clinicians are well aware of existing pharmacologically-induced immune deficient status in kidney-transplanted patients that will favor their susceptibility to bacterial or viral infections. Previous studies indicated that advanced Stage 4-5 Chronic Kidney Disease might also be regarded as an immune deficiency-like status as well, even though the mechanisms are not fully understood. Here, we analyzed the ex vivo frequency and the functional properties of both conventional and innate-like T (ILT) lymphocyte subsets in the peripheral blood of 35 patients on hemodialysis, 29 kidney transplanted patients and 38 healthy donors. We found that peripheral blood cell count of ILT cells, as iNKT (invariant Natural Killer T) and MAIT (mucosal-associated invariant T), were significantly decreased in hemodialyzed patients compared to healthy controls. This deficiency was also observed regarding conventional T cells, including the IL-17-producing CD4(+) Th17 cells. Pertaining to regulatory T cells, we also noticed major modifications in the global frequency of CD4(+)CD25(+)Foxp3(+) T lymphocytes, including the resting suppressive CD45RA(+)Foxp3lo and activated suppressive CD45RA-Foxp3hi T cell subpopulations. We found no significant differences between the immune status of hemodialyzed and kidney-transplanted subjects. In conclusion, we demonstrated that both ILT and conventional T cell numbers are equally impaired in hemodialyzed and kidney-transplanted patients. PMID- 25144743 TI - Structural and biochemical characterization of the Cop9 signalosome CSN5/CSN6 heterodimer. AB - The Cop9 signalosome complex (CSN) regulates the functional cycle of the major E3 ubiquitin ligase family, the cullin RING E3 ubiquitin ligases (CRLs). Activated CRLs are covalently modified by the ubiquitin-like protein Nedd8 (neural precursor cell expressed developmentally down-regulated protein 8). CSN serves an essential role in myriad cellular processes by reversing this modification through the isopeptidase activity of its CSN5 subunit. CSN5 alone is inactive due to an auto-inhibited conformation of its catalytic domain. Here we report the molecular basis of CSN5 catalytic domain activation and unravel a molecular hierarchy in CSN deneddylation activity. The association of CSN5 and CSN6 MPN (for Mpr1/Pad1 N-terminal) domains activates its isopeptidase activity. The CSN5/CSN6 module, however, is inefficient in CRL deneddylation, indicating a requirement of further elements in this reaction such as other CSN subunits. A hybrid molecular model of CSN5/CSN6 provides a structural framework to explain these functional observations. Docking this model into a published CSN electron density map and using distance constraints obtained from cross-linking coupled to mass-spectrometry, we find that the C-termini of the CSN subunits could form a helical bundle in the centre of the structure. They likely play a key scaffolding role in the spatial organization of CSN and precise positioning of the dimeric MPN catalytic core. PMID- 25144744 TI - Lactobacillus gasseri SBT2055 induces TGF-beta expression in dendritic cells and activates TLR2 signal to produce IgA in the small intestine. AB - Probiotic bacteria provide benefits in enhancing host immune responses and protecting against infection. Induction of IgA production by oral administration of probiotic bacteria in the intestine has been considered to be one reason for this beneficial effect, but the mechanisms of the effect are poorly understood. Lactobacillus gasseri SBT2055 (LG2055) is a probiotic bacterium with properties such as bile tolerance, ability to improve the intestinal environment, and it has preventive effects related to abdominal adiposity. In this study, we have found that oral administration of LG2055 induced IgA production and increased the rate of IgA(+) cell population in Peyer's patch and in the lamina propria of the mouse small intestine. The LG2055 markedly increased the amount of IgA in a co-culture of B cells and bone marrow derived dendritic cells (BMDC), and TLR2 signal is critical for it. In addition, it is demonstrated that LG2055 stimulates BMDC to promote the production of TGF-beta, BAFF, IL-6, and IL-10, all critical for IgA production from B cells. Combined stimulation of B cells with BAFF and LG2055 enhanced the induction of IgA production. Further, TGF-beta signal was shown to be critical for LG2055-induced IgA production in the B cell and BMDC co-culture system, but TGF-beta did not induce IgA production in a culture of only B cells stimulated with LG2055. Furthermore, TGF-beta was critical for the production of BAFF, IL-6, IL-10, and TGF-beta itself from LG2055-stimulated BMDC. These results demonstrate that TGF-beta was produced by BMDC stimulated with LG2055 and it has an autocrine/paracrine function essential for BMDC to induce the production of BAFF, IL-6, and IL-10. PMID- 25144747 TI - Surface micro/nanotopography, wetting properties and the potential for biomimetic icephobicity of skunk cabbage Symplocarpus foetidus. AB - Lotus (Nelumbo nucifera) is known for its two remarkable properties: superhydrophobicity and thermogenesis; however, the relationship between these two properties remains obscure. Most botanists agree that thermogenesis helps to attract pollinators, while non-wetting helps to catch pollinators and prevents contamination. Here we investigate the surface micro- and nanotopography and wetting properties of eastern skunk cabbage (Symplocarpus foetidus), another thermogenic plant, which is known for its ability to melt snow. The skunk cabbage leaves are hydrophobic but not superhydrophobic, and they have high contact angle hysteresis (similar to the rose petal effect). We develop a heat transfer model to relate icephobicity with heat transfer and discuss the biomimetic potential that both thermogenic and superhydrophobic plants may have for icephobicity in soft materials. PMID- 25144745 TI - Sparsity and compressed coding in sensory systems. AB - Considering that many natural stimuli are sparse, can a sensory system evolve to take advantage of this sparsity? We explore this question and show that significant downstream reductions in the numbers of neurons transmitting stimuli observed in early sensory pathways might be a consequence of this sparsity. First, we model an early sensory pathway using an idealized neuronal network comprised of receptors and downstream sensory neurons. Then, by revealing a linear structure intrinsic to neuronal network dynamics, our work points to a potential mechanism for transmitting sparse stimuli, related to compressed sensing (CS) type data acquisition. Through simulation, we examine the characteristics of networks that are optimal in sparsity encoding, and the impact of localized receptive fields beyond conventional CS theory. The results of this work suggest a new network framework of signal sparsity, freeing the notion from any dependence on specific component-space representations. We expect our CS network mechanism to provide guidance for studying sparse stimulus transmission along realistic sensory pathways as well as engineering network designs that utilize sparsity encoding. PMID- 25144746 TI - Helicobacter pylori promotes epithelial-mesenchymal transition in gastric cancer by downregulating programmed cell death protein 4 (PDCD4). AB - Helicobacter pylori, a Gram-negative, microaerophilic bacterium found in the stomach, is assumed to be associated with carcinogenesis, invasion and metastasis in digestive diseases. Cytotoxin-associated gene A (CagA) is an oncogenic protein of H. pylori that is encoded by a Cag pathogenicity island related to the development of gastric cancer. The epithelial-mesenchymal transition (EMT) is the main biological event in invasion or metastasis of epithelial cells. H. pylori may promote EMT in human gastric cancer cell lines, but the specific mechanisms are still obscure. We explored the underlying molecular mechanism of EMT induced by H. pylori CagA in gastric cancer. In our article, we detected gastric cancer specimens and adjacent non-cancerous specimens by immunohistochemistry and found increased expression of the EMT-related regulatory protein TWIST1 and the mesenchymal marker vimentin in cancer tissues, while programmed cell death factor 4 (PDCD4) and the epithelial marker E-cadherin expression decreased in cancer specimens. These changes were associated with degree of tissue malignancy. In addition, PDCD4 and TWIST1 levels were related. In gastric cancer cells cocultured with CagA expression plasmid, CagA activated TWIST1 and vimentin expression, and inhibited E-cadherin expression by downregulating PDCD4. CagA also promoted mobility of gastric cancer cells by regulating PDCD4. Thus, H. pylori CagA induced EMT in gastric cancer cells, which reveals a new signaling pathway of EMT in gastric cancer cell lines. PMID- 25144750 TI - Atomistic origin of superior performance of ionic liquid electrolytes for Al-ion batteries. AB - Encouraged by recent experimental findings, here we report on an in silico investigation to probe the atomistic origin behind the superior performance of ionic liquids (ILs) over traditional carbonate electrolytes for Al-ion batteries. Fundamental insights from computationally derived thermodynamic and kinetic considerations coupled with an atomistic-level description of the solvation dynamics is used to elucidate the performance improvements. The formation of low stability ion-solvent complexes in ILs facilitates rapid Al-ion solvation desolvation and translates into favorable transport properties (viscosity and ionic conductivity). Our results offer encouraging prospects for this approach in the a priori prediction of optimal IL formulations for Al-ion batteries. PMID- 25144749 TI - The 2012 Madeira dengue outbreak: epidemiological determinants and future epidemic potential. AB - Dengue, a vector-borne viral disease of increasing global importance, is classically associated with tropical and sub-tropical regions around the world. Urbanisation, globalisation and climate trends, however, are facilitating the geographic spread of its mosquito vectors, thereby increasing the risk of the virus establishing itself in previously unaffected areas and causing large-scale epidemics. On 3 October 2012, two autochthonous dengue infections were reported within the Autonomous Region of Madeira, Portugal. During the following seven months, this first 'European' dengue outbreak caused more than 2000 local cases and 81 exported cases to mainland Europe. Here, using an ento-epidemiological mathematical framework, we estimate that the introduction of dengue to Madeira occurred around a month before the first official cases, during the period of maximum influx of airline travel, and that the naturally declining temperatures of autumn were the determining factor for the outbreak's demise in early December 2012. Using key estimates, together with local climate data, we further propose that there is little support for dengue endemicity on this island, but a high potential for future epidemic outbreaks when seeded between May and August-a period when detection of imported cases is crucial for Madeira's public health planning. PMID- 25144748 TI - Assembly and architecture of the EBV B cell entry triggering complex. AB - Epstein-Barr Virus (EBV) is an enveloped double-stranded DNA virus of the gammaherpesvirinae sub-family that predominantly infects humans through epithelial cells and B cells. Three EBV glycoproteins, gH, gL and gp42, form a complex that targets EBV infection of B cells. Human leukocyte antigen (HLA) class II molecules expressed on B cells serve as the receptor for gp42, triggering membrane fusion and virus entry. The mechanistic role of gHgL in herpesvirus entry has been largely unresolved, but it is thought to regulate the activation of the virally-encoded gB protein, which acts as the primary fusogen. Here we study the assembly and function of the reconstituted B cell entry complex comprised of gHgL, gp42 and HLA class II. The structure from negative-stain electron microscopy provides a detailed snapshot of an intermediate state in EBV entry and highlights the potential for the triggering complex to bring the two membrane bilayers into proximity. Furthermore, gHgL interacts with a previously identified, functionally important hydrophobic pocket on gp42, defining the overall architecture of the complex and playing a critical role in membrane fusion activation. We propose a macroscopic model of the initiating events in EBV B cell fusion centered on the formation of the triggering complex in the context of both viral and host membranes. This model suggests how the triggering complex may bridge the two membrane bilayers, orienting critical regions of the N- and C- terminal ends of gHgL to promote the activation of gB and efficient membrane fusion. PMID- 25144751 TI - Use of the SNOT-22 and UPSIT to appropriately select pediatric patients with cystic fibrosis who should be referred to an otolaryngologist: cross-sectional study. AB - IMPORTANCE: Sinonasal disease and, specifically, nasal polyps, occur frequently in children with cystic fibrosis (CF). As survival rates have improved, it has become imperative that otolaryngologists become involved in the care of patients with CF to provide appropriate medical and surgical interventions for sinonasal disease. Despite significant variability in the subjective reporting of clinical symptoms, previous work has suggested there may be a relationship between clinical indicators and sinonasal disease in this population. OBJECTIVE: To determine whether the 22-item Sino-Nasal Outcome Test (SNOT-22), the University of Pennsylvania Smell Identification Test (UPSIT), and other measures of sinonasal disease could be used to predict the presence of subclinical nasal polyps in children with CF. DESIGN, SETTING, AND PARTICIPANTS: This was a cross sectional study performed from May 2012 through April 2013 at a cystic fibrosis clinic at BC Children's Hospital in Vancouver, British Columbia, Canada. There were 72 eligible children with CF for this study (with a confirmed diagnosis of CF based on genetic testing; their ages ranged from 6 to 18 years, and they were not actively being treated by an otolaryngologist). Thirty-seven of these patients (23 males, 14 females) consented to participate in this study. Twenty three declined participation, and 12 could not be contacted. MAIN OUTCOMES AND MEASURES: Potential clinical predictors for the presence of subclinical nasal polyps were determined a priori. All 37 recruited participants completed a full study assessment. Nasal endoscopy (the gold standard) was performed to determine the presence of nasal polyps. Potential predictors that were assessed included age, sex, genotype, pancreatic function, SNOT-22 and UPSIT scores, oral culture swab result, and severity of forced expiratory volume in 1 second (FEV(1)). RESULTS: A SNOT-22 score of greater than 11 was the only statistically significant predictor of nasal polyps (P = .04). The positive predictive value was 68.1%, the negative predictive value was 66.7%, and the positive likelihood ratio was 1.82. CONCLUSIONS AND RELEVANCE: Given that the SNOT-22 is easy to administer and inexpensive, this sinus disease-specific questionnaire seems to be an appropriate tool for routine use by respirologists when assessing patients with CF to help predict subclinical nasal polyps. PMID- 25144752 TI - Genetic polymorphisms affect efficacy and adverse drug reactions of DMARDs in rheumatoid arthritis. AB - Disease-modifying antirheumatic drugs (DMARDs) and biological agents are critical in preventing the severe complications of rheumatoid arthritis (RA). However, the outcome of treatment with these drugs in RA patients is quite variable and unpredictable. Drug-metabolizing enzymes (dihydrofolate reductase, cytochrome P450 enzymes, N-acetyltransferases, etc.), drug transporters (ATP-binding cassette transporters), and drug targets (tumor necrosis factor-alpha receptors) are coded for by variant alleles. These gene polymorphisms may influence the pharmacokinetics, pharmacodynamics, and side effects of medicines. The cause for differences in efficacy and adverse drug reactions may be genetic variation in drug metabolism among individuals. Polymorphisms in drug transporter genes may change the distribution and excretion of medicines, and the sensitivity of the targets to drugs is strongly influenced by genetic variations. In this article, we review the genetic polymorphisms that affect the efficacy of DMARDs or the occurrence of adverse drug reactions associated with DMARDs in RA. PMID- 25144753 TI - Emerging therapies for hemophilia: a new era of care and the role of the interdisciplinary team. AB - The introduction of new hemophilia management therapies, targeting extended half lives through bioengineering, ushers in an era of potential promise and increasing complexity, more so for those with hemophilia B than hemophilia A. Questions arise for patients, caregivers, and hemophilia treatment center (HTC) staff about how to assess and incorporate novel therapies and how to determine whether new therapies offer a distinct advantage over established treatment routines. Nurses and other interdisciplinary HTC staff are well positioned to assess, educate, and support patients and families in navigating this rapidly changing landscape. To support these challenging efforts, this review offers a perspective on issues affecting therapeutic transitions and provides tools to foster ongoing adherence. PMID- 25144754 TI - Outcomes of peptic ulcer bleeding following treatment with proton pump inhibitors in routine clinical practice: 935 patients with high- or low-risk stigmata. AB - OBJECTIVE: To assess rates of further bleeding, surgery and mortality in patients hospitalized owing to peptic ulcer bleeding. MATERIALS AND METHODS: Consecutive patients hospitalized for peptic ulcer bleeding and treated with a proton pump inhibitor (PPI) (esomeprazole or pantoprazole) were identified retrospectively in 12 centers in Spain. Patients were included if they had high-risk stigmata (Forrest class Ia-IIb, underwent therapeutic endoscopy and received intravenous PPI >=120 mg/day for >=24 h) or low-risk stigmata (Forrest class IIc-III, underwent no therapeutic endoscopy and received intravenous or oral PPI [any dose]). RESULTS: Of 935 identified patients, 58.3% had high-risk stigmata and 41.7% had low-risk stigmata. After endoscopy, 88.3% of high-risk patients and 22.1% of low-risk patients received intravenous PPI therapy at doses of at least 160 mg/day. Further bleeding within 72 h occurred in 9.4% and 2.1% of high- and low-risk patients, respectively (p < 0.001). Surgery to stop bleeding was required within 30 days in 3.5% and 0.8% of high- and low-risk patients, respectively (p = 0.007). Mortality at 30 days was similar in both groups (3.3% in high-risk and 2.3% in low-risk patients). CONCLUSION: Among patients hospitalized owing to peptic ulcer bleeding and treated with PPIs, patients with high-risk stigmata have a higher risk of further bleeding and surgery, but not of death, than those with low-risk stigmata. PMID- 25144755 TI - Famous landmark identification in amnestic mild cognitive impairment and Alzheimer's disease. AB - BACKGROUND: Identification of famous landmarks (FLI), famous faces (FFI) and recognition of facial emotions (FER) is affected early in the course of Alzheimer's disease (AD). FFI, FER and FLI may represent domain specific tasks relying on activation of distinct regions of the medial temporal lobe, which are affected successively during the course of AD. However, the data on FFI and FER in MCI are controversial and FLI domain remains almost unexplored. OBJECTIVES: To determine whether and how are these three specific domains impaired in head to head comparison of patients with amnestic MCI (aMCI) single domain (SD-aMCI) and multiple domain (MD-aMCI). We propose that FLI might be most reliable in differentiating SD-aMCI, which is considered to be an earlier stage of AD pathology spread out, from the controls. PATIENTS AND METHODS: A total of 114 patients, 13 with single domain (SD-aMCI) and 30 with multiple domains (MD-aMCI), 29 with mild AD and 42 controls underwent standard neurological and neuropsychological evaluations as well as tests of FLI, FER and FFI. RESULTS: Compared to the control group, AD subjects performed worse on FFI (p = 0.020), FER (p<0.001) and FLI (p<0.001), MD-aMCI group had significantly worse scores only on FLI (p = 0.002) and approached statistical significance on FER (0.053). SD-aMCI group performed significantly worse only on FLI (p = 0.028) compared to controls. CONCLUSIONS: Patients with SD-aMCI had an isolated impairment restricted to FLI, while patients with MD-aMCI showed impairment in FLI as well as in FER. Patients with mild dementia due to AD have more extensive impairment of higher visual perception. The results suggest that FLI testing may contribute to identification of patients at risk of AD. We hypothesize that clinical examination of all three domains might reflect the spread of the disease from transentorhinal cortex, over amygdala to fusiform gyrus. PMID- 25144758 TI - Aqueous extracts of the marine brown alga Lobophora variegata inhibit HIV-1 infection at the level of virus entry into cells. AB - In recent years, marine algae have emerged as a rich and promising source of molecules with potent activities against various human pathogens. The widely distributed brown alga Lobophora variegata that is often associated with tropical coral reefs exerts strong antibacterial and antiprotozoal effects, but so far has not been associated with specific anti-viral activities. This study investigated potential HIV-1 inhibitory activity of L. variegata collected from different geographical regions, using a cell-based full replication HIV-1 reporter assay. Aqueous L. variegata extracts showed strong inhibitory effects on several HIV-1 strains, including drug-resistant and primary HIV-1 isolates, and protected even primary cells (PBMC) from HIV-1-infection. Anti-viral potency was related to ecological factors and showed clear differences depending on light exposition or epiphyte growth. Assays addressing early events of the HIV-1 replication cycle indicated that L. variegata extracts inhibited entry of HIV-1 into cells at a pre fusion step possibly by impeding mobility of virus particles. Further characterization of the aqueous extract demonstrated that even high doses had only moderate effects on viability of cultured and primary cells (PBMCs). Imaging based techniques revealed extract effects on the plasma membrane and actin filaments as well as induction of apoptosis at concentrations exceeding EC50 of anti-HIV-1 activity by more than 400 fold. In summary, we show for the first time that L. variegata extracts inhibit HIV-1 entry, thereby suggesting this alga as promising source for the development of novel HIV-1 inhibitors. PMID- 25144760 TI - Molecular encapsulation beyond the aperture size limit through dissociative linker exchange in metal-organic framework crystals. AB - Under linker exchange conditions, large guests with molecular diameters 3-4 times the framework aperture size have been encapsulated into preformed nanocrystals of the metal-organic framework ZIF-8. Guest encapsulation is facilitated by the formation of short-lived "open" states of the pores upon linker dissociation. Kinetic studies suggested that linker exchange reactions in ZIF-8 proceed via a competition between dissociative and associative exchange mechanisms, and guest encapsulation was enhanced under conditions where the dissociative pathway predominates. PMID- 25144756 TI - Schistosome syntenin partially protects vaccinated mice against Schistosoma mansoni infection. AB - BACKGROUND: Schistosomiasis is a neglected tropical disease caused by several species of trematode of the genus Schistosoma. The disease affects more than 200 million people in the world and causes up to 280,000 deaths per year, besides having high morbidity due to chronic illness that damages internal organs. Current schistosomiasis control strategies are mainly based on chemotherapy, but many researchers believe that the best long-term strategy to control disease is a combination of drug treatment and immunization with an anti-schistosome vaccine. Among the most promising molecules as vaccine candidates are the proteins present in the tegument and digestive tract of the parasite. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we describe for the first time Schistosoma mansoni syntenin (SmSynt) and we evaluate its potential as a recombinant vaccine. We demonstrate by real-time PCR that syntenin is mainly expressed in intravascular life stages (schistosomula and adult worms) of the parasite life cycle and, by confocal microscopy, we localize it in digestive epithelia in adult worms and schistosomula. Administration of siRNAs targeting SmSynt leads to the knock-down of syntenin gene and protein levels, but this has no demonstrable impact on parasite morphology or viability, suggesting that high SmSynt gene expression is not essential for the parasites in vitro. Mice immunization with rSmSynt, formulated with Freund's adjuvant, induces a Th1-type response, as suggested by the production of IFN-gamma and TNF-alpha by rSmSynt-stimulated cultured splenocytes. The protective effect conferred by vaccination with rSmSynt was demonstrated by 30-37% reduction of worm burden, 38-43% reduction in the number, and 35-37% reduction in the area, of liver granulomas. CONCLUSIONS/SIGNIFICANCE: Our report is the first characterization of syntenin in Schistosoma mansoni and our data suggest that this protein is a potential candidate for the development of a multi-antigen vaccine to control schistosomiasis. PMID- 25144759 TI - Hydrogen sulfide regulates cardiovascular function by influencing the excitability of subfornical organ neurons. AB - Hydrogen sulfide (H2S), a gasotransmitter endogenously found in the central nervous system, has recently been suggested to act as a signalling molecule in the brain having beneficial effects on cardiovascular function. This study was thus undertaken to investigate the effect of NaHS (an H2S donor) in the subfornical organ (SFO), a central nervous system site important to blood pressure regulation. We used male Sprague-Dawley rats for both in vivo and in vitro experiments. We first used RT-PCR to confirm our previous microarray analyses showing that mRNAs for the enzymes required to produce H2S are expressed in the SFO. We then used microinjection techniques to investigate the physiological effects of NaHS in SFO, and found that NaHS microinjection (5 nmol) significantly increased blood pressure (mean AUC = 853.5+/-105.7 mmHg*s, n = 5). Further, we used patch-clamp electrophysiology and found that 97.8% (88 of 90) of neurons depolarized in response to NaHS. This response was found to be concentration dependent with an EC50 of 35.6 uM. Coupled with the depolarized membrane potential, we observed an overall increase in neuronal excitability using an analysis of rheobase and action potential firing patterns. This study has provided the first evidence of NaHS and thus H2S actions and their cellular correlates in SFO, implicating this brain area as a site where H2S may act to control blood pressure. PMID- 25144762 TI - An upconverted photonic nonvolatile memory. AB - Conventional flash memory devices are voltage driven and found to be unsafe for confidential data storage. To ensure the security of the stored data, there is a strong demand for developing novel nonvolatile memory technology for data encryption. Here we show a photonic flash memory device, based on upconversion nanocrystals, which is light driven with a particular narrow width of wavelength in addition to voltage bias. With the help of near-infrared light, we successfully manipulate the multilevel data storage of the flash memory device. These upconverted photonic flash memory devices exhibit high ON/OFF ratio, long retention time and excellent rewritable characteristics. PMID- 25144761 TI - Sox17 regulates insulin secretion in the normal and pathologic mouse beta cell. AB - SOX17 is a key transcriptional regulator that can act by regulating other transcription factors including HNF1beta and FOXA2, which are known to regulate postnatal beta cell function. Given this, we investigated the role of SOX17 in the developing and postnatal pancreas and found a novel role for SOX17 in regulating insulin secretion. Deletion of the Sox17 gene in the pancreas (Sox17 paLOF) had no observable impact on pancreas development. However, Sox17-paLOF mice had higher islet proinsulin protein content, abnormal trafficking of proinsulin, and dilated secretory organelles suggesting that Sox17-paLOF adult mice are prediabetic. Consistant with this, Sox17-paLOF mice were more susceptible to aged-related and high fat diet-induced hyperglycemia and diabetes. Overexpression of Sox17 in mature beta cells using Ins2-rtTA driver mice resulted in precocious secretion of proinsulin. Transcriptionally, SOX17 appears to broadly regulate secretory networks since a 24-hour pulse of SOX17 expression resulted in global transcriptional changes in factors that regulate hormone transport and secretion. Lastly, transient SOX17 overexpression was able to reverse the insulin secretory defects observed in MODY4 animals and restored euglycemia. Together, these data demonstrate a critical new role for SOX17 in regulating insulin trafficking and secretion and that modulation of Sox17 regulated pathways might be used therapeutically to improve cell function in the context of diabetes. PMID- 25144764 TI - Association Between Lymphatic Malformations of the Mediastinum and Congenital Venous Ectasia: Is It Just Coincidental? AB - The association between lymphatic malformations and congenital venous ectasia is extremely rare, and the relative rarity of both entities makes it difficult to determine the relationship between the two. Here we present four new cases and review the current literature. We hypothesize that there might be a strong association between mediastinal lymphatic malformations and segmental phlebectasia; furthermore, there is a molecular background that may justify the association between these two entities. PMID- 25144765 TI - Probiotic Claims for Gastrointestinal Conditions: Stretching the Truth? AB - ABSTRACT Probiotics are live micro-organisms that confer a health benefit on the host when administered in adequate dosages and have been extensively studied for treatment of gastrointestinal (GI) disorders. While a growing body of evidence from randomized controlled trials supports the use of probiotics for a variety of GI conditions, the media and internet are saturated with advertisements falsely claiming that specific probiotic strains or strain combinations can improve, or even cure, many GI complaints. These unsubstantiated claims regarding probiotic efficacy are rampant and remain largely unregulated. The probiotic industry is strongly encouraged to close the gap between marketing hype and scientific discovery. Additionally, US regulators are encouraged to improve enforcement efforts in response to misleading probiotic advertising. PMID- 25144763 TI - Early-life hepatitis e infection in pigs: the importance of maternally-derived antibodies. AB - Passive immunity (PI), acquired through colostrum intake, is essential for piglet protection against pathogens. Maternally-derived antibodies (MDAs) can decrease the transmission of pathogens between individuals by reducing shedding from infected animals and/or susceptibility of naive animals. Only a limited number of studies, however, have been carried out to quantify the level of protection conferred by PI in terms of transmission. In the present study, an original modeling framework was designed to estimate parameters governing the transmission of infectious agents in the presence and absence of PI. This epidemiological model accounts for the distribution of PI duration and two different forces of infection depending on the serological status of animals after colostrum intake. A Bayesian approach (Metropolis-Hastings algorithm) was used for parameter estimation. The impact of PI on hepatitis E virus transmission in piglets was investigated using longitudinal serological data from six pig farms. A strong impact of PI was highlighted, the efficiency of transmission being on average 13 times lower in piglets with maternally-derived antibodies than in fully susceptible animals (range: 5-21). Median infection-free survival ages, based on herd-specific estimates, ranged between 8.7 and 13.8 weeks in all but one herd. Indeed, this herd exhibited a different profile with a relatively low prevalence of infected pigs (50% at slaughter age) despite the similar proportions of passively immune individuals after colostrum intake. These results suggest that the age at HEV infection is not strictly dependent upon the proportion of piglets with PI but is also linked to farm-specific husbandry (mingling of piglets after weaning) and hygiene practices. The original methodology developed here, using population-based longitudinal serological data, was able to demonstrate the relative impact of MDAs on the transmission of infectious agents. PMID- 25144767 TI - High-efficiency synergistic conversion of CO2 to methanol using Fe2O3 nanotubes modified with double-layer Cu2O spheres. AB - Cuprous oxide/hematite nanotubes (Cu2O/Fe2O3NTs) were prepared by a potentiostatic electrodeposited method, in which different structured Cu2O materials were modified onto Fe2O3 NTs surface. Among them, the material with double-layer Cu2O spheres (Cu2O/Fe2O3 NTs-30) showed excellent photoelectrocatalytic (PEC) properties with a suitable energy band gap (1.96 eV) and a smaller overpotential (0.18 V). Furthermore, Cu2O/Fe2O3 NTs-30 showed two types of synergisms in the PEC reduction of CO2: (i) between electrocatalysis and photocatalysis and (ii) between Cu2O and Fe2O3NTs. The faradaic efficiency and methanol yield reached 93% and 4.94 mmol L(-1) cm(-2) after 6 h, respectively. PMID- 25144766 TI - Fetal growth retardation and lack of hypotaurine in ezrin knockout mice. AB - Ezrin is a membrane-associated cytoplasmic protein that serves to link cell membrane proteins with the actin-based cytoskeleton, and also plays a role in regulation of the functional activities of some transmembrane proteins. It is expressed in placental trophoblasts. We hypothesized that placental ezrin is involved in the supply of nutrients from mother to fetus, thereby influencing fetal growth. The aim of this study was firstly to clarify the effect of ezrin on fetal growth and secondly to determine whether knockout of ezrin is associated with decreased concentrations of serum and placental nutrients. Ezrin knockout mice (Ez(-/-)) were confirmed to exhibit fetal growth retardation. Metabolome analysis of fetal serum and placental extract of ezrin knockout mice by means of capillary electrophoresis-time-of-flight mass spectrometry revealed a markedly decreased concentration of hypotaurine, a precursor of taurine. However, placental levels of cysteine and cysteine sulfinic acid (precursors of hypotaurine) and taurine were not affected. Lack of hypotaurine in Ez(-/-) mice was confirmed by liquid chromatography with tandem mass spectrometry. Administration of hypotaurine to heterogenous dams significantly decreased the placenta-to-maternal plasma ratio of hypotaurine in wild-type fetuses but only slightly decreased it in ezrin knockout fetuses, indicating that the uptake of hypotaurine from mother to placenta is saturable and that disruption of ezrin impairs the uptake of hypotaurine by placental trophoblasts. These results indicate that ezrin is required for uptake of hypotaurine from maternal serum by placental trophoblasts, and plays an important role in fetal growth. PMID- 25144770 TI - Organocatalytic amination of alkyl ethers via n-Bu4NI/t-BuOOH-mediated intermolecular oxidative C(sp(3))-N bond formation: novel synthesis of hemiaminal ethers. AB - A novel method for constructing the hemiaminal ether framework under metal-free conditions has been developed. It involves direct organocatalytic amination of alkyl ethers through intermolecular oxidative C(sp(3))-N bond formation, with t BuOOH being the oxidant and n-Bu4NI as the catalyst. PMID- 25144769 TI - The N-reductive system composed of mitochondrial amidoxime reducing component (mARC), cytochrome b5 (CYB5B) and cytochrome b5 reductase (CYB5R) is regulated by fasting and high fat diet in mice. AB - The mitochondrial amidoxime reducing component mARC is the fourth mammalian molybdenum enzyme. The protein is capable of reducing N-oxygenated structures, but requires cytochrome b5 and cytochrome b5 reductase for electron transfer to catalyze such reactions. It is well accepted that the enzyme is involved in N reductive drug metabolism such as the activation of amidoxime prodrugs. However, the endogenous function of the protein is not fully understood. Among other functions, an involvement in lipogenesis is discussed. To study the potential involvement of the protein in energy metabolism, we tested whether the mARC protein and its partners are regulated due to fasting and high fat diet in mice. We used qRT-PCR for expression studies, Western Blot analysis to study protein levels and an N-reductive biotransformation assay to gain activity data. Indeed all proteins of the N-reductive system are regulated by fasting and its activity decreases. To study the potential impact of these changes on prodrug activation in vivo, another mice experiment was conducted. Model compound benzamidoxime was injected to mice that underwent fasting and the resulting metabolite of the N reductive reaction, benzamidine, was determined. Albeit altered in vitro activity, no changes in the metabolite concentration in vivo were detectable and we can dispel concerns that fasting alters prodrug activation in animal models. With respect to high fat diet, changes in the mARC proteins occur that result in increased N-reductive activity. With this study we provide further evidence that the endogenous function of the mARC protein is linked with lipid metabolism. PMID- 25144768 TI - Polymorphisms in K13 and falcipain-2 associated with artemisinin resistance are not prevalent in Plasmodium falciparum isolated from Ugandan children. AB - The emergence of resistance to artemisinin derivatives in Southeast Asia, manifested as delayed clearance of Plasmodium falciparum following treatment with artemisinins, is a major concern. Recently, the artemisinin resistance phenotype was attributed to mutations in portions of a P. falciparum gene (PF3D7_1343700) encoding kelch (K13) propeller domains, providing a molecular marker to monitor the spread of resistance. The P. falciparum cysteine protease falcipain-2 (FP2; PF3D7_1115700) has been shown to contribute to artemisinin action, as hemoglobin degradation is required for potent drug activity, and a stop mutation in the FP2 gene was identified in parasites selected for artemisinin resistance. Although delayed parasite clearance after artemisinin-based combination therapy (ACT) has not yet been noted in Uganda and ACTs remain highly efficacious, characterizing the diversity of these genes is important to assess the potential for resistance selection and to provide a baseline for future surveillance. We therefore sequenced the K13-propeller domain and FP2 gene in P. falciparum isolates from children previously treated with ACT in Uganda, including samples from 2006-7 (n = 49) and from 2010-12 (n = 175). Using 3D7 as the reference genome, we identified 5 non-synonymous polymorphisms in the K13-propeller domain (133 isolates) and 35 in FP2 (160 isolates); these did not include the polymorphisms recently associated with resistance after in vitro selection or identified in isolates from Asia. The prevalence of K13-propeller and FP2 polymorphisms did not increase over time, and was not associated with either time since prior receipt of an ACT or the persistence of parasites >=2 days following treatment with an ACT. Thus, the K13-propeller and FP2 polymorphisms associated with artemisinin resistance are not prevalent in Uganda, and we did not see evidence for selection of polymorphisms in these genes. PMID- 25144773 TI - Hepatitis B vaccine responsiveness and clinical outcomes in HIV controllers. AB - BACKGROUND: Hepatitis B virus (HBV) vaccine responsiveness is associated with reduced risk of AIDS or death in HIV-infected individuals. Although HIV controllers (HIC) typically have favorable immunologic and clinical characteristics compared to non-controllers, vaccine responsiveness has not been studied. METHODS AND FINDINGS: In the U.S. Military HIV Natural History Study, HBV vaccine response was defined as antibody to hepatitis B surface antigen (anti HBs) >= 10 IU/L after last vaccination. For determination of vaccine responsiveness, HIC (n = 44) and treatment-naive non-controllers (n = 476) were not on highly active antiretroviral therapy (HAART) when vaccinated while treated non-controllers (n = 284) received all HBV vaccine doses during viral load (VL) suppressive HAART. Progression to AIDS or death was also compared for all HIC (n = 143) and non-controllers (n = 1566) with documented anti-HBs regardless of the timing of HBV vaccination. Positive vaccine responses were more common in HIC (65.9%) compared to HAART-naive non-controllers (36.6%; P<0.001), but similar to non-controllers on HAART (59.9%; P = 0.549). Factors associated with vaccine response for HIC compared to HAART-naive non-controllers include HIC status (OR 2.65, 95% CI 1.23-5.89; P = 0.014), CD4 count at last vaccination (OR 1.28, 1.15 1.45 for every 100 cells/uL; P<0.001), and number of vaccine doses administered (OR 0.56, 0.35-0.88; P = 0.011). When HIC were compared to non-controllers on HAART, only CD4 count at last vaccination was significant (OR 1.23, 1.1-1.38 for every 100 cells/uL; P<0.001). The rate of AIDS or death per 100 person/years for HIC compared to non-controllers was 0.14 (95% CI 0-0.76) versus 0.98 (95% CI 0.74 1.28) for vaccine responders and 0 (95% CI 0-2.22) versus 4.11 (95% CI 3.38-4.96) for non-responders, respectively. CONCLUSIONS: HIC have improved HBV vaccine responsiveness compared to treatment-naive non-controllers, but similar to those on VL-suppressive HAART. Progression to AIDS or death can be predicted by HBV vaccine responder status for non-controllers, however these events are rarely observed in HIC. PMID- 25144772 TI - Complement activation by merozoite antigens of Plasmodium falciparum. AB - BACKGROUND: Complement (C) is a crucial part of the innate immune system and becomes over activated during malaria, resulting in depletion of C components, especially those for lectin pathway (LP), thereby compromising the host's innate defense. In this study, involvement of P. falciparum antigens in C activation was investigated. METHODS: A highly synchronous culture of the Dd2 clone of P. falciparum was established in a serum free medium. Supernatants harvested from rings, trophozoites and schizonts at various parasite densities were tested for ability to activate C by quantifying amount of C3b deposited on erythrocytes (E). Uninfected sham culture was used as control. Remnants of each C pathway were determined using Wieslab complement System Screenkit (Euro-diagnostica, Sweden). To identify MBL binding antigens of LP, culture supernatants were added to MBL sepharose columns and trapped antigens eluted with increasing concentrations of EDTA (10 mM, 50 mM and 100 mM) and then desalted before being tested for ability to activate C. The EDTA eluate with highest activity was run on a polyacrylamide gel and silver stained proteins analyzed by mass spectroscopy. RESULTS: Antigens released by P. falciparum growing in culture activated C leading to C3b deposition on E. Maximal activation at 7% parasitemia was associated with schizont stage (36.7%) compared to 22% for rings, 21% for trophozoites and 3% for sham culture. All the three pathways of C were activated, with highest activation being for the alternative pathway (only 6% of C activation potential remained), 65% for classiical and 43% for the LP. Seven MBL binding merozoite proteins were identified by mass spectrometry in the 50 mM EDTA eluate. CONCLUSIONS: MBL binding merozoite adhesins with ability to activate C pathway were identified. The survival advantage for such pronounced C activation is unclear, but opsonisation could facilitate recognition and invasion of E. PMID- 25144771 TI - Immunization with Hexon modified adenoviral vectors integrated with gp83 epitope provides protection against Trypanosoma cruzi infection. AB - BACKGROUND: Trypanosoma cruzi is the causative agent of Chagas disease. Chagas disease is an endemic infection that affects over 8 million people throughout Latin America and now has become a global challenge. The current pharmacological treatment of patients is unsuccessful in most cases, highly toxic, and no vaccines are available. The results of inadequate treatment could lead to heart failure resulting in death. Therefore, a vaccine that elicits neutralizing antibodies mediated by cell-mediated immune responses and protection against Chagas disease is necessary. METHODOLOGY/PRINCIPAL FINDINGS: The "antigen capsid incorporation" strategy is based upon the display of the T. cruzi epitope as an integral component of the adenovirus' capsid rather than an encoded transgene. This strategy is predicted to induce a robust humoral immune response to the presented antigen, similar to the response provoked by native Ad capsid proteins. The antigen chosen was T. cruzi gp83, a ligand that is used by T. cruzi to attach to host cells to initiate infection. The gp83 epitope, recognized by the neutralizing MAb 4A4, along with His6 were incorporated into the Ad serotype 5 (Ad5) vector to generate the vector Ad5-HVR1-gp83-18 (Ad5-gp83). This vector was evaluated by molecular and immunological analyses. Vectors were injected to elicit immune responses against gp83 in mouse models. Our findings indicate that mice immunized with the vector Ad5-gp83 and challenged with a lethal dose of T. cruzi trypomastigotes confer strong immunoprotection with significant reduction in parasitemia levels, increased survival rate and induction of neutralizing antibodies. CONCLUSIONS/SIGNIFICANCE: This data demonstrates that immunization with adenovirus containing capsid-incorporated T. cruzi antigen elicits a significant anti-gp83-specific response in two different mouse models, and protection against T. cruzi infection by eliciting neutralizing antibodies mediated by cell-mediated immune responses, as evidenced by the production of several Ig isotypes. Taken together, these novel results show that the recombinant Ad5 presenting T. cruzi gp83 antigen is a useful candidate for the development of a vaccine against Chagas disease. PMID- 25144774 TI - The MAP kinase p38 is part of Drosophila melanogaster's circadian clock. AB - All organisms have to adapt to acute as well as to regularly occurring changes in the environment. To deal with these major challenges organisms evolved two fundamental mechanisms: the p38 mitogen-activated protein kinase (MAPK) pathway, a major stress pathway for signaling stressful events, and circadian clocks to prepare for the daily environmental changes. Both systems respond sensitively to light. Recent studies in vertebrates and fungi indicate that p38 is involved in light-signaling to the circadian clock providing an interesting link between stress-induced and regularly rhythmic adaptations of animals to the environment, but the molecular and cellular mechanisms remained largely unknown. Here, we demonstrate by immunocytochemical means that p38 is expressed in Drosophila melanogaster's clock neurons and that it is activated in a clock-dependent manner. Surprisingly, we found that p38 is most active under darkness and, besides its circadian activation, additionally gets inactivated by light. Moreover, locomotor activity recordings revealed that p38 is essential for a wild type timing of evening activity and for maintaining ~ 24 h behavioral rhythms under constant darkness: flies with reduced p38 activity in clock neurons, delayed evening activity and lengthened the period of their free-running rhythms. Furthermore, nuclear translocation of the clock protein Period was significantly delayed on the expression of a dominant-negative form of p38b in Drosophila's most important clock neurons. Western Blots revealed that p38 affects the phosphorylation degree of Period, what is likely the reason for its effects on nuclear entry of Period. In vitro kinase assays confirmed our Western Blot results and point to p38 as a potential "clock kinase" phosphorylating Period. Taken together, our findings indicate that the p38 MAP Kinase is an integral component of the core circadian clock of Drosophila in addition to playing a role in stress-input pathways. PMID- 25144775 TI - Mycobacterial and HIV infections up-regulated human zinc finger protein 134, a novel positive regulator of HIV-1 LTR activity and viral propagation. AB - BACKGROUND: Concurrent occurrence of HIV and Tuberculosis (TB) infections influence the cellular environment of the host for synergistic existence. An elementary approach to understand such coalition at the molecular level is to understand the interactions of the host and the viral factors that subsequently effect viral replication. Long terminal repeats (LTR) of HIV genome serve as a template for binding trans-acting viral and cellular factors that regulate its transcriptional activity, thereby, deciding the fate of HIV pathogenesis, making it an ideal system to explore the interplay between HIV and the host. METHODOLOGY/PRINCIPAL FINDINGS: In this study, using biotinylated full length HIV 1 LTR sequence as bait followed by MALDI analyses, we identified and further characterized human-Zinc-finger-protein-134 (hZNF-134) as a novel positive regulator of HIV-1 that promoted LTR-driven transcription and viral production. Over-expression of hZNF-134 promoted LTR driven luciferase activity and viral transcripts, resulting in increased virus production while siRNA mediated knockdown reduced both the viral transcripts and the viral titers, establishing hZNF-134 as a positive effector of HIV-1. HIV, Mycobacteria and HIV-TB co infections increased hZNF-134 expressions in PBMCs, the impact being highest by mycobacteria. Corroborating these observations, primary TB patients (n = 22) recorded extraordinarily high transcript levels of hZNF-134 as compared to healthy controls (n = 16). CONCLUSIONS/SIGNIFICANCE: With these observations, it was concluded that hZNF-134, which promoted HIV-1 LTR activity acted as a positive regulator of HIV propagation in human host. High titers of hZNF-134 transcripts in TB patients suggest that up-regulation of such positive effectors of HIV-1 upon mycobacterial infection can be yet another mechanism by which mycobacteria assists HIV-1 propagation during HIV-TB co-infections. hZNF-134, an uncharacterized host protein, thus assumes a novel regulatory role during HIV host interactions. Our study provides new insights into the emerging role of zinc finger proteins in HIV-1 pathogenesis. PMID- 25144776 TI - Ex-ante benefit-cost analysis of the elimination of a Glossina palpalis gambiensis population in the Niayes of Senegal. AB - BACKGROUND: In 2005, the Government of Senegal embarked on a campaign to eliminate a Glossina palpalis gambiensis population from the Niayes area (~ 1000 km(2)) under the umbrella of the Pan African Tsetse and Trypanosomosis Eradication Campaign (PATTEC). The project was considered an ecologically sound approach to intensify cattle production. The elimination strategy includes a suppression phase using insecticide impregnated targets and cattle, and an elimination phase using the sterile insect technique, necessary to eliminate tsetse in this area. METHODOLOGY/PRINCIPAL FINDINGS: Three main cattle farming systems were identified: a traditional system using trypanotolerant cattle and two "improved" systems using more productive cattle breeds focusing on milk and meat production. In improved farming systems herd size was 45% lower and annual cattle sales were ?250 (s.d. 513) per head as compared to ?74 (s.d. 38) per head in traditional farming systems (p<10-3). Tsetse distribution significantly impacted the occurrence of these farming systems (p = 0.001), with 34% (s.d. 4%) and 6% (s.d. 4%) of improved systems in the tsetse-free and tsetse-infested areas, respectively. We calculated the potential increases of cattle sales as a result of tsetse elimination considering two scenarios, i.e. a conservative scenario with a 2% annual replacement rate from traditional to improved systems after elimination, and a more realistic scenario with an increased replacement rate of 10% five years after elimination. The final annual increase of cattle sales was estimated at ~ ?2800/km(2) for a total cost of the elimination campaign reaching ~ ?6400/km(2). CONCLUSION/SIGNIFICANCE: Despite its high cost, the benefit-cost analysis indicated that the project was highly cost-effective, with Internal Rates of Return (IRR) of 9.8% and 19.1% and payback periods of 18 and 13 years for the two scenarios, respectively. In addition to an increase in farmers' income, the benefits of tsetse elimination include a reduction of grazing pressure on the ecosystems. PMID- 25144777 TI - The liver in pediatric gastrointestinal disease. AB - Hepatic involvement is often encountered in gastrointestinal (GI) diseases, in part because of the close anatomic and physiologic relations between the liver and GI tract. Drainage of the mesenteric blood supply to the portal vein permits absorbed and/or translocated nutrients, toxins, bacterial elements, cytokines, and immunocytes to gain hepatic access. Liver problems in digestive disorders may range from nonspecific hepatocellular enzyme elevations to significant pathologic processes that may progress to end-stage liver disease. Hepatobiliary manifestations of primary GI diseases in childhood and adolescence are not uncommon and include several well-described associations, such as sclerosing cholangitis with inflammatory bowel disease. Liver damage may also result from the effects of drugs used to treat GI diseases, for example, the hepatotoxicity of immunomodulatory therapies. This review highlights the important features of the hepatic and biliary abnormalities associated with 3 common pediatric GI conditions: inflammatory bowel disease, celiac disease, and cystic fibrosis. PMID- 25144778 TI - Low bone mineral mass is associated with decreased bone formation and diet in girls with Rett syndrome. AB - OBJECTIVE: The aim of the present study was to characterize biomarkers of bone turnover and their relation with bone mineral mass in a cross-sectional cohort of girls with Rett syndrome (RTT) and to examine the role of dietary, biochemical, hormonal, and inflammatory factors on bone mineral mass and bone biomarkers in this disorder. METHODS: Total body bone mineral content (BMC) and bone mineral density (BMD) were determined by dual-energy x-ray absorptiometry. Dietary nutrient intakes were determined from 3-day food records. Biomarkers of bone turnover, bone metabolites, vitamin D metabolites, hormones, and inflammatory markers were measured by standard clinical laboratory methods. RESULTS: Serum osteocalcin, bone alkaline phosphatase, and C-telopeptide showed significant inverse relations with age in the RTT cohort. Mean osteocalcin concentrations were significantly lower and mean bone alkaline phosphatase concentrations were significantly higher for individual age groups in the RTT cohort than mean values for their respective age ranges in the reference population. Significant inverse associations were identified between urinary calcium losses, expressed as calcium:creatinine ratios, and total body BMC and BMD z scores. Dietary protein, calcium, and phosphorus intakes, expressed as a proportion of Dietary Reference Intakes for age and sex, showed significant positive associations with total body BMD z scores. CONCLUSIONS: The present study suggests decreased bone formation instead of increased bone resorption may explain in part the deficits in bone mineral mass in RTT and that attention to the adequacy of dietary protein, calcium, and phosphorus intakes may offer an opportunity to improve bone health in RTT. PMID- 25144781 TI - An on-chip Cell-SELEX process for automatic selection of high-affinity aptamers specific to different histologically classified ovarian cancer cells. AB - Ovarian cancer (OvCa) is the second most common type of gynecological cancer. More seriously, the prognosis for survival is relatively poor if an early OvCa diagnosis is not achieved. However, it is extremely challenging to diagnose very early stage OvCa, when treatments are the most effective, because of the lack of specific and sensitive biomarkers. Therefore, in order to achieve early detection of OvCa, screening and identifying biomarkers with high specificity and affinity are greatly needed. In this study, an integrated microfluidic system capable of performing cell-based systematic evolution of ligands by an exponential enrichment (Cell-SELEX) process was developed for automatic, high-throughput screening of multiple cell lines to competitively select aptamer-based biomarkers for OvCa. This on-chip Cell-SELEX process only required five rounds of aptamer selection, which is much faster than using a conventional SELEX process (22 rounds). Using this on-chip process, 13 aptamers specific to OvCa cells were successfully screened and three of them showed high affinity towards target cells with dissociation constants of 1.8 nM, 8.3 nM, and 1.3 nM. Analysis of stained fluorescence images and competitive testing against multiple cancer cell lines (cervical cancer, breast cancer, lung cancer, and liver cancer) were performed to verify the specificity of these selected aptamers. The results demonstrated that this developed system could perform the on-chip Cell-SELEX selection successfully and could be applied for personalized aptamer screening or targeted therapy monitoring in the near future. PMID- 25144780 TI - Determinants of influenza transmission in South East Asia: insights from a household cohort study in Vietnam. AB - To guide control policies, it is important that the determinants of influenza transmission are fully characterized. Such assessment is complex because the risk of influenza infection is multifaceted and depends both on immunity acquired naturally or via vaccination and on the individual level of exposure to influenza in the community or in the household. Here, we analyse a large household cohort study conducted in 2007-2010 in Vietnam using innovative statistical methods to ascertain in an integrative framework the relative contribution of variables that influence the transmission of seasonal (H1N1, H3N2, B) and pandemic H1N1pdm09 influenza. Influenza infection was diagnosed by haemagglutination-inhibition (HI) antibody assay of paired serum samples. We used a Bayesian data augmentation Markov chain Monte Carlo strategy based on digraphs to reconstruct unobserved chains of transmission in households and estimate transmission parameters. The probability of transmission from an infected individual to another household member was 8% (95% CI, 6%, 10%) on average, and varied with pre-season titers, age and household size. Within households of size 3, the probability of transmission from an infected member to a child with low pre-season HI antibody titers was 27% (95% CI 21%-35%). High pre-season HI titers were protective against infection, with a reduction in the hazard of infection of 59% (95% CI, 44%-71%) and 87% (95% CI, 70%-96%) for intermediate (1?20-1?40) and high (>=1?80) HI titers, respectively. Even after correcting for pre-season HI titers, adults had half the infection risk of children. Twenty six percent (95% CI: 21%, 30%) of infections may be attributed to household transmission. Our results highlight the importance of integrated analysis by influenza sub-type, age and pre-season HI titers in order to infer influenza transmission risks in and outside of the household. PMID- 25144782 TI - Size-controlled synthesis of mesoporous palladium nanoparticles as highly active and stable electrocatalysts. AB - We report a solution phase synthesis of monodispersed mesoporous Pd nanoparticles (MPNs) with narrow particle size distributions. The average particle sizes can be controlled to a range of 25 nm to 42 nm, by utilizing cationic surfactants (as structure-directing agents) and triblock copolymers (as protective agents for controlled Pd deposition). The obtained MPNs exhibit very high electrocatalytic activity in formic acid oxidation. PMID- 25144779 TI - Chemotherapy-Induced Peripheral Neuropathy in Pediatric Cancer Patients. AB - Chemotherapy-induced peripheral neuropathies (CIPNs) are an increasingly common neuropathic and pain syndrome in adult and pediatric cancer patients and survivors [1-69]. However, symptoms associated with CIPNs are often undiagnosed, under-assessed, and communications problems between clinicians, family members, and patients have been observed [70-73]. Less is known about the prevalence and impact of CIPNs on pediatric cancer populations [70-71]. This article aims to provide a brief understanding of CIPNs in pediatric populations, and to review the evidence for both its prevention and treatment. PMID- 25144784 TI - From the Editor-in-Chief. PMID- 25144785 TI - End-of-life decisions - some international comparisons. AB - Healthcare professionals often confront difficult issues in end-of-life care. Caregivers who question futile care and treatment can find themselves at odds with patients, family members and surrogates who stress patient autonomy. Many developed nations recognize hospital ethics committees as appropriate venues for discussion of end-of-life care, and palliative care initiatives in many hospitals play important roles in patient care at the end of life. As health systems worldwide confront diminishing resources and endless questioning on expenditures, the concept of medical futility has taken on increasing prominence. Medical professionals know intuitively that certain interventions near the end of life can neither extend life nor improve the quality of life remaining. In addition to medical futility, concerns about international economic pressures and enhanced recognition of patient autonomy lead to questions as to the appropriateness of withdrawing life-sustaining treatment, assisted suicide and euthanasia. While some appellate courts seem willing to entertain questions on the legal rights of patients to access certain end-of-life measures, legislative bodies appear reluctant to legalize assisted suicide and euthanasia. PMID- 25144783 TI - Pooled segregant sequencing reveals genetic determinants of yeast pseudohyphal growth. AB - The pseudohyphal growth response is a dramatic morphological transition and presumed foraging mechanism wherein yeast cells form invasive and surface-spread multicellular filaments. Pseudohyphal growth has been studied extensively as a model of conserved signaling pathways controlling stress responses, cell morphogenesis, and fungal virulence in pathogenic fungi. The genetic contribution to pseudohyphal growth is extensive, with at least 500 genes required for filamentation; as such, pseudohyphal growth is a complex trait, and linkage analysis is a classical means to dissect the genetic basis of a complex phenotype. Here, we implemented linkage analysis by crossing each of two filamentous strains of Saccharomyces cerevisiae (Sigma1278b and SK1) with an S288C-derived non-filamentous strain. We then assayed meiotic progeny for filamentation and mapped allelic linkage in pooled segregants by whole-genome sequencing. This analysis identified linkage in a cohort of genes, including the negative regulator SFL1, which we find contains a premature stop codon in the invasive SK1 background. The S288C allele of the polarity gene PEA2, encoding Leu409 rather than Met, is linked with non-invasion. In Sigma1278b, the pea2 M409L mutation results in decreased invasive filamentation and elongation, diminished activity of a Kss1p MAPK pathway reporter, decreased unipolar budding, and diminished binding of the polarisome protein Spa2p. Variation between SK1 and S288C in the mitochondrial inner membrane protein Mdm32p at residues 182 and 262 impacts invasive growth and mitochondrial network structure. Collectively, this work identifies new determinants of pseudohyphal growth, while highlighting the coevolution of protein complexes and organelle structures within a given genome in specifying complex phenotypes. PMID- 25144786 TI - The experiences of making infant feeding choices by African, Caribbean and Black HIV-positive mothers in Ontario, Canada. AB - Mothers in HIV-endemic countries are advised to exclusively breastfeed their babies until six months because of lack of resources and better chances for child survival, while in developed countries, replacement feeding is advised. What are the experiences of HIV-positive women who migrate from HIV-endemic countries to developed countries, when making infant feeding choices? METHODS: In-depth interviews and focus group discussions with a total of 25 women living with HIV in Toronto and Hamilton, Ontario. RESULTS: Free infant formula alleviates the practical constraints in making infant feeding choices. However, cultural beliefs and social expectations constrain HIV-positive mothers' decision not to breastfeed. This is further complicated by the different policies. Service providers should understand the psychological and emotional experiences of the mothers in order to provide the appropriate support. Peers could be potential sources of support. The differences in policies are issues of global justice that need to be addressed. PMID- 25144787 TI - Consistency and quality check of survey data in India. AB - OBJECTIVE: Reliability of survey responses on topics such as utilization of health facilities by mother and child has long been a subject of concern. This paper explores consistency of responses from the same individuals over time on utilization of health services involving child delivery and child care. METHODS: A sub-sample survey was carried out by an independent monitoring agency in 13 states as a part of a larger Coverage Evaluation Survey of all states of India in 2009 by UNICEF, to recheck the responses to improve data quality. Our randomly chosen sub-sample consisted of 510 questionnaires regarding mothers and 497 regarding children. Differences of responses were noted and conveyed to field agencies to rectify recurring errors. Statistical analysis was conducted to find consistency of responses. RESULTS: Matching between the original and rechecked responses varied. Generally, however, the overall match was greater than 90%. CONCLUSION: Findings suggest that response inconsistencies and the manner in which they are resolved are shown to have important implications for the overall estimate of indicators of utilization of health facilities. The monitoring exercise has, therefore, addressed the quality and consistency issue, which needs further consideration in large-scale surveys. Otherwise, it poses a validity threat to data quality and results on which national policy is framed. PMID- 25144788 TI - Neighbourhood variation and inequity of primary health service use by mothers from London-Middlesex, Ontario. AB - OBJECTIVE: Primary health service use (P-HSU) may be influenced by contextual characteristics and is equitable when driven by need. Contextual effects and inequity of maternal P-HSU were determined. METHODS: Participant data from a London-Middlesex, Ontario, prenatal cohort were linked by residential address to contextual characteristics. Multilevel logistic regression estimated contextual effects and tested for effect measure modification of need factors. RESULTS: Maternal P-HSU varied between neighbourhoods. The effect of obesity was different for rural mothers living in low- (OR = 0.26) and middle-income households (OR = 0.15) and for urban mothers living in high-income households (OR = 2.82). The effect of having a health condition was greatest in mothers with three or more children (OR = 2.41). DISCUSSION: Differences in maternal P-HSU exist between neighbourhoods, and enabling factors modified need factors' effects, identifying subgroups of mothers with inequitable P-HSU. RESULTS have the potential to inform Canadian health policy with regard to contextual effects and inequity of P-HSU. PMID- 25144789 TI - Protection of health workers, patients and facilities in times of violence - report. PMID- 25144790 TI - Novel ruthenium sensitizers having different numbers of carboxyl groups for dye sensitized solar cells: effects of the adsorption manner at the TiO2 surface on the solar cell performance. AB - Two novel ruthenium sensitizers having multiple carboxyl groups ((TBA)[Ru{4'-(3,4 dicarboxyphenyl)-4,4"-dicarboxyterpyridine}(NCS)3] (TUS-21) and (TBA)[Ru{4'-(3 carboxyphenyl)-4,4"-dicarboxyterpyridine}(NCS)3] (TUS-37); TBA = tetrabutylammonium) have been synthesized as improved model sensitizers for the previously reported ruthenium sensitizer TUS-20 ((TBA)[Ru{4'-(3,4 dicarboxyphenyl)terpyridine}(NCS)3]). The absorption maxima of two MLCT bands and the absorption onsets of TUS-21 and TUS-37 were shifted to longer wavelengths of about 30 nm in comparison to those of TUS-20 by introducing a carboxyl group to the each terminal pyridine ring of the terpyridine ligand. TUS-21 and TUS-37 showed quite similar adsorption behaviors to the TiO2 surface, and this adsorption behavior was found to be different from that of TUS-20. ATR-IR measurements revealed that TUS-21 and TUS-37 bind to the TiO2 surface by using two carboxyl groups at the 3-position of the phenyl ring and at one of the terminal pyridine rings of the terpyridine ligand, while TUS-20 is reported to bind by using two carboxyl groups at the 3,4-dicarboxyphenyl unit. The dye sensitized solar cell (DSC) with TUS-21 exhibited 10.2% conversion efficiency, which is much higher than that of the DSC with TUS-20 (7.5%), under AM 1.5 (100 mW/cm(2)) irradiation. PMID- 25144791 TI - Relationship between native-state solubility and non-native aggregation of recombinant human granulocyte colony stimulating factor: practical implications for protein therapeutic development. AB - Prescreening methods are needed in the biotechnology industry for rapid selection of protein therapeutic candidates and formulations of low aggregation propensity. In recent reports solubility measurements have shown promise as one such method, although the connection between protein solubility and non-native aggregation is not well understood. In the present investigation, recombinant human granulocyte colony stimulating factor (rhGCSF) was used to explore this relationship since it was previously shown to rapidly undergo non-native aggregation/precipitation under physiological conditions in a reaction attenuated by the addition of sucrose [Krishnan, S.; et al. Biochemistry 2002, 41, 6422-6431]. Strong correlations were found between rhGCSF non-native aggregation and both solubility and thermal stability as a function of sucrose concentration. We believe these results make sense in the context of an rhGCSF aggregation mechanism where loss of monomer to insoluble aggregate is limited by association to an observable dimer from a less soluble (and aggregation competent) intermediate species that exists in a temperature sensitive pre-equilibrium with the native monomer. Both solubility and measures of conformational stability report on the position of this equilibrium and therefore the concentration of reactive intermediate. Interestingly, aggregation also correlated with rhGCSF solubility as a function of salting-in concentrations of phosphate since both are dependent on the colloidal stability of the reactive intermediate but not with conformational stability. In lieu of a complete understanding of the aggregation processes that limit protein therapeutic shelf life, these results highlight the potential of using simple solubility measurements as an additional tool in the biotechnology prescreening repertoire. PMID- 25144793 TI - Correlates of age at attainment of developmental milestones in HIV-infected infants receiving early antiretroviral therapy. AB - BACKGROUND: Infant HIV-1 infection is associated with impaired neurologic and motor development. Antiretroviral therapy (ART) has the potential to improve developmental outcomes but the relative contributions of pre-ART disease status, growth, treatment regimen and ART response during infancy are unknown. METHODS: Kenyan ART-naive infants <5-months old initiated ART and had monthly assessment of age of full neck control, unsupported walking and monosyllabic speech during 24 months of follow-up. Pre-ART and post-ART correlates of age at milestone attainment were evaluated using t tests or multivariate linear regression. RESULTS: Among 99 infants, pre-ART correlates of later milestone attainment included: underweight and stunted (neck control, walking and speech, all P values <0.05), missed prevention of mother-to-child transmission (P = 0.04) (neck control), previous hospitalization, World Health Organization (WHO) Stage III/IV, low CD4 count, and wasting (speech and walking, all P values <0.05), and low maternal CD4 (speech, P = 0.04). Infants initiated ART at a median of 14 days following enrollment. Infants receiving nevirapinevs lopinavir/ritonavir-based ART attained later speech (18.1 vs. 15.5 months, P = 0.003) [corrected]. Adjusting for pre-ART level, lower 6-month gain in CD4% was associated with later walking (0.18 months earlier per unit increase in CD4%; P = 0.004) and speech (0.12 months earlier per unit increase in CD4%; P = 0.05), and lower 6-month gains in weight-for-age (P = 0.009), height-for-age (P = 0.03) and weight-for height (P = 0.02) were associated with later walking. CONCLUSION: In HIV-infected infants, compromised pre-ART immune and growth status, poor post-ART immune and growth responses, and use of nevirapine- vs. lopinavir/ritonavir-based ART were each associated with later milestone attainment [corrected]. The long-term consequences of these delays are unknown. PMID- 25144794 TI - Time to symptom resolution in young children treated for pulmonary tuberculosis. AB - BACKGROUND: Response to treatment may be useful for diagnostic confirmation of childhood tuberculosis (TB). We aimed to evaluate time to symptom resolution in children treated for pulmonary TB. METHODS: We compared pulmonary TB cases and noncases, classified by a published diagnostic algorithm, in South African children younger than 2. TB treatment was prescribed independently on clinical grounds. We analyzed independent determinants of baseline symptom resolution by Cox regression. RESULTS: One hundred and ninety-one symptomatic children, median age 12 months, were prescribed for TB treatment. Chest radiograph features of TB were associated with longer time to resolution of cough (adjusted hazard ratio, AHR 0.31), wheeze (AHR 0.26) and failure to thrive (AHR 0.41), (all P < 0.05). However, median duration of baseline cough (63 vs. 70 days, P = 0.98), wheeze (62 vs. 68 days, P = 0.87) and failure to thrive (76 vs. 66 days, P = 0.59) did not differ in TB cases (n = 48) versus noncases (n = 46). CONCLUSIONS: Baseline symptoms take more than 60 days to resolve in the majority of young children after starting TB treatment. Furthermore, since time to resolution does not differentiate TB cases from noncases; clinical response to treatment is not an appropriate diagnostic criterion for pediatric trials of TB diagnostics, drugs and vaccines. PMID- 25144795 TI - Use of antibiotics in children: a Danish nationwide drug utilization study. AB - BACKGROUND: We aimed to describe the use of systemic antibiotics among children in Denmark. METHODS: National data on drug use in Denmark were extracted from the Danish National Prescription Database. We used prescription data for all children in Denmark aged 0 to 11 years from January 1, 2000 to December 31, 2012. RESULTS: We obtained data on 5,884,301 prescriptions for systemic antibiotics issued to 1,206,107 children. The most used single substances were phenoxymethylpenicillin (45%), amoxicillin (34%) and erythromycin (6%). The highest incidence rate of antibiotic treatment episodes was observed among children younger than 2 at 827 per 1000 children in 2012. Incidence rates were relatively stable throughout the study period. One-year prevalences in 2012 were 485, 363 and 190 per 1000 children among children aged 0-1, 2-4 and 5-11, respectively. A gradual shift from narrow-spectrum penicillin V to the broader-spectrum amoxicillin was found among children younger than 5. The use of macrolides decreased slightly, especially among those aged 0-1. Minor regional differences were noted, with somewhat higher use in the Capital Region. Skewness in use was most notable among those aged 0-1. There was little evidence of heavy users. CONCLUSION: Prescribing rate of antibiotics to children in Denmark remained stable at a high level from 2000 to 2012. An increase in the use of broad-spectrum beta-lactam penicillin was noted, but otherwise the prescribing pattern adhered well to National guidelines with respect to choice of antibiotics. PMID- 25144796 TI - Intracranial Mycobacterium abscessus infection in a healthy toddler. AB - We present the first case of pediatric intracranial Mycobacterium abscessus infection in a 16-month-old female with neurofibromatosis type 1. We describe a successful treatment regimen including excisional biopsy combined with high-dose steroids and 16 weeks of triple antimicrobial therapy that resulted in clinical cure and an excellent neurologic outcome. PMID- 25144797 TI - Kingella kingae DNA in langerhans cell histiocytosis of bone. AB - Langerhans cell histiocytosis of bone is a rare pediatric neoplastic disorder of unclear pathogenesis. We report the case of a 3-year-old girl who presented with Langerhans cell histiocytosis of the ilium in which Kingella kingae was detected. Our findings argue for the search for K. kingae by polymerase chain reaction in children with Langerhans cell histiocytosis of bone. PMID- 25144798 TI - Childhood meningitis caused by Streptococcus bovis group: clinical and biologic data during a 12-year period in France. AB - BACKGROUND: Bacterial meningitis (BM) is a major cause of morbidity and mortality in children. Sporadic cases of Streptococcus bovis have been described in neonates and infants. To assess the epidemiologic, clinical and biologic characteristics of this meningitis, we used the French Surveillance Network for BM in children. METHODS: Two hundred and twenty-seven pediatric wards working with 168 microbiology departments throughout France were asked to report all cases of BM in patients <18 years. Diagnosis was based on a combination of fever, meningeal signs and a positive cerebrospinal fluid (CSF) culture and/or a positive polymerase chain reaction in the CSF and/or positive blood culture associated with pleiocytosis. RESULTS: Among 4806 cases of BM recorded in 12 years (2001-2012), 23 cases were caused by S. bovis (0.5%). All were infants. Among them, 15 cases (65.2%) occurred in the neonatal period. The majority occurred in premature infants (73.9%). In 21 cases, the diagnosis was based on a positive CSF culture. Blood culture was positive in 17 children. When S. bovis subtype was identified, it was type 2 (Streptococcus gallolyticus pasteurianus) in 80% of cases. All infants received antibiotic therapy with parenteral penicillin and/or third-generation cephalosporin combined with an aminoglycoside. The duration of treatment ranged from 10 to 25 days. Of the 23 patients, 17 (73.9%) had a second lumbar puncture and in all those cases, the CSF was sterile. No deaths or neurologic complications were reported. CONCLUSION: BM due to S. bovis is rare and primarily affects infants, particularly premature infants. Antibiotic treatment is effective with low morbidity and mortality. PMID- 25144799 TI - Use of interferon-gamma release assays to calculate the annual risk of tuberculosis infection. AB - The objective was to assess the annual risk of tuberculosis infection by means of tuberculin skin testing (TST) in children, evaluating whether QuantiFERON-TB Gold In-Tube (QFN-G-IT) could improve the accuracy. On the basis of the positive TST results, the global annual incidence was estimated at 0.78%, with an increase in the prevalence from 0.64% to 1.68% in 2 years. However, QFN-G-IT was only positive in 6 of the 25 children with positive TST. The confirmation of the positive TST results by QFN-G-IT provided more accurate annual incidence estimation. PMID- 25144800 TI - Nasal carriage of methicillin-resistant Staphylococcus aureus during the first 2 years of life in children in northern Taiwan. AB - BACKGROUND: Most reported studies of methicillin-resistant Staphylococcus aureus (MRSA) carriage have represented 1 time point. To better understand dynamic changes of nasal MRSA carriage, we conducted this longitudinal study in Taiwan. METHODS: We recruited 304 newborn babies and obtained samples from nares for detection of S. aureus within 3 days of life, and obtained further samples periodically up to 2 years of age. A total of 12 samplings were attempted to be obtained. RESULTS: Totally, 273 subjects with >=9 samples were included for analysis. One hundred and ten subjects (40%) harbored MRSA, on one or more occasions; of these 82 (75%) had >=2 positive specimens and 84 (76%) had colonization <=4 months of age. Fourteen infants (5.1%) carried MRSA within 3 days of life, the rate peaked at the age of 2 months (21%) and it was lowest (3.1%) at the age of 18 months. All but 4 first MRSA isolates from the colonized subjects carried either staphylococcal cassette chromosome (SCCmec) IV or V(T). Of 32 subjects with >=4 MRSA isolates, all isolates from the same subject were genetically indistinguishable in 17 (53%) and genetically related in an additional 9 (28%). Five episodes of skin and soft tissue infections (SSTIs) were identified in 4 subjects. CONCLUSION: In Taiwan, during the first 2 years of life, two-fifths of the children ever harbored MRSA, whereas fewer than 2% of them had SSTIs. Three-fourths of the colonization occurred within the first 4 months and were persistent. More than half of the persistent colonizing isolates were genetically indistinguishable. PMID- 25144792 TI - Synthesis of nucleoside phosphate and phosphonate prodrugs. PMID- 25144801 TI - Aspergillus mediastinitis presenting as superior mediastinal syndrome in an immunocompetent child. AB - We report a case of mediastinal mass caused by a fungal infection in an immunocompetent child. The patient presented with superior mediastinal syndrome along with a swelling in the chest wall. Cytology and culture demonstrated Aspergillus flavus. The child was treated with voriconazole, which resulted in clinical response. PMID- 25144802 TI - 32nd annual meeting of the European Society for Pediatric Infectious Diseases in Dublin, Ireland. PMID- 25144804 TI - Xenobiotic-urea conjugates; chemical or biological? AB - 1. Although the major pathways involved in drug metabolism have been elucidated, there remain those routes that may be considered as minor, esoteric, or even artifactual. 2. Conjugation with urea, an abundant, non-toxic, small water soluble molecule, is such a disputed and debatable Phase II pathway. 3. The present article collates data gleaned from the literature concerning xenobiotic urea conjugation, presents pertinent information resurrecting the controversy and poses questions as to the nature of the phenomenon. PMID- 25144805 TI - Trends in the incidence and treatment of necrotizing soft tissue infections: an analysis of the National Hospital Discharge Survey. AB - Necrotizing soft tissue infections are a rare but potentially fatal condition of the soft tissues caused by virulent, toxin-producing bacteria. In the United States, there is an estimated annual incidence of 0.04 cases per 1000 annually, but previous estimates of the Centers for Disease Control and Prevention had the incidence at 500 to 1500 cases yearly. Early reports of mortality were variable with rates ranging from 46 to 76% but outcomes have been improving over time. The National Hospital Discharge Survey was analyzed to study current trends in the demographics, incidence, use, and mortality of patients diagnosed with necrotizing soft tissue infections. The authors analyzed the 1999, 2002, and 2007 National Hospital Discharge Survey by using a sampling weighting method. A total of 13,648 cases of necrotizing soft tissue infections were identified in 2007. This represents an increase from 12,153 cases in 2002 and 6612 cases in 1999. In the 9 years from 1999 to 2007 the gross incidence of necrotizing soft tissue infections more than doubled. Hospital stay was essentially unchanged within study years, at 16 days. Mean age increased from approximately 50 years in 1999 to 54 years in 2007. Further, mortality went from 10.45% in 1999 to 9.75% in the 2007 survey. The population-adjusted incidence rate increased 91% in the studied years. Rising use of immunosupression, exponential growth in the incidence of obesity, and type 2 diabetes could be a major contributing factor. The mortality rate is far below the rate in reports published from as early as 20 years ago, and at 9.75% compares with modern case series, but is a more accurate measure of mortality in this condition. PMID- 25144803 TI - Immunoprecipitation of amyloid fibrils by the use of an antibody that recognizes a generic epitope common to amyloid fibrils. AB - Amyloid fibrils are associated with many maladies, including Alzheimer's disease (AD). The isolation of amyloids from natural materials is very challenging because the extreme structural stability of amyloid fibrils makes it difficult to apply conventional protein science protocols to their purification. A protocol to isolate and detect amyloids is desired for the diagnosis of amyloid diseases and for the identification of new functional amyloids. Our aim was to develop a protocol to purify amyloid from organisms, based on the particular characteristics of the amyloid fold, such as its resistance to proteolysis and its capacity to be recognized by specific conformational antibodies. We used a two-step strategy with proteolytic digestion as the first step followed by immunoprecipitation using the amyloid conformational antibody LOC. We tested the efficacy of this method using as models amyloid fibrils produced in vitro, tissue extracts from C. elegans that overexpress Abeta peptide, and cerebrospinal fluid (CSF) from patients diagnosed with AD. We were able to immunoprecipitate Abeta(1 40) amyloid fibrils, produced in vitro and then added to complex biological extracts, but not alpha-synuclein and gelsolin fibrils. This method was useful for isolating amyloid fibrils from tissue homogenates from a C. elegans AD model, especially from aged worms. Although we were able to capture picogram quantities of Abeta(1-40) amyloid fibrils produced in vitro when added to complex biological solutions, we could not detect any Abeta amyloid aggregates in CSF from AD patients. Our results show that although immunoprecipitation using the LOC antibody is useful for isolating Abeta(1-40) amyloid fibrils, it fails to capture fibrils of other amyloidogenic proteins, such as alpha-synuclein and gelsolin. Additional research might be needed to improve the affinity of these amyloid conformational antibodies for an array of amyloid fibrils without compromising their selectivity before application of this protocol to the isolation of amyloids. PMID- 25144806 TI - The trauma bubble: patient and family experience of serious burn injury. AB - The aim of this study was to understand the lived experience of burn injury for Australian patients and families. Of specific interest was the period covering emergency and inhospital care and early experiences of transition into the community. Eighteen participants including patients with serious burn injury and close family members engaged in indepth, semistructured interviews. Data were analysed using Heideggerian phenomenology and were interpreted within the framework of Merleau-Ponty's philosophy of the body. Participants experienced substantial emotional trauma that was unrelated to burn size or severity. Emotional distress was highest amongst people with facial burns. Strong recollections of the accident and poorly managed pain seemed to exacerbate the experience of trauma. Patients described physical otherness, memories of consuming, embodied pain, and recycling of the initial catastrophe. Family members expressed vicarious suffering and were confronted by the physical otherness of their loved one. Participants were isolated in their "bubble of trauma" as they tried to contain grief and loss, and protect loved ones from their distress. Emotional trauma persisted after discharge challenging family functioning and adjustment. These findings support a systematic approach to identifying and responding to the emotional needs of patients and family, including early information about possible emotional reactions to traumatic events and proactive engagement with psychology services. Best practice approaches for early pain management should be a focus for both clinical care and further research. PMID- 25144807 TI - Wound healing trajectories in burn patients and their impact on mortality. AB - The rate of wound healing and its effect on mortality has not been well described. The objective of this article is to report wound healing trajectories in burn patients and analyze their effects on in-hospital mortality. The authors used software (WoundFlow) to depict burn wounds, surgical results, and healing progression at multiple time points throughout admission. Data for all patients admitted to the intensive care unit with >= 20% TBSA burned were collected retrospectively. The open wound size (OWS), which includes both unhealed burns and unhealed donor sites, was measured. We calculated the rate of wound closure (healing rate), which we defined as the change in OWS/time. We also determined the time delay (DAYS) from day of burn until day on which there was a reduction in OWS < 10%. Data are medians [interquartile range]. There were 38 patients with complete data; 25 had documentation of successful healing (H), and 13 did not (NH). H differed from NH on age (38 years [32-57] vs 63 [51-74]), body mass index (27 [21-28] vs 32 [19-52]), 24-hour fluid resuscitation (12 L [10-16] vs 18 [15 20]), pressors during first 48 hours (72% vs 100%), use of renal replacement therapy (32% vs 92%), and mortality (4% vs 100%). Repeated measures analysis of covariance showed a significant difference between survivors and nonsurvivors on OWS as a function of time (P<.001). Patients with a positive healing rate (+2%/day) after postburn day 20 had 100% survival whereas those with a negative healing rate (-2%/day) had 100% mortality. For H patients, median DAYS was 41 (28 54); median DAYS/TBSA was 1.3 (1.0-1.9). Survivors had a 0.62% drop in OWS/day, or 4.3%/week. In this cohort of patients with >= 20% TBSA, there was a difference in mortality after postburn day 20, between patients with a positive healing rate (+2%/day, 100% survival) and those with a negative healing rate (-2%/day, 100% mortality, P < .05). PMID- 25144808 TI - Estimation of burn depth at burn centers in the United States: a survey. AB - Accurate burn depth estimation remains one of the foundations of optimal burn care. The method by which burn depth is determined has traditionally been clinical examination alone. This continues to hold true in the United States, despite a plethora of literature supporting the use of more accurate modalities such as laser Doppler imaging (LDI). LDI has widespread use in burn centers in the United Kingdom and around the world. Thus, the reason for a lack of use in U.S. burn centers remains elusive. A survey of U.S. burn center directors was conducted to assess their current practices and attitudes with regard to burn depth estimation at U.S. burn centers in an effort to answer this question. Surveys were returned from 68 burn center directors (49% response rate). All respondents reported using clinical examination in their current practice for the daily evaluation of acute burns, with a biopsy being the next most commonly used modality. The most preferred modality was also clinical examination (60%), followed by LDI (6%) and biopsy (4%). The top three modalities ranked as "most promising" for daily use were clinical examination, LDI, and noncontact/high frequency ultrasound. Directors identified the top three limitations to the use of new technology as cost (72%), availability (63%), and lack of support by evidence to date (35%). Future studies may need to focus on overcoming these perceived limitations before the widespread use of LDI or other new modalities will be realized at burn centers in the United States. PMID- 25144809 TI - One burn, one standard. PMID- 25144810 TI - Active dynamic infrared thermal imaging in burn depth evaluation. AB - The aim of this study was to find the relationship between active dynamic thermography (ADT) with cold excitation and burn depth. This new modality of evaluation of burns seems to be an attractive proposal for quantitative classification, allowing proper choice of burn wound treatment: conservative or surgical, especially compared with static thermography. The work was an in vivo experiment on domestic pigs, and a small number of patients were also diagnosed as part of the study. Statistical analysis showed a high correlation between the ADT synthetic parameter--thermal time constant, tau--and the classification of burn wounds that were predicted to heal within 3 weeks and so were treated conservatively and those that were predicted to not heal within 3 weeks and so were surgically treated. The results of the study show an accuracy of 60.7% for clinical evaluation, 69.6% for static thermography, 83.0% for ADT, and 84.0% for histopathologic assessment. The authors have concluded that the ADT method with cold excitation is suitable for the qualitative and quantitative assessment of burn depth. PMID- 25144811 TI - Trends in bacterial wound isolates and antimicrobial susceptibility in a pediatric burn hospital. AB - The purpose of this retrospective study was to collate data dealing with organisms cultured from the burn patients and evaluate trends in antimicrobial susceptibility. All cultures collected from each acute admission patient between 2004 and 2011 in the 30-bed pediatric burn hospital were evaluated for their annual frequency and antimicrobial susceptibility. Duplicate cultures were excluded. Staphylococcus aureus was isolated most frequently (25% of total isolates; range, 69-408 isolates/yr), followed by Pseudomonas aeruginosa (13%; range, 40-202 isolates/yr), coagulase-negative staphylococci (9%; range, 2-188 isolates/yr), Enterobacter cloacae (8%; range, 22-128 isolates/yr), and Escherichia coli (6%; range, 19-91 isolates/yr). This rank order remained relatively consistent during the period of study. The emergence of methicillin resistant S. aureus increased from 20% in 2004 to about 45% in 2009 to 2011. Susceptibility to vancomycin was still 100%. In comparing periods 2004 to 2007 and 2008 to 2011, P. aeruginosa showed increased susceptibility to cefepime (from 76% to 84%) and the aminoglycosides (from 68% to 81%), whereas susceptibility to piperacillin-tazobactam remained high (from 91% to 93%). E. cloacae demonstrated 90 to 100% susceptibility to aminoglycosides, cefepime, and imipenem. E. coli showed an increased rate of resistance to ceftazidime but was still susceptible to imipenem and amikacin. S. aureus and P. aeruginosa continue to be the most prevalent organisms cultured from our pediatric burn population. Almost half of the staphylococcal isolates were methicillin-resistant S. aureus. Despite widespread use of piperacillin-tazobactam, P. aeruginosa susceptibility remained high. Several classes of antimicrobials continued to demonstrate good to excellent activity against the majority of organisms cultured from the burn patients. PMID- 25144812 TI - Hospital-acquired pressure ulcer prevention: a burn surgeon's team approach. AB - Hospital-acquired pressure ulcers (HAPUs) are a problem that has been under increased scrutiny in recent years. To help reduce the incidence of HAPUs and to improve their management, a burn unit-centered wound care team was established. The team decided to pursue two goals: to identify opportunities for improvement that may help prevent HAPUs and to evaluate all available support surfaces to identify those that might best help with pressure redistribution. To identify opportunities for improvement, the team studied each new case of HAPUs throughout our hospital with a forensic chart review for a 3-year period. To identify the best support surfaces to help reduce the incidence of pressure ulcers, we evaluated all support surfaces available at our institution by pressure mapping in healthy volunteers. From 3 years of collecting and reporting data for quality improvement, we identified 23 patients with HAPUs and obtained more than 800 data sets from pressure mapping in healthy volunteers. Most (23/24; 96%) patients with HAPUs identified in this series had undergone a surgical procedure. The results of the quality improvement studies are presented. We conclude that prevention planning of HAPUs needs to be improved in patients undergoing surgery, in particular. No single support surface can prevent pressure ulcers, but use of overlays may help reduce peak pressures over bony prominences. PMID- 25144813 TI - Palmar crease release and secondary full-thickness skin grafts for contractures in primary full-thickness skin grafts during growth spurts in pediatric palmar hand burns. AB - Pediatric palmar hand burns are a difficult problem because of the serious hand deformity, with functional impairment resulting from rapid growth. In cases of severe pediatric palmar hand burns, a secondary full-thickness skin graft after a primary full-thickness skin graft offers a reliable way of obtaining the required functional and aesthetic outcomes.This study retrospectively evaluated 28 children who required palmar crease releases and secondary full-thickness skin grafts during the past 12 years. The case records were reviewed for sex and age distributions, injury mechanism, and time interval between the primary and secondary full-thickness skin grafts. Surgical procedures included secondary full thickness skin grafts and incisional releases of grafted skin on the involved creases. There were 19 men and 9 women. The mean age at the time of the burn injury was 10.1 months (range, 5-19 months). The mean age at the time of the secondary full-thickness skin graft was 8.3 years (range, 3-17 years). The most common mechanism of burn injury was steam (n = 24). The median time interval from the primary to the secondary full-thickness skin graft was 67 months (range, 8 156 months). The number of released creases was 81. The number of palmar web contractures in 23 patients was 52. A secondary full-thickness skin graft was more frequently necessary in patients with a primary full-thickness skin graft in the proximal digital crease and palmar web areas. All patients achieved adequate digital length and palmar web contour after surgery. Our patients should be observed until the rapid pubertal growth period. PMID- 25144815 TI - Structure, stability, and spectroscopic properties of H-bonded complexes of HOSO and CH3SO with H2O. AB - Quantum chemical calculations have been carried out to investigate the structure and stability of 1:1 and 1:2 HOSO-water and CH3SO-water complexes. All of the geometries have been optimized at the DFT and at the CCSD levels of theory using 6-311++G(2df,2pd) and aug-cc-pVDZ basis sets, respectively. The energetics of the hydrogen-bonded complexes are reported at G4 and CBS-QB3 levels of theory. A general characteristic future of the minimum-energy structure complexes is cyclic double H bonding for 1:1 complexes and cyclic triple H bonding for 1:2 complexes. Calculations predict relative large binding energies of 8.2 and 16.8 kcal mol(-1) for 1:1 and 1:2 HOSO-water complexes, respectively, at the CBS-QB3 level of theory. CH3SO-water complexes have somewhat lower stability; the binding energy of 3.8 kcal mol(-1) for the 1:1 CH3SO-water complex increases to 9.5 kcal mol(-1) for the 1:2 complex. The calculated shifts in vibrational frequencies due to complex formation show that the frequencies and intensities of H-bonded OH stretching regions are most affected by complex formation. The large frequency shift is mainly oriented to these OH bonds involved in H-bonding interactions. Vertical electronic excitation energies and the corresponding oscillator strengths have been calculated for the representative radical-water complexes using the TDDFT method and aug-cc-pVTZ basis set. No significant excitation energy difference was observed between the low-lying electronic states of either HOSO within the HOSO-water complexes or CH3SO within the CH3SO-water 1:1 complexes. PMID- 25144814 TI - Estrogen treatment of acetic acid burns to the vagina, cervix, and perineum: a case report and review of the literature. AB - In colposcopic evaluation of the cervix, acetic acid of 3 to 5% is commonly used for identification of preneoplastic and neoplastic cells. Acetic acid is a known caustic substance and has the potential to cause irritation and chemical burns when there is sufficient concentration or duration of contact. The authors present a unique case of a woman who inadvertently received undiluted acetic acid during a routine colposcopy, resulting in significant chemical burns of the vagina, cervix, and perineum. Her burns were treated with topical estrogen cream of 1 g twice daily applied directly to the wounds. The burn wounds were fully healed within 8 weeks without complication or additional treatment. At 6 months after the injury, the patient was allowed to engage in sexual activity, and vaginal dilation and pelvic floor therapy were initiated. At 12 months postinjury, her only symptomatic scarring at the left vaginal wall continues to improve. Thus, topical estrogen treatment of 1 g applied twice daily should be continued until burn scar maturation is complete and treatment improvement plateaus in cases of burns to the vagina, cervix, and perineum. This case is further clinical evidence of estrogen's positive effect on wound healing and its potential role in burn treatment. PMID- 25144816 TI - Short hydrogen bonds and negative charge in photoactive yellow protein promote fast isomerization but not high quantum yield. AB - Biological signal transduction by photoactive yellow protein (PYP) in halophilic purple sulfur bacteria is initiated by trans-to-cis isomerization of the p coumaric acid chromophore (pCa) of PYP. pCa is engaged in two short hydrogen bonds with protein residues E46 and Y42, and it is negatively charged at the phenolate oxygen. We investigated the role in the isomerization process of the E46 short hydrogen bond and that of the negative charge on the anionic phenolate moiety of the chromophore. We used wild-type PYP and the mutant E46A, in protonated and deprotonated states (referred to as pE46A and dpE46A, respectively), to reduce the number of hydrogen bond interactions between the pCa phenolate oxygen and the protein and to vary the negative charge density in the chromophore-binding pocket. Their effects on the yield and rate of chromophore isomerization were determined by ultrafast spectroscopy. Molecular dynamics simulations were used to relate these results to structural changes in the mutant protein. We found that deprotonated pCa in E46A has a slower isomerization rate as the main part of this reaction was associated with time constants of 1 and 6 ps, significantly slower than the 0.6 ps time constant in wild-type PYP. The quantum yield of isomerization in dpE46A was estimated to be 30 +/- 2%, and that of pE46A was 32 +/- 3%, very close to the value determined for wtPYP of 32 +/- 2%. Relaxation of the isomerized product state I0 to I1 was faster in dpE46A. We conclude that the negative charge on pCa stabilized by the short hydrogen bonds with E46 and Y42 affects the rate of isomerization but not the quantum yield of isomerization. With this information, we propose a scheme for the potential energy surfaces involved in the isomerization and suggest protein motions near the pCa backbone as key events in successful isomerization. PMID- 25144818 TI - Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities--long-term follow-up of a randomised trial. AB - INTRODUCTION: Isolated limb perfusion (ILP) is a treatment option most commonly used in the treatment of melanoma in-transit metastases of the extremities. The principle idea is to surgically isolate a region of the body and then deliver a high concentration of a chemotherapeutic agent together with hyperthermia. There have been three randomised trials exploring whether adjuvant ILP to patients with recurrent or high-risk primary melanomas increases survival; one of these trials has now been updated with a 25-year follow-up. METHODS: The original study randomised 69 patients (between 1981 and 1989) with their first satellite or in transit recurrence to either wide excision (WE group, n = 36 patients) or to WE and adjuvant ILP (WE + ILP group, n = 33 patients). Follow-up data 25 years later concerning survival and cause of death was retrieved from the Swedish National Cause of Death Register. RESULTS: In the WE + ILP group there were 20 deaths (61%) due to melanoma compared with 26 deaths (72%) in the WE group (p = 0.31). Median melanoma-specific survival was 95 months for WE + ILP compared to 38 months for the WE group, an almost 5 year benefit without statistical significance (p = 0.24). DISCUSSION: There is no evidence that adjuvant ILP prolongs survival in patients with high-risk or recurrent melanoma; however, the existing randomised trials are largely underpowered to detect such a difference. New studies are exploring systemic immunological effects of ILP, and a combination of regional therapy and immunotherapy may serve as a rationale for new trials using ILP in the future. PMID- 25144817 TI - Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer. AB - PURPOSE: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population. PATIENTS AND METHODS: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21-35 days, followed immediately by chest wall MLHT for 1 hour at 40-42 degrees C. In the first trial 18 subjects received LTLD at 20, 30, or 40 mg/m2; in the second trial, 11 subjects received LTLD at 40 or 50 mg/m2. RESULTS: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256 mg/m2 of prior anthracyclines and a median dose of 61 Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50 mg/m2, with seven subjects (24%) developing reversible grade 3-4 neutropenia and four (14%) reversible grade 3-4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30 66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses. CONCLUSION: LTLD at 50 mg/m2 and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population. PMID- 25144819 TI - Microwave ablation of malignant hepatic tumours: intraperitoneal fluid instillation prevents collateral damage and allows more aggressive case selection. AB - PURPOSE: Theaim of this peper was to retrospectively review our experience utilising protective fluid instillation techniques during percutaneous microwave ablation of liver tumours to determine if fluid instillation prevents non-target injuries and allows a more aggressive case selection. MATERIALS AND METHODS: This institute review board-approved, U.S. Health Insurance Portability and Accountability Act-compliant, retrospective study reviewed percutaneous microwave ablation of 151 malignant hepatic tumours in 87 patients, comparing cases in which protective fluid instillation was performed with those where no fluid was utilised. In cases utilising hydrodisplacement for bowel protection, a consensus panel evaluated eligibility for potential ablation without hydrodisplacement. Patient age, tumour size, local tumour progression rate, length of follow-up, complications, displacement distance/artificial ascites thickness, and treatment power/time were compared. RESULTS: Fluid administration was utilised during treatment in 29/151 of cases: 10/29 for protection of bowel (8/10 cases not possible without fluid displacement), and 19/29 for body wall/diaphragm protection. Local tumour progression was higher when hydrodisplacement was used to protect bowel tissue; this may be due to lower applied power due to operator caution. Local tumour progression was not increased for artificial ascites. There was no difference in complications between the fluid group and controls. CONCLUSION: Intraperitoneal fluid administration is a safe and effective method of protecting non-target structures during percutaneous hepatic microwave ablation. While hydrodisplacement for bowel protection allows more aggressive case selection, these cases were associated with higher rates of local tumour progression. PMID- 25144820 TI - Percutaneous microwave ablation for liver tumours adjacent to the marginal angle. AB - PURPOSE: This study was designed to describe the technical essentials of microwave ablation (MWA) for tumours adjacent to the liver marginal angle (LMA) and to determine the feasibility, safety and efficacy of this approach. MATERIALS AND METHODS: A total of 22 patients with primary or metastatic liver tumours adjacent to the LMA were enrolled. There were 19 small tumours (<=3 cm) and three larger tumours (>3 cm) with maximum diameters ranging from 0.7-2.7 cm (mean 1.7 +/- 0.6 cm) and 4.7-6.6 cm (mean 5.4 +/- 1.0 cm), respectively. For small tumours the entire acute angle was segmentally blocked utilising MWA. For larger tumours, the feeding arteries were initially blocked with ethanol before conformal ablation. Artificial ascites, real-time monitoring, small ethanol doses, colour Doppler flow imaging or contrast enhanced ultrasound guidance was used as an additional technique to assist with ablation. Contrast imaging was performed to evaluate the ablative efficacy. Treatment responses, local tumour progression (LTP) and complications were recorded. RESULTS: All patients achieved a complete response. LTP was identified in two cases (9.1%) during the 4.5 month median follow-up period (range 2-29 months). A total of five additional sessions were performed, and secondary effectiveness was achieved in patients with LTP. No major complications were observed. CONCLUSIONS: Percutaneous MWA is a new promising technique for tumours adjacent to the LMA, especially in cases with small tumours. Technical improvements to this procedure are expected to improve the results for large tumours abutting the LMA. PMID- 25144821 TI - Differential response of MCF7, MDA-MB-231, and MCF 10A cells to hyperthermia, silver nanoparticles and silver nanoparticle-induced photothermal therapy. AB - PURPOSE: Silver nanoparticles (Ag NP) can generate heat upon exposure to infrared light. The in vitro response of breast cell lines to Ag NP, both with and without nanoparticle-induced heating was evaluated. MATERIALS AND METHODS: Ag NP heat generation, intracellular silver concentration, and cell viability of MDA-MB-231, MCF7, and MCF 10A breast cells with Ag NP alone, or after exposure to 0.79 or 2.94 W/cm2 of 800 nm light were evaluated. RESULTS: The concentration of Ag NP to induce sufficient heat for cell death, upon exposure to 800 nm light, was 5-250 MUg/mL. Clonogenics assay indicates a cytotoxic response of MCF7 (45% decrease) and MDA-MB-231 (80% decrease) cells to 10 ug/mL, whereas MCF 10A had a 25% increase. Without Ag NP, MDA-MB-231 cells were more susceptible to hyperthermia, compared to MCF7 and MCF 10A cells. Clonogenics assay of Ag NP-induced photothermal ablation demonstrated that MCF 10A cells have the highest survival fraction. MCF7 cells had more silver in the cytoplasm, MDA-MB-231 cells had more in the nuclei, and MCF 10A cells had equivalent concentrations in the cytoplasm and nuclei. CONCLUSIONS: Ag NP are effective photothermal agents. A secondary benefit is the differential response of breast cancer cells to Ag NP-induced hyperthermia, due to increased intracellular silver content, compared to non tumorigenic breast epithelial cells. PMID- 25144822 TI - Microarray analysis of intestinal immune-related gene expression in heat-stressed rats. AB - PURPOSE: This study aimed to investigate immune-related gene expression in rat small intestine after heat stress. MATERIALS AND METHODS: Twelve Sprague Dawley (SD) rats were randomly divided into control and heat-stressed groups. Rats in both groups were housed at 25 degrees C with 60% relative humidity. The heat stressed group was subjected to 40 degrees C for 2 h/day for 3 days. After heat stress, the mRNA expression profile of small intestine epithelial tissue was evaluated by microarray analysis. RESULTS: A total of 23 genes related to immune responses were significantly altered, of which 12 genes were up-regulated and 11 genes were down-regulated. CONCLUSIONS: Microarray analysis demonstrated the JAK STAT pathway had a potentially important role in the regulation of inflammation in the small intestine, and changes in antigen presentation might reduce intestinal immune responses after heat stress. PMID- 25144823 TI - Parametric study of irreversible electroporation with different needle electrodes: electrical and thermal analysis. AB - PURPOSE: Irreversible electroporation (IRE) is a new tumour ablation method used in cancer treatment procedures. In a successful IRE treatment it is crucial to impose minimum thermal damage to the tumour and its surrounding healthy tissue, while subjecting the entire tumour to a strong electric field. METHOD: Here we present a 3D model of a subcutaneous tumour in a four-layer skin using a geometry based finite element approach. Four common needle electrode configurations were studied in this paper. The study evaluated six essential factors which are important in the electrical and thermal distributions in tumour and normal tissue. RESULTS: The results revealed that a hexagonal 3 * 3 geometry provides the maximum electrical coverage of the tumour, compared to other electrode configurations. However, in some cases the hexagonal 2 * 2 geometry can ablate the entire tumour with less damage to normal tissue. We found that the deeper insertion of 2- and 4-electrode geometries can lead to more damage to healthy tissue. The results also indicate that the insertion of the electrodes into tumour tissue can increase thermal damage dramatically due to existing large electrical conductivity. CONCLUSION: These findings suggest that needle electrodes should not be placed within the tumour tissue if the goal is to prevent thermal damage. This method can be used as a trade-off between electric field coverage in tumour tissue and thermal damage to both tumour and normal tissue. PMID- 25144824 TI - An artificial tongue fluorescent sensor array for identification and quantitation of various heavy metal ions. AB - Herein, a small-molecule fluorescent sensor array for rapid identification of seven heavy metal ions was designed and synthesized, with its sensing mechanism mimicking that of a tongue. The photoinduced electron transfer and intramolecular charge transfer mechanism result in combinatorial interactions between sensor array and heavy metal ions, which lead to diversified fluorescence wavelength shifts and emission intensity changes. Upon principle component analysis (PCA), this result renders clear identification of each heavy metal ion on a 3D spatial dispersion graph. Further exploration provides a concentration-dependent pattern, allowing both qualitative and quantitative measurements of heavy metal ions. On the basis of this information, a "safe-zone" concept was proposed, which provides rapid exclusion of versatile hazardous species from clean water samples based on toxicity characteristic leaching procedure standards. This type of small-molecule fluorescent sensor array could open a new avenue for multiple heavy metal ion detection and simplified water quality analysis. PMID- 25144825 TI - Palladium-catalyzed ortho-acylation of 2-benzyl-1,2,3-triazoles with aldehydes. AB - A palladium-catalyzed ortho-acylation of 2-benzyl-1,2,3-triazoles with aldehydes as an acyl source was developed. A wide variety of ketones containing 1,2,3 triazoles were obtained in good to excellent yields. This methodology provides a convenient access to the acylation of 2-substituted-1,2,3-triazoles. PMID- 25144826 TI - KdpFABC reconstituted in Escherichia coli lipid vesicles: substrate dependence of the transport rate. AB - KdpFABC complexes were reconstituted in Escherichia coli lipid vesicles, and ion pumping was activated by addition of ATP to the external medium which corresponds to the cytoplasm under physiological conditions. ATP-driven potassium extrusion was studied in the presence of various substrates potentially influencing transport rate. The pump current was detected as a decrease of the membrane potential by the voltage-sensitive dye DiSC3(5). The results indicate that high cytoplasmic K(+) concentrations have an inhibitory effect on the KdpFABC complex. The pump current decreased to ~25% of the maximal value at 140 mM K(+) and minimal Mg(2+)concentrations. This effect could be counteracted with increased Mg(2+) concentrations on the cytoplasmic side. This observation may be explained by the Gouy-Chapman effect of two Mg(2+) ions probably bound with a K1/2 of 0.8 mM close to the entrance of the access channel to the binding sites. This factor ensures that under physiological conditions the rate-limiting effect of K(+) release is significantly reduced. Also both ADP and inorganic phosphate are able to reduce the turnover rate of the pump by reversing the phosphorylation step (Ki of 151 MUM) and the dephosphorylation step (Ki of 268 MUM), respectively. In the case of the DDM-solubilized KdpFABC complex, activation energy under turnover conditions was previously found to be 55 kJ/mol, and the o-vanadate inhibition constant is shown here to be ~1 MUM, which is in agreement with values reported for other P-type ATPases. In the case of the reconstituted enzyme, however, significant differences were observed that have to be assigned to effects of the lipid bilayer environment. The activation energy was increased by a factor of 2, whereas the inhibition by o-vanadate became reduced in a way that only ~66% of the enzyme could be inhibited and the inhibition constant was increased to a value of ~60 MUM. PMID- 25144828 TI - ICF-CY code set for infants with early delay and disabilities (EDD Code Set) for interdisciplinary assessment: a global experts survey. AB - PURPOSE: Comprehensive description of functioning is important in providing early intervention services for infants with developmental delay/disabilities (DD). A code set of the International Classification of Functioning, Disability and Health: Children and Youth Version (ICF-CY) could facilitate the practical use of the ICF-CY in team evaluation. The purpose of this study was to derive an ICF-CY code set for infants under three years of age with early delay and disabilities (EDD Code Set) for initial team evaluation. METHODS: The EDD Code Set based on the ICF-CY was developed on the basis of a Delphi survey of international professionals experienced in implementing the ICF-CY and professionals in early intervention service system in Taiwan. RESULTS: Twenty-five professionals completed the Delphi survey. A total of 82 ICF-CY second-level categories were identified for the EDD Code Set, including 28 categories from the domain Activities and Participation, 29 from body functions, 10 from body structures and 15 from environmental factors. CONCLUSIONS: The EDD Code Set of 82 ICF-CY categories could be useful in multidisciplinary team evaluations to describe functioning of infants younger than three years of age with DD, in a holistic manner. Future validation of the EDD Code Set and examination of its clinical utility are needed. IMPLICATIONS FOR REHABILITATION: The EDD Code Set with 82 essential ICF-CY categories could be useful in the initial team evaluation as a common language to describe functioning of infants less than three years of age with developmental delay/disabilities, with a more holistic view. The EDD Code Set including essential categories in activities and participation, body functions, body structures and environmental factors could be used to create a functional profile for each infant with special needs and to clarify the interaction of child and environment accounting for the child's functioning. PMID- 25144827 TI - Study design implications of death and hospitalization as end points in idiopathic pulmonary fibrosis. AB - BACKGROUND: The feasibility of an interventional clinical trial in idiopathic pulmonary fibrosis (IPF) using death and hospitalization as primary end points is an area of uncertainty. Using data from a large well-characterized clinical trial population, this article aims to illustrate the impact of cohort enrichment and study duration on sample size requirements for IPF clinical trials in which death alone or death plus hospitalization serve as the primary end point. METHODS: Event rate estimates for death and hospitalization were determined from patients enrolled in National Institutes of Health-sponsored IPF Clinical Research Network clinical trials. Standard equations were applied to estimate the total sample size required for varying gender, age, and pulmonary function (GAP) stage-based cohorts. RESULTS: Risk estimates for death and hospitalization in the clinical trial cohort were substantially lower than those published. An IPF trial with death as its primary end point enrolling subjects designated as GAP stage 1 and 2 over 1 year with a minimum follow-up of 1 year would require an estimated 7,986 subjects to achieve 90% power for a hazard ratio of 0.70. Alternatively, an IPF trial with death plus hospitalization as its primary end point enrolling subjects with GAP stage 2 and 3 over 2 years with a minimum follow-up of 1 year would require an estimated 794 subjects for the same power and hazard ratio. CONCLUSIONS: Study design decisions, in particular cohort enrichment strategies, have a substantial impact on sample size requirements for IPF clinical trials using time-to-event primary end points such as death and death plus hospitalization. PMID- 25144829 TI - Response to Gladwell et al.: concerns about safety for GET. PMID- 25144830 TI - Determination of the minimal clinically important difference on the Australian therapy outcome measures for occupational therapy (AusTOMs-OT). AB - PURPOSE: Outcome measures must be responsive to change (able to show statistically significant change) and must also produce information on the degree of change that is clinically significant, or the minimal clinically important difference (MCID). This research sought to establish the MCID for four domains of the Australian Therapy Outcome Measures for Occupational Therapy (AusTOMs-OT). METHODS: Using a criterion approach, 30 international clinicians were surveyed about their perceptions of the MCID for AusTOMs-OT. Second, using a distribution based approach, the MCID was calculated as half of the standard deviation (SD) of the AusTOMs-OT raw scores for a sample of 787 clients. RESULTS: Just over half the clinicians surveyed indicated that a one-point change represented the MCID for AusTOMs-OT for three domains, and 0.5-point change showed MCID for the final domain. The data analysed for the distribution-based calculation indicated that the half SD ranged from 0.51 to 0.61. CONCLUSION: Using both criterion and distribution-based approaches, this research empirically demonstrated that a change on the four domains of the AusTOMs-OT of between 0.51 and 1 point shows MCID. Considering these findings, and for ease of clinical interpretation, it is recommended that a one-point shift be adopted as the MCID across all domains. IMPLICATIONS FOR REHABILITATION: The AusTOMs-OT have been previously shown to be valid and reliable outcome measures for use with all client groups across all settings including rehabilitation. So that rehabilitation professionals can interpret outcomes data from AusTOMs-OT, information must be available on the degree of change that is clinically significant (also referred to as the minimal clinically important difference or MCID). Using empirical calculations as well as clinician opinion, it is recommended that a one-point shift be used as the minimal clinically important difference for the AusTOMs-OT. PMID- 25144831 TI - Post-concussion return to play and return to school guidelines for children and youth: a scoping methodology. AB - PURPOSE: The objective of this study was to identify and describe management strategies to ensure safe return to activity (RTA) and return to school (RTS) of children with mild traumatic brain injury (MTBI) and determine whether they are evidence-based. METHODS: A scoping methodology was conducted using research published between 1990 and 2013, gray literature and clinical expertise. Once the data had been charted, an expert panel of physicians and clinicians was consulted to inform and validate study findings. An analytical and thematic framework was used to examine the study findings. RESULTS: A total of 400 potentially relevant published articles, 100 websites and 24 iPad Applications were found. Ten articles and three web-based resources met inclusion criteria and were included in the final review. Nine articles recommended a more conservative approach to RTA, as well as identified a step-wise or severity-oriented approach. General recommendations were also found regarding safe RTS. One study recommended a stepwise RTS protocol for children. CONCLUSIONS: This scoping methodology determined that the most comprehensive guidelines for management are focused on adults. Evidence concerning prolonged recovery patterns in children and the impact of concussion on the developing brain suggests that pediatric-specific guidelines are needed for RTA and RTS after MTBI/concussion. IMPLICATIONS FOR REHABILITATION: Although concussion in children is an increasing concern, it has been determined that the most comprehensive guidelines for management are focused on adults. These guidelines are primarily consensus-based and are not proven fact through quality research. Evidence concerning prolonged recovery patterns in youth and the impact of concussion on the developing brain suggest that pediatric guidelines should be more conservative than for adults. Therefore, pediatric specific guidelines need to be developed for return to activity and return to school after MTBI/concussion. PMID- 25144832 TI - Biofunctionalized rebar graphene (f-RG) for label-free detection of cardiac marker troponin I. AB - One-step microwave-assisted unscrolling of carbon nanotubes to form functionalized rebar graphene (f-RG) is reported. The well-characterized f-RG on an interdigitated electrode biochip in a FET configuration showed enhanced electronic properties, as demonstrated with I-V characteristics. The developed device was biofunctionalized with specific anti-cTnI antibodies exhibiting a shift of threshold voltage from -2.15 V to -0.5 V and decrease in electron mobility from 3.609 * 10(4) to 8.877 * 10(3) cm(2) V(-1) s(-1). The new sensing strategy holds great promise for its applicability in diagnostics exhibiting high sensitivity (~ 1 pg/mL) and specificity toward cardiac marker (cTnI). PMID- 25144833 TI - The evolving tale of immunomodulatory drugs and cereblon. AB - The immunomodulatory drugs (IMiDs), of which thalidomide was the first in class, have had a complex therapeutic history. Although these drugs are now widely used to treat multiple myeloma, the precise molecular mechanism of action of these agents has remained elusive. The finding that IMiDs bind cereblon, with subsequent activation of E3-ubiquitin ligase activity and degradation of the key transcription factors IKZF1 and IKZF3, has provided insight into these drugs but leaves many questions unanswered. PMID- 25144835 TI - Composition-dependent photoluminescence intensity and prolonged recombination lifetime of perovskite CH3NH3PbBr(3-x)Cl(x) films. AB - Mixed halide perovskites CH3NH3PbBr3-xClx (x = 0.6-1.2) with different compositions of halogens exhibit drastically changed optical properties. In particular, the thin films prepared with these perovskites demonstrate extraordinary photoluminescence emission intensities and prolonged recombination lifetimes up to 446 ns, which are desirable for light emitting and photovoltaic applications. PMID- 25144834 TI - Enhanced synapse remodelling as a common phenotype in mouse models of autism. AB - Developmental deficits in neuronal connectivity are considered to be present in patients with autism spectrum disorders (ASDs). Here we examine this possibility by using in vivo spine imaging in the early postnatal cortex of ASD mouse models. Spines are classified by the presence of either the excitatory postsynaptic marker PSD-95 or the inhibitory postsynaptic marker gephyrin. ASD mouse models show consistent upregulation in the dynamics of PSD-95-positive spines, which may subsequently contribute to stable synaptic connectivity. In contrast, spines receiving inputs from the thalamus, detected by the presence of gephyrin clusters, are larger, highly stable and unaffected in ASD mouse models. Importantly, two distinct mouse models, human 15q11-13 duplication and neuroligin 3 R451C point mutation, show highly similar phenotypes in spine dynamics. This selective impairment in dynamics of PSD-95-positive spines receiving intracortical projections may be a core component of early pathological changes and be a potential target of early intervention. PMID- 25144836 TI - Reproducibility of lymphoscintigraphic evaluation of the upper limb. AB - BACKGROUND: Although reproducibility studies are missing, a lymphoscintigraphic evaluation of the upper limb is often used in routine practice to diagnose lymphedema and in clinical research, for example, to investigate the effect of a physical treatment. Therefore, the aim of the present study was to investigate the reproducibility of the lymphoscintigraphic evaluation of the upper limb. METHODS AND RESULTS: In breast cancer patients, 20 lymphoscintigraphic evaluations of the upper limb were performed on two test occasions with an interval of 1 week. (99m)Tc nanocol was injected subcutaneously in the hand. A standardized protocol was applied. In the early phase, two static images of the injection places were taken and in between dynamic images of both axilla during 40 min (15 min rest, 15 min squeezing a ball, and 15 min rest). After a break of 70 min, a static image of the injection places and of the axilla was made. At the end, a partial whole body image was acquired. A strong reproducibility was found for the following quantitative variables (ICC 0.75 to 0.85): change of uptake in axilla during the break; change of extraction from hands during the break; and extraction and uptake in the late phase. The other quantitative variables (i.e., extraction form the hands in the early phase, time of arrival, accumulation rate, and uptake in axilla in the early phase) had weak to moderatie reproducibility (ICC 0.07 to 0.70). All qualitative variables (i.e., number of lymph nodes in the axilla, upper arm and elbow/lower arm, gradation of lymph collectors in upper or lower arm and of dermal backflow, and presence of lymph collaterals) had strong to very strong reproducibility (ICC 0.76 to 1.00). CONCLUSION: A lymphoscintigraphy of the upper limb is a reproducible imaging tool to assess lymph transport quantitatively and qualitatively. PMID- 25144838 TI - Enhancing oxygen reduction reaction activity of Pt-shelled catalysts via subsurface alloying. AB - Despite remarkable efforts have been put into the field of Pt-shelled catalysts containing an atomically thin Pt surface layer for the oxygen reduction reaction (ORR) in the last decade, further development of new Pt-shelled catalysts is still necessary. Here, a new set of Pt-shelled catalysts by subsurface alloying with early transition metals such as Mn and Fe is predicted to be a good candidate for the ORR by using density functional theory (DFT) calculations. Trends in oxygen reduction activity of Pt-alloy catalysts are determined with calculations of oxygen binding by using the slab and cluster models. It is found that the subsurface alloys by the incorporation of submonolayer M (M = Mn and Fe) into Pt(111) in the slab model result in the enhancement of ORR activity, compared with the well-known Pt(111)-skin-M, pure Pt, and Pt3M alloy catalysts. For the cluster model, the Pt12Mn and Pt12Fe clusters are also found to be the optimal catalysts for the ORR. It is expected that this work can open up new opportunities for enhancing the ORR activity of Pt-alloy catalysts by subsurface alloying. PMID- 25144837 TI - Psychosocial, educational and communicative interventions for patients with cachexia and their family carers. AB - PURPOSE OF REVIEW: Cancer cachexia has a substantial impact on both patients and their family carers. It has been acknowledged as one of the two most frequent and devastating problems of advanced cancer. The impact of cachexia spans biopsychosocial realms. Symptom management in cachexia is fraught with difficulties and globally, there remains no agreed standard care or treatment for this client group. There is a need to address the psychosocial impact of cachexia for both patients and their family carers. RECENT FINDINGS: Patients living at home and their family carers are often left to manage the distressing psychosocial impacts of cancer cachexia themselves. Successful symptom management requires healthcare professionals to address the holistic impact of cancer cachexia. High quality and rigorous research details the existential impact of cachexia on patients and their family carers. This information needs to inform psychosocial, educational and communicative supportive healthcare interventions to help both patients and their family carers better cope with the effects of cachexia. SUMMARY: Supportive interventions need to inform both patients and their family carers of the expected impacts of cachexia, and address how to cope with them to retain a functional, supported family unit who are informed about and equipped to care for a loved one with cachexia. PMID- 25144839 TI - [Kyphoplasty in the treatment of osteoporotic spine fractures - experience with 1069 cases]. AB - BACKGROUND: Kyphoplasty has been established as treatment for painful osteoporotic vertebral compression fractures for over ten years. Its effectiveness has been substantiated in multiple clinical studies. Not only is prompt pain reduction achieved, but according to a new, large, long-term study, long-term survival is also increased. PATIENTS: Balloon kyphoplasty was performed for 1069 patients between 01.01.2008 and 31.12.2013. In all cases, pain was rated more than 6/10 points, and a recent fracture was evident on cross-sectional imaging (CT or MRT STIR T2) performed to supplement spine X-rays. Average patient age was 77 +/- 5.2 years. 73 % of patients were female. Treated fracture levels ranged from T 3 to L 5. METHODS: A single level was treated in 627 cases, two levels were treated simultaneously in 246 cases, three levels in 73 cases, and four levels in 29 cases. Average operative time for all patients was 35 minutes. Pain was reduced from 8.0 +/- 1.0 preoperative to 2.2 +/- 1.3 points postoperative in visual analogue scale (p < 0.1). Average intrahospital time was 9 days. Asymptomatic cement leckages were seen in 20 % of the cases. 855 were released home from the hospital and 210 patients went on to rehabilitation. Seven major complications (0.9 %) occurred during the hospital time (four mortalities during hospital admission, three neurological deficits, one lateral implant protrusion and a subdural bleeding). CONCLUSION: Kyphoplasty is a good procedure for treating painful osteoporotic fractures from the lumbar to the thoracic spine. Major complications occur rarely after kyphoplasty; however, they must be considered and clarified. PMID- 25144840 TI - [Editorial for the Journal of Orthopedics and Trauma Surgery]. PMID- 25144841 TI - [Stem cell-based therapy in orthopaedics and trauma surgery - current concepts]. AB - Over the last few years, numerous new treatment methods have been developed for musculoskeletal diseases. Some of these new methods are based on the targeted use of stem cells to initiate healing processes, to compensate for deficits or to activate the regeneration of tendons, muscles, bones and cartilage. This goal can be achieved through the direct use of stem cells on or in a carrier material or through a combination with tissue engineering. In this article, we give a short overview of the possible fields of application of inducible pluripotent haematopoietic, and adult stem cells as well as on their use in musculoskeletal tissue. Furthermore, we provide a summary of the current legal situation concerning the application of stem cells in humans. PMID- 25144842 TI - [Classification of haematogenous and post-traumatic osteomyelitis]. AB - A classification of osteomyelitis must reflect the complexity of the disease and, moreover, provide conclusions for the treatment. The classification is based on the following eight parameters: source of infection (OM [osteomyelitis]/OT [post traumatic OM]), anatomic region, stability of affected bone (continuity of bone), foreign material (internal fixation, prosthesis), range of infection (involved structures), activity of infection (acute, chronic, quiescent), causative microbes (unspecific and specific bacteria, fungi) and comorbidity (immunosuppressive diseases, general and local). In the long version of the classification, which was designed for scientific studies, the parameters are named by capital letters and specified by Arabic numbers, e.g., an acute, haematogenous osteomyelitis of a femur in an adolescent with diabetes mellitus, caused by Staphylococcus aureus, multi-sensible is coded as: OM2 Lo33 S1a M1 In1d Aa1 Ba2a K2a. The letters and numbers can be found in clearly arranged tables or calculated by a freely available grouper on the internet (www.osteomyelitis.exquit.net). An equally composed compact version of the classification for clinical use includes all eight parameters, but without further specification. The above-mentioned example in the compact version is: OM 3 S a Ba2 K2. The short version of the classification uses only the first six parameters and excludes causative microbes and comorbidity. The above mentioned example in the short version is: OM 3 S a. The long version of the classification describes an osteomyelitis in every detail. The complexity of the patient's disease is clearly reproducible and can be used for scientific comparisons. The for clinical use suggested compact and short versions of the classification include all important characteristics of an osteomyelitis, can be composed quickly and distinctly with the help of tables and provide conclusions for the individual treatment. The freely available grouper (www.osteomyelitis.exquit.net) creates all three versions of the classification in one step. PMID- 25144843 TI - [The sterno-vertebral instability - a new classification and therapeutic options]. AB - INTRODUCTION: Sternal fractures in the context of high velocity trauma are commonly referred to as impact injuries. In general, these are considered to be treated conservatively. In the literature, there are only a few studies and a small number of cases. We know that not only high velocity accidents cause combined trauma of sternum and spine, but also low velocity traumas in the elderly are relatively common. How should such combinations of injuries be treated? MATERIAL AND METHOD: Based on 11 patients from the years 2005 to 2013 with different combinations of sternal and spinal injuries, we distinguish the therapeutic approach of ventral, dorsal or combined stabilisation, with the help of a four-column classification of these injuries. RESULTS: We classify sternovertebral injury into 4 types. First the descendant type with an injury from C I to C VII and sternum, second the horizontal type (T I to T XII and sternum), third the ascendant type (L I to L V and sternum) and fourth a dissociative type. The recommended therapy of the descendant type is dorsoventral stabilisation of the spinal column plus stabilisation of the sternum. The horizontal type should be treated with dorsal stabilisation of the spine and stabilisation of the sternum. The ascendant type should be supplied with dorsoventral stabilisation of the spinal column and conservative therapy of the sternum. In case of the dissociative type one should supply each injury independently. CONCLUSION: The literature on sternal injuries and their treatment is low. Combinations of sternum and spine injuries have not yet been processed systematically in literature. Thus, there is no concerted standard of therapeutic options. The very rare occurrence of this injury combination often leads to this injury type being forgotten in the primary evaluation of casualties. PMID- 25144844 TI - [Clinical aspects of the problem of vertebral metastases, possibilities of modern treatment methods, considering especially radiofrequency ablation]. AB - From 100,000 people in Germany, statistically calculated, 441 males and 350 females suffer from a cancer disease. In about 50 to 80 % of patients with breast or prostate carcinoma bone metastases are registered, which is connected, among others, with a high risk for pathological fractures and other debilitating diseases. The diagnosis of bone metastases is done by conventional X-ray equipment, CT, MRI, and especially with the help of skeletal scintigraphy. For therapy bisphosphonates, anti-hormones and chemotherapeutic agents as drugs are used. Furthermore, radiotherapy, radionuclides, surgery and ablative procedures are applied. A more recent technical method is the STARTM Tumour Ablation System (RFA), by which minimally invasively an electrode is introduced into the vertebral bodies. The system ensures precise control and thus a targeted ablation of the metastases. Several publications and reports describing a combined application demonstrate the synergistic effectiveness of RFA and radiofrequency kyphoplasty. PMID- 25144845 TI - [The clinical outcome after occipitocervical fusion due to metastases of the upper cervical spine: a consecutive case series and a systematic review of the literature]. AB - BACKGROUND: Increasing incidences of osseous metastatic malignancies and higher life expectancy in patients are resulting in a raise of occipitocervical metastases. Those patients with infaust prognosis have a significantly reduced quality of life. In Germany, between 800 and 1680 new cases per year are expected. Treatment algorithms include the evaluation of the general condition, the operability of visceral metastases, the tumor localization, the sensitivity to chemo-/radiotherapy, the fracture risk and the extent of neurological deficits and myelopathies. MATERIAL/METHODS: A systematic review on clinical studies or case series in posterior occipitocervical fusions due to metastases to the craniocervical transition yielded nine publications with 48 patients without neurological deficit. The mean survival time in the given follow-up was 6.44 months (n = 26; SD: 5,28; 95 % CI: 4.3-8.57). When measured, the clinical outcome was improved towards the VAS, the DENIS Pain Scale and the quality of life through the activities of daily living (ADL). We searched our clinical database for occipitocervical stabilizations in patients with craniocervical metastases. The prospectively collected data included the preoperative Tokuhashi score, SIN score, neurological status, length of hospitalization, perioperative course/loss of blood/complication rate, as well as the Karnofsky- index and pain measured by VAS preoperatively and in follow-up. RESULTS: Six patients were treated in this consecutive case series. The median age was 72 years (min./max.: 65/82), the average BMI 31.75 (min./max.: 19.3/38.1). The mean preoperative Karnofsky-index was 35 % (min./max.: 23.99/46.01; 95 % CI: 8.39) the mean preoperative Tokuhashi score 7 (min./max.: 4/10), the mean preoperative VAS7 (min./max.: 4.8/9.2; 95 % CI: 1.68). There were no perioperative complications. In the follow-up, one patient showed a loosening of the screws in the osteolytic massae laterales and one patient suffered from a construct failure after fall. DISCUSSION: Metastases of the craniocervical transition are rare. The initial treatment of instability includes the application of a rigid Miami-J-collar or a Halo fixator. The decision for an operative procedure must accurately assess the individual patient characteristics to provide him a balanced concept between operational risk and clinical benefit. The assessment should be based on the life expectation and the expected quality of life in dependency of the respective therapeutic concept and its risks. The sole posterior stabilization of craniocervical instability through occipitocervical fusion leads to a reduction of pain, has a low perioperative risk, and may prevent a hospitalization. It is justified for selected patients to receive this treatment to help alleviate pain and to improve their quality of life. From our experience, rare cases of pain without instability should undergo conservative treatment in the first line. Due to the low availability of data on the manifestation and the clinical course of craniocervical metastases, there is a need for the collection of both the descriptive patient data include the radiographic findings as well as the clinical outcome and socio-economic factors using appropriate scoring systems. PMID- 25144846 TI - [Soft tissue tumor near the joint: hibernoma]. AB - Joint associated tumors must undergo histological analysis, since not only inflammatory, but also benign and malign tumors exist in this location. We report a well circumscribed tumor, located in the elbow that histologically turned out to be a hibernoma. Complete surgical excision is the therapy of choice and recurrences are rare. To rule out liposarcoma with hibernoma like changes, fluorescence in-situ hybridisation has been performed and showed no MDM-2 amplification. Hibernomas are tumors of brown adipose tissue that may be localized next to joints. PMID- 25144848 TI - [Outcomes after operative treatment of distal radius fractures - an analysis of 721 patients]. AB - AIM OF THE STUDY: Treatment strategies in distal radius fractures differ nationally and internationally. Conservative and operative treatment options compete as well as implants, postoperative therapy regimens and the necessity of implant removal. In our institution operative treatment is favoured. In the following the results of 721 surgically treated patients are presented. PATIENTS: PATIENTS who underwent operative treatment of their distal radius fractures in our institution between 2008 and 2011 were retrospectively analysed. Following patient characteristics have been surveyed regarding age, sex, location of plate osteosynthesis, operation time, time of cast immobilisation and complications like infections, tendon ruptures, need of revision surgery. RESULTS: 721 patients (mean age: 59.03 years) were retrospectively analysed. 514 of them (71.29 %) were female. Time of operation was after a mean duration of 5.48 days. In 558 (77.39 %) patients we performed palmar plate osteosynthesis. 89 (12.34 %) had dorsal plate osteosynthesis and 74 (10.3 %) cases were treated with either K-wires or screws. 18 (2.5 %) patients had concomitant traumatic carpal tunnel syndrome and a concomitant SL rupture was seen in 38 (5.27 %) patients. 40 (5.55 %) patients underwent operative revision because of posttraumatic carpal tunnel syndrome (n = 15), tendon ruptures (n = 7), malposition of screws (n = 6), loss of reduction (n = 6) and infection (n = 3). Mean duration of in-hospital stay after operation was 6.6 days. Implant removal was performed in 77 (10.7) patients; 59 (8.2 %) patients had palmar plate osteosynthesis and 18 (2.5 %) patients had dorsal plating. CONCLUSION: Because of the low complication rate after operative treatment of distal radius fractures, osteosynthesis of this fracture seems to be warranted. Regarding the patients' higher age we have seen an unexpectedly long in-hospital stay with a mean time of 6.6 days. Herein attempts should be made to reduce time of in-hospital stay. In our opinion implant removal should not be recommended routinely. PMID- 25144847 TI - [Quality of post-operative pain therapy after subacromial decompression of the shoulder with resection of the lateral clavicula by arthroscopy]. AB - BACKGROUND: Shoulder impingement is one of the most common orthopaedic arthropathies. A minimally invasive surgery is indicated in cases of persistent symptoms or non-responders to conservative pain therapy. Normally, strong postoperative pain of the shoulder requires an effective pain therapy. PATIENTS/MATERIAL AND METHODS: 100 patients suffering from shoulder impingement with involvement of the acromioclavicular joint (55 male, 45 female, mean age 56, age range 37-78 years) were operated in 2007 and 2008 in the department of orthopaedics of the LVR-hospital. We aimed to evaluate the value of a subacromial pain catheter with ropivacaine (n = 33) compared to a conservative pain therapy ("Wurzburger Schmerztropf"/tramadol, novaminsulfon and metroclopramid and "Hettinger Infusion"/tramadol, novaminsulfon, dimenhydrinate as needed) alone (n = 34) or with an additional intraoperative administration of a single dose of ropivacaine (n = 33) after arthroscopic subacromial decompression of the shoulder with resection of the lateral clavicula. Additionally, patients of all three groups received a baseline analgesia with cryotherapy and diclofenac. RESULTS: Patients who received pain therapy by subacromial catheter reported less pain in the first 48 hours after surgery compared to ropivacaine intraoperatively and a standard pain therapy. Although all three methods achieved a significant pain reduction in the postoperative period, patients with subacromial catheter claimed the highest satisfaction with the therapy. Moreover, we could show that the subacromial pain catheter is a very efficient method with a high acceptance by the patients which is easy to perform and free of complications when considering the respective hygienic measures. PMID- 25144849 TI - [Evaluation of radiation exposure of personnel in an orthopaedic and trauma operation theatre using the new real-time dosimetry system "dose aware"]. AB - AIM: There is a positive correlation between operation time and staff exposure to radiation during intraoperative use of C-arm fluoroscopy. Due to harmful effects of exposure to long-term low-dose radiation for both the patient and the operating team it should be kept to a minimum. AIM of this study was to evaluate a novel dosimeter system called Dose Aware(r) (DA) enabling radiation exposure feedback of the personal in an orthopaedic and trauma operation theatre in real time. METHOD: Within a prospective study over a period of four month, DA was applied by the operation team during 104 orthopaedic and trauma operations in which the C-arm fluoroscope was used in 2D-mode. During ten operation techniques, radiation exposure of the surgeon, the first assistant, the theatre nurse and the anaesthesiologist was evaluated. RESULTS: Seventy-three operations were analysed. The surgeon achieved the highest radiation exposure during dorsolumbar spinal osteosynthesis, kyphoplasty and screw fixation of sacral fractures. The first assistant received a higher radiation exposure compared to the surgeon during plate osteosynthesis of distal radius fractures (157 %), intramedullary nailing of pertrochanteric fractures (143 %) and dorsolumbar spinal osteosynthesis (240 %). During external fixation of ankle fractures (68 %) and screw fixation of sacral fractures (66 %) radiation exposure of the theatre nurse exceeded 50 % of the surgeon's radiation exposure. During plate osteosynthesis of distal radius fractures (157 %) and intramedullary splinting of clavicular fractures (115 %), the anaesthesiologist received a higher radiation exposure than the surgeon. CONCLUSION: The novel dosimeter system DA provides real-time radiation exposure feedback of the personnel in an orthopaedic and trauma operation theatre for the first time. Data of this study demonstrate that radiation exposure of the personnel depends on the operation type. The first assistant, the theatre nurse and the anaesthesiologist might be exposed to higher radiation doses than the surgeon. DA might help to increase awareness concerning irradiation in an orthopaedic and trauma operation theatre and might enhance staff compliance in using radiation protection techniques. PMID- 25144850 TI - [Association between Hindfoot Alignment and Localisation of Osteochondral Lesions of the Talus]. AB - BACKGROUND: Osteochondral lesions (OCL) of the talus show a distinct distribution pattern. Vascular, metabolic, idiopathic, and biomechanical factors have been proposed as influencing factors. However, the association of hindfoot alignment and the location of talar OCL is not known. MATERIALS AND METHODS: In 22 patients undergoing autologous osteochondral transplantation for OCL of the talus we collected preoperative data on radiographic hindfoot alignment and clinical performance using the AOFAS score and the VAS for pain. The inter-observer reliability between two investigators was calculated. The association between hindfoot alignment and OCL location was statistically assessed. RESULTS: The preoperative AOFAS score was 64.1 +/- 13.9 points and the VAS 5.1 +/- 1.4. The mean measurement difference between the two observers was less than 0.5 degrees and the reliability of the measurements was good with a high association (kappa = 0.83). Surprisingly, the location of the OCL of the talus was independent from hindfoot alignment (p = 0.766). CONCLUSION: In our study the hindfoot alignment showed no association with the location of OCL of the talus. Hence, hindfoot alignment per se does not correlate with the localisation of talar OCL. PMID- 25144851 TI - [Does the ideal total knee arthroplasty for younger patients exist?]. AB - BACKGROUND: A total knee arthroplasty (TKA) is still not able to reinstate the physiological kinematics of the knee. This results in a considerable number of unsatisfied patients, especially if they are younger and active. Recently developed TKA systems claim to consider these biomechanical properties. The current study investigates the outcome (range of motion, stability) of the new ATTUNETM TKA system (DePuy, Warsaw, IN, USA) in in young patients. MATERIAL AND METHODS: This was a prospective study design (55 patients, 55 knees, age < 70 years, 01/2012-07/2012). Patients received an ATTUNETM TKA and were examined preoperatively and at 6 months postoperatively for range of motion and stability (Knee Society score). RESULTS: Age: 63 +/- 8 years; range of motion increased from 112.33 +/- 13.6 degrees to 123.60 +/- 11,1 degrees (p < 0.001). Coronal stability improved significantly (preoperatively vs. postoperatively, p < 0.001). Sagittal stability was not significantly different (preoperatively vs. postoperatively, p > 0.05). CONCLUSION: The data of this study show improved early functional results in younger patients in comparison to the current literature. However, until now no existing TKA system can be identified as ideal. But taking recent biomechanical knowledge into consideration, modern TKA designs have the potential to improve the functional outcome. Especially for younger patients with superior muscle-status and coordinative abilities this seems beneficial. PMID- 25144852 TI - [Fractures of the acetabulum: complications and joint replacement]. AB - Acetabular fractures assume a special role amongst the fractures of the pelvis, because they involve a major weight-bearing joint. As those fractures mostly result from exposure to great force, and because of their location in an anatomically complex region, a high rate of complications has to be anticipated. Besides general and perioperative complications long-term consequences, especially post-traumatic arthrosis, are relevant problems when it comes to treating fractures of the acetabulum. The primary reconstruction of the acetabulum, as well as a possibly necessary prosthetic replacement of the hip joint, makes high demands on the diagnostic and operative capabilities of the attending physician. Exact knowledge of the specific risks and pitfalls for each type of fracture and for the specific surgical techniques is crucial for a successful treatment. Due to the much worse long-term outcome when compared to primary total hip replacement in patients with osteoarthritis, acetabular fractures should, regardless of the patient's age, whenever possible be treated by operative reconstruction. PMID- 25144853 TI - Effect of GutsyGum(tm), A Novel Gum, on Subjective Ratings of Gastro Esophageal Reflux Following A Refluxogenic Meal. AB - Chewing gum alleviates symptoms of gastro-esophageal reflux (GER) following a refluxogenic meal. GutsyGum(tm), a chewing gum developed to alleviate the symptoms of GER contains calcium carbonate, with a proprietary blend of licorice extract, papain, and apple cider vinegar (GiGs(r)). The efficacy of GutsyGum(tm) was determined in alleviating the symptoms of GER after a refluxogenic meal compared to placebo gum. This double-blind, placebo-controlled-crossover trial with a one-week washout between treatments had 24 participants with a history of GER consume a refluxogenic meal and then chew GutsyGum(tm) or placebo gum. Participants completed GER symptom questionnaires, consisting of symptom based 10 cm Visual Analogue Scales, immediately following the meal and then at regular intervals out to four hours postmeal. Adjusted mean +/- SEM heartburn score (15 min postmeal to 240 min) was significantly lower in GutsyGum(tm) than in placebo gum treatment (0.81 +/- 0.20 vs. 1.45 +/- 0.20 cm; p = 0.034). Mean acid reflux score was significantly lower in GutsyGum(tm) than in placebo treatment (0.72 +/- 0.19 vs. 1.46 +/- 0.19 cm; p = 0.013). There were no significant differences for any of the secondary outcomes. However, pain approached significance with less pain reported in GutsyGum(tm) versus placebo treatment (0.4 +/- 0.2 vs. 0.9 +/- 0.2 cm; p = 0.081). Although nausea (p = 0.114) and belching (p = 0.154) were lower following GutsyGum(tm), the difference was not statistically significant. GutsyGum(tm) is more effective than a placebo gum in alleviating primary symptoms of heartburn and acid reflux (Clinical Trial Registration: ACTRN12612000973819). PMID- 25144855 TI - Et3N-catalyzed tandem formal [4 + 3] annulation/decarboxylation/isomerization of methyl coumalate with imine esters: access to functionalized azepine derivatives. AB - An unprecedented catalytic tandem formal [4 + 3] cycloaddition/decarboxylation/isomerization of methyl coumalate and imine esters is successfully developed. This tandem reaction only requires Et3N as the mild base affording a series of highly functionalized seven-membered heterocyclic azepine derivatives in good yields with excellent regioselectivities. PMID- 25144854 TI - Impact of multiple negative charges on blood clearance and biodistribution characteristics of 99mTc-labeled dimeric cyclic RGD peptides. AB - This study sought to evaluate the impact of multiple negative charges on blood clearance kinetics and biodistribution properties of (99m)Tc-labeled RGD peptide dimers. Bioconjugates HYNIC-P6G-RGD2 and HYNIC-P6D-RGD2 were prepared by reacting P6G-RGD2 and P6D-RGD2, respectively, with excess HYNIC-OSu in the presence of diisopropylethylamine. Their IC50 values were determined to be 31 +/- 5 and 41 +/ 6 nM, respectively, against (125)I-echistatin bound to U87MG glioma cells in a whole-cell displacement assay. Complexes [(99m)Tc(HYNIC-P6G RGD2)(tricine)(TPPTS)] ((99m)Tc-P6G-RGD2) and [(99m)Tc(HYNIC-P6D RGD2)(tricine)(TPPTS)] ((99m)Tc-P6D-RGD2) were prepared in high radiochemical purity (RCP > 95%) and specific activity (37-110 GBq/MUmol). They were evaluated in athymic nude mice bearing U87MG glioma xenografts for their biodistribution. The most significant difference between (99m)Tc-P6D-RGD2 and (99m)Tc-P6G-RGD2 was their blood radioactivity levels and tumor uptake. The initial blood radioactivity level for (99m)Tc-P6D-RGD2 (4.71 +/- 1.00%ID/g) was ~5* higher than that of (99m)Tc-P6G-RGD2 (0.88 +/- 0.05%ID/g), but this difference disappeared at 60 min p.i. (99m)Tc-P6D-RGD2 had much lower tumor uptake (2.20-3.11%ID/g) than (99m)Tc-P6G-RGD2 (7.82-9.27%ID/g) over a 2 h period. Since HYNIC-P6D-RGD2 and HYNIC-P6G-RGD2 shared a similar integrin alphavbeta3 binding affinity (41 +/- 6 nM versus 31 +/- 5 nM), the difference in their blood activity and tumor uptake is most likely related to the nine negative charges and high protein binding of (99m)Tc-P6D-RGD2. Despite its low uptake in U87MG tumors, the tumor uptake of (99m)Tc-P6D-RGD2 was integrin alphavbeta3-specific. SPECT/CT studies were performed using (99m)Tc-P6G-RGD2 in athymic nude mice bearing U87MG glioma and MDA-MB-231 breast cancer xenografts. The SPECT/CT data demonstrated the tumor targeting capability of (99m)Tc-P6G-RGD2, and its tumor uptake depends on the integrin alphavbeta3 expression levels on tumor cells and neovasculature. It was concluded that the multiple negative charges have a significant impact on the blood clearance kinetics and tumor uptake of (99m)Tc-labeled dimeric cyclic RGD peptides. PMID- 25144856 TI - Instillation versus inhalation of multiwalled carbon nanotubes: exposure-related health effects, clearance, and the role of particle characteristics. AB - Inhaled multiwalled carbon nanotubes (MWCNTs) may cause adverse pulmonary responses due to their nanoscale, fibrous morphology and/or biopersistance. This study tested multiple factors (dose, time, physicochemical characteristics, and administration method) shown to affect MWCNT toxicity with the hypothesis that these factors will influence significantly different responses upon MWCNT exposure. The study is unique in that (1) multiple administration methods were tested using particles from the same stock; (2) bulk MWCNT formulations had few differences (metal content, surface area/functionalization); and (3) MWCNT retention was quantified using a specialized approach for measuring unlabeled MWCNTs in rodent lungs. Male Sprague-Dawley rats were exposed to original (O), purified (P), and carboxylic acid functionalized (F) MWCNTs via intratracheal instillation and inhalation. Blood, bronchoalveolar lavage fluid (BALF), and lung tissues were collected at postexposure days 1 and 21 for quantifying biological responses and MWCNTs in lung tissues by programmed thermal analysis. At day 1, MWCNT instillation produced significant BALF neutrophilia and MWCNT-positive macrophages. Instilled O- and P-MWCNTs produced significant inflammation in lung tissues, which resolved by day 21 despite MWCNT retention. MWCNT inhalation produced no BALF neutrophilia and no significant histopathology past day 1. However, on days 1 and 21 postinhalation of nebulized MWCNTs, significantly increased numbers of MWCNT-positive macrophages were observed in BALF. Results suggest (1) MWCNTs produce transient inflammation if any despite persistence in the lungs; (2) instilled O-MWCNTs cause more inflammation than P- or F-MWCNTs; and (3) MWCNT suspension media produce strikingly different effects on physicochemical particle characteristics and pulmonary responses. PMID- 25144858 TI - Betaine homocysteine methyltransferase (BHMT) as a specific and sensitive blood marker for acute liver injury. AB - We developed a high-performance ELISA assay and measured serum BHMT levels in healthy individuals and patients with acute liver injury (ALI). The detection range of this ELISA assay was from 1.56 to 100 ng/ml. BHMT levels are significantly higher in ALI groups. In the healthy group (n = 244), the median value (interquartile range, IQR 0-56.40) was 1.83 ng/ml. In the ALI group (n = 42), the median value of BHMT was 748.48 ng/ml (IQR, 0-51095.92). ROC curve analysis demonstrated good sensitivity (0.86) and specificity (0.98). In addition, in five ALI cases with time course samples available, BHMT and ALT both followed the "rise and fall" temporal pattern with the disease progression. However, the slopes of BHMT curves were steeper than ALT curves. And in three out of the five cases, BHMT levels peaked 1 day earlier than ALT levels be a sensitive marker with good prognostic value. PMID- 25144860 TI - An in situ, in vivo murine model for the study of laryngotracheal stenosis. AB - IMPORTANCE: Laryngotracheal stenosis (LTS) lacks an ideal animal model to study its unique wound-healing pathophysiology and the effect of interventions. OBJECTIVE: To present an in vivo, in situ mouse model of LTS that can be used to investigate its pathophysiology, mechanisms, and interventions for treatment. DESIGN, SETTING, AND SUBJECTS: Prospective controlled animal study performed at an academic animal research facility on 87 C57BL/6 mice. INTERVENTIONS: Experimental mice (n = 40) underwent bleomycin-coated wire-brush injury to the larynx and trachea, while mechanical injury controls (n = 32) underwent phosphate buffered saline-coated wire-brush injury. Normal controls (n = 9) underwent no intervention, and mock surgery controls (n = 6) underwent anterior transcervical tracheal exposure only. Laryngotracheal complexes were harvested at days 7, 14, and 21 after injury. At the respective time points, mice in the chemomechanical and mechanical injury groups were killed, and their laryngotracheal complexes were harvested for histologic analysis. Normal and mock surgery controls were killed and then underwent histologic analysis. MAIN OUTCOMES AND MEASURES: The primary outcome measure was lamina propria thickness. RESULTS: The chemomechanical injury group maintained a significant increase in lamina propria thickness through day 21 compared with uninjured controls at day 7 (82.7 vs 41.8 MUm; P<.05), day 14 (93.5 vs 26.0 MUm; P<.05), and day 21 (91.2 vs 40.8 MUm; P<.05). Compared with the mechanical injury group, the chemomechanical injury group demonstrated a significantly increased thickness at 21 days (91.2 vs 33.7 MUm; P<.05). CONCLUSIONS AND RELEVANCE: Chemomechanical initiation of fibrosis in situ creates a viable mouse model of LTS that incorporates the physiologic circulatory supply and airflow. This small-animal model may be used to investigate the pathogenesis and inflammatory mechanisms of iatrogenic LTS and test therapeutic interventions to reverse or reduce the development of fibrosis. PMID- 25144859 TI - A novel pain interprofessional education strategy for trainees: assessing impact on interprofessional competencies and pediatric pain knowledge. AB - BACKGROUND: Health care trainees/students lack knowledge and skills for the comprehensive clinical assessment and management of pain. Moreover, most teaching has been limited to classroom settings within each profession. OBJECTIVES: To develop and evaluate the feasibility and preliminary outcomes of the 'Pain Interprofessional Education (IPE) Placement', a five-week pain IPE implemented in the clinical setting. The utility (content validity, readability, internal consistency and practical considerations) of the outcome measures was also evaluated. METHODS: A convenience sample of 21 trainees from eight professions was recruited over three Pain-IPE Placement cycles. Pre- and postcurriculum assessment included: pain knowledge (Pediatric Pain Knowledge and Attitudes Survey), IPE attitudes (Interdisciplinary Education Perception Scale [IEPS]) and IPE competencies (Interprofessional Care Core Competencies Global Rating Scales [IPC-GRS]), and qualitative feedback on process/acceptability. RESULTS: Recruitment and retention met expectations. Qualitative feedback was excellent. IPE measures (IEPS and IPC-GRS) exhibited satisfactory utility. Postcurriculum scores improved significantly: IEPS, P<0.05; IPC-GRS constructs, P<0.01; and competencies, P<0.001. However, the Pediatric Pain Knowledge and Attitudes Survey exhibited poor utility in professions without formal pharmacology training. Scores improved in the remaining professions (n=14; P<0.01). DISCUSSION: There was significant improvement in educational outcomes. The IEPS and IPC-GRS are useful measures of IPE-related learning. At more advanced training levels, a single pain-knowledge questionnaire may not accurately reflect learning across diverse professions. CONCLUSION: The Pain-IPE Placement is a successful collaborative learning model within a clinical context that successfully changed interprofessional competencies. The present study represents a first step at defining and assessing change in interprofessional competencies gained from Pain IPE. PMID- 25144861 TI - Current challenges in handling genetic data. AB - In no other field of biomedicine has such revolutionary change taken place in recent decades as it has in molecular genetics. The accumulated knowledge in this field will not only enable clinicians to make new treatment decisions in future, but will also help to save on healthcare costs. A positive test result will be the prerequisite for carrying out targeted drug treatment (companion diagnostics). Specific molecular diagnostics provide doctors with additional information that was not previously available, enabling them to optimise treatment accordingly. At the same time, prognostic tests mean that targeted preventive measures can be taken. Highly informative non-invasive tests will enable early detection and prevention to play a greater role. Technological breakthroughs, such as high-throughput sequencing, will lead to a flood of data in the future. The challenge lies in the quality of interpretation, which means extracting useful information for doctor and patient. Unlike data collection, interpretation is complex and expensive: it requires a high degree of expertise and a lot of resources. At the same time, experts stress that - as well as improvements in the accuracy and speed of data analysis - defined quality criteria must be generated for reliable interpretation of results. These challenges need to be tackled so that the population can benefit to the utmost from the opportunities offered by these developments: rapidly available and informative tests for targeted therapies based on high-quality data. PMID- 25144864 TI - Preferential solvation of metastable phases relevant to topological control within the synthesis of metal-organic frameworks. AB - A combined density functional theory and molecular dynamics study has been used to study reactions relevant to the crystallization of a model cluster based upon the metastable phase NH2-MOF-235(Al), which has been previously shown to be an important intermediate in the synthesis of NH2-MIL-101(Al). The clusters studied were of the form Al3O(BDC)6(DMF)n(H2O)m(+), where BDC(-) = NH2 benzenedicarboxylate and DMF = dimethylformamide (n = 1-3; m = {n - 3}). The ionic bonding interaction of the Al3O(7+) core with BDC(-) is much stronger than that with a coordinated solvent and is independent of the bulk solvent medium (water or DMF). The exchange reactions of a coordinated solvent are predicted to be facile, and the dynamic solvent organization indicates that they are kinetically allowed because of the ability of the solvent to migrate into the cleft created by the BDC-Al3O-BDC coordination angle. As BDC(-) binds to the Al3O(7+) core, the solvation free energy (G(solv)) of the cluster becomes less favorable, presumably because of the overall hydrophobicity of the cluster. These data indicate that as the crystal grows there is a balance between the energy gained by BDC(-) coordination and an increasingly unfavorable G(solv). Ultimately, unfavorable solvation energies will inhibit the formation of quantifiable metal-organic framework (MOF) crystals unless solution-phase conditions can be used to maintain thermodynamically favorable solute-solvent interactions. Toward this end, the addition of a cosolvent is found to alter solvation of Al3O(BDC)6(DMF)3(+) because more hydrophobic solvents (DMF, methanol, acetonitrile, and isopropyl alcohol) preferentially solvate the MOF cluster and exclude water from the immediate solvation shells. The preferential solvation is maintained even at temperatures relevant to the hydrothermal synthesis of MOFs. While all cosolvents exhibit this preferential solvation, trends do exist. Ranking the cosolvents based upon their observed ability to exclude water from the MOF cluster yields acetonitrile < DMF ~ methanol < isopropyl alcohol. These observations are anticipated to impact the intermediate and final phases observed in MOF synthesis by creating favorable solvation environments for specific MOF topologies. This adds further insight into recent reports wherein DMF has been implicated in the reactive transformation of NH2-MOF 235(Al) to NH2-MOF-101(Al), suggesting that that DMF additionally plays a vital role in stabilizing the metastable NH2-MOF-235(Al) phase early in the synthesis. PMID- 25144857 TI - Business and continuity of operations: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement. AB - BACKGROUND: During disasters, supply chain vulnerabilities, such as power, transportation, and communication, may affect the delivery of medications and medical supplies and hamper the ability to deliver critical care services. Disasters also have the potential to disrupt information technology (IT) in health-care systems, resulting in interruptions in patient care, particularly critical care, and other health-care business functions. The suggestions in this article are important for all of those involved in a large-scale pandemic or disaster with multiple critically ill or injured patients, including front-line clinicians, hospital administrators, and public health or government officials. METHODS: The Business and Continuity of Operations Panel followed the American College of Chest Physicians (CHEST) Guidelines Oversight Committee's methodology in developing key questions regarding medication and supply shortages and the impact disasters may have on healthcare IT. Task force members met in person to develop the 13 key questions believed to be most relevant for Business and Continuity of Operations. A systematic literature review was then performed for relevant articles and documents, reports, and gray literature reported since 2007. No studies of sufficient quality were identified upon which to make evidence-based recommendations. Therefore, the panel developed expert opinion based suggestions using a modified Delphi process. RESULTS: Eighteen suggestions addressing mitigation strategies for supply chain vulnerabilities including medications and IT were generated. Suggestions offered to hospitals and health system leadership regarding medication and supply shortages include: (1) purchase key medications and supplies from more than one supplier, (2) substituted medications or supplies should ideally be similar to those already used by an institution's providers, (3) inventories should be tracked electronically to monitor medication/supply levels, (4) consider higher inventories of medications and supplies known or projected to be in short supply, (5) institute alternate use protocols when a (potential) shortage is identified, and 6) support government and nongovernmental organizations in efforts to address supply chain vulnerability. Health-care IT can be damaged in a disaster, and hospitals and health system leadership should have plans for urgently reestablishing local area networks. Planning should include using portable technology, plans for providing power, maintenance of a patient database that can accompany each patient, and protection of patient privacy. Additionally, long-term planning should include prioritizing servers and memory disk drives and possibly increasing inventory of critical IT supplies in preparedness planning. CONCLUSIONS: The provision of care to the critically ill or injured during a pandemic or disaster is dependent on key processes, such as the supply chain, and infrastructure, such as IT systems. Hospitals and health systems will help minimize the impact of medication and supply shortages with a focused strategy using the steps suggested. IT preparedness for maintaining local area networks, functioning clinical information systems, and adequate server and memory storage capacity will greatly enhance preparedness for hospital and health system clinical and business operations. PMID- 25144865 TI - Accuracy of TNM staging in colorectal cancer: a review of current culprits, the modern role of morphology and stepping-stones for improvements in the molecular era. AB - Colorectal cancer (CRC) is the third most common cancer worldwide. Survival is largely stage-dependant, guided by the tumor-node-metastases (TNM) system for TNM assessment. Histopathological evaluation, including assessment of lymph node status, is important for correct TNM staging. However, recent updates in the TNM system have resulted in controversy. A continued debate on definitions resulting in potential up- and downstaging of patients, which may obscure survival data, has led the investigators to investigate other or alternative staging tools. Consequently, additional prognostic factors have been searched for using the regular light microscopy. Among the factors evaluated by histopathology include the evaluation of tumor budding and stromal environment, angiogenesis, as well as involvement of the immune system (including the 'Immunoscore'). We review the current role of histopathology, controversies in TNM-staging and suggested alternatives to better predict outcome for CRC patients in the era of genomic medicine. PMID- 25144866 TI - An economical and environmentally friendly oxidative biaryl coupling promoted by activated MnO2. AB - An activated manganese dioxide (MnO2)-BF3.OEt2 oxidation system was developed to efficiently mediate the intramolecular as well as intermolecular biaryl coupling. The oxidative coupling proceeds smoothly at ambient temperature to deliver the corresponding five- to eight-membered tricyclic products in good to excellent yields. The employment of the combination of MnO2 and BF3.OEt2 is attractive on the basis of economical and environmental issues. PMID- 25144867 TI - Flow-induced immobilization of glucose oxidase in nonionic micellar nanogels for glucose sensing. AB - A simple microfluidic platform was utilized to immobilize glucose oxidase (GOx) in a nonionic micellar scaffold. The immobilization of GOx was verified by using a combination of cryogenic electron microscopy (cryo-EM), scanning electron microscopy (SEM), and ultraviolet spectroscopy (UV) techniques. Chronoamperometric measurements were conducted on nanogel-GOx scaffolds under different glucose concentrations, exhibiting linear amperometric responses. Without impacting the lifetime and denaturation of GOx, the nonionic nanogel provides a favorable microenvironment for GOx in biological media. This flow induced immobilization method in a nonionic nanogel host matrix opens up new pathways for designing a simple, fast, biocompatible, and cost-effective process to immobilize biomolecules that are averse to ionic environments. PMID- 25144868 TI - Stoichiometry of the calcineurin regulatory domain-calmodulin complex. AB - Calcineurin is an essential serine/threonine phosphatase that plays vital roles in neuronal development and function, heart growth, and immune system activation. Calcineurin is unique in that it is the only phosphatase known to be activated by calmodulin in response to increasing intracellular calcium concentrations. Calcium-loaded calmodulin binds to the regulatory domain of calcineurin, resulting in a conformational change that removes an autoinhibitory domain from the active site of the phosphatase. We have determined a 1.95 A crystal structure of calmodulin bound to a peptide corresponding to its binding region from calcineurin. In contrast to previous structures of this complex, our structure has a stoichiometry of 1:1 and has the canonical collapsed, wraparound conformation observed for many calmodulin-substrate complexes. In addition, we have used size-exclusion chromatography and time-resolved fluorescence to probe the stoichiometry of binding of calmodulin to a construct corresponding to almost the entire regulatory domain from calcineurin, again finding a 1:1 complex. Taken in sum, our data strongly suggest that a single calmodulin protein is necessary and sufficient to bind to and activate each calcineurin enzyme. PMID- 25144869 TI - How confident do you feel? AB - In this issue of Neuron, Fetsch et al. (2014) show that microstimulation of motion-sensitive neurons in the visual cortex (MT/MST) of primates mimics the addition of sensory information for which the stimulated neurons are selective. Such microstimulation increases the confidence that monkeys have in their decisions about motion direction. PMID- 25144870 TI - Oscillatory substrates of fear and safety. AB - Oscillatory activity in the basolateral amygdala (BLA) is critical for emotional behavior. In this issue of Neuron, Stujenske et al. (2014) describe novel dynamics of BLA theta-gamma-coupled neuronal oscillations associated with conditioned and innate fear. PMID- 25144871 TI - Measuring the functional organization of the neocortex at large and small scales. AB - Sensory cortices are commonly structured topographically; however, the extent to which this organization principle is preserved at the microcircuit level is debated. In this issue of Neuron, Issa et al. (2014) revisit this question by combining calcium imaging in awake mice at large scales encompassing the whole auditory cortex and small scales providing single-cell resolution. PMID- 25144872 TI - Modeling neuronal vulnerability in ALS. AB - Using computational models of motor neuron ion fluxes, firing properties, and energy requirements, Le Masson et al. (2014) reveal how local imbalances in energy homeostasis may self-amplify and contribute to neurodegeneration in ALS. PMID- 25144873 TI - Schizophrenia genetics comes of age. AB - The new GWAS from the Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) clearly validates a genetic approach to understanding schizophrenia. The challenge now remains to track down the contributing genes and to develop appropriate models to elucidate the biological effects of the contributing variants. PMID- 25144874 TI - Can we reconcile the declarative memory and spatial navigation views on hippocampal function? AB - Some argue that hippocampus supports declarative memory, our capacity to recall facts and events, whereas others view the hippocampus as part of a system dedicated to calculating routes through space, and these two contrasting views are pursued largely independently in current research. Here we offer a perspective on where these views can and cannot be reconciled and update a bridging framework that will improve our understanding of hippocampal function. PMID- 25144878 TI - Electrochemical control of a non-covalent binding between ferrocene and beta cyclodextrin. AB - The forces required for the detachment of ferrocene (Fc) from beta-cyclodextrin (betaCD) in a single host (betaCD)-guest (Fc) complex were investigated using force spectroscopy under electrochemical conditions. The redox state of the guest Fc moiety as well as the structure of the supporting matrix was found to decisively affect the nanomechanical properties of the complex. PMID- 25144876 TI - Synapse-specific control of experience-dependent plasticity by presynaptic NMDA receptors. AB - Sensory experience orchestrates the development of cortical circuitry by adaptively modifying neurotransmission and synaptic connectivity. However, the mechanisms underlying these experience-dependent modifications remain elusive. Here we demonstrate that visual experience suppresses a presynaptic NMDA receptor (preNMDAR)-mediated form of timing-dependent long-term depression (tLTD) at visual cortex layer (L) 4-2/3 synapses. This tLTD can be maintained during development, or reinstated in adulthood, by sensory deprivation. The changes in tLTD are mirrored by changes in glutamate release; visual deprivation enhances both tLTD and glutamate release. These effects require the GluN3A NMDAR subunit, the levels of which are increased by visual deprivation. Further, by coupling the pathway-specific optogenetic induction of tLTD with cell-type-specific NMDAR deletion, we find that visual experience modifies preNMDAR-mediated plasticity specifically at L4-L2/3 synapses. PMID- 25144877 TI - Fear and safety engage competing patterns of theta-gamma coupling in the basolateral amygdala. AB - Theta oscillations synchronize the basolateral amygdala (BLA) with the hippocampus (HPC) and medial prefrontal cortex (mPFC) during fear expression. The role of gamma-frequency oscillations in the BLA is less well characterized. We examined gamma- and theta-frequency activity in recordings of neural activity from the BLA-HPC-mPFC circuit during fear conditioning, extinction, and exposure to an open field. In the BLA, slow (40-70 Hz) and fast (70-120 Hz) gamma oscillations were coupled to distinct phases of the theta cycle and reflected synchronous high-frequency unit activity. During periods of fear, BLA theta-fast gamma coupling was enhanced, while fast gamma power was suppressed. Periods of relative safety were associated with enhanced BLA fast gamma power, mPFC-to-BLA directionality, and strong coupling of BLA gamma to mPFC theta. These findings suggest that switches between states of fear and safety are mediated by changes in BLA gamma coupling to competitive theta frequency inputs. PMID- 25144880 TI - Unveiling how an archetypal fluorescent protein operates: theoretical perspective on the ultrafast excited state dynamics of GFP variant S65T/H148D. AB - Green fluorescent protein variant S65T/H148D has been reported to host a photocycle involving the photoinduced proton transfer reaction between the chromophore and residue Asp148 under 50 fs and without a measurable kinetic isotope effect, and experimental evidence is suggestive of the existence of a highly delocalized proton between these residues. The blinding speed at which this biological system undergoes proton transfer has been ascribed to the extreme increase of acidity of the GFP chromophore in the electronic excited state where proton transfer takes place. This work strives to present a coherent, complete, and balanced description of the dynamics of this specific variant of GFP in which it will be shown that this increase of acidity is insufficient to explain the behavior observed. This study tracks the behavior of this photosystem to the delicate interplay between structure and dynamics shown in the presence of solvent. In this way, it has been found that the dynamics of this protein intertwines its structure with the intervening solvent to give rise to effectively degenerate situations in what concerns the reactants and products of the proton transfer reaction in ground and, most importantly, photoexcited state, in terms of potential energy profiles associated with the proton migration. Under these conditions, proton transfer can occur in accordance with the experimental data available. This set of characteristics is possibly common to a host of other proton transfer based fluorescent proteins, and helps promoting GFP S65T/H148D to a case of archetypal significance. Thus, our results can be useful to understand the way many fluorescent proteins work and, more generally, the molecular basis for proton transfer reactions in proteins. PMID- 25144879 TI - Defining the molecular basis of amyloid inhibitors: human islet amyloid polypeptide-insulin interactions. AB - Human islet amyloid polypeptide (hIAPP or Amylin) is a 37 residue hormone that is cosecreted with insulin from the pancreatic islets. The aggregation of hIAPP plays a role in the progression of type 2 diabetes and contributes to the failure of islet cell grafts. Despite considerable effort, little is known about the mode of action of IAPP amyloid inhibitors, and this has limited rational drug design. Insulin is one of the most potent inhibitors of hIAPP fibril formation, but its inhibition mechanism is not understood. In this study, the aggregation of mixtures of hIAPP with insulin, as well as with the separate A and B chains of insulin, were characterized using ion mobility spectrometry-based mass spectrometry and atomic force microscopy. Insulin and the insulin B chain target the hIAPP monomer in its compact isoform and shift the equilibrium away from its extended isoform, an aggregation-prone conformation, and thus inhibit hIAPP from forming beta-sheets and subsequently amyloid fibrils. All-atom molecular modeling supports these conclusions. PMID- 25144881 TI - Identification and yields of 1,4-hydroxynitrates formed from the reactions of C8 C16 n-alkanes with OH radicals in the presence of NO(x). AB - A series of C8-C16 n-alkanes were reacted with OH radicals in the presence of NOx in an environmental chamber and particulate 1,4-hydroxynitrate reaction products were collected by filtration, extracted, and analyzed by high-performance liquid chromatography with UV absorption and electron ionization mass spectrometry (HPLC/UV/MS). Observed mass spectral patterns can be explained by using proposed ion fragmentation mechanisms, permitting the identification of each hydroxynitrate isomer. Reversed-phase retention of these compounds was dictated by the length of the longer of two alkyl chains attached to the 1,4 hydroxynitrate subunit. 1,4-Hydroxynitrates were quantified in particles using an authentic analytical standard for calibration, and the results were combined with gas chromatography measurements of the n-alkanes to determine the molar yields. Yields based on analyses of particles increased with increasing carbon number from 0.00 for C8 to an average plateau value of 0.130 +/- 0.008 for C14-C16, due primarily to corresponding increases in gas-to-particle partitioning. The value at the plateau, where essentially all 1,4-hydroxynitrates were in particles, was equal to the average total yield of C14-C16 1,4-hydroxynitrates. The average branching ratio for the formation of C14-C16 1,4-hydroxynitrates from the reaction of NO with the corresponding 1,4-hydroxyperoxy radicals was 0.184 +/- 0.011. This value is ~20% higher than the plateau value of 0.15 for reactions of secondary 1,2-hydroxyperoxy radicals and ~40% lower than the plateau value of 0.29 for reactions of secondary alkyl peroxy radicals, both of which were reported previously. The branching ratios determined here were used with values reported previously to calculate the yields of C7-C18 alkyl nitrates, 1,4 hydroxynitrates, and 1,4-hydroxycarbonyls, the three products formed from the reactions of these n-alkanes. PMID- 25144875 TI - More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration. AB - Members of the low-density lipoprotein (LDL) receptor gene family have a diverse set of biological functions that transcend lipid metabolism. Lipoprotein receptors have broad effects in both the developing and adult brain and participate in synapse development, cargo trafficking, and signal transduction. In addition, several family members play key roles in Alzheimer's disease (AD) pathogenesis and neurodegeneration. This Review summarizes our current understanding of the role lipoprotein receptors play in CNS function and AD pathology, with a special emphasis on amyloid-independent roles in endocytosis and synaptic dysfunction. PMID- 25144882 TI - Inter-rater reliability of physiotherapists using the Pirani scoring system for clubfoot: comparison with a modified five-point scale. AB - This study examines inter-rater reliability between physiotherapists using the Pirani scoring system for clubfoot, and whether the addition of two scale points to give a modified five-point severity scale improves reliability. A total of 65 infant feet were assessed by two raters, with 21 different rater combinations used. The Pirani scoring system was found to be a reliable assessment tool when used by physiotherapists to score clubfoot, with a minimum of fair to good inter rater reliability demonstrated across all clinical signs. The modified five-point scale proved significantly more reliable than the three-point scale; however, the benefit is not sufficient to warrant varying the original three-point scale. PMID- 25144883 TI - Do normal hips dislocate? AB - There have been a small number of case reports describing late normal-hip dislocations in children who were later diagnosed with developmental dysplasia of the hip. Here, we contest the assumption that normal hips can dislocate. We argue that (as in our case) the ultrasound scans in all published case reports on late dislocated normal hips did not show results that were entirely normal and therefore, so far, there has been no convincing evidence of a dislocation of a normal hip. We also want to highlight the importance of meticulous ultrasound and clinical assessments of high-risk children by an experienced orthopaedic surgeon. PMID- 25144884 TI - Chronic recurrent multifocal Q fever osteomyelitis in children: a case report and review of the literature: Retracted. AB - Q fever is a common worldwide zoonosis that is often difficult to diagnose because of its variety and the fact that its clinical symptoms are highly unspecific. We present a rare case of chronic multifocal osteomyelitis caused by Coxiella burnetti in a 2-year-old girl, which has recurred on many occasions, although the patient is under treatment with the most widely accepted approaches from other studies. A systemic review of the little published literature on this patients shows that there is no universal consensus with regard to the most adequate treatment. PMID- 25144885 TI - Prospective evaluation of the use of Mitchell shoes and dynamic abduction brace for idiopathic clubfeet. AB - Ponseti treatment for clubfoot has been successful, but recurrence continues to be an issue. After correction, patients are typically braced full time with a static abduction bar and shoes. Patient compliance with bracing is a modifiable risk factor for recurrence. We hypothesized that the use of Mitchell shoes and a dynamic abduction brace would increase compliance and thereby reduce the rate of recurrence. A prospective, randomized trial was carried out with consecutive patients treated for idiopathic clubfeet from 2008 to 2012. After casting and tenotomy, patients were randomized into either the dynamic or static abduction bar group. Both groups used Mitchell shoes. Patient demographics, satisfaction, and compliance were measured with self-reported questionnaires throughout follow up. Thirty patients were followed up, with 15 in each group. Average follow-up was 18.7 months (range 3-40.7 months). Eight recurrences (26.7%) were found, with four in each group. Recurrences had a statistically significant higher number of casts and a longer follow-up time. Mean income, education level, patient-reported satisfaction and compliance, and age of caregiver tended to be lower in the recurrence group but were not statistically significant. No differences were found between the two brace types. Our study showed excellent patient satisfaction and reported compliance with Mitchell shoes and either the dynamic or static abduction bar. Close attention and careful education should be directed towards patients with known risk factors or difficult casting courses to maximize brace compliance, a modifiable risk factor for recurrence. PMID- 25144886 TI - Good partnership between sulfur and fluorine: sulfur-based fluorination and fluoroalkylation reagents for organic synthesis. PMID- 25144887 TI - Functional anatomy of the mediastinal lymph nodes in rats. AB - BACKGROUND: The lymphatic system remains poorly recognized, yet for oncological reasons, it appears to be of great interest to both scientists and physicians. METHODS AND RESULTS: Protocols were performed on 55 adult male Wistar rats. All procedures were conducted after intraperitoneal administration of 4% chloral hydrate and artificial ventilation. The observations of the rats' anatomy of lymphatic structures and observations of lymphatic drainage were conducted after injection of the tracer (ink suspension and/or 1% solution of fluorescein isothiocyanate dextran) into the thoracic wall, intraperitoneally, and into bile ducts, as well as after experimental cutting of the outflow of the lymph from the liver to the mediastinal lymph nodes. The author's own terminology was suggested: medial mediastinal lymph node and lateral mediastinal lymph node. The presence of the tracer was found in the mediastinal nodes after its injection into the posterior wall of the thoracic wall, intraperitoneally, and into bile ducts. After injection into bile ducts, the tracer was observed only in the left mediastinal nodes. After experimental cutting of the basic outflow of the lymph from the liver to the mediastinal nodes, the whole outflow took place through the thoracic duct to the left venous angle. CONCLUSIONS: 1. The locations of the lymph nodes in the thorax as well as the drainage area of those nodes are asymmetrical. 2. Left-sided nodes show larger range of drainage. 3. Cutting the basic lymph outflow from the liver to the mediastinal nodes stops immunological information being transferred to regional nodes of the liver situated in the mediastinum. PMID- 25144890 TI - Outcomes of individuals with profound and partial biotinidase deficiency ascertained by newborn screening in Michigan over 25 years. AB - PURPOSE: Biotinidase deficiency, if untreated, usually results in neurological and cutaneous symptoms. Biotin supplementation markedly improves and likely prevents symptoms in those treated early. All states in the United States and many countries perform newborn screening for biotinidase deficiency. However, there are few studies about the outcomes of the individuals identified by newborn screening. METHODS: We report the outcomes of 142 children with biotinidase deficiency identified by newborn screening in Michigan over a 25-year period and followed in our clinic; 22 had profound deficiency and 120 had partial deficiency. RESULTS: Individuals with profound biotinidase and partial deficiency identified by newborn screening were started on biotin therapy soon after birth. With good compliance, these children appeared to have normal physical and cognitive development. Although some children exhibited mild clinical problems, these are unlikely attributable to the disorder. Biotin therapy appears to prevent the development of neurological and cutaneous problems in our population. CONCLUSION: Individuals with biotinidase deficiency ascertained by newborn screening and treated since birth appeared to exhibit normal physical and cognitive development. If an individual does develop symptoms, after compliance and dosage issues are excluded, then other causes must be considered.Genet Med 17 3, 205-209. PMID- 25144888 TI - Adverse events in cancer patients with sickle cell trait or disease: case reports. AB - PURPOSE: Given the relatively high prevalence of sickle cell trait and disease among African Americans and established racial disparities in cancer outcomes, we reviewed the literature regarding adverse events in cancer patients with these hematologic genotypes. Erythrocyte sickling can result from extreme hypoxia and other physiologic stressors, as might occur during cancer therapy. Further, tumoral hypoxia, a poor prognostic and predictive factor, could lead to a cycle of local sickling and increased hypoxia. METHODS: A search of PubMed produced 150 publications, most of which were excluded because of incidental relevance. Eleven case reports of patients diagnosed from 1993 to 2013 were reviewed. RESULTS: Two reports of patients with sickle cell trait describe an abundance of sickled erythrocytes within tumors, and a third report describes sickling-related events requiring multiday hospitalization. Eight reports of patients with sickle cell disease delineated multiorgan failure, vaso-occlusive crises, and rapid renal deterioration. Hypothesized triggers are delayed clearance of anticancer agents attributable to baseline kidney damage, activation of vasoadherent neutrophils from treatment to counter chemotherapy-induced neutropenia, hypoxia from general anesthesia, and intratumoral hypoxia. CONCLUSION: Clinical implications include pretreatment genotyping for prophylaxis, dose adjustment, and enhanced patient monitoring. With the current lack of high-quality evidence, however, the scope of poor outcomes remains unknown. PMID- 25144891 TI - Mild therapeutic hypothermia does not reduce thrombin-induced brain injury. AB - Secondary neurodegeneration occurs hours to days after an intracerebral hemorrhage (ICH). Thrombin, a protease important in clotting, is one of the causes of this injury. Presently, we evaluated whether hypothermia mitigates thrombin-induced cerebral edema, cell death, and behavioral impairment. Rats were given a striatal infusion of thrombin, which models thrombin-mediated injury occurring after ICH, followed an hour later by whole-body cooling (33 degrees C), local brain hypothermia (~ 33 degrees C), or normothermia. Thrombin caused significant edema at 24 hours (~ 5% increase in water) that was not mitigated by whole-body or brain-selective cooling. Other rats were infused with thrombin and systemically cooled for 72 hours. At a 14-day survival they had similar walking impairments and brain tissue loss (~ 45 mm(3)) as normothermic rats. However, cooled animals had significantly more degenerating neurons in the peri-lesion zone (p=0.035), which were rare in normothermic rats. Thus, it appears that some cell death was increased or delayed by hypothermia. In summary, we did not find that hypothermia reduced thrombin-induced neurotoxicity. This suggests that cooling does not effectively target thrombin-mediated secondary degeneration after ICH, which may partly explain why cooling is often not robustly neuroprotective in rodent ICH studies. These findings also indicate that therapeutic hypothermia could be improved by the addition of drugs to minimize thrombin toxicity. PMID- 25144889 TI - Informed consent for biobanking: consensus-based guidelines for adequate comprehension. AB - PURPOSE: Federal regulations and best practice guidelines identify categories of information that should be communicated to prospective biobank participants during the informed consent process. However, uncertainty remains about which of this information participants must understand to provide valid consent. METHODS: We conducted a Delphi process to define "adequate comprehension" in the context of biobanking consent. The process involved an iterative series of three online surveys of a diverse panel of 51 experts, including genome scientists, biobank managers, ethics and policy experts, and community and participant representatives. We sought consensus (>70% agreement) concerning what specific details participants should know about 16 biobank consent topics. RESULTS: Consensus was achieved for 15 of the 16 consent topics. The exception was the comprehension needed regarding the Genetic Information Nondiscrimination Act. CONCLUSION: Our Delphi process was successful in identifying a concise set of key points that prospective participants must grasp to provide valid consent for biobanking. Specifying the level of knowledge sufficient for individuals to make an informed choice provides a basis for improving consent forms and processes, as well as an absolute metric for assessing the effectiveness of other interventions to improve comprehension.Genet Med 17 3, 226-233. PMID- 25144892 TI - Comparative field study: impact of laboratory assay variability on the assessment of recombinant factor IX Fc fusion protein (rFIXFc) activity. AB - Due to variability in the one-stage clotting assay, the performance of new factor IX (FIX) products should be assessed in this assay. The objective of this field study was to evaluate the accuracy of measuring recombinant FIX Fc fusion protein (rFIXFc) activity in clinical haemostasis laboratories using the one-stage clotting assay. Human haemophilic donor plasma was spiked with rFIXFc or BeneFIX(r) at 0.80, 0.20, or 0.05 IU/ml based on label potency. Laboratories tested blinded samples using their routine one-stage assay and in-house FIX plasma standard. The mean spike recoveries for BeneFIX (n=30 laboratories) were 121 %, 144 %, and 168 % of expected at nominal 0.80, 0.20, and 0.05 IU/ml concentrations, respectively. Corresponding rFIXFc spike recoveries were 88 %, 107 %, and 132 % of expected, respectively. All BeneFIX concentrations were consistently overestimated by most laboratories. rFIXFc activity was reagent dependent; ellagic acid and silica gave higher values than kaolin, which underestimated rFIXFc. BeneFIX demonstrated significantly reduced chromogenic assay activity relative to one-stage assay results and nominal activity, while rFIXFc activity was close to nominal activity at three concentrations with better dilution linearity than the typical one-stage assay. In conclusion, laboratory- and reagent-specific assay variabilities were revealed, with progressively higher variability at lower FIX concentrations. Non-parallelism against the FIX plasma standard was observed in all one-stage assays with rFIXFc and BeneFIX, leading to significant overestimation of FIX activity at lower levels and generally high inter-laboratory variability. Compared to the accuracy currently achieved in clinical laboratories when measuring other rFIX products, most laboratories measured rFIXFc activity with acceptable accuracy and reliability using routine one-stage assay methods and commercially available plasma standards. PMID- 25144893 TI - Integrated use of bedside lung ultrasound and echocardiography in acute respiratory failure: a prospective observational study in ICU. AB - BACKGROUND: It has been suggested that the complementary use of echocardiography could improve the diagnostic accuracy of lung ultrasonography (LUS) in patients with acute respiratory failure (ARF). Nevertheless, the additional diagnostic value of echocardiographic data when coupled with LUS is still debated in this setting. The aim of the current study was to compare the diagnostic accuracy of LUS and an integrative cardiopulmonary ultrasound approach (thoracic ultrasonography [TUS]) in patients with ARF. METHODS: We prospectively recruited patients consecutively admitted for ARF to the ICU of a university teaching hospital over a 12-month period. Inclusion criteria were age >= 18 years and the presence of criteria for severe ARF justifying ICU admission. We compared both LUS and TUS approaches and the final diagnosis determined by a panel of experts using machine learning methods to improve the accuracy of the final diagnostic classifiers. RESULTS: One hundred thirty-six patients were included (age, 68 +/- 15 years; sex ratio, 1). A three-dimensional partial least squares and multinomial logistic regression model was developed and subsequently tested in an independent sample of patients. Overall, the diagnostic accuracy of TUS was significantly greater than LUS (P < .05, learning and test sample). Comparisons between receiver operating characteristic curves showed that TUS significantly improves the diagnosis of cardiogenic edema (P < .001, learning and test samples), pneumonia (P < .001, learning and test samples), and pulmonary embolism (P < .001, learning sample). CONCLUSIONS: This study demonstrated for the first time to our knowledge a significantly better performance of TUS than LUS in the diagnosis of ARF. The value of the TUS approach was particularly important to disambiguate cases of hemodynamic pulmonary edema and pneumonia. We suggest that the bedside use of artificial intelligence methods in this setting could pave the way for the development of new clinically relevant integrative diagnostic models. PMID- 25144896 TI - Electrocatalysis of formic acid on palladium and platinum surfaces: from fundamental mechanisms to fuel cell applications. AB - Formic acid as a natural biomass and a CO2 reduction product has attracted considerable interest in renewable energy exploitation, serving as both a promising candidate for chemical hydrogen storage material and a direct fuel for low temperature liquid fed fuel cells. In addition to its chemical dehydrogenation, formic acid oxidation (FAO) is a model reaction in the study of electrocatalysis of C1 molecules and the anode reaction in direct formic acid fuel cells (DFAFCs). Thanks to a deeper mechanistic understanding of FAO on Pt and Pd surfaces brought about by recent advances in the fundamental investigations, the "synthesis-by-design" concept has become a mainstream idea to attain high-performance Pt- and Pd-based nanocatalysts. As a result, a large number of efficient nanocatalysts have been obtained through different synthesis strategies by tailoring geometric and electronic structures of the two primary catalytic metals. In this paper, we provide a brief overview of recent progress in the mechanistic studies of FAO, the synthesis of novel Pd- and Pt-based nanocatalysts as well as their practical applications in DFAFCs with a focus on discussing studies significantly contributing to these areas in the past five years. PMID- 25144894 TI - Comparative efficacy and safety of multiple routes of direct CNS administration of adeno-associated virus gene transfer vector serotype rh.10 expressing the human arylsulfatase A cDNA to nonhuman primates. AB - Metachromatic leukodystrophy (MLD), a fatal disorder caused by deficiency of the lysosomal enzyme arylsulfatase A (ARSA), is associated with an accumulation of sulfatides, causing widespread demyelination in both central and peripheral nervous systems. On the basis of prior studies demonstrating that adeno associated virus AAVrh.10 can mediate widespread distribution in the CNS of a secreted lysosomal transgene, and as a prelude to human trials, we comparatively assessed the optimal CNS delivery route of an AAVrh.10 vector encoding human ARSA in a large animal model for broadest distribution of ARSA enzyme. Five routes were tested (each total dose, 1.5 * 10(12) genome copies of AAVrh.10hARSA-FLAG): (1) delivery to white matter centrum ovale; (2) deep gray matter delivery (putamen, thalamus, and caudate) plus overlying white matter; (3) convection enhanced delivery to same deep gray matter locations; (4) lateral cerebral ventricle; and (5) intraarterial delivery with hyperosmotic mannitol to the middle cerebral artery. After 13 weeks, the distribution of ARSA activity subsequent to each of the three direct intraparenchymal administration routes was significantly higher than in phosphate-buffered saline-administered controls, but administration by the intraventricular and intraarterial routes failed to demonstrate measurable levels above controls. Immunohistochemical staining in the cortex, white matter, deep gray matter of the striatum, thalamus, choroid plexus, and spinal cord dorsal root ganglions confirmed these results. Of the five routes studied, administration to the white matter generated the broadest distribution of ARSA, with 80% of the brain displaying more than a therapeutic (10%) increase in ARSA activity above PBS controls. No significant toxicity was observed with any delivery route as measured by safety parameters, although some inflammatory changes were seen by histopathology. We conclude that AAVrh.10-mediated delivery of ARSA via CNS administration into the white matter is likely to be safe and yields the widest distribution of ARSA, making it the most suitable route of vector delivery. PMID- 25144895 TI - Synthetic omega-3 epoxyfatty acids as antiproliferative and pro-apoptotic agents in human breast cancer cells. AB - omega-3-17,18-Epoxyeicosapentaenoic acid decreases cell proliferation and activates apoptosis, whereas its regioisomers stimulate growth. We evaluated synthetic omega-3 epoxides of saturated fatty acids as antiproliferative and pro apoptotic agents in MDA-MB-231 breast cancer cells. The epoxides, but not their urea, amide, or carbamate isosteres, impaired ATP production, enhanced caspase-3 activity, and activated c-jun-N-terminal-kinase signaling, leading to cyclin D1 down-regulation and cell cycle arrest in G1-phase. Fatty acid omega-3 monoepoxides may represent a novel class of antitumor agents. PMID- 25144897 TI - Transfusion-free management of gastrointestinal bleeding: the experience of a bloodless institute. AB - GOALS: The Institute for Patient Blood Management and Bloodless Medicine at the Englewood Hospital has considerable experience in managing patients with gastrointestinal bleeding who do not accept blood-derived products. We present our data and experience over the last 8 years in managing such patients. BACKGROUND: There is paucity of data on management and outcomes of gastrointestinal bleeding in patients who do not accept blood-derived products. STUDY: We performed a retrospective study of patients from 2003 to 2011 presenting with gastrointestinal bleeding who do not accept blood-derived products. Inclusion criteria were either overt bleeding with a presenting hemoglobin (Hb) of <12 g/dL or a decrease in Hb of >1.5 g/dL. RESULTS: Ninety-six patients who met the inclusion criteria were included. Forty-one upper and 48 lower gastrointestinal bleeding sources were identified. Mean Hb was 8.8 g/dL and mean nadir was 6.9 g/dL. Among 37 patients (80.5%) with Hb <=6.0 g/dL, 30 (81%) survived. Four of 7 patients (57%) with a Hb <3 g/dL survived. The overall mortality rate was 10.4%. In unadjusted logistic regression models, age [1.06 (1.01-1.12 y)], admission to ICU [6.37(1.27-31.9)], and anticoagulation use [6.95 (1.57-30.6)] were associated with increased mortality. Initial Hb [0.68 (0.51 0.92)] and nadir Hb [0.48 (0.29-0.78)] inversely predicted mortality. CONCLUSIONS: These results suggest that transfusion-free management of gastrointestinal hemorrhage can be effective with mortality comparable with the general population accepting medically indicated transfusion. Management of these patients is challenging and requires a dedicated multidisciplinary team approach knowledgeable in techniques of blood conservation. PMID- 25144898 TI - Survival benefit of neoadjuvant chemotherapy for resectable cancer of the gastric and gastroesophageal junction: a meta-analysis. AB - BACKGROUND: The objective of the present meta-analysis was to estimate the magnitude of survival benefits of neoadjuvant chemotherapy (NAT) in resectable cancer of the gastric and gastroesophageal junction. MATERIALS AND METHODS: We searched PubMed, Embase, the Cochrane Library, ISI Web of Knowledge, Chinese biomedical literature database, Chinese Scientific Journals full-text database of retrieved articles from their inception to 2013. Two reviewers independently retrieved study and data extraction of included studies. Results regarding the overall survival and progression-free survival in the meta-analysis were expressed as hazard ratios (HRs) with 95% confidence intervals (CI). RESULTS: Twelve randomized control trials (n=1755) were eligible for final meta-analysis. NAT was associated with a statistically significant benefit in terms of overall survival (HR=0.72; 95% CI, 0.56-0.93, P=0.01), progression-free survival (HR=0.73; 95% CI, 0.62-0.87, P=0.0003), 5-year survival rate [relative risk (RR)=1.36; 95% CI, 1.10-1.67, P=0.0004], and curative resection rate (RR=1.11; 95% CI, 1.03-1.20, P=0.009). Five-year survival rate increased from 30% to 42% with NAT. No significant difference with regards to overall postoperative complications rate (RR=1.08; 95% CI, 0.92-1.27, P=0.28) was found between 2 groups. CONCLUSION: There is convincing evidence for a survival benefit of NAT over surgery alone in patient with cancer of the gastric and gastroesophageal junction. PMID- 25144899 TI - Computed tomography colonography: ready for prime time for colon cancer screening? AB - In 2008, results from the landmark American College of Radiology Imaging Network (ACRIN) trial provided evidence supporting the use computed tomography colonography (CTC) as a comparable alternative to colonoscopy for colorectal cancer (CRC) screening. Subsequently, however, the United States Preventive Task Force decided against a recommendation in support of CTC for CRC screening. Following soon after, the Centers for Medicare and Medicaid Services (CMS) made noncoverage decision for the use of CTC in CRC screening. Since that decision, there have been a number of publications on CTC and CRC screening with a strong push from the radiology community to reassess CTC as a viable option. The purpose of this review was to address focused questions concerning the use of CTC in CRC screening, through an analysis of the available scientific evidence in an effort to provide recommendations for clinicians, patients, and payors who may evaluate the role of CTC for CRC screening. PMID- 25144900 TI - Rates of Suboptimal Preparation for Colonoscopy Differ Markedly Between Providers: Impact on Adenoma Detection Rates. AB - GOALS: We sought to determine if providers who have higher standards for optimal bowel preparation might be more fastidious in their examination of the colon and, therefore, have higher adenoma detection rates (ADRs). BACKGROUND: ADRs are a reliable and objective marker of colonoscopy performance. Suboptimal bowel preparation impacts upon adenoma detection; however, physicians have varying standards for grading bowel preparation. STUDY: Endoscopy reports of patients who underwent screening colonoscopy in 2011 at 1 academic medical center were reviewed. Bowel preparations labeled "fair," "poor," or "unsatisfactory" were considered suboptimal. The ADR was calculated for each endoscopy provider and was correlated with the provider's suboptimal preparation rate. Logistic regression was used to determine independent predictors of adenoma detection. RESULTS: 1649 examinations from 11 separate gastroenterologists were included. Preparation was suboptimal in 22% of examinations overall. The rate of suboptimal preparations varied widely among providers, ranging from 3% to 40%. Overall ADR was 23%, with a range of 13% to 31%. Providers' suboptimal preparation rate was not significantly correlated with ADR (r=-0.22, P=0.51). After adjusting for age and sex, adenoma detection was not associated with provider suboptimal preparation rate (P=0.28). CONCLUSIONS: Rates of suboptimal preparation vary widely between providers, but were not correlated with ADR. This suggests that a high suboptimal preparation rate is not a marker of higher quality standards and expectations by the provider. The impact of physician personality traits on colonoscopy performance requires further study. PMID- 25144901 TI - Determining cut-off points for enhanced liver fibrosis panel. PMID- 25144904 TI - Electrokinetics as an alternative to neutron reflectivity for evaluation of segment density distribution in PEO brushes. AB - Unravelling details of charge, structure and molecular interactions of functional polymer coatings defines an important analytical challenge that requires the extension of current methodologies. In this article we demonstrate how streaming current measurements interpreted with combined self consistent field (SCF) and soft surface electrokinetic theories allow the evaluation of the segment distribution within poly(ethylene oxide) (PEO) brushes beyond the resolution limits of neutron reflectivity technique. PMID- 25144903 TI - Effects of voluntary physical exercise, citicoline, and combined treatment on object recognition memory, neurogenesis, and neuroprotection after traumatic brain injury in rats. AB - The biochemical and cellular events that lead to secondary neural damage after traumatic brain injury (TBI) contribute to long-term disabilities, including memory deficits. There is a need to search for single and/or combined treatments aimed at reducing these TBI-related disfunctions. The effects of citicoline and of voluntary physical exercise in a running wheel (3 weeks), alone or in combination, on TBI-related short-term (3 h) and long-term (24 h) object recognition memory (ORM) deficits and on neurogenesis and neuroprotection were examined using a rodent model of TBI (controlled cortical impact injury). Citicoline improved memory deficits at the two times tested, while physical exercise only in the long-term test. Physical exercise had a clear neuroprotective effect as indicated by reduced interhemispheric differences in hippocampal formation and lateral ventricle volumes and in density of mature neurons in the hilus of the dentate gyrus and the perirhinal cortex. Physical exercise also increased cell proliferation and neurogenesis in the granular cell layer of the dentate gyrus. Some degree of neuroprotection of citicoline was suggested by reduced interhemispheric differences in the volume of the hippocampal formation. Contrary to what was expected, the effects of citicoline and physical exercise did not sum up. Further, a negative interference between both treatments was found in several behavioral and histological variables. The promising profiles of both treatments as therapeutic tools in TBI when applied singly underscore the need to perform further works looking for other combined treatment regimens that increase the benefit of each treatment alone. PMID- 25144905 TI - Tandem phosphorothioate modifications for DNA adsorption strength and polarity control on gold nanoparticles. AB - Unmodified DNA was recently used to functionalize gold nanoparticles via DNA base adsorption. Compared to thiolated DNA, however, the application of unmodified DNA is limited by the lack of sequence generality, adsorption polarity control and poor adsorption stability. We report that these problems can be solved using phosphorothioate (PS) DNA. PS DNA binds to gold mainly via the sulfur atom and is thus less sequence dependent. The adsorption affinity is ranked to be thiol > PS > adenine > thymine. Tandem PS improves adsorption strength, allows tunable DNA density, and the resulting conjugates are functional at a low cost. PMID- 25144906 TI - C11/C9 helices in crystals of alphabeta hybrid peptides and switching structures between helix types by variation in the alpha-residue. AB - Close-packed helices with mixed hydrogen bond directionality are unprecedented in the structural chemistry of alpha-polypeptides. While NMR studies in solution state provide strong evidence for the occurrence of mixed helices in (betabeta)n and (alphabeta)n sequences, limited information is currently available in crystals. The peptide structures presented show the occurrence of C11/C9 helices in (alphabeta)n peptides. Transitions between C11 and C11/C9 helices are observed upon varying the alpha-amino acid residue. PMID- 25144907 TI - Study of weathering effects on the distribution of aromatic steroid hydrocarbons in crude oils and oil residues. AB - The composition and distribution of triaromatic steroid hydrocarbons in oil residues after biodegradation and photo-oxidation processes were detected, and the diagnostic ratios for oil spill identification were developed and evaluated based on the relative standard deviation (RSD) and the repeatability limit. The preferential loss of C27 methyl triaromatic steranes (MTAS) relative to C28 MTAS and C29 MTAS was shown during the photo-oxidation process. In contrast to the photochemical degradation, the MTAS with the original 20R biological configuration was preferentially degraded during the biodegradation process. The RSD of most of the diagnostic ratios of MTAS ranged from 9 to 84% during the photo-oxidation process. However, the RSDs of such ratios derived from MTAS were all <5% even in high biodegradation, and such parameters may also provide new methods on oil spill identification. The parameters of monoaromatic sterane and monoaromatic sterane are not used well for oil spill identification after photo oxidation. The triaromatic steroid hydrocarbons retained their molecular compositions after biodegradation and photo-oxidation and most of the diagnostic ratios derived from them could be efficiently used in oil spill identification. PMID- 25144908 TI - Conformal sulfated zirconia monolayer catalysts for the one-pot synthesis of ethyl levulinate from glucose. AB - Here we describe a simple route to creating conformal sulphated zirconia monolayers throughout an SBA-15 architecture that confers efficient acid catalysed one-pot conversion of glucose to ethyl levulinate. PMID- 25144910 TI - Proteostasis: bad news and good news from the endoplasmic reticulum. AB - The endoplasmic reticulum (ER) is an intracellular compartment dedicated to the synthesis and maturation of secretory and membrane proteins, totalling about 30% of the total eukaryotic cells proteome. The capacity to produce correctly folded polypeptides and to transport them to their correct intra- or extracellular destinations relies on proteostasis networks that regulate and balance the activity of protein folding, quality control, transport and degradation machineries. Nutrient and environmental changes, pathogen infection aging and, more relevant for the topics discussed in this review, mutations that impair attainment of the correct 3D structure of nascent polypeptide chains may compromise the activity of the proteostasis networks with devastating consequences on cells, organs and organisms' homeostasis. Here we present a review of mechanisms regulating folding and quality control of proteins expressed in the ER, and we describe the protein degradation and the ER stress pathways activated by the expression of misfolded proteins in the ER lumen. Finally, we highlight select examples of proteopathies (also known as conformational disorders or protein misfolding diseases) caused by protein misfolding in the ER and/or affecting cellular proteostasis and therapeutic interventions that might alleviate or cure the disease symptoms. PMID- 25144912 TI - Factors that determine prolonged cecal intubation time during colonoscopy: impact of visceral adipose tissue. AB - OBJECTIVE: Various factors including age, sex, body mass index (BMI) and history of operation have been linked to the colonoscopic intubation time. The aims of this study were to identify the factors predicting cecal intubation time (CIT) and to evaluate the effect of the visceral adipose tissue (VAT) area on CIT. MATERIAL AND METHODS: A total of 1386 consecutive subjects who underwent colonoscopy and abdominal CT on the same day for a health checkup at a single health care center in Korea from August to December 2011 were studied prospectively. Age, sex, BMI, height, waist circumference, history of operation, symptoms of irritable bowel syndrome, bowel preparation status, experience of colonoscopists, VAT amount on abdominal CT and time required to reach the cecum were analyzed. RESULTS: The mean age of the subjects was 53.0 +/- 9.6 years, and 63.5% were male. The median CIT was 271 s. Univariate analyses showed that female gender, old age, shorter height, lower BMI, prior history of surgery and lower VAT were associated with longer CIT. To adjust for confounding effects of the gender, we investigated the genders separately in multivariate analysis. Older age and lower VAT were associated with prolonged CIT. However, the significance of association of VAT on prolonged CIT disappeared in women. CONCLUSION: This study demonstrates that CIT is prolonged by lower VAT area in men. This is the first study to demonstrate a direct association between VAT area and CIT. PMID- 25144913 TI - Ferrocenyl-substituted tris(pyrazolyl)borates--a new ligand type combining redox activity with resistance to hydrogen atom abstraction. AB - The low-temperature syntheses of ferrocenyl-substituted tris(pyrazolyl)borate ligands Tp(Fc*) (hydrobis(3-ferrocenylpyrazolyl)mono(5 ferrocenylpyrazolyl)borate), Tp(Fc,Me*) (hydrobis(3-ferrocenyl-5 methylpyrazolyl)mono(5-ferrocenyl-3-methylpyrazolyl)borate), and Tp(Fc,iPr) (hydrotris(3-ferrocenyl-5-isopropylpyrazolyl)borate) are reported. The Tl salts of Tp(Fc*) and Tp(Fc,Me*) can be thermally isomerized to the symmetric Tp(Fc) (hydrotris(3-ferrocenylpyrazolyl)borate) and Tp(Fc,Me) (hydrotris(3-ferrocenyl-5 methylpyrazolyl)borate) species, respectively. Conversely, upon heating, the thermal isomerization of Tp(Fc,iPr) results in the generation of a mixture of regioisomers. These ligands display a reversible three-electron oxidation. The preparations of Tp(CF3,Fc)Tl (hydrotris(3-trifluoromethyl-5 ferrocenylpyrazolyl)borate) and PhTp(Fc) (phenyltris(3 ferrocenylpyrazolyl)borate) are also reported. PMID- 25144914 TI - Enantioselective copper catalysed C-H insertion reaction of 2-sulfonyl-2 diazoacetamides to form gamma-lactams. AB - The first examples of asymmetric copper-catalysed intramolecular C-H insertion reactions of 2-sulfonyl-2-diazoacetamides are described; trans gamma-lactams with up to 82% ee are achieved with the CuCl2-bisoxazoline-NaBARF catalyst system. The reactions generally display high efficiency and high trans selectivity, and also a strong regiochemical preference for insertion to lead to the formation of 5 membered rings over 4-membered rings. In cases where there are competing C-H insertion pathways available, to form sulfolanes or thiopyrans, only the insertion into the amide chain to form gamma-lactams is observed. With phenylsulfonyl derivatives, a minor competing C-H insertion pathway leading to beta-lactams is seen; interestingly, changing the identity of the copper ligand changes the product ratio of beta/gamma-lactams. The copper catalysed reactions compare favorably in terms of efficiency and enantioselectivity to the corresponding reactions catalysed by commercially available chiral rhodium catalysts. PMID- 25144909 TI - The effects of prior authorization policies on medicaid-enrolled children's use of antipsychotic medications: evidence from two mid-Atlantic states. AB - OBJECTIVE: The purpose of this study was to examine the impact of prior authorization policies on the receipt of antipsychotic medication for Medicaid enrolled children. METHODS: Using de-identified administrative Medicaid data from two large, neighboring, mid-Atlantic states from November 2007 through June 2011, we identified subjects <18 years of age using antipsychotics, from the broader group of children and adolescents receiving behavioral health services or any psychotropic medication. Prior authorization for antipsychotics was required for children in State A <6 years of age from September 2008, and for children <13 years of age from August 2009. No such prior authorizations existed in State B during that period. Filled prescriptions were identified in the data using national drug codes. Using a triple-difference strategy (using differences among the states, time periods, and differences in antidepressant prescribing rates among states over the same time periods), we examined the effect of the prior authorization policy on the rate at which antipsychotic prescriptions were filled for Medicaid-enrolled children and adolescents. RESULTS: The impact of prior authorization policies on antipsychotic medication use varied by age: Among 6-12 year old children, the impact of the prior authorization policy on antipsychotic medication prescribing was a modest but statistically significant decrease of 0.47% after adjusting for other factors; there was no effect of the prior authorization among children 0-5 years. CONCLUSIONS: Prior authorization policies had a modest but statistically significant effect on antipsychotic use in 6-12 year old children, but had no impact in younger children. Future research is needed to understand the utilization and clinical effects of prior authorization and other policies and interventions designed to influence antipsychotic use in children. PMID- 25144915 TI - Preparation and validation of low cost microfluidic chips using a shrinking approach. AB - The present paper describes the production of microfluidic chips using an approach based on shrinkable biocompatible polymers (i.e. agarose) for the production of size controlled microfluidic channels. In addition, all steps of chip production were carried out using an inexpensive approach that uses low cost chemicals and equipment. The produced chips were then validated by producing monodisperse polymeric microparticles for drug delivery and hydrogel microfibers for cell embedding. PMID- 25144916 TI - Estuarine pollution of metals in China: science and mitigation. PMID- 25144918 TI - Group 1 and 2 and early transition metal complexes bearing N-heterocyclic carbene ligands: coordination chemistry, reactivity, and applications. PMID- 25144917 TI - Exploring regions of conformational space occupied by two-domain proteins. AB - The presence of heterogeneity in the interdomain arrangement of several biomolecules is required for their function. Here we present a method to obtain crucial clues to distinguish between different kinds of protein conformational distributions based on experimental NMR data. The method explores subregions of the conformational space and provides both upper and lower bounds of probability for the system to be in each subregion. PMID- 25144919 TI - Crystal structure, matrix-isolation FTIR, and UV-induced conformational isomerization of 3-quinolinecarboxaldehyde. AB - The crystal structure of 3-quinolinecarboxaldehyde (3QC) has been solved, and the compound has been shown to crystallize in the space group P21/c (monoclinic) with a = 6.306(4), b = 18.551(11), c = 6.999(4) A, beta = 106.111(13) degrees , and Z = 4. The crystals were found to exhibit pseudomerohedral twinning with a twin law corresponding to a two-fold rotation around the monoclinic (100) reciprocal lattice axis (or [4 0 1] in direct space). Individual molecules adopt the syn conformation in the crystal, with the oxygen atom of the aldehyde substituent directed toward the same side of the ring nitrogen atom. In the gas phase, the compound exists in two nearly isoenergetic conformers (syn and anti), which could be successfully trapped in solid argon at 10 K, and their infrared spectra are registered and interpreted. Upon in situ irradiation of matrix-isolated 3QC with UV light (lambda > 315 nm), significant reduction of the population of the less stable anti conformer was observed, while that of the conformational ground state (syn conformer) increased, indicating occurrence of the anti -> syn isomerization. Upon irradiation at higher energy (lambda > 235 nm), the syn -> anti reverse photoreaction was observed. Interpretation of the structural, spectroscopic, and photochemical experimental data received support from quantum chemical theoretical results obtained at both DFT/B3LYP (including TD-DFT investigation of excited states) and MP2 levels, using the 6-311++G(d,p) basis set. PMID- 25144920 TI - LPXRFa, the piscine ortholog of GnIH, and LPXRF receptor positively regulate gonadotropin secretion in Tilapia (Oreochromis niloticus). AB - LPXRFamide (LPXRFa) peptides have been characterized for their ability to inhibit gonadotropin (GTH) release in birds and stimulate growth hormone (GH) release in frogs. However, their involvement in regulating the reproductive hypothalamo pituitary-gonadal axis in mammals and fish is inconclusive. To study the role of LPXRFa peptides in the regulation of GTH secretion, we cloned tilapia LPXRFa and LPXRF receptor (LPXRF-R). Processing of the tilapia preproLPXRFa liberated three mature LPXRFa peptides that varied in size and post-translational modifications. Phylogenetic analysis of LPXRFa and the closely related RFamide peptide PQRFa showed clear clustering of each peptide sequence with its orthologs from various vertebrates. Signal-transduction analysis of the tilapia LPXRF-R in COS-7 cells showed clear stimulation of CRE-dependent luciferase activity, whereas the human NPFFR1 showed suppression of forskolin-induced CRE-dependent activity in this system. Administration of the tilapia pyroglutaminated LPXRFa-2 peptide to primary cell culture of tilapia pituitaries, or to reproductive female tilapia by ip injection, positively regulated both LH and FSH release in vivo and in vitro. Using double-labeled fluorescent in-situ hybridization and immunofluorescence, betaLH cells were found to co-express both tilapia lpxrf and tilapia lpxrf-r mRNA, whereas some of the betaFSH cells coexpressed only lpxrf-r mRNA. No coexpression of tilapia lpxrf-r was identified in GH-positive cells. These findings suggest that the LPXRFa system is a potent positive regulator of the reproductive neuroendocrine axis of tilapia. PMID- 25144921 TI - Changes in RFamide-related peptide-1 (RFRP-1)-immunoreactivity during postnatal development and the estrous cycle. AB - GnRH is a key player in the hypothalamic control of gonadotropin secretion from the anterior pituitary gland. It has been shown that the mammalian counterpart of the avian gonadotropin inhibitory hormone named RFamide-related peptide (RFRP) is expressed in hypothalamic neurons that innervate and inhibit GnRH neurons. The RFRP precursor is processed into 2 mature peptides, RFRP-1 and RFRP-3. These are characterized by a conserved C-terminal motif RF-NH2 but display highly different N termini. Even though the 2 peptides are equally potent in vitro, little is known about their relative distribution and their distinct roles in vivo. In this study, we raised an antiserum selective for RFRP-1 and defined the distribution of RFRP-1-immunoreactive (ir) neurons in the rat brain. Next, we analyzed the level of RFRP-1-ir during postnatal development in males and females and investigated changes in RFRP-1-ir during the estrous cycle. RFRP-1-ir neurons were distributed along the third ventricle from the caudal part of the medial anterior hypothalamus throughout the medial tuberal hypothalamus and were localized in, but mostly in between, the dorsomedial hypothalamic, ventromedial hypothalamic, and arcuate nuclei. The number of RFRP-1-ir neurons and the density of cellular immunoreactivity were unchanged from juvenile to adulthood in male rats during the postnatal development. However, both parameters were significantly increased in female rats from peripuberty to adulthood, demonstrating prominent gender difference in the developmental control of RFRP-1 expression. The percentage of c-Fos-positive RFRP-1-ir neurons was significantly higher in diestrus as compared with proestrus and estrus. In conclusion, we found that adult females, as compared with males, have significantly more RFRP-1-ir per cell, and these cells are regulated during the estrous cycle. PMID- 25144922 TI - Leptin resistance is not the primary cause of weight gain associated with reduced sex hormone levels in female mice. AB - Several studies have shown that estrogens mimic leptin's effects on energy balance regulation. However, the findings regarding the consequences of reduced sex hormone levels on leptin sensitivity are divergent. In the present study, we employed different experimental paradigms to elucidate the interaction between estrogens, leptin, and energy balance regulation. We confirmed previous reports showing that ovariectomy caused a reduction in locomotor activity and energy expenditure leading mice to obesity and glucose intolerance. However, the acute and chronic anorexigenic effects of leptin were preserved in ovariectomized (OVX) mice despite their increased serum leptin levels. We studied hypothalamic gene expression at different time points after ovariectomy and observed that changes in the expression of genes involved in leptin resistance (suppressors of cytokine signaling and protein-tyrosine phosphatases) did not precede the early onset of obesity in OVX mice. On the contrary, reduced sex hormone levels caused an up regulation of the long form of the leptin receptor (LepR), resulting in increased activation of leptin signaling pathways in OVX leptin-treated animals. The up regulation of the LepR was observed in long-term OVX mice (30 d or 24 wk after ovariectomy) but not 7 days after the surgery. In addition, we observed a progressive decrease in the coexpression of LepR and estrogen receptor-alpha in the hypothalamus after the ovariectomy, resulting in a low percentage of dual labeled cells in OVX mice. Taken together, our findings suggest that the weight gain caused by reduced sex hormone levels is not primarily caused by induction of a leptin-resistance state. PMID- 25144924 TI - Pharmaceutical quality of eight generics of ceftriaxone preparation for injection in Eastern Asia. AB - OBJECTIVES: To compare the pharmaceutical quality of original and generic ceftriaxone sodium preparations for injection produced in Eastern Asia. METHODS: Standard physical and chemical laboratory tests were performed. Participants/material: Ceftriaxone (Rocephin(r), Roche, Switzerland) was the reference material. Generics produced in China, India, and Indonesia were sampled in China and Myanmar within their expiration dates. RESULTS: Eight generics obtained from Eastern Asia markets in January 2013 were analysed. All eight generics failed the specifications in three or more tests. Residues of solvents and metals were detected in all generics, four were not particle free, and two were not sterile. CONCLUSIONS: All tested generic ceftriaxone products failed to meet the pharmaceutical quality standards of the branded original. The high levels of impurities and the identified contamination of particles and residues are of clinical concern, as they could impact tolerability and safety in patients in need of an effective parenteral antibiotic. PMID- 25144926 TI - Functionalization of fatty acid vesicles through newly synthesized bolaamphiphile DNA conjugates. AB - The surface functionalization of fatty acid vesicles will allow their use as nanoreactors for complex chemistry. In this report, the tethering of several DNA conjugates to decanoic acid vesicles for molecular recognition and synthetic purposes was explored. Due to the highly dynamic nature of these structures, only one novel bola-amphiphile DNA conjugate could interact efficiently with or spontaneously pierce into the vesicle bilayers without jeopardizing their self assembly or stability. This molecule was synthesized via a Cu(I)-catalyzed [3 + 2] azide-alkyne cycloaddition (click reaction), and consists of a single hydrocarbon chain of 20 carbons having on one end a triazole group linked to the 5'-phosphate of the nucleic acid and on the other side a hydroxyl-group. Its insertion was so effective that a fluorescent label on the DNA complementary to the conjugate could be used to visualize fatty acid structures. PMID- 25144925 TI - Self-healing gels based on constitutional dynamic chemistry and their potential applications. AB - As representative soft materials with widespread applications, gels with various functions have been developed. However, traditional gels are vulnerable to stress induced formation of cracks. The propagation of these cracks may affect the integrity of network structures of gels, resulting in the loss of functionality and limiting the service life of the gels. To address this challenge, self healing gels that can restore their functionalities and structures after damage have been developed as "smart" soft materials. In this paper, we present an overview of the current strategies for synthesizing self-healing gels based on the concept of constitutional dynamic chemistry, which involves molecular structures capable of establishing dynamic networks based upon physical interactions or chemical reactions. The characterization methods of self-healing gels and the key factors that affect self-healing properties are analyzed. We also illustrate the emerging applications of self-healing gels, with emphasis on their usage in industry (coatings, sealants) and biomedicine (tissue adhesives, agents for drug or cell delivery). We conclude with a perspective on challenges facing the field, along with prospects for future development. PMID- 25144923 TI - The use of protein-DNA, chromatin immunoprecipitation, and transcriptome arrays to describe transcriptional circuits in the dehydrated male rat hypothalamus. AB - The supraoptic nucleus (SON) of the hypothalamus is responsible for maintaining osmotic stability in mammals through its elaboration of the antidiuretic hormone arginine vasopressin. Upon dehydration, the SON undergoes a function-related plasticity, which includes remodeling of morphology, electrical properties, and biosynthetic activity. This process occurs alongside alterations in steady state transcript levels, which might be mediated by changes in the activity of transcription factors. In order to identify which transcription factors might be involved in changing patterns of gene expression, an Affymetrix protein-DNA array analysis was carried out. Nuclear extracts of SON from dehydrated and control male rats were analyzed for binding to the 345 consensus DNA transcription factor binding sequences of the array. Statistical analysis revealed significant changes in binding to 26 consensus elements, of which EMSA confirmed increased binding to signal transducer and activator of transcription (Stat) 1/Stat3, cellular Myelocytomatosis virus-like cellular proto-oncogene (c-Myc)-Myc-associated factor X (Max), and pre-B cell leukemia transcription factor 1 sequences after dehydration. Focusing on c-Myc and Max, we used quantitative PCR to confirm previous transcriptomic analysis that had suggested an increase in c-Myc, but not Max, mRNA levels in the SON after dehydration, and we demonstrated c-Myc- and Max like immunoreactivities in SON arginine vasopressin-expressing cells. Finally, by comparing new data obtained from Roche-NimbleGen chromatin immunoprecipitation arrays with previously published transcriptomic data, we have identified putative c-Myc target genes whose expression changes in the SON after dehydration. These include known c-Myc targets, such as the Slc7a5 gene, which encodes the L-type amino acid transporter 1, ribosomal protein L24, histone deactylase 2, and the Rat sarcoma proto-oncogene (Ras)-related nuclear GTPase. PMID- 25144928 TI - Structural Basis of the Toxicity of Chemicals in Cultured Human HeLa Cells. AB - The newly developed "chemical diversity approach" was used to determine whether or not it is likely that a panel of in vitro cell toxicity assays capable of predicting in vivo eye irritation could be assembled. The analyses, based upon available and validated structure-activity relationship models of toxicity in cultured human HeLa cells and murine Balb/c 3T3 cells, indicate that a battery of cytotoxicity tests could provide a viable alternative to the animal-based procedure. PMID- 25144927 TI - Freedom to Perform Animal Experiments: "The lady [and her109 co-signatories] doth protest too much, methinks. . . ". PMID- 25144929 TI - New aspects of cholecystokinin processing and visualisation in the rat brain by using antibodies raised in chickens and rabbits. PMID- 25144930 TI - A battery of cell toxicity assays as predictors of eye irritation: a feasibility study. AB - The newly developed "chemical diversity approach" was used to determine whether or not it is likely that a panel of in vitro cell toxicity assays capable of predicting in vivo eye irritation could be assembled. The analyses, based upon available and validated structure-activity relationship models of toxicity in cultured human HeLa cells and murine Balb/c 3T3 cells, indicate that a battery of cytotoxicity tests could provide a viable alternative to the animal-based procedure. PMID- 25144931 TI - A Computer-Based Structure-Activity Relationship Method for Predicting the Toxic Effects of Organic Chemicals from Onedimensional Representations of their Molecular Structures. AB - A computer-based method is presented for the analysis and interpretation of structural formulae characterising chemical molecules. This method was developed to enable a computer to identify substructures of chemical molecules that are relevant in the context of specific toxicological questions. The new computer based structure-examination method was used to develop the "structure" parts of several electronic structure-activity relationship models (SAR models) for analysing and interpreting the structural formula of a chemical from its one dimensional representation, by applying recursive principles and identifying partial isomorphic graphs. The structure-examination method is designed as part of an open-endpoint procedure to be used in expert systems, and could be applied in the construction of SAR models for almost all toxicological endpoints. The system was satisfactorily tested by identifying substructures relevant to severely damaging effects on skin and eyes. PMID- 25144932 TI - Synthesis of ultrafine Pt nanoparticles stabilized by pristine graphene nanosheets for electro-oxidation of methanol. AB - In this study, the pristine graphene nanosheets (GNS) derived from chemical vapor deposition process were employed as catalyst support. In spite of the extremely hydrophobic GNS surface, ultrafine Pt nanoparticles (NPs) were successfully assembled on the GNS through a surfactant-free solution process. The evolution of Pt NPs in the GNS support was studied using transmission electron microscopy. It was found that the high-energy surface sites in the GNS, such as edges and defects, played a critical role on anchoring and stabilizing Pt nuclei, leading to the formation of Pt NPs on the GNS support. The concentration of the Pt precursor, i.e., H2PtCl6 solution had significant effects on the morphology of Pt/GNS hybrids. The resulting Pt/GNS hybrids were examined as catalysts for methanol electro-oxidation. It was indicated that the electrochemical active surface area and catalytic activity of the Pt/GNS hybrids were highly dependent on Pt loadings. The superior activity of the catalysts with low Pt loadings was attributed to the presence of Pt subnanoclusters as well as the strong chemical interaction of Pt NPs with the GNS support. PMID- 25144934 TI - Shell-sheddable, pH-sensitive supramolecular nanoparticles based on ortho ester modified cyclodextrin and adamantyl PEG. AB - We report a new type of pH-sensitive supramolecular aggregates which possess a programmable character of sequential dePEGylation and degradation. As a platform of designing and building multifunctional supramolecular nanoparticles, a family of 6-OH ortho ester-modified beta-cyclodextrin (beta-CD) derivatives have been synthesized via the facile reaction between beta-CD and cyclic ketene acetals with different alkyl lengths. These asymmetric acid-labile beta-CD derivatives formed amphiphilic supramolecules with adamantane-modified PEG through host-guest interaction in polar solvents such as ethanol. The supramolecules can self assemble in water to form acid-labile supramolecular aggregates. The results of TEM and light scattering measurements demonstrate that the size and morphology of the aggregates are influenced by the alkyl or PEG length and the host-guest feed ratio. By carefully balancing the alkyl and PEG lengths and adjusting the host guest ratio, well-dispersed vesicles (50-100 nm) or sphere-like nanoparticles (200-500 nm) were obtained. Zeta potential measurements reveal that these supramolecular aggregates are capable of being surface-functionalized via dynamic host-guest interaction. The supramolecular aggregates were stable at pH 8.4 for at least 12 h as proven by the (1)H NMR and LLS measurements. However, rapid dePEGylation occurred at pH 7.4 due to the hydrolysis of the ortho ester linkages locating at the interface, which resulted in aggregation of the dePEGylated hydrophobic inner cores. Upon further decreasing the pH to 6.4, the hydrophobic cores were further degraded due to the acid-accelerated hydrolysis of the ortho esters. The incubation stability of the acid-labile supramolecular aggregates in neutral buffer could be improved by incorporating hydrophobic poly(epsilon caprolactone) into the core of the aggregates. PMID- 25144936 TI - Neutrophil extracellular traps (NETs) and the role of platelets in infection. AB - In addition to playing a central role in normal haemostasis, platelets make important contributions to host inflammatory and immune responses to injury or infection. Under pathophysiological conditions where platelet function is not tightly controlled, platelets also play critical roles in pathogenic processes underlying cardiovascular disease, uncontrolled inflammation, coagulopathy and in tumour metastasis. Neutrophil extracellular traps (NETs) are webs of histone modified nuclear material extruded from activated neutrophils during inflammatory responses and these degranulation events can be directly triggered by platelet/neutrophil engagement. Emerging research describes how NETs influence platelet function, particularly in the setting of infection and inflammation. Especially intriguing is the potential for platelet-driven coagulation to be modulated by NETs in plasma and interstitial spaces. These findings also reveal new perspectives related to improved therapy for venous thrombosis. PMID- 25144935 TI - Probing molecular pathways for DNA orientational trapping, unzipping and translocation in nanopores by using a tunable overhang sensor. AB - Nanopores provide a unique single-molecule platform for genetic and epigenetic detection. The target nucleic acids can be accurately analyzed by characterizing their specific electric fingerprints or signatures in the nanopore. Here we report a series of novel nanopore signatures generated by target nucleic acids that are hybridized with a probe. A length-tunable overhang appended to the probe functions as a sensor to specifically modulate the nanopore current profile. The resulting signatures can reveal multiple mechanisms for the orientational trapping, unzipping, escaping and translocation of nucleic acids in the nanopore. This universal approach can be used to program various molecular movement pathways, elucidate their kinetics, and enhance the sensitivity and specificity of the nanopore sensor for nucleic acid detection. PMID- 25144940 TI - In situ growth of matchlike ZnO/Au plasmonic heterostructure for enhanced photoelectrochemical water splitting. AB - In this paper, we report a novel matchlike zinc oxide (ZnO)/gold (Au) heterostructure with plasmonic-enhanced photoelectrochemical (PEC) activity for solar hydrogen production. The matchlike heterostructure with Au nanoparticles coated on the tip of ZnO nanorods is in situ grown on a zinc (Zn) substrate by using a facile hydrothermal and photoreduction combined approach. This unique heterostructure exhibits plasmonic-enhanced light absorption, efficient charge separation and transportation properties with tunable Au contents. The photocurrent density of the matchlike ZnO/Au heterostructure reaches 9.11 mA/cm(2) at an applied potential of 1.0 V (vs Ag/AgCl) with an Au/Zn atomic ratio of 0.039, which is much higher than that of the pristine ZnO nanorod array (0.33 mA/cm(2)). Moreover, the solar-to-hydrogen conversion efficiency of this special heterostructure can reach 0.48%, 16 times higher than that of the pristine ZnO nanorod array (0.03%). What is more, the efficiency could be further improved by optimizing the Au content of the heterostructure. The formation mechanism of such a unique heterostructure is proposed to explain the plasmonic-enhanced PEC performance. This study might contribute to the rational design of the visible light-responsive plasmonic semiconductor/metal heterostructure photoanode to harvest the solar spectrum. PMID- 25144937 TI - Ribosomal protein S27-like is a physiological regulator of p53 that suppresses genomic instability and tumorigenesis. AB - Cell-based studies showed that several Mdm2-binding ribosomal proteins, upon overexpression, stabilize and activate p53. In contrast, here we show in a mouse knockout study that Mdm2-binding ribosomal protein S27-like (Rps27l), upon disruption, activates p53. Germline inactivation of Rps27l triggers ribosomal stress to stabilize Mdm2, which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase towards p53, leading to p53-dependent apoptotic depletion of hematopoietic stem cells and postnatal death, which is rescued by Trp53 deletion. Paradoxically, while increased p53 is expected to inhibit tumorigenesis, Rps27l-/-;Trp53+/- mice develop lymphomas at higher incidence with p53 loss-of-heterozygosity and severe genome aneuploidy, suggesting that Rps27l disruption impose a selection pressure against p53. Thus, Rps27l has dual functions in p53 regulation: under Trp53+/+ background, Rps27l disruption triggers ribosomal stress to induce p53 and apoptosis, whereas under Trp53+/- background, Rps27l disruption triggers genomic instability and Trp53 deletion to promote tumorigenesis. Our study provides a new paradigm of p53 regulation. PMID- 25144941 TI - Managing risk during transition to new ISO tubing connector standards. PMID- 25144939 TI - Extensive translation of small Open Reading Frames revealed by Poly-Ribo-Seq. AB - Thousands of small Open Reading Frames (smORFs) with the potential to encode small peptides of fewer than 100 amino acids exist in our genomes. However, the number of smORFs actually translated, and their molecular and functional roles are still unclear. In this study, we present a genome-wide assessment of smORF translation by ribosomal profiling of polysomal fractions in Drosophila. We detect two types of smORFs bound by multiple ribosomes and thus undergoing productive translation. The 'longer' smORFs of around 80 amino acids resemble canonical proteins in translational metrics and conservation, and display a propensity to contain transmembrane motifs. The 'dwarf' smORFs are in general shorter (around 20 amino-acid long), are mostly found in 5'-UTRs and non-coding RNAs, are less well conserved, and have no bioinformatic indicators of peptide function. Our findings indicate that thousands of smORFs are translated in metazoan genomes, reinforcing the idea that smORFs are an abundant and fundamental genome component. PMID- 25144938 TI - A RanGTP-independent mechanism allows ribosomal protein nuclear import for ribosome assembly. AB - Within a single generation time a growing yeast cell imports ~14 million ribosomal proteins (r-proteins) into the nucleus for ribosome production. After import, it is unclear how these intrinsically unstable and aggregation-prone proteins are targeted to the ribosome assembly site in the nucleolus. Here, we report the discovery of a conserved nuclear carrier Tsr2 that coordinates transfer of the r-protein eS26 to the earliest assembling pre-ribosome, the 90S. In vitro studies revealed that Tsr2 efficiently dissociates importin:eS26 complexes via an atypical RanGTP-independent mechanism that terminates the import process. Subsequently, Tsr2 binds the released eS26, shields it from proteolysis, and ensures its safe delivery to the 90S pre-ribosome. We anticipate similar carriers-termed here escortins-to securely connect the nuclear import machinery with pathways that deposit r-proteins onto developing pre-ribosomal particles. PMID- 25144945 TI - When did we become the enemy? PMID- 25144942 TI - Erich Langer: the last Jewish dermatologist in Nazi Berlin. 532-41. AB - Nazi anti-Semitism had a considerable impact on dermatology during the period 1933 to 1945. Before World War II, dermatology in German-speaking lands was at the forefront of medicine, and about 25% of the dermatologists were Jewish. Many perished during the Holocaust; others emigrated from Germany and played a major role in advancing dermatology in their new homes, especially in the United States. Erich Langer (1891-1957) was almost unique, because he survived the entire period in Berlin. Langer had been chief of dermatology at Berlin-Britz, a large city hospital, before 1933 but was discharged almost immediately after the Nazi takeover because of his Jewish roots. In June 1945 he returned to his old department and resumed charge. He became one of the key figures in rebuilding German dermatology in the immediate postwar years. He served as first chair of dermatology at the new Free University in Berlin, started two journals, and wrote several books. Until recently, very little was known about Erich Langer's mysterious tale of survival and how he evaded Nazi roundups. Fortunately, we have discovered considerable archival material that has allowed us to piece together, for the first time, a detailed account of Langer's courageous and remarkable story as the last Jewish dermatologist inNazi Berlin. PMID- 25144946 TI - It's about content. PMID- 25144947 TI - The practice of health management. PMID- 25144949 TI - Polio, conflict and distrust: a global public health emergency. PMID- 25144950 TI - Medact relaunched: a renewed call for health professionals to campaign for social justice. PMID- 25144948 TI - Excellence and evidence in staffing: a data-driven model for excellence in staffing (2nd edition). AB - The Patient Protection and Affordable Care Act (PPACA, 2010) and the Institute of Medicine's (IOM, 2011) Future of Nursing report have prompted changes in the U.S. health care system. This has also stimulated a new direction of thinking for the profession of nursing. New payment and priority structures, where value is placed ahead of volume in care, will start to define our health system in new and unknown ways for years. One thing we all know for sure: we cannot afford the same inefficient models and systems of care of yesterday any longer. The Data-Driven Model for Excellence in Staffing was created as the organizing framework to lead the development of best practices for nurse staffing across the continuum through research and innovation. Regardless of the setting, nurses must integrate multiple concepts with the value of professional nursing to create new care and staffing models. Traditional models demonstrate that nurses are a commodity. If the profession is to make any significant changes in nurse staffing, it is through the articulation of the value of our professional practice within the overall health care environment. This position paper is organized around the concepts from the Data-Driven Model for Excellence in Staffing. The main concepts are: Core Concept 1: Users and Patients of Health Care, Core Concept 2: Providers of Health Care, Core Concept 3: Environment of Care, Core Concept 4: Delivery of Care, Core Concept 5: Quality, Safety, and Outcomes of Care. This position paper provides a comprehensive view of those concepts and components, why those concepts and components are important in this new era of nurse staffing, and a 3 year challenge that will push the nursing profession forward in all settings across the care continuum. There are decades of research supporting various changes to nurse staffing. Yet little has been done to move that research into practice and operations. While the primary goal of this position paper is to generate research and innovative thinking about nurse staffing across all health care settings, a second goal is to stimulate additional publications. This includes a goal of at least 20 articles in Nursing Economic$ on best practices in staffing and care models from across the continuum over the next 3 years. PMID- 25144951 TI - Use of complex systems modelling to strengthen public health's role in preventing war. PMID- 25144952 TI - Building medical education and research capacity in areas of conflict and instability: experiences of the OxPal Medlink in the occupied Palestinian territories. AB - Medical education and research capacity are often neglected in areas of conflict and instability. Physical and geographical barriers to accessing clinical learning environments, lack of dedicated teaching hospitals and frequent economic sanctions may all stunt the growth of a robust teaching culture in such regions. Here, we focus on the unique geopolitical situation of the occupied Palestinian territories and present our experiences with the OxPal MedLink, a web-based distance-learning collaboration which aims to address the educational needs of Palestinian medical students. PMID- 25144953 TI - The role of academic research and teaching in addressing health in situations of conflict and instability. AB - The key roles of academic research and teaching in addressing health in situations of conflict and instability are to better inform and better equip actors with the knowledge and skills to address health problems. The four key contributions of research are: quantifying the health problem, examining the contextual circumstances, investigating the epidemiology of health problems and evaluation of health care and humanitarian interventions. The role of teaching can complement research by distributing its' findings in addition to teaching skill sets to apply this knowledge and conduct further research. Academic research and teaching both play imperative roles in enabling more successful approaches in addressing health in situations of conflict and instability. PMID- 25144954 TI - Treating substance abuse as a consequence of conflict and displacement: a call for a more inclusive global mental health. AB - In settings of conflict and displacement, the provision of appropriate mental health services is essential. While most mental health research has focused on identifying rates of post-traumatic stress and other common disorders in post conflict settings, there has been little recognition of substance abuse as both a cause and consequence of mental health problems. Problems that arise when people begin to abuse substances to cope with the severe stress of emergency situations include the depletion of finite family and community resources, violence, exploitation, neglect of children and other protection threats. As a case in point, refugee camps on the Thai-Burma border have become a fertile breeding ground for drug and alcohol addiction. A more inclusive view of global mental health--one that addresses the problems of substance use in post-conflict and displacement contexts--will better enable health professionals to make meaningful contributions to conflict resolution and longer-term peace-building processes. PMID- 25144955 TI - Grassroots medical peace building: training Palestinian physicians in Israel. AB - Based on new scholarship on the importance of health in times of conflict, this paper examines the training of Palestinian physicians in Israel from the 1990s to 2010 as a test case for the theory. It shows that although Israeli governments have adopted a passive policy towards such training, and the Palestinian Authority is officially against such cooperation; in practice, individuals and hospitals on both sides work at the grassroots level with the aid of several NGOs to increase cooperation. Thus, grassroots activities are leading to better cooperation between Jewish and Palestinian health professionals, improving Palestinian health capabilities and establishing a bridgehead for better professional cooperation when a peace settlement is achieved. Health, like other social areas, is part of the explanation why the conflict remains stable and how mutual beneficial cooperation has planted the seeds for future cooperation. PMID- 25144956 TI - ["Born in Brazil"]. PMID- 25144957 TI - [Inclusion on the playground]. PMID- 25144958 TI - [Autoimmune thyroiditis in childhood]. PMID- 25144959 TI - [Touching with respect - and the appropriate massage oil. Massage oil expert panel at the 18th annual congress of the DGBM]. PMID- 25144961 TI - [Inquiry]. PMID- 25144960 TI - [Child abuse - a taboo subject]. PMID- 25144962 TI - [European comparative GesinE study on education in health specialties presented]. PMID- 25144963 TI - [The first 1000 years of life are decisive. Gynecologist and midwife, pediatrician and medical personnel with responsibility for long-term health]. PMID- 25144965 TI - [Therapeutic touch. A nursing intervention as a chance - also for personal health care]. PMID- 25144966 TI - Sex-specific age-related changes of information processing rate indicators during childhood and adolescence. AB - Despite the relevant findings on non-average information processing rate (IPR) indicators-intelligence relation, and on age-related changes of some of these indicators during aging, the research on sex-specific age-related changes of these indicators during childhood and adolescence are lacking. In a transversal study, 1197 school children (598 girls) aged 8-18 have been individually measured on 5 IPR indicators--two averages (mean_t, median_t) and three non-averages (min_t, max_t, sd_t). The results corroborated the expected non-linear changes of average IPR indicators in the observed developmental period, whereby the sex difference in related developmental patterns was detected: marked age-related decrement in girls ceased at the age of 12, and in boys around the age of 13-14, after which progress in both sexes gradually ceased by the age of 18 and was less pronounced in girls. Generally similar non-linear age-related decrements of non average indicators were registered, but they showed mutual intensity differences at specific ages and sex difference in developmental patterns was detected, analogously to average indicators. Systematic sex differences in the whole observed period were obtained only in two non-average indicators: girls showed minor sd_t and boys showed minor min_t. In specific age groups, a number of sex differences were obtained that are explainable by two possible mechanisms: earlier maturation in girls and sex bias of the IPR task content. The justifiability of separate, average and non-average, IPR indicators application was corroborated by their distribution form differences, by mutual, predominantly low and medium correlations, by the different intensity of their developmental changes and by their different ability to detect sex differences. For all registered phenomena, the theoretical and/or empirical explanations were offered from the domain of sex specific intellectual, motor and neural development, and it has been shown that non-average IPR indicators do register age and sex differences, which average indicators do not manage to register. PMID- 25144967 TI - Risk behaviors for getting HIV infection among university students in Serbia. AB - The objective of this study was to determine risk-taking behaviors forgetting HIV infection among university students in Serbia. The study is based on a cross sectional survey. Five hundred forty four undergraduate, first year students from two Belgrade universities were selected through random sampling, to answer a self administrated anonymous questionnaire. Data were collected from 252 students from the Faculties of Medical Sciences, University of Belgrade (FMS) and 292 students from the Faculties of Arts, University of Arts Belgrade (FA). The differences between two groups of students and between students with risk and non-risk behavior were assessed by the chi2 and t-test. Besides that, multivariate techniques such as factor analysis and multivariate logistic regression were used in statistical analysis. Smoking (Odds Radio - OR = 5.05, 95% Confidence Interval - CI = 3.10-8.24), studying FA, (OR = 4.17, 95% CI = 2.69-6.46), male sex (OR = 3.85, 95% CI = 2.38-6.25), committing offences (OR = 1.51, 95% CI = 1.09-2.08) and older age (OR = 1.31, 95% CI = 1.10-1.55) were the most significant factors connected with the risk-taking behaviors for HIV transmission among the students. In conclusion, HIV prevention efforts must be sustained and designed to reach young people and to prevent patterns of risky behaviors before they start. PMID- 25144969 TI - Mosquito survey during West Nile virus outbreak 2012 in northeast Croatia. AB - During the August and September 2012, seven human cases of the West Nile neuro invasive disease were reported in Croatia. Medical entomology research on a potential vectors during the outbreak was supported by the Ministry of Health. A mosquito survey has been done in 64 sites in three eastern Croatian counties (Osijek-Baranja County, Vukovar-Srijem county and in Brod-Posavina county). Dry ice baited CDC traps were used for mosquito sampling in a period from the 10th to 25th September 2012. A total of 1785 mosquitoes were collected and 5 species were determined. The most numerous species were Aedes vexans with 1634 specimens, a Culex pipiens c., the potential vector of WNV, was present with 6.39%, in 114 specimens. That species was present in 43 out of 64 investigated sites. Vector control included both the control of mosquito larvae and the adults. Treatments have been done on 184 small breeding sites and on 2900 ha of an urban area. PMID- 25144968 TI - Prevalence, attitudes and knowledge about HIV HBV and HCV infections among inmates in prisons Prilep and Bitola--a pilot study. AB - Prisons are associates as facilities liable of high risk of infection disease, as a result of the possibility of transmission of infections in prisons surroundings. Investigations carried out in correctional facilities around the world have shown a high prevalence of blood borne hepatitis viruses and HIV. The study was aimed at confirming prevalence of HIV hepatitis B and hepatitis C among prisoners in Bitola's, and Prilep's prisons, existing of co-infection as well to assess knowledge and attitudes related to HIV, HBV and HCV infections. In this cross-sectional study 200 prisoners have participated, providing answers to structured questionnaire and in order to analyze blood for HIV, HBV and HCV, rapid blood tests in detecting antibodies has been used. Prevalence of HCV is 0.20, HBV 0.17 and HIV prevalence is 0. Co-infection prevalence of HCV/HBV is 0.07 from the total number of examinees. As for the manner of infection with HIV virus 22% are familiar with the fact that persons cannot be infected by HIV if they have only one sexual partner who is not infected and have no other partners, and for the protection of HIV and Hepatitis B by correct use of condoms-58% have given correct answers. PMID- 25144970 TI - An investigation of the role of job satisfaction in employees' organizational citizenship behavior. AB - Job satisfaction, as an integral part of organizational environment, can affect organizational citizenship behavior. Therefore, the present paper aimed at determination of the relationship between these two factors among the employees to provide an appropriate model. The population of this study consisted of all employees of Golestan Province industry, mine and trade organization (Iran), the number of whom is 154, out of which, 120 employees were selected as a sample by the simple random sampling method. For collecting the data, two questionnaires of job satisfaction and organizational citizenship behavior were applied, and the obtained data was analyzed using the statistical methods of Kolmogorov-Smirnov test, Spearman's correlation, Pearson's correlation coefficient, Regression analysis, F-test and T-test. From the results, it was found that the variable of job satisfaction had a significant positive relationship with organizational citizenship behavior and one unit increase in organizational citizenship behavior is resulted from 0.622 unit increase in job satisfaction. PMID- 25144971 TI - Validation of the Slovenian version of patient assessment of chronic illness care (PACIC) in patients with coronary heart disease. AB - The Chronic Care Model (CCM) is a conceptual framework that supports the evidence based proactive and planned care of chronic diseases. Our aim was to validate a Slovenian translation of Patient Assessment of Chronic Illness Care (PACIC)--a self-reported instrument designed to measure the extent to which patients with chronic illnesses receive care congruent with CCM--on a sample of patients with coronary heart disease. Secondary analysis of patients' evaluation of general practice care (EPA Cardio study) was done in patients with coronary heart disease in Slovenia. Patients completed a written questionnaire, which included the instrument for assessing chronic illness care (PACIC), the EUROPEP questionnaire and demographical data. Internal consistency was expressed in terms of Cronbach's alpha. Reliability was expressed as the intra class correlation coefficient (ICC). Correlation between PACIC and EUROPEP was considered as a measure of construct validity. Factor analysis was done to identify number and types of domains in the instrument. Questionnaires of 843 patients were analysed. The mean age was 68.2 (SD 11.1) years, 34.6% of participants were female. 32.7% of PACIC questionnaires were not completely fulfilled. The internal consistency of the entire questionnaire assessed by Cronbach's alpha was 0.953 and reliability was 0.937. Construct validity was confirmed with important and significant correlation between PACIC and EUROPEP questionnaire (Spearman's correlation coefficient = 0.60, p < 0.001). Principal component factor analysis identifies two major factors which we labeled according to the PACIC domains as "Patient activation, decision support and problem solving" and "Goal settings and coordination". A translated and validated Slovenian version of PACIC questionnaire is now available. Further research on its validity in other groups of chronically ill patients and the use of instrument for monitoring changes of chronic care over time is recommended. PMID- 25144972 TI - Body mass index, waist circumference and waist-to-hip-ratio in the prediction of obesity in Turkish teenagers. AB - The aim of this study was to identify the usefulness of body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) in screening for obesity in teenagers by using the receiver operating characteristic (ROC). To select the sample set in this cross-sectional study, a stratified random sampling approach was utilized. Weight, height, WC, hip circumference and body fat percentage (BFP) were measured in 1118 children of both genders (597 boys and 521 girls), aged from 10 to 15 years old. Percentiles of BMI and Centers for Disease Control and Prevention-United States (CDC-US)-growth chart for boys and girls aged from 10 to 15 years old were presented. ROC analyses were then used to evaluate the performances of three anthropometric indices; BMI, WC and WHR had strong positive correlations with BFP (r = 0.49-0.77) in both girls and boys within indicated age group. The area under the curves (AUCs) were high in both girls and boys for BMI, 0.795 and 0.893, respectively, and WC, 0.767 and 0.853, respectively, and were a little lower, 0.747 and 0.783, respectively, for WHR. In conclusion, this study demonstrates that the prevalence of being overweight and obese among teenagers of both sexes in our data set does not differ from CDC-US-growth chart. In addition, BMI and WC are two important predictors for teenagers to become overweight and obese, while WHR is less useful for this purpose. PMID- 25144973 TI - Comparing women doing regular exercise with sedentary women in terms of certain blood parameters, leptin level and body fat percentage. AB - This study aims to compare the women engaged in doing regular exercise and those having done exercise previously and now not doing it or never done it before in terms of such blood values as leptin, cholesterol, insulin, glucose, triglyceride levels and body fat percentage (BFP) and to investigate the effects of regular exercise on these values. The participants of the study consisted of 35 (sportswomen) women doing regular exercise and 35 healthy and sedentary female university students never involved in doing regular exercise before. With the permission of the ethics committee, measuring was made. The mean (X) age of those doing regular exercise was 18.03 +/- 0.81 years, X height was 163.62 +/- 5.28 cm, X weight was 57.12 +/- 5.77 kg, and training background 7.34 +/- 1.75 years. X age of sedentary group was 18.91 +/- 0.72 years, X height was 164.45 +/- 5.44 cm, X weight was 58.15 +/- 4.68 kg. Statistically significant differences were found between the two groups in terms of the values of HDL and Triglyceride (p < 0.05), Total Cholesterol (p < 0.01), leptin, BFP, and insulin (p < 0.001). The other variables exhibited no statistically significant difference (p > 0.05). The increase in serum leptin levels is directly correlated with BFP. It has also been observed that regular exercise, as it reduces BFP, suppresses serum leptin levels. Regular exercise is significant in the regulation of body weight and prevention of obesity. It is concluded that if regular and moderate exercise is supplemented by good nutrition to avoid cardiovascular risk factor, to reduce LDL level, to bring about an increase in the level of HDL, this creates a positive influence on hormones and body fats and that exercise could be an important factor in enhancing the quality of life. PMID- 25144974 TI - Correlations of skinfold thicknesses and circumferences at exactly defined body sites with leptin in 10-12-year-old boys with different BMIs. AB - The aim of this study was to investigate the correlations of leptin with values of skinfold thicknesses and circumferences in 10-12-year-old boys (N = 248) and these correlations were additionally studied in boys with different BMI subgroups (normal N = 190, overweight N = 34 and obese N = 24). In total, 9 skinfolds and 13 circumferences were measured using the recommendations of ISAK. Fasting leptin concentrations were also determined. No significant differences emerged between the three subgroups in age and Tanner stage. Skinfold thicknesses, circumferences and leptin concentrations were significantly higher in overweight and obese groups. In the total group, the correlation (partial correlation, eliminating age and Tanner stage) between separate skinfold thicknesses and leptin was higher than r = 0.70. The sum of 9 skinfold thicknesses correlated significantly to leptin in all groups (r = 0.558-0.779). In the obese group, triceps, biceps and front thigh skinfold thicknesses did not correlate (p > 0.05) with leptin. In the total group, all measured circumferences correlated significantly to leptin concentration (r = 0.328-0.724). However, in the obese group, the measured circumferences did not correlate to leptin (p > 0.05). Waist-to-hip ratio correlated with leptin only in the total group of boys. It was concluded that as a rule, close correlations emerged between leptin and skinfold thicknesses and circumferences. The strongest correlation with leptin was found with the sum of 9 skinfolds and waist-to-hip ratio. PMID- 25144975 TI - Inheritance of quantitative dermatoglyphic traits with asymmetry and diversity in Muzeina Bedouin tribe: a small isolated and consanguineous population from South Sinai. AB - The genetic factors contribute significantly to the determination of dermatoglyphic traits is well established. However, the controversies in views and findings of this issue are still inconclusive. The present study is an attempt to evaluate the inheritance of quantitative dermatoglyphic traits with asymmetry (DA and FA) and diversity (Div) through sibling correlations. Data include 218 individuals from (88 families) in a small isolate, the nomadic tribe Muzeina with a high degree of consanguinity (0.09) from South Sinai. Statistical analyses include sibling correlations, cross-correlations and genetic correlation (GC)--a ratio of sibling cross-correlation between traits divided on square root of the both traits sibling correlation product. The familial correlation coefficients for quantitative dermatoglyphic traits are perhaps expected lower in such a small isolated and consanguineous population than our previous studied in Indian populations and Chuvashian populations from Russia. These results indicate a simpler genetic basis due to high degree (0.09 inbreeding coefficient) of consanguinity in Muzeina Bedouin tribe. There is no evidence of major gene involvement, although a little genetic effect obtained from familial correlations on asymmetry (DA and FA) and diversity (Div) traits through sibling correlations. The significant interaction between sexes was found, which contradicts with the other populations perhaps due to high level of consanguinity. Lower correlation coefficients than in other non-consanguineous populations for quantitative dermatoglyphic traits indicate a simpler genetic basis due to high degree of inbreeding coefficient (0.09) in Muzeina. Dermatoglyphic asymmetry and diversity traits may be due to environmental factors rather than dominance in Bedouins, although a little genetic effect was found suggests a measure of developmental instability in human (FA). PMID- 25144976 TI - The relationship between body structure and the socio-economic status in Hungarian children and adolescents. AB - Among the numerous factors that influence the pattern of children's growth and development there are factors of the changeable socio-economic environment. The inequalities among the socio-economic strata in the Hungarian society have increased during last decades. The main objective of the study was to examine the body structure of children and adolescents living in different socio-economic backgrounds. The subjects of the present paper (9479 boys, 9304 girls) were examined in the 2nd Hungarian National Growth Study 2003-2006. Body structure was assessed by some absolute body dimensions, BMI, body composition and body shape indices. Children were grouped into relatively good, average and poor socio economic subgroups by considering the education and occupation of the parents as well as the number of children in the family. Significant differences were found in the body structure of children varying in the socio-economic background: the better the socio-economic conditions the higher stature in both genders, while the lower relative fatness was found only in pubertal girls. The prevalence of unhealthy nutritional statuses (both underweight and overweight/ obese) was significantly lower in children living in better socio-economic conditions in both genders. Differences that were found in the body structure of children living in different socio-economic backgrounds emphasize the importance of using reference growth values layered also to socio-economic strata for screening nutritional status in childhood and adolescence. PMID- 25144977 TI - Efficiency of alkaline hydrolysis method in environment protection. AB - Development of new technologies for the efficient use of proteins of animal origin, apart from heat treatment in rendering facilities that was used to date, has become the primary goal of the integral waste management system. The emergence of bovine spongiform encephalopathy in Europe and in the World in the 1990s opened up new questions regarding medical safety and use of meat bone meal in the animal feed, which is produced by processing animal waste. Animal waste is divided into three categories, out of which the first category is high-risk waste. Alkaline hydrolysis is alternative method for management of animal by products not intended for human diet and imposes itself as one of the solutions for disposal of high-risk proteins. The paper will present the analyses of animal by-products not intended for human diet treated in laboratory reactor for alkaline hydrolysis, as one of the two recognized methods in EU for the disposal of this type of material and use in fertilization. PMID- 25144978 TI - Effects of air pollution on growth in schoolchildren. AB - The growth is considered a very sensitive indicator of the impact of environment of the health status of children. The aim of the study was to investigate whether air pollution is related to children's growth. The subjects were 1059 pupils, aged 7-11 years, living for more than ten years in the same home in the city of Nis (Serbia). Exposed group of children (N = 545) were attending the school located in a city area with a high level of air pollution, while the children (N = 514), in the comparison group, designed as non-exposed group, were attending the school in the area with a lower level of air pollution. The air concentrations of black smoke, nitrogen dioxide, sulfur dioxide and lead in sediment matter were determined in ten-year period. Air pollution is associated with children's height and weight, specially before the age of 9 years. There was a significant difference in the prevalence of thinness in children exposed to higher concentrations of air pollutants (p = 0.038). It might be possible that air pollution negatively contributed to the growth rate in urban children. PMID- 25144979 TI - Anthropometric methods in evaluation of chronic obstructive pulmonary disease. AB - Chronic Obstructive Pulmonary Disease (COPD) is mainly expressed by weight loss with especially fat-free mass (FFM) depletion and a low body weight correlates with increased mortality and a poor prognosis. We investigated whether anthropometric body composition equations could be used for evaluation of the body composition in COPD. Thirty clinically stable patients with COPD and 13 healthy age matched control subjects underwent the skinfolds and circumference measurements in addition to body mass index (BMI) calculations. Body fat mass (BFM) and FFM were determined by using anthropometric equations. The percent BFM, predicted from body density either using Siri's or Brozek's equations was determined lower than that of calculated with equations by using BMI, age and gender. The values of BFM and body weight were reduced in patients with FEV1 < % predicted compared to other participants. The FFM values also dropped depending on the severity of COPD. BMI was not statistically different among the participants while FFM index (FFMI) reflected the nutritional status of the disorders. Anthropometric equations easily and cost effectively applied for prediction of % BFM, FFM, and FFMI in patients with COPD. In addition, the FFMI can be possibly used for expressing COPD severity. PMID- 25144980 TI - The radiological estimation of vertebral body volumes on the thoracic and lumbal spine. AB - The aim of this work is to radiologicaly estimate the width, height and depth of bodies of thoracic and lumbal vertebras. Charts of one hundred and seventeen patients with implanted internal fixateur on the thoracic and lumbal spine, between 01.01.2008. and 31.3.2010. at the Department of Orthopedics and Traumatology - Clinical Centre Sarajevo, were retrieved, and only 14 patients, with totally 46 vetrtebras have meet including criteria (clearly visible measured structures on X-ray and CT scans, and data about implants dimensions). Digitalized anteroposterior and laterolateral X-ray, and transversal and sagital CT scans were basic inputs for measurement of height, width and depth of the vertebral body--CH, CW, CD. The correction of enlargement on X-ray pictures was performed according to known dimensions of implants and the length scale on CT scans. Enlargement of those parameters, from T1 to L5 spine level was from 60 to 100%, except the stagnation in the mid-thoracic region, and decreasing of corporal depth on the L5 vertebra (CD/L5), in comparison to the fourth vertebra (CD/L4). The clinical importance of this work is in estimation and comparison of dimensions of vertebral bodies measured on X-ray and CT scans, as the basic inputs during surgical procedures of vertebroplasty and anterior spondilodesis. PMID- 25144981 TI - Sport skill level and gender with relation to age, physical development and special fitness of the participants of Olympic volleyball tournament Beijing 2008. AB - The aim of this study was to provide an answer to the question whether and how age, body height, body mass, body mass index and results from fitness tests are related to sport skill level and gender of the participants of the Olympic volleyball tournament. Two-Way ANOVA was used to find the dependency of the variables on the factor of sport skill level (A--teams which took places 1 to 4, B--places from 5 to 8; C--places from 9 to 12) and gender (F--female; M--male). Statistical significance was set at p < 0.05. The Bonferroni's adjustment was carried out for three p = 0.017 and fifteen p = 0.003 pairs of comparisons). The M and F athletes included in A-C groups (N = 48 in each group) were than compared to the classification in the neural network of Probabilistic Neural Network (PNN). A combined effect of the factors of sports level and gender on the height of attack jump (F = 4.13; p = 0.02) and block jump (F = 9.22; p < 0.001) was identified. The level of achievement was modified by the differences between the men and women. A significant advantage over the groups B and C was found for attack height and block height. In the group A, the differences between the results obtained for women and men in the ranges of attack and block with respect to the net height were not significant. Mean range of block jump did not match up to attack jump, particularly in women. The application of PNN network showed that age, BMI, relative attack jump and block jump are good predictors of sport results. The percentage of properly classified players in the group of men was lower than in women (42.4 vs. 56.3%). In this regard, big differences were found at the lower level of sport results: A (77.1 vs. 79.2%), B (25.0 vs. 25.0%) and C (25.0 vs. 64.6%). In conclusion, selection for national teams should take into consideration the players with long competitive experience with adequate weight/height ratios, who exhibit good training adaptations to jumping exercise. PMID- 25144982 TI - Morphological profile of different types of top young female European basketball players. AB - Basketball is a team sport involving several types of players who differ in terms of body height and other morphological dimensions. This study aimed to establish and analyze the morphological characteristics of top young female European basketball players, the development levels of the morphological characteristics of three basic types of such players and any differences among them. The sample of subjects comprised 115 female basketball players aged 14.64 (+/- 0.48) years. They were divided into three groups according to their playing position: guard (N = 51), forward (N = 33) and center (N = 31). The study applied 23 morphological measures, based on which the somatotype components, percentages of bone, muscle and fat tissue and other morphological indexes were calculated. Statistically significant differences (p < 0.05) were established between individual types of players in terms of their body height, body mass and the three somatotype components, by using a one-way analysis of variance, whereas no such differences were identified in terms of their bone, muscle and fat tissue percentages. There were no differences even after the effect of body height was eliminated by using a multivariate analysis of covariance. The effect of the covariate was only statistically significant in terms of bone tissue percentage. The results of the study thus refute the assumption that it is possible to differentiate player types according to their proportions of fat and muscle tissue. PMID- 25144983 TI - Short-term power output and local muscular endurance of young male soccer players according to playing position. AB - Although the contribution of anaerobic power in soccer performance is recognized and there is evidence that many anthropometric and physiological characteristics vary according to playing position, the association between playing position and short-term power output, and local muscular endurance is not well studied, especially in young players. Therefore, the aim of the present study is to examine whether this component of sport-related physical fitness of young soccer players varies according to playing position. Young male (N = 296; aged 10.94 21.00 y), classified in five two-year age-groups, and adults (N = 30; aged 21.12 31.59 y), all members of competitive soccer clubs, performed the 30-s Wingate anaerobic test against braking force 0.075 kg x kg(-1) of body mass. One-way analysis of variance (ANOVA) revealed significant differences between age groups with regard to peak power in absolute, P(peak) (F5,320 = 86.7, p < 0.001), and in relative to body mass values, rP(peak) (F5,320 = 43.27, p < 0.001), mean power in absolute, P(mean) (F5,313 = 108.97, p < 0.001), and in relative values, rP(mean) (F5,313 = 41.64, p < 0.001), while there was no difference with respect to fatigue index, FI (F5,312 = 1.09, p = 0.370). One-way analysis of covariance, considering age as covariate, did not reveal any significant differences among playing position groups with regard to P(peak) (F3,289 = 1.46, p = 0.226), rP(peak) (F3,289 = 0.87, p = 0.457) and P(mean) (F3,283 = 0.31, p = 0.817), while goalkeepers had lower rP(mean) than defenders, midfielders and forwards (F3,283 = 6.32, p < 0.001). One-way ANOVA revealed differences with regard to FI (F3,283 = 5.97, p < 0.001), according to which goalkeepers had higher values than defenders and midfielders. Compared with data from previous studies in general population, participants had superior short-term power output and local muscular endurance. Both these anaerobic parameters were in direct relationship with age (r = 0.64, p < 0.001, and r = 0.68, p < 0.001 respectively), even when the influence of body mass was partitioned out (r = 0.50, p < 0.001 in both cases). The comparison between playing positions revealed similar alactic anaerobic profile for all groups, and indicated local muscular endurance as the anaerobic parameter that discriminated goalkeepers from outfield players. PMID- 25144984 TI - Correlation between agility and sprinting according to student age. AB - The purposes of the study were to assess sprinting and agility performance characteristics and to determine the relationship between these two motor skills in elementary education students. Sprinting and agility performance were assessed in 176 children (88 boys and 88 girls) divided into three groups: Group 1 (G1, N = 98; 48 boys and 50 girls), from the first year of elementary education; Group 2 (G2, N = 38; 15 boys and 23 girls), from the second year of elementary education; Group 3 (G3, N = 40; 25 boys and 15 girls), from the third year of elementary education. Significant differences (p < 0.001) were found in agility ability among the groups and between G1-G3 and G2-G3 in the 5 and 15 m sprint. Regarding gender of the students of the same age, significant differences (p < 0.001) between boys and girls in group G1 and G2 were obtained in the 5 and 15 m sprint. The correlation between agility and acceleration was significant but moderate (0.3 < r < 0.7) in all groups (G1, G2, and G3), in most cases. When the gender factor was included, the results were heterogeneous. Assessing this correlation according to age and gender produced heterogeneous results. For this reason, we think that both are independent qualities and that age and gender are two factors that influence the correlation results. PMID- 25144985 TI - Demographic, anthropometric and socioeconomic characteristics of functional constipation in Eastern Croatia. AB - Aim of the research is to establish the prevalence of constipation in Osjecko baranjska County, to establish its specific characteristics and to determine the effect of demographic, anthropometric and socioeconomic factors. It is a cross sectional study conducted in 2010. on systematic sample of 900 subjects between 20 and 69 years of age. Every subject was sent an invitation letter and a Rome III diagnostic questionnaire for one of the disorders. A scoring algorithm was used to confirm or exclude the diagnosis of functional constipation. The chi square test (chi2 test), t-test and logistic regression were used for analysis. The prevalence of constipation in our study was 22.19%, which is higher than the prevalence in most other countries, where it ranges from 5% to 18%. In our study statistically significant variables were: place of current residence (urban), education level (high school), marital status (divorced people), a larger number of household members and a lower health status by self-assessment. According to t test persons with constipation on average are older, have higher average BMI and lower average grade valued financial status of households and their health. There were a greater number of subjects that had at least one alarm symptom or some of the psychosocial factors and they often suffered from a chronic disease. Functional constipation presents a significant health problem. Rome III survey questionnaire proved to be an acceptable method for diagnosing this functional disorder in clinical-consilliary and primary health care, and for persons showing signs of alarm and needing further diagnostic treatment. PMID- 25144986 TI - The evolvement of the renographic curve pattern in early childhood. AB - The purpose of this study was to evaluate renographic parameters obtained from healthy renal units (RUs) in newborns and infants with unilateral kidney condition. Thirty three children including twenty newborns, referred to Technetium-99m mercaptoacetyltriglycine (Tc-99m MAG3) diuretic scintigraphy due to unilateral kidney condition entered the study. Only contralateral, healthy RUs were analyzed. Since many children returned for follow up, there were altogether 78 dynamic studies included. Kidney length was compared to ultrasound measurements. Renographic curve parameters (time to maximum counts, T max and time to half maximum counts, T1/2 max) were evaluated. The results showed that the kidney length measured on Tc-99m MAG3 scintigraphy correlated well with ultrasound measurements. Regarding the renographic curve parameters, in the newborn period a significantly shorter T max (mean T max 3.65 +/- 1.2 min, p = 0.026) was found compared to the group of two months old infants (5.12 +/- 2.2 min). In older age groups mean T max gradually shortened again. On the contrary, T1/2 max was significantly longer in newborn and early infant period than in older age groups (16.7 +/- 8.2 min, p = 0.018), but generally showed variable values until the age of three years. It can be concluded that it is important to be aware of possible diversities of renographic curve pattern of healthy kidneys in early childhood, especially in the elimination part. Therefore, when interpreting a dynamic renal study, one should also consider other parameters like kidney growth, morphology and differential function, which can be reliably monitored with repeated Tc-99m MAG3 scintigraphy, to discern between normal and pathologic finding. PMID- 25144987 TI - Association between socioeconomic status and obesity in children. AB - The perception of obesity among people has not changed significantly regardless numerous public educational programs. Reasons for obesity pandemics are numerous and complex, but can be mostly resumed to life-style changes. The aim of this research was to determine connection between socioeconomic factors and obesity with children of our region. Study included pupils aged 7-8 from 19 first grades in 8 primary schools in Osijek-Baranya County. Body height and weight were measured and socioeconomic data status were collected. Socioeconomic status included data on marital status, educational level, employment, number of children in the family, kindergarten attendance and urban/rural location and also smoking habits of parents. BMI was calculated as a parameter for obesity assessment according to Croatian reference values. Total of 372 children were measured. There were 6.5% of overweight children (BMI between 90th and 97th percentile) and 2.4% of obese children (BMI above 97th percentile). The prevalence of obese children in our research was 8.9%. Obesity is not influenced by rural/urban residence, marital status of parents, number of children in the family, mother's education, or by parents' smoking habits. Positive correlation between obesity and father's education and parents' unemployment was found. Available literature data, same as our study, did not show consistent association between socioeconomic factors and obesity with children. Contradictory results of different studies can be a result of a small sample, difference in study design and different criteria for defining categories within investigated socioeconomic factor. PMID- 25144988 TI - Sex ratio at birth in Croatia: update. AB - There is strong evidence that the sex ratio at birth is partially determined by environmental and social factors. The modern change in those factors serves as an explanation for the secular decline in sex ratio at birth in most of the industrialized countries. This article is the reexamination of the results from my previous communication in which no trend in sex ratio at birth was established for the Croatian data from 1946 to 2007. The data for the years 2008 to 2011 were added, which didn't result with the detection of a significant change in sex ratio at birth by the regression analysis or by the Box-Jenkins time series analysis. Although the numerous factors associated with the decline in sex ratio at birth did occur during the studied period (e.g. increased exposure to the environmental pollution through food, air and water, the rise of the obesity and diabetes incidence, the economic crisis etc.), it appears that none of them made the measurable impact on sex ratio at birth. Also, the possible marginally significant decline in sex ratio at birth could be the result of a high sex ratio at birth immediately after the World War II. The results of this study caution against rapid generalization of the factors found to influence the sex ratio at birth in the epidemiological and clinical studies on the population level data. PMID- 25144989 TI - Irritable bowel syndrome in Croatia. AB - There are three epidemiological studies of irritable bowel syndrome (IBS) that were conducted in Croatia (in the area of Zagreb in 2002, Bjelovarsko-bilogorska County in 2008, and finally in Osjecko-baranjska County in 2011). The aim of this study is to analyze the anthropometric, demographic and socioeconomic characteristics of IBS in Croatia comparing these three studies. The studies included a questionnaire based on Rome criteria. Study population matched the adult population of Croatia according last available census (1991, 2001 resp.). Studies showed a high prevalence of IBS and some common factors relevant for development of IBS were determined such as gender, body mass index and lower level of education. There is a need for further investigations in coastal Croatia applying a uniform questionnaire on anthropometric, demographic and socioeconomic characteristics of IBS and Rome III criteria, diagnostic questionnaires and scoring algorithm for functional gastrointestinal disorders developed by Rome Foundation applicable in clinical practice and population studies, regarding the significant high prevalence of IBS in our country. PMID- 25144990 TI - Surgical treatment of prolactinomas--our experience. AB - The dilemma of whether to apply surgical or drug treatment to prolactinomas has been ongoing for the past 30 years. The aim of this study is to compare the early postoperative values of prolactin (PRL) in two groups of patients with prolactinomas: those who underwent primary surgical-treatment, and those who underwent surgery after a dopamine agonist (DA) therapy. We present the results of surgical treatment on a series of 161 patients with prolactinomas. Surgery was the primary treatment in 65 patients, while 96 patients had surgery following a long-term treatment with a DA. All surgically treated prolactinomas were operated in the standard transsphenoidal, microsurgical approach. The criteria for hyperprolactinemia remission was a PRL level under 25 ng/ml. Early normalization of PRL was achieved in 92% of those patients who underwent primary surgical treatment, yet it was achieved in only 42% of patients who were operated on after receiving a long-term drug treatment with a DA. The highest prevalence of postoperative normalization of PRL was achieved in a group of patients with microadenomas who were primarily operated on (98%). The worst results in postoperative normalization of PRL were found in the group of patients with macroadenomas who received a long-term drug treatment with a DA first. These results show our surgical experience in treating prolactinomas. Using surgical treatment, the best clinical outcome was achieved with microprolactinomas and intrasellar, well-confined macroprolactinomas. Nevertheless, we stress the need of an individualized approach and recommend treatment in multidisciplinary centres for pituitary diseases. PMID- 25144991 TI - Laparoscopic surgery for large hydatide liver cyst after two previous laparotomies. AB - Laparoscopic surgery for hepatic echinococcosis is a technically difficult and demanding surgical procedure even for the most experienced abdominal surgeon. Surgery is performed after the conservative treatment with albendazole for 28 days. We report a case of laparoscopic partial pericystectomy with biliostasis and omentoplasty in a patient with two previously open surgeries (laparotomies)- right subcostal laparotomy for acute inflammation of the gallbladder and right pararectal laparotomy for perforated gangrenous appendix. The patient underwent extensive laparoscopic adhesiolysis due to pronounced intra-abdominal adhesions to gain access to a large hydatid cyst with the diameter of 11 cm. Laparoscopic surgery is much less traumatic to the patient with a better cosmetic effect. PMID- 25144992 TI - Effect of unilateral ureteral obstruction and anti-angiotensin II treatment on renal tubule cell apoptosis and interstitial fibrosis in rats. AB - Unilateral ureteral obstruction (UUO) results in a number of pathophysiological and morphological changes in the renal parenchyma, including interstitial inflammation and fibrosis, apoptotic changes of tubular and interstitial cells. Recent studies have indicated an association between renin-angiotensin system and apoptotic alterations in the kidney after unilateral obstructive nephropathy. In this study, the effect of ACE inhibitors and AT1 receptor antagonists on tubular cell apoptosis and interstitial fibrosis in obstructive nephropathy after UUO in rats was investigated. The study was conducted on Wistar rats with unilaterally ligated ureter and sham operated animals (control group). The rats with UUO were treated with ACE inhibitor (cilazapril) or AT1 receptor antagonists (losartan) and control group was treated with H2O. Sham-operated animals were treated in the same way. Tubular and interstitial cell apoptosis was detected morphologically by hematoxylin and eosin (HE) staining and terminal deoxynucleotidyl transferase mediated nick end-labeling (TUNEL). The area of intersitial fibrosis was determined using computer-assisted image processing after Gomory silver impregnation of paraffin sections. All experimental animal groups with unilateral ureter ligation showed a significantly increased number of apoptotic tubular and interstitial cells in the obstructed kidney compared with the contralateral, unobstructed kidney. Histomorphometric analysis of renal interstitial fibrotic changes in the groups of rats treated with losartan or water showed a statistically significant difference (p < 0.05) between the operated and sham- operated animals. In conclusion, following UUO there is a significantly increased number of apoptotic tubular cells and interstitial fibrosis in the ipsilateral kidney compared with the contralateral kidney. ACE inhibitors and AT1 receptor antagonists could not decrease the extent of renal cells apoptosis and interstitial fibrosis after UUO. PMID- 25144993 TI - A study on utilization of oral contraceptives in the City of Zagreb (2008-2010). AB - Main aim of this study is to quantify and analyze the utilization and utilization trends of oral hormonal contraceptives in the City of Zagreb, 2008-2010, and to propose potential interventions, if necessary. Data gathered from Zagreb pharmacies were assessed by Anatomical Therapeutic Chemical Classification of drugs and Daily Defined Dose methodology. An alarming decrease in total utilization of hormonal contraceptives by 76% from 2008-2009 was found as the main result of this study. A major decrease by 95.5% in utilization of G03AB04 subgroup, sequential combined oral contraceptives, was noted in the year 2009. The subgroup G03AC0, progesterone-only pill group, showed a stable trend, and it became the most utilized subgroup in 2010, due to the decrease in utilization of both fixed and sequential combined oral contraceptives. Utilization of oral contraceptives in Croatia is not regulated adequately, since such dynamics in utilization can occur unnoticed. Measures need to take place in order to improve this situation. Proposed measures include organized farmacovigilance, prescription based on guidelines, and strict screening for risk factors in women seeking oral contraception. More research is required in Croatia to understand the pattern of utilization of hormonal contraceptives and to find the true cause of decrease in utilization of oral contraceptives. PMID- 25144995 TI - Bone remodeling after supracondylar humeral fracture in children. AB - The aim of this study was to evaluate bone remodeling in treated supracondylar humeral fractures in children. The study was carried out at the Department of Pediatric Surgery of University Hospital Rijeka on 58 patients with an average of 6.2 years, followed up during 1 to 7 years. The Baumann angle of the humerus was measured by five observers on the anteroposterior radiographs of the injured elbow right after the surgery, and on routine follow-up. The results obtained were compared with the results of the Baumann angle on the healthy arm, and statistically processed. There was a significant difference in number of cases that showed an increase of Baumann angle, when related to cases with no change of the angle or its decrease. The mean value change of Baumann angle in cases of its increase was 4.22 degrees and in cases of its decrease 2.65 degrees. Because of relatively low mean values of the angles of remodelation, we concluded that an adequate reduction is essential to prevent malunion in supracondylar humeral fractures. PMID- 25144994 TI - Imbalanced concentrations of serum lipids and lichen planus. AB - The aim of this study was to analyze possible connection between the lichen planus and imbalanced concentrations of serum lipids and to evaluate the impact of various dietary regimes (used in the regulation of imbalanced concentrations of serum lipids) on the regression of lichen planus lesions. Research was conducted as a case-control study comprised of 72 patients with Lichen Planus and 30 participants from control group, treated at the Clinic for Dermatology and Venereology of the Clinical-Hospital Centre Osijek, Eastern Croatia, during 2010 and 2011. LP cases were diagnosed with both a clinical examination conducted by a dermatovenerology consultant and by patohistological diagnostic. Serum lipid levels (total cholesterol, LDL-cholesterol, triglycerides, HDL-cholesterol) were determined by the classic laboratory diagnostics in both investigated groups (LP patients and control group). The present study has confirmed that there is a strong connection between the imbalanced concentrations of one or more serum lipids (cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides) and the occurrence of LP which is important in the therapeutic approach to patients with this disease. PMID- 25144996 TI - Patient satisfaction after revision hip arthroplasty or resection hip arthroplasty due to periprosthetic infection. AB - In this retrospective study we have analysed 10-year period results of all type periprosthetic hip joint infection treatments at our Department. Data for 73 patients were analysed and functional status for 41 patients evaluated. A smaller proportion of patients (45%) with resection arthroplasty as the definitive solution were satisfied. These were mostly females with numerous comorbidities and lower functional demands. Much better results were achieved in 2-stage revision arthroplasty group. In conclusion whenever possible revision arthroplasty should be done because probability of re-infection is much lower than was previously believed, and the functional status of patients and their general life satisfaction is much higher. PMID- 25144997 TI - Value of cytology in small cell lung carcinoma diagnostic--single-center study. AB - Small cell carcinoma of the lung (SCLC) together with the large cell neuroendocrine carcinoma (LCNEC), typical carcinoid (TC), and atypical carcinoid (AC) make a group of morphologically identifiable neuroendocrine tumors. The differential diagnosis of SCLC includes, first of all, other neuroendocrine tumors, and primary or metastatic non-small cell carcinomas. Although the criteria for the morphologic separation from other tumors of the lung are defined, in everyday practice it can be a problem, both in cytology and with histological samples. Accurate and early differentiation of the SCLC is important because it exhibits aggressive behavior, rapid growth, early spread to distant sites, but also exquisite sensitivity to chemotherapy and radiation. The study included 127 patients who underwent bronchoscopic examination or percutaneous transthoracic fine-needle aspiration (PTTFNA) during the period from early 2003 to 2007 in University Hospital Center Osijek whose cytological diagnosis was SCLC. The value of cytological diagnosis was determined by comparing it with histological findings obtained from a biopsy sample during bronchoscopy or on a resection specimen in 50 patients. In the remaining 77 patients, histological verification of cytological diagnosis was not made and the patients were treated based on cytological diagnosis of small cell carcinoma. In 76% of cases (38/50) cytological diagnosis of small cell lung carcinoma was also confirmed histologically. In 8% of cases (4/50) adenocarcinoma was histologically confirmed, in 10% (5/50) of the cases the squamous carcinoma was confirmed, and there was one case of urothelial carcinoma, one case of sarcoma and one undifferentiated carcinoma. Cytological diagnosis of SCLC was made in all cases in a brush smear while the catheter aspirate was positive in only 32 cases (25.8%). Median survival in the group of patients with histologically confirmed small cell cancer was 238 days, for women 250 days, and for men 237 days. Cumulative survival was 63.2% for 6 months, 26.3% for 12 months, 13.2% for 18 months and 7.9% for two years. In conclusion, cytology is a reliable and relatively non-invasive method for patients. Our results confirm that there is a good correlation between cytology and histology diagnoses, especially when it comes to malignant lesions. In determining the type of tumor cytology must be supported with additional methods, especially in cases when it is not possible to take samples for histological verification. PMID- 25144998 TI - Diagnostic value of cytology of voided urine. AB - There are 961 new cases and approximately 366 deaths from urothelial carcinoma registered annually in Croatia. Exfoliative urinary cytology has important role in detection of high grade urinary tumors, invasive and in situ lesions respectively. In contrast to cystoscopy and biopsy, cytology is a noninvasive method which is easily repeated. The aim of this retrospective study was to assess value of urinary cytology in our institution. For this purpose only patients with histological diagnosis and clinical follow up were considered. There were 138 urine specimens with cytological diagnosis of dyskaryosis, suspicious for malignancy or malignant and histology and follow up data examined at our Department of Clinical Cytology between 2004 and 2011. Cytological diagnosis suspicious for malignancy and malignant were considered positive and the results were correlated with histological diagnosis according to the WHO histological classification of tumors of the urinary tract. Patients with negative histological findings were followed for the next two years. The positive predictive value of cytological detection of malignant urothelial lesions was 91.8%. In 10 cases cytological diagnosis of malignancy was not confirmed histologically or clinically which makes the total of 8.2% of false positive reports. Of the total of detected malignant urothelial lesions 90.9% are high grade lesions and only 9.1% low-grade lesions; 67.3% are invasive lesions and 32.7% non-invasive lesions. Cytological findings of dyskariotyc cells requires further urological investigation because such findings in further processing prove the presence of tumor in 93.8% of cases. In conclusion: cytology is very good diagnostic tool for detection of high grade invasive and noninvasive carcinomas of the urinary tract. In order to make it more efficient we need to study its limits carefully, define diagnostic criteria and reach consensus in nomenclature. PMID- 25144999 TI - Respiratory distress syndrome in newborns of gestational age of over 32 weeks. AB - Albeit the aetiology of the respiratory distress syndrome (RDS) is well known, the paper shall demonstrate that the causes of RDS changed over the years 2006 and 2010. This retrospective study comprises analysis of the data collected from 60 newborns of over 32 weeks gestation with RDS in the Neonatal Intensive Care Unit at the Clinical Hospital Centre in Osijek. The focus of the paper lies in the difference in the incidence of RDS over two research periods (2006 and 2010), the most common and possible causes of RDS in newborns of over 32 weeks gestation as well as in the potential changes in the aetiology over the two research periods. An increase in the incidence of RDS was established in 2010, but it was statistically significant only for newborns of gestational age of 35 1/7 to 36 6/7 weeks. The most common cause of RDS in both research periods was sepsis, which decreased in its share in 2010, whereas the incidence of asphyxia and complications during pregnancy increased. The new potential cause in 2010 was maternal thrombophilia. The share of unknown causes of RDS decreased, although not significantly so. The results of the research indicate that the causes of RDS changed over the observed periods and that further research should focus on thrombophilia and other complications during pregnancy with the aim of reducing morbidity and improving neonatal outcomes as well as further reducing the incidence of RDS with unknown causes in newborns. PMID- 25145000 TI - Malignant neoplasms of respiratory and intrathoracic organs (C30-C39) in the Osijek-Baranja County, Croatia. AB - The Institute of Public Health of the Osijek-Baranja County in collaborate with different county institutes provide updated information on the cancer occurrence and trends in the Osijek-Baranja County (OBC). The cancers were defined according to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10), codes of malignant neoplasms of respiratory and intrathoracic organs (C30-C39). The aim of this article was to show the size of cancer problem with the C30-C39 cancer group in the Osijek-Baranja County (OBC). This article processes data on cancer incidence and mortality, appertaining age distribution, median age, cancer survival and length of stay in hospital collected in period 2001-2009. Out of all patients diagnosed with C30-C39 cancers, there were 18.2% of females and 81.8% of males. The total incidence rate in males (119.5/100,000) decreases while the total mortality rate (110.9/100,000) does not change in 9-year period. In the same period, the total mortality rate in females (15.7/100,000) increase moderately. The age-standardized incidence rate was six times higher in males than in females. The overall median age at diagnosis of C30-C39 cancers of both genders was 64.5 years, which exceeds the average age at diagnosis of cancer in general in the OBC by 4.8 years. Five-year relative survival rate was 14.8%, 19.7% for females and 13.7% for males. Male lung and bronchus cancer patients (C34) were 1 year younger at diagnosis of cancer than the respective female patients. An average C30-C39 cancer patient was hospitalized 2.0 times during the course of their illness while the median length of stay in hospital amounted to 16.1 days. The number of hospital admissions in both genders decreased over the 2001-2009 period. In both genders, the total length of stay in hospitals was slightly reduced. Females spent 0.4 days more in hospital than males. The overall incidence and mortality rate in the OBC were among the highest in Europe. However, these rates in females reached neither the Croatian nor the EU average. Other data are similar to those in Europe. PMID- 25145001 TI - Cardiovascular drugs consumption--comparison between two Croatian regions, City of Zagreb and Lika-Senj County. AB - The aim of this paper is to determine the differences in the outpatient consumption of cardiovascular drugs between Croatian regions: the City of Zagreb and Lika-Senj County. The data on the number of packages and the purchase price for each drug have been obtained from all pharmacies in Lika-Senj County and all pharmacies in the City of Zagreb. Defined daily doses/1000 inhabitants/day (DDD/1000/day) was calculated for every drug in accordance with its code name and Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) index of the World Health Organization (WHO) for 2007. For drug combinations without defined daily doses, equivalent doses (ED) were used. The quality of drug prescribing within the group of cardiovascular drugs was assessed using the Drug Utilization (DU90%) method and the adherence of the DU90% segment to the guidelines for prescribing individual drug groups. The statistical significance of differences in results between the City of Zagreb and Lika-Senj County was tested using the chi-square test at the level of statistical significance p < 0.05. The comparison of the share of the five most often prescribed drug groups in Lika-Senj County has shown statistically significant differences when compared to the City of Zagreb (chi2 = 28.93, df = 4, p < 0.001). The total outpatient consumption of cardiovascular drugs in the City of Zagreb and Lika-Senj County differs significantly. The consumption, quality of prescribing drugs and cost/DDD in the City of Zagreb is higher than in Lika-Senj County; in the City of Zagreb, newer and more expensive drugs are prescribed to a higher extent. PMID- 25145002 TI - The role of antibiotic prophylaxis in preterm premature rupture of membranes. AB - Preterm premature rupture of membranes (PPROM) occurs in 3 percent of all pregnancies and is responsible for, or associated with, approximately one-third of preterm births causing significant perinatal morbidity and fetal death. Preterm infants are very vulnerable to respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), periventricular leucomalacia (PVL), other neurological sequelae, infection and necrotizing enterocolitis (NEC). Chorioamnionitis based on clinical criteria occurs in approximately 3-30% of all PPROM pregnancies. The aim of this study was to analyze the role of antibiotic prophylaxis in delivery delay on neonatal outcome (body weight, Apgar scores, pulmonary complications, neurological complications--abnormal cerebral ultrasound scan prior to hospital discharge, perinatal infections) and to determine the possibility of an optimal antibiotic regimen. Therefore we retrospectively analyzed last 5 years of data from patients treated in our center and provided a coherent overview of the clinical course and outcome of patients with PPROM treated with prophylactic antibiotics and antenatal corticosteroids. There were 324 preterm newborns which fulfilled the inclusion criteria for our study; 190 in Study group (received empiric i.v. antibiotics) and 134 in Control group (without antibiotic). We found significant difference in gestational age (p < 0.0001), birth weight (p < 0.0001), Apgar scores (p < 0.0001) maternal C-reactive protein level (p < 0.0001) and latency period (5.54 days vs. 11.33 days, p = 0.001) between the groups. Histologic chorioamnionitis was significantly more frequent in s Study group (14.2% vs. 36.3%, p < 0.0001). We found significant difference in neonatal outcome according the different antibiotic treatment. Antenatal antibiotics and corticosteroid therapies have clear benefits and should be offered to all women without contraindications. PMID- 25145003 TI - Importance of interleukin 6 in pathogenesis of inflammatory bowel disease. AB - Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is an uncontrolled chronic inflammation of the gastrointestinal tract caused by an interaction of diverse genes and environmental factors. There is growing evidence that cytokine production plays an important role in IBD. One of the key roles in signaling pathway in development of IBD is performed by interleukin 6 (IL-6), although molecular mechanism of this pathway is not yet fully understood. In order to assess the clinical relevance of IL-6 serum concentration in patients with CD and UC we performed cross-sectional, case-control study of IL-6 levels in patients' and healthy blood donors' sera. A total of 100 CD and UC patients and 71 healthy blood donors were investigated. Clinical activity of CD and UC was evaluated using the Crohn's disease activity index and Truelove-Witt's criteria, respectively. Quantitative assessment of serum IL-6 was performed with solid phase, enzyme-labeled, chemiluminescent sequential immunometric assay. Our results indicate that serum IL-6 is a clinically relevant parameter for CD and UC that strongly correlates with inflammatory activity of disease. We confirmed and extended the role of cytokine production patterns for IBD presentation in Croatian population. PMID- 25145004 TI - Peripheral arterial catheter related infections in the neurosurgical intensive care unit. AB - Intravascular device infections could be serious complications with significant contributable morbidity and mortality. The aim of this prospective clinical study is to demonstrate the infection rate related to peripheral arterial catheters and their clinical significance in neurosurgical intensive care unit (ICU) patients. After removal, all arterial catheter tips were cultivated by semiquantitative method and clinical data were collected. During a period of two years, 186 arterial catheters were placed in 105 neurosurgical ICU patients. In 6 cases (3.2%) infection was presumably related to the arterial catheter. The rate of such probable catheter related infections was found to be 5/1000 catheter days. The isolated microorganisms were: Methicillin resistant Staphylococcus epidermidis (MRSE) in 4 cases, Corynebacterium species and Candida albicans each in one case respectively. Thirteen cases (7.0%) were interpreted as contamination and one as colonization. An association was found between the presence of infection from different sources and significant bacterial growth on the catheter. Patients with positive catheter culture had a significantly longer ICU stay, more cumulative catheter days, and a higher mortality rate than those with sterile catheters. We can conclude that the rate of probable peripheral arterial catheter related infection is low. A higher mortality rate in patients who experienced probable catheter related infection does not seem to be a consequence of the aforementioned infection. A more suitable explanation would be that patients with nosocomial infections and higher mortality risk have prolonged ICU stays. There is an increased chance of developing a catheter related infection in those patients who have more cumulative catheter days. PMID- 25145005 TI - Dental caries experience and tobacco use in 19-year-old Croatian army recruits. AB - The aim of this study is to investigate caries prevalence and smoking habit in the population of 19-year-old Croatian male recruits. Dental examination of 505 male recruits was conducted in 2001 in the military centre in Koprivnica. Caries status was described by the FS-T (Filled and Sound Teeth) index and DMFT (Decayed, Missing and Filled Teeth) index. Mean DMFT scores were 7.32 and FST 23.56. There was a significant statistical difference in comparison of smoking habits depending on the reason to visit the dentist (p = 0.001). The subjects who do not smoke tobacco have less decayed teeth (DT index with p < 0.001), and more teeth with fillings and/or sound teeth (FT with p = 0.005 and FST with p = 0.004). There is no statistically significant difference for the DMFT (p = 0.657) and MT (p = 0.703). In conclusion, it showed that FS-T is a more appropriate index for describing variation in the population with higher caries experience. In the population of Croatian recruits, there were an astonishing 58.6% of smokers. PMID- 25145006 TI - Analysis of abutment teeth in partially edentulous patients. AB - The aim of the study was to examine changes in the position of the abutment teeth (AT), size of undercuts for a denture clasp, as well as an existence of an adequate preparation of abutment teeth. A total of 156 casts of partially edentulous jaws, with 460 AT, were analyzed. The size of undercuts, a degree of abutment rotation, inclination and migration were measured using a dental parallelometer. The abutment teeth position was related to the level of occlusal plane in a dental articulator. Furthermore, the existence of an adequate preparation of abutment teeth, as well as a type of a denture and a type of a denture retention element were also considered. Analysis were carried out twice on casts made from a hard stone, the first time before the denture treatment had begun and the second time on the new casts obtained after new dentures had been delivered. The first analysis (prior dental treatment) revealed that a total of 33.9% of the analyzed AT were rotated, 31.3% were inclined, 12.1% had migrated, and 57.3% were elongated above the occlusal plane. On the casts obtained after the new dentures had been made, it was observed that none of the AT had an adequate preparation. Only 37.6% of all retention elements were located in adequate undercut positions on the AT. Upon the results of the present study a conclusion can be established that many abutment teeth are rotated, elongated, inclined, and migrated, which point to a requirement for AT preparation prior the manufacture of new denture; however none of the AT was adequately prepared considering insertion plane and many denture elements were located in an inadequate undercut size. PMID- 25145007 TI - Taekwondo coaches knowledge about prevention and management of dental trauma. AB - The aim of this study was to assess level of knowledge about prevention and dental trauma management among taekwondo coaches in Croatia. The questionnaire submitted to the taekwondo coaches contained 16 items about dental trauma prevention and management. The questionnaires were filled in by 131 taekwondo coaches; 28 females and 103 males. Descriptive statistics was used to describe and analyze the obtained data. The coaches were familiar with dental injuries in high percentage: 41 (31.3%) have observed dental injury and 36 (27.5%) have experienced a dental injury themselves. Eight of them had tooth avulsion, fourteen crown fracture, and eight had tooth luxation. About half of all interviewed coaches 68 (52.7%) were aware of the possibility of replanting avulsed teeth. Twenty six (19.8%) were familiar with the tooth rescue kit. Only 99 out of 131 coaches (75.6%) have used a mouthguard. The obtained results show low knowledge about possibilities for prevention of dental trauma. Insufficient use of mouthguards in this contact sport requires more attention of dentists and coaches education about dental trauma prevention. PMID- 25145008 TI - Trigeminal neuralgia--case and treatment analysis at the Department of Oral Surgery of the University Hospital Dubrava. AB - The aim of the study was to explore certain risk factors for trigeminal neuralgia (TN), assess the prevalence of misdiagnoses of TN made by primary care dentists, compare the treatment practice for TN at the Department of Oral Surgery with the guidelines, and the importance of interdisciplinary approach in TN treatment. The study included 237 patient records (70 men and 167 women, aged 5-91 years) referred to the Department under the diagnosis of TN. From their medical records, demographic data, referral diagnose, clinical diagnose, additional diagnostic procedures and treatment were analysed. Neuralgia of the trigeminal nerve affects predominantly elderly female population, while the impact of the season on the incidence of the disease has not been determined. The most common therapy used at the Department were blockades, carbamazepine or their combination. 63.3% patients were referred for further diagnostic tests following the first examination. The number of misdiagnosed cases referred by primary care dentists (33.6%) points that better training in diagnosing TN is needed for the dental practitioners. The treatment methods at the Department need to be harmonized with the latest guidelines on neuralgia treatment. Due to the complexity of etiological factors, an interdisciplinary approach is necessary. PMID- 25145009 TI - Determining the quality of life after removing of impacted lower wisdom tooth using the principal component analysis method. AB - The main objective of this study was to determine to what extent a detailed oral instruction about treatment after surgical removal of a lower wisdom tooth affects postoperative quality of life (QoL). The research on QoL after removal of a lower wisdom tooth was conducted with 108 patients. Depending on the type of information given to each respondent individually, the examinees were divided into two groups: a test group which was given detailed written and oral instructions, and a control group which received only written instructions about treatment after the surgery. In this research the QoL was examined using modified Oral Health Impact Profile-14 (OHIP-14) criterion four, seven and thirty days after the operation depending on the type of information previously provided to the respondents. In order to reduce the dimensionality of the obtained data sets, as well as in order to explain the relationship between the examined variables that are interrelated the principal component analysis (PCA) was applied. Both groups expressed satisfaction with the postoperative period for the individual variables investigated in modified OHIP-14 questionnaire, with the intensity and the order of the major components of satisfaction determined by the PCA differing between the two groups of the patients. On the fourth postoperative day, the test group expressed the highest level of satisfaction with sleep, physical appearance and the ability to eat. In the later postoperative period the test group (on the seventh and thirtieth day) had the highest level of satisfaction with the absence of discomfort during removal of sutures, satisfaction with performed treatment, and the ability to eat. Detailed preoperative oral instructions to patients can significantly improve the quality of life after operative removal of a lower wisdom tooth. PMID- 25145010 TI - Alzheimer and Lewy body pathology or Creutzfeldt-Jakob disease. AB - The objective of this work is to describe the neuropathological findings of a patient clinically presenting with rapidly progressive nonspecific neurological symptoms suggestive of Creutzfeldt-Jakob disease. Methods used were clinical description with laboratory analyses, repeated electroencephalogram, cerebral computed tomography, magnetic resonance imaging studies and details on neuropathological work-up. Neuropathological examination excluded Creutzfeldt Jakob disease. By contrast other neurodegenerative changes combining Alzheimer type pathology and Lewy body pathology were detected as the most likely substrate of neurological symptoms. Dementia with Lewy bodies should be included in the differential diagnosis in individuals presenting with rapidly progressive dementia. PMID- 25145011 TI - Information retrieval and terminology extraction in online resources for patients with diabetes. AB - Terminology use, as a mean for information retrieval or document indexing, plays an important role in health literacy. Specific types of users, i.e. patients with diabetes need access to various online resources (on foreign and/or native language) searching for information on self-education of basic diabetic knowledge, on self-care activities regarding importance of dietetic food, medications, physical exercises and on self-management of insulin pumps. Automatic extraction of corpus-based terminology from online texts, manuals or professional papers, can help in building terminology lists or list of "browsing phrases" useful in information retrieval or in document indexing. Specific terminology lists represent an intermediate step between free text search and controlled vocabulary, between user's demands and existing online resources in native and foreign language. The research aiming to detect the role of terminology in online resources, is conducted on English and Croatian manuals and Croatian online texts, and divided into three interrelated parts: i) comparison of professional and popular terminology use ii) evaluation of automatic statistically-based terminology extraction on English and Croatian texts iii) comparison and evaluation of extracted terminology performed on English manual using statistical and hybrid approaches. Extracted terminology candidates are evaluated by comparison with three types of reference lists: list created by professional medical person, list of highly professional vocabulary contained in MeSH and list created by non-medical persons, made as intersection of 15 lists. Results report on use of popular and professional terminology in online diabetes resources, on evaluation of automatically extracted terminology candidates in English and Croatian texts and on comparison of statistical and hybrid extraction methods in English text. Evaluation of automatic and semi-automatic terminology extraction methods is performed by recall, precision and f-measure. PMID- 25145012 TI - Depression, anxiety and cognitive dysfunction in patients with type 2 diabetes mellitus--a study of adult patients with type 2 diabetes mellitus in Osijek, Croatia. AB - Aim of the study was to determine the rate of depression and anxiety in the patients with diagnosed Type 2 Diabetes mellitus (DM), and also to determine the state of the congnitive functions in patients with Type 2 Diabetes mellitus compared with the control group. Study was designed as a epidemiological cross sectional study, sample consisted of 108 patients, 66 of the patients were diagnosed with Type 2 Diabetes mellitus, and 42 were control group. All of them were interviewed by psychiatrist and tested through clinical interview with Hamilton depression rating scale, Hamilton Anxiety rating scale, Mini mental state examination and questionnaire about sociodemografic data. Results show that group of patients with DM were statistically significant more depressed than the control group of the patients (p = 0.035). Pathological anxiety measured by Hamilton Anxiety Rating Scale (HAM-A) appeared in 34 DM patients and 7 of the patients in control group, which is also statistically significant difference (p = 0.002). Evaluation of the cognitive status done with Mini Mental State Examination (MMSE showed us the patients with DM presented more cognitive dysfunctions compared with the control group. We can conclude that the high prevalence of psychiatric disorders in diabetic patients points to the need for greater investment in appropriate diagnostic evaluation of patients that consider mental issues. PMID- 25145014 TI - Political myths and totalitarianism: an anthropological analysis of their causal interrelationship. AB - This paper discusses the key political, anthropological and socio-cultural functions of political myths in the appearance and functioning of totalitarian regimes. A special emphasis is put on structural elements of the myth (mythemes) and the mythic content (narratives) in the processes of artificial construction of a new society (community) based on the myth-inspired ideological postulates. The paper argues that the establishment of totalitarianism marked a certain anthropological devolution. This devolution, in turn, proceeds through the deconstruction of civil society as an organic social sphere and the artificial construction of a new political community based on ideological postulates and political myths. In support of this assertion, it is first shown how the mythical narratives--transformed into political concepts and programs--were the basis of (re)interpretation of the world, society and individual, and essentially determined the nature and functioning of the totalitarian regimes. Then, the specific political myths are analyzed and compared, as well as their content and origin, and particularly their dual function. It in turn is analyzed in the framework of the classical society-community dichotomy, where the (civil) society is founded socio-politically on the social contract, and the (political) community socio-anthropologically on political myth. In a situation of identity and legitimacy crisis, anomie and the weakening of social cohesion--the characteristic conditions of the great economic and political crisis of the early twentieth century that enabled the emergence of totalitarianism--society as a contracting community does not work. A strong need for meaning (at the individual and societal level) affects the citizens' susceptibility to (political) concepts of (re)constitution of (political) community with which they can identify. Right there, totalitarian movements use the cohesive power of the political myth that replaces the rationally based constitution of society, and becomes a means of ideological mystification and political manipulation. Affecting the mind of the citizens, it moves their feelings and motivations and directs their behavior toward the goals of the totalitarian political power. Recent iterations of totalitarianism (Great-Serbian aggression), with the same tragic consequences, were a warning on the actuality of political myths and the danger of a resurgence of totalitarian tendencies. PMID- 25145013 TI - A study on the quality of outpatient prescription of psychopharmaceuticals in the City of Zagreb 2006-2009. AB - The lack of Croatian studies which could determine the justifiability of excessive psychopharmaceutical utilization was an encouragement to conduct this research. Furthermore, regarding the conduction of this study, it would be possible to determine whether the trend of drug utilization has increased, decreased or perhaps stabilized. The data on the outpatient utilization of psycholeptics and psychoanaleptics were collected from all Zagreb pharmacies, 2006-2009. Based on the collected data for all N05 and N06 groups of drugs, the defined daily doses (DDD) and DDD per thousand inhabitants per day (DDD/TID) have been calculated using the Anatomical-Therapeutic-Chemical classification (ATC) for 2006, 2007, 2008 and 2009. To indicate the quality of drug prescription the Drug Utilization 90% (DU 90%) method was used. Moreover, in order to determine a more precise quality of individual drug group prescriptions, the indicators have been calculated by determining the proportion of the total utilization of individual therapeutic and pharmacological therapeutic subgroups in DDD/TID a day. The utilization of anxiolytics (N05B) accounts for most of the psycholeptic utilization in the City of Zagreb throughout the entire study period. In the study period, the utilization of antidepressants has slightly increased, by 10.5%, taking the first and the last years of the period into account. In 2006, 5 benzodiazepines and the hypnotic zolpidem, as well as 5 selective serotonin reuptake inhibitors (SSRIs) and 1 third generation antipsychotic (olanzapin) were found in the DU 90% segment. In 2009, the DU 90% segment also comprised 5 benzodiazepines and the hypnotic zolpidem, as well as 6 SSRIs and 1 third generation antipsychotic (olanzapin). In the City of Zagreb, a general insight into the quality of psychopharmaceutical prescriptions indicates stability in comparison to earlier studies. The ratio index of the first generation antipsychotic utilization, compared to the third generation antipsychotics, shows an increase in the quality of prescription. Also, the ratio index of total tricyclic antidepressants (TCA) and SSRI utilization indicates improvement in quality of prescription. The ratio index of the entire outpatient utilization of anxiolytics and antidepressants expressed in DDD/TID unfortunately shows a very mild increase of prescription quality. Benzodiazepines accounted for more than 50% of the outpatient utilization of psychopharmaceuticals throughout the study period, which proves the need for precise guidelines as the most significant means of drug rationalization and utilization. It is necessary to identify priorities and problems in order to solve them successfully, by monitoring drug utilization and prescription on a national level. Results demonstrate that within the primary health care system, there is a need for constant education on rational prescription of this drug group. PMID- 25145015 TI - The inscription of medicus of the XIth legion from Burnum. AB - The archaeological site at Burnum is the subject of scientific research conducted since 2003 in the area of the ancient agglomeration by the members of the Chair of Ancient Archaeology of the Department of Archaeology of the University of Zadar, accompanied by partners--Krka National Park, City Museum of Drnis and Laboratory of Archaeological and Topographic Survey of the Department of Archaeology of the University of Bologna. Epigraphic and onomastic analysis of known inscriptions has one of the main roles within the interdisciplinary studies and, in a matter of study of a mere site, is in the scientific focus since the 19th century. Since Burnum becomes a military stronghold at the beginning of the 1st century AD on which legionary and auxiliary forts have been built, it is not surprising that the majority of the inscriptions are mentioning soldiers of units that have been placed at Burnum. Majority of the inscriptions mention the soldiers of the XIth legion--a unit which was stationed at Burnum from 10 to 69 AD. This article deals with another piece of epigraphic evidence of the military personnel of the XIth legion in the province of Dalmatia, where a military physician (medicus legionis XI) has been confirmed for the first time. It is very important to mention that we are dealing with the oldest known physician who held his medical service on the territory of the Roman province of Dalmatia. PMID- 25145016 TI - Spondylolisthesis in an Etruscan woman from Spina (Ferrara, Italy): an iron age case report. AB - Spondylolisthesis consists of the slippage of a vertebra in relation to the one beneath. It is caused by separation of the neural arch from the vertebral body (spondylolysis), and predominantly occurs at the isthmus (pars interarticularis). Originally thought to be a congenital anomaly, its strict correlation with certain activities that seem to exert stress on lower spine was later demonstrated. This paper describes a case of progression of spondylolysis to spondylolisthesis found on an adult female skeleton from the Etruscan necropolis of Spina (Ferrara, Italy). The case in question was identified among 209 skeletons exhumed at Spina. As spondylolisthesis is strictly connected with activities that exert stress on lower spine, the evidence suggests that this woman was engaged in stressful physical activity, perhaps related to the specific trade function of the site. PMID- 25145017 TI - Skeletal remains from late Roman period: "as old as Diocletian's Palace". AB - In 2000, human skeletal remains were discovered in Split (Croatia). As archaeologists confirmed, it was an ancient skeleton accompanied by ceramics and bracelet characteristic for late Roman period whose possible violent death was excluded. The bone sample was radiocarbon dated by AMS to 1750 years. DNA was successfully extracted from the bone sample and subsequently typed using mt DNA and STR systems. The metal content was determined by atomic absorption spectrometry (AAS) in flame mode. Mercury concentration was determined by direct consecutive measures taken with a mercury analyzer. According to our results, we consider that the bones could belong to the one of the last citizens of the Diocletian's Palace. PMID- 25145018 TI - Camurati-Engelmann disease in a family from Croatian Island: an old bone scan confirmed pattern of inheritance. AB - 34-year old patient had history of muscular wasting, easy fatigability, pain in extremities and waddling gait since age of four. During the time, neuromuscular disease was suspected, but not confirmed. Elevated bone alkaline phosphatase as well as other bone turnover markers (osteocalcin, procollagen, telopeptide) indicated further skeletal evaluation. Symmetrical enhanced uptake on technetium methylene diphosphonate [99mTc]MPD bone scintigraphy at diaphyses of longitudinal bones and scull matched cortical thickening of long bones and sclerosis of the scull seen at radiograms. Those findings pointed to Camurati-Engelmann disease misdiagnosed for the long time. This rare genetic autosomal dominant disorder was retrospectively diagnosed in asymptomatic father too on the basis of bone scans done long time ago. Old family member scans confirmed heredity pattern of the disease. PMID- 25145019 TI - Partial monosomy 2p and partial trisomy 4q due to paternal translocation t(2;4)(p25.1;q31.3). AB - Clinical features in patients with segmental aneuploidy often vary depending on the size of the chromosomal segment involved. Monosomy 2p is usually observed as a part of more complex syndromes among probands of balanced reciprocal translocation carriers. Patients with dup4q syndrome have variable clinical features, which are both related to the size of duplicated segment of the 4q and specific associated monosomy. Clinical findings of our patient were compatible with those previously reported in dup4q and del2p patients. Herein are presented the clinical and cytogenetic findings in a 4-year-old female with an unbalanced karyotype 46,XX,der(2)t(2;4)(p25.1;q31.3)pat. Clinical phenotypes of 2p;4q translocation cases are variable, because the involved breakpoints vary case-by case. We also compare similarity of the clinical features of our proband and other patients carrying either duplication of the distal part of 4q and patients carrying a deletion of distal part of 2p as described in the literature. To our knowledge, this is the first case of partial trisomy 4q accompanied with partial monosomy 2p. PMID- 25145020 TI - Leiomyosarcoma of the spermatic cord with scalp metastasis: case report and literature review. AB - Herein we present 82-year-old man with leiomyosarcoma arising from the spermatic cord with scalp metastasis, five years after primary surgical treatment. Complete surgical excision is required in such cases, as well as precise evaluation of further therapy. Paratesticular leiomyosarcoma is a rare entity, malignant mesenchimal tumor of smooth muscle differentiation. Although leiomyosarcomas of different localizations have well-known metastatic potential, cutaneous metastases are extremely rare with only 16 cases described in the literature. To our knowledge there are no reported cases of the paratesticular leiomyosarcoma metastatic to the skin. This article reviews the literature regarding paratesticular leiomyosarcoma presentation, diagnosis and treatment. PMID- 25145021 TI - Osteogenesis imperfecta--multi-systemic and life-long disease that affects whole family. AB - Osteogenesis imperfecta or brittle bone disease, a heritable disorder of connective tissue, is the most common of the inherited disorders primarily affecting bone. There are approximately 400 individuals with OI in Croatia alone. It is estimated that twice that number is present, represented by individuals with mild OI in whom the diagnosis has not been made. Due to the relatively low number of patients in the general population, treating physicians have limited experience with this disease, either with children or adults. The basis of this disease in European populations is mostly the result of defects in the structure or processing of collagen type I, an important protein of the extracellular matrix of many tissues. Presently, molecular defects in 16 different genes have been discovered to result in at least one type of OI of which 14 are not COL1 mutation loci. Although fractures occurring with no injury or minor injury are the hallmark of OI, other non-mineralized tissues can be affected as well and the pathological changes can be present in skin, tendons, eyes, teeth and blood vessels. Clinical manifestations are very heterogeneous and numerous signs and symptoms such as blue sclera, deafness, abnormal teeth development, joint hypermobility, increased risk of hernias, capillary fragility, aneurysms etc. Although there is no cure for this disease, there are specific therapies that can reduce the pain and complications associated with OI. The purpose of this review is to provide a brief overview of the molecular basis of this disease, describe clinical presentations, as well as to present orthopaedic therapeutic modalities for the patients with OI. PMID- 25145022 TI - The life and work of Ksenija Atanasijevic (1894-1981)--psychology and anthropology as the inevitability and necessity of philosophy. AB - Ksenja Atanasijevic (1894-1981) was the first woman in Serbia to obtain a Ph.D. in philosophy. Going through numerous psychological metamorphoses in her lifetime and confronted with numerous challenges, Ksenija Atanasijevic developed a specific philosophical-psychological system of consolation prominently featuring the concepts of happiness, bliss, moderation, courage and wisdom. Modifying the original teachings of Democritus and Epicurus, Ksenija Atanasijevic developed a distinctive anthropology based on confrontation with but equally the overcoming of obstacles, both internal (spiritual) as well as external ones. The philosopheress developed a reflexive and indeed metaphysical defensive psychotherapeutical skill at the root of which was cleansing the soul, as well as dedication to the realm of fancy, fantasy and imagination. Ksenija Atanasijevic also had precious literary talent which was best expressed in her analyses of the poetry and prose of great Serbian writers (Pandurovic, Njegos, Nastasijevic, etc.). It is quite certain that this, with Anica Savic-Rebac, definitely greatest Serbian philosopheress, through personal suffering, creative solitude and shrouded desperation built an utterly authentic and harmonious system of philosophical comfort. PMID- 25145023 TI - Human papillomavirus-related diseases of the female lower genital tract: oncogenic aspects and molecular interaction. AB - The causal role of human papillomavirus (HPV) in all cancers of the uterine cervix has been firmly established biologically and epidemiologically. Most cancers of both the vulva and the vagina are also induced by HPV. Papillomaviruses are perfectly adapted to their natural host tissue, the differentiating epithelial cell of skin or mucosae, and exploit the cellular machinery for their own purposes. The infectious cycle is initiated once the infectious particles reach the basal layer of the epithelium, where they bind to and enter the cells. The critical molecules in the process of virus replication are the viral proteins E6 and E7, which interact with a number of cellular proteins. In experimental system these interactions have been shown to induce proliferation and eventually immortalization and malignant transformation of cells. Binding of E7 to pRb activates the E2F transcription factor, which then triggers the expression of proteins necessary for DNA replication. Unscheduled S phase would normally lead to apoptosis by the action of p53. However, in HPV infected cells, this process is counteracted by the viral E6 protein, which targets p53 for proteolytic degradation. Besides blocking p53 function in regulation of apoptosis, high-risk HPV proteins interact with both extrinsic and intrinsic apoptotic pathways. As an aberration of virus infection, constant activity of the viral proteins E6 and E7 leads to increasing genomic instability, accumulation of oncogene mutations, further loss of cell-growth control and ultimately cancer. The immune system uses innate and adaptive immunity to recognize and combat foreign agents that invade the body, but these methods are sometimes ineffective against human papillomavirus. HPV has several mechanisms for avoiding the immune system. Furthermore, HPV infections disrupt cytokine expression with the E6 and E7 oncoproteins, particularly targeting the expression of interferon genes. Approximately 10% of individuals develop a persistent infection, and it is this cohort who is at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma. PMID- 25145024 TI - Holistic approach to human health and disease: life circumstances and inner processing. AB - Human body is dinamic, energetic system under the influences of food intake, environment, interpersonal relationships, inheritance, culture and human activities. The environmental and psychosocioeconomic factors affect the individual's health altering the performance of biological systems effecting disease risk and disease progression. The concerns in modern society are more and more devoted to stress and its influences on health. Life span is extended but the quality of life, well-being and productivity usually do not follow that extention. Body is a flow of energy and dynamic communications with inside and outside environment. The way to improve health is to address its social determinants. Only in sinergy the questions about disease and health could be better understood. It is not enough to diagnose illness, important is to diagnose circumstances and environmental influences that consequently lead to disease. Emotional disruptions make base for physical disruptions. Social gradient and stress involving personal life and work is a significant factor in physical and mental illness. The best indicator of the successful social policy result is the sense of well-being of the inhabitants. Holistic approach to a patient and discussions about the influences in patient's life can lead to a better health outcome. Anthropology studies people's habits, means and conditions of life and can be the bridge between the medicine and the life circumstances that put people's health at risk providing important insights into health and disease and assist in public health policies, preventive measures and health improvement of the populations. PMID- 25145025 TI - Dumping and illegal transport of hazardous waste, danger of modern society. AB - Increasing the production of hazardous waste during the past few years and stricter legislation in the area of permanent disposal and transportation costs were significantly elevated above activities. This creates a new, highly lucrative gray market which opens the way for the criminalization. Of great importance is the identification of illegal trafficking of hazardous waste since it can have a significant impact on human health and environmental pollution. Barriers to effective engagement to prevent these activities may vary from region to region, country to country, but together affect the ability of law enforcement authorities to ensure that international shipments of hazardous waste comply with national laws and maritime regulations. This paper will overview the legislation governing these issues, and to analyze the barriers to their implementation, but also try to answer the question of why and how this type of waste traded. Paper is an overview of how Croatia is prepared to join the European Union in this area and indicates the importance and necessity of the cooperation of all of society, and international organizations in the fight with the new trend of environmental crime. PMID- 25145026 TI - In memoriam. Vida Brodar (15.07.1925, Maribor - 24.04. 2014, Ljubljana). PMID- 25145027 TI - Ensuring fairness in medical account resolution. PMID- 25145029 TI - Determining who should oversee meaningful use. AB - Although initial efforts to achieve meaningful use of electronic health records often were launched by key technical staff, these individuals may not be the best suited to manage a meaningfuluse program over the long term. The quality department may be the best candidate for assuming this responsibility because it is more likely to foster greater physician buy-in and acceptance of program objectives. If IT is to retain responsibility for the program, it will likely require the support of a strong analyst team. PMID- 25145028 TI - 5 ways to use medical technology assessments to reduce costs. PMID- 25145030 TI - Leveraging the delay in ICD-10. AB - With ICD-10 implementation pushed back a year until October 2015, organizations that were preparing for a 2014 start date may wonder whether they need to adjust their readiness programs. Organizations should keep moving forward in most areas of their programs to avoid losing momentum and having to repeat their efforts. Staff education is one area in which organizations may need to slow down until closer to the new deadline, given the difficulty of retaining complex information. PMID- 25145031 TI - Thomas Lee: the value of alleviating patient suffering. PMID- 25145032 TI - Creating a culture for value measurement. AB - OSF HealthCare's executive dashboard provides: A detailed view of top-level measures to frame OSF's mission and vision for all stakeholders. An easily understood, holistic snapshot of performance An assessment of relationships among system goals, initiatives, and results. Explicit understanding of the organization's priority performance measures and the extent to which they need to improve. A vehicle for transitioning to a value-based business model. PMID- 25145033 TI - Improving clinicians' access to cost data. AB - Bringing clinical and financial data together is critical to effectively running and operating service lines. Helping clinicians use cost data to make decisions requires a shared vision and a partnership between finance leaders and physicians. Hosting a "jam session" of technical, financial, and clinical experts can accelerate an organization's business intelligence strategy. Labor and supply costs represent the most actionable cost data for clinicians. Clinician buy-in hinges on education and support. It is important to focus on easy wins at the beginning of the project. PMID- 25145034 TI - Avoiding revenue loss due to 'lesser of' contract clauses. AB - Finance managers seeking to avoid lost revenue attributable to lesser-of-charge or-fixed-fee (lesser-of) clauses in their contracts should: Identify payer contracts that contain lesser-of clauses. Prepare lesser-of lost-revenue reports for non-bundled and bundled rates. For claims with covered charges below the bundled rate, identify service codes associated with the greatest proportion of total gross revenue and determine new, higher charge levels for those codes. Establish an approach for setting charges for non-bundled fee schedules to address lost-revenue-related issues. Incorporate changes into overall strategic or hospital zero-based pricing modeling and parameters. PMID- 25145035 TI - Calculating the true cost of robotic hysterectomy. AB - Although robotic hysterectomy does not produce significantly better outcomes than laparoscopic hysterectomy, hospitals may feel pressure from patients and clinicians to use the robotic procedure. Hospitals that opt for robotic hysterectomy over laparoscopic hysterectomy face not only higher variable costs, but also an opportunity cost in the form of lost surgical capacity. Estimating the opportunity cost of performing robotic hysterectomy provides crucial data for hospital executives in deciding whether to invest in the procedure. PMID- 25145036 TI - Leveraging mergers or affiliations to achieve transformation. PMID- 25145037 TI - Using the board quality committee to drive the value proposition. PMID- 25145038 TI - A road map to success for ACOs. PMID- 25145039 TI - Development and application of an aerosol screening model for size-resolved urban aerosols. AB - Predictive models of vehicular ultrafine particles less than 0.1 microm in diameter (UFPs*) and other urban pollutants with high spatial and temporal variation are useful and important in applications such as (1) decision support for infrastructure projects, emissions controls, and transportation-mode shifts; (2) the interpretation and enhancement of observations (e.g., source apportionment, extrapolation, interpolation, and gap-filling in space and time); and (3) the generation of spatially and temporally resolved exposure estimates where monitoring is unfeasible. The objective of the current study was to develop, test, and apply the Aerosol Screening Model (ASM), a new physically based vehicular UFP model for use in near-road environments. The ASM simulates hourly average outdoor concentrations of roadway-derived aerosols and gases. Its distinguishing features include user-specified spatial resolution; use of the Weather Research and Forecasting (WRF) meteorologic model for winds estimates; use of a database of more than 100,000 road segments in the Los Angeles, California, region, including freeway ramps and local streets; and extensive testing against more than 9000 hours of observed particle concentrations at 11 sites. After initialization of air parcels at an upwind boundary, the model solves for vehicle emissions, dispersion, coagulation, and deposition using a Lagrangian modeling framework. The Lagrangian parcel of air is subdivided vertically (into 11 levels) and in the crosswind direction (into 3 parcels). It has overall dimensions of 10 m (downwind), 300 m (vertically), and 2.1 km (crosswind). The simulation is typically started 4 km upwind from the receptor, that is, the location at which the exposure is to be estimated. As parcels approach the receptor, depending on the user-specified resolution, step size is decreased, and crosswind resolution is enhanced through subdivision of parcels in the crosswind direction. Hourly concentrations and size distributions of aerosols were simulated for 11 sites in the Los Angeles area with large variations in proximal traffic and particle number concentrations (ranging from 6000 to 41,000/cm3). Observed data were from the 2005-2007 Harbor Community Monitoring Study (HCMS; Moore et al. 2009), in Long Beach, California, and the Coronary Health and Air Pollution Study (CHAPS; Delfino et al. 2008), in the Los Angeles area. Meteorologic fields were extracted from 1-km-resolution meteorologic simulations, and observed wind direction and speed were incorporated. Using on road and tunnel measurements, size-resolved emission factors ranging from 1.4 x 10(15) to 16 x 10(15) particles/kg fuel were developed specifically for the ASM. Four separate size-resolved emissions were used. Traffic and emission factors were separately estimated for heavy-duty diesel and light-duty vehicles (LDV), and both cruise and acceleration emission factors were used. The light-duty cruise size-resolved number emission factor had a single prominent mode at 12 nm. The diesel cruise size-resolved number emission factor was bimodal, with a large mode at 16 nm and a secondary mode at around 100 nm. Emitted particles were assumed to be nonvolatile. Data on traffic activity came from a 2008 travel demand model, supplemented by data on diurnal patterns. Simulated ambient number size distributions and number concentrations were compared to observations taking into account estimated losses from particle transmission efficiency in instrument inlet tubing. The skill of the model in predicting number concentrations and size distributions was mixed, with some promising prediction features and some other areas in need of substantial improvement. For long-term (-15-day) average concentrations, the variability from site to site could be modeled with a coefficient of determination (r2) of 0.76. Model underprediction was more common than overprediction. The average of the absolute normalized bias was 0.30; in other words, long-term mean particle concentrations at each site were on average predicted to within 30% of the measured values. Observed 24-hour number concentrations were simulated to within a factor of 1.6 on 48% of days at HCMS sites and 81% at CHAPS sites, lower than the original design goal of 90%. Extensive evaluation of hourly concentrations, diurnal patterns, sizedistributions, and directional patterns was performed. At two sites with heavy freeway and heavy-duty-vehicle (HDV) influences and extensive size-resolved measurements, the ASM made significant errors in the diurnal pattern, concentration, and mode position of the aerosol size distribution. Observations indicated a shift in concentrations and size distributions corresponding to the afternoon development of offshore wind at the HCMS sites. The model did not reproduce the changes in particles associated with this wind shift and suffered from overprediction for particles of less than 15 nm and underprediction for particles of between 15 and 500 nm, raising doubt about the applicability of the HDV emission factors and the model's assumptions that particles were nonvolatile. The model's temporal prediction skill at individual monitoring sites was variable; the index of agreement (IOA) for hourly values at single sites ranged from 0.30 to 0.56. The model's ability to reproduce diurnal patterns in aerosol concentrations was site dependent; midday underprediction as well as underprediction for particle sizes greater than 15 nm were typical errors. Despite some problems in model skill, the number of time periods and locations evaluated as well as the extent of our qualitative and quantitative evaluations versus physical measurements well exceeded other published size-resolved modeling efforts. As a trial of a typical application, the sensitivity of the concentrations at each receptor site to LDV traffic, HDV traffic, and various road classes was evaluated. The sensitivity of overall particle numbers to all types of traffic ranged from 0.87 at the site with the heaviest traffic to 0.28 at the site with the lightest traffic, meaning that a 1% reduction in traffic could yield a reduction in particle number of 0.87% to 0.28%. Key conclusions and implications of the study are the following: 1. That variable-resolution (down to 10 m) modeling in a relatively simple framework is feasible and can support most of the applications mentioned above; 2. That model improvements will be required for some applications, especially in the areas of the HDV emission factor and the parameterization of meteorologic dispersion; 3. That particle loss from instrument transmission efficiency can be significant for particles smaller than 50 nm, and especially significant for particles smaller than 20 nm. In cases where loss corrections are not accounted for, or are inaccurate, this loss can cause disagreements in observation-model and observation-observation comparisons. 4. That LDV traffic exposures likely exceed HDV traffic exposures in some locations; 5. That variable step size and adaptive parcel width are critical to balancing computational efficiency and resolution; and 6. That the effects of roadways on air quality depend on both traffic volume and distance--in other words, low traffic volumes at close proximity need to be considered in health and planning studies just as much as do high traffic volumes at distances up to several kilometers. Future improvements to the model have been identified. They include improved emission factors; integration with the U.S. Environmental Protection Agency (EPA) Motor Vehicle Emission Simulator (MOVES) model; nesting with three-dimensional (3D) Eulerian models such as the Community Multi-scale Air Quality (CMAQ) model; increased emission dependence on acceleration, load, grade, and speed as well as evaporation and condensation of semivolatile aerosol species; and modeling of carbon dioxide (CO2) as an on-road and near-road dilution tracer. In addition, comparison with other statistically and physically based models would be highly beneficial. PMID- 25145041 TI - Looking forward. The ACS leadership development.program. PMID- 25145042 TI - Making the transition from mentee to mentor. PMID- 25145043 TI - What does the ACA mean for residents and their future practice? PMID- 25145044 TI - Surgical education and training at the crossroads between medical school and residency. PMID- 25145040 TI - Personal exposure to mixtures of volatile organic compounds: modeling and further analysis of the RIOPA data. AB - INTRODUCTION: Emission sources of volatile organic compounds (VOCs*) are numerous and widespread in both indoor and outdoor environments. Concentrations of VOCs indoors typically exceed outdoor levels, and most people spend nearly 90% of their time indoors. Thus, indoor sources generally contribute the majority of VOC exposures for most people. VOC exposure has been associated with a wide range of acute and chronic health effects; for example, asthma, respiratory diseases, liver and kidney dysfunction, neurologic impairment, and cancer. Although exposures to most VOCs for most persons fall below health-based guidelines, and long-term trends show decreases in ambient emissions and concentrations, a subset of individuals experience much higher exposures that exceed guidelines. Thus, exposure to VOCs remains an important environmental health concern. The present understanding of VOC exposures is incomplete. With the exception of a few compounds, concentration and especially exposure data are limited; and like other environmental data, VOC exposure data can show multiple modes, low and high extreme values, and sometimes a large portion of data below method detection limits (MDLs). Field data also show considerable spatial or interpersonal variability, and although evidence is limited, temporal variability seems high. These characteristics can complicate modeling and other analyses aimed at risk assessment, policy actions, and exposure management. In addition to these analytic and statistical issues, exposure typically occurs as a mixture, and mixture components may interact or jointly contribute to adverse effects. However most pollutant regulations, guidelines, and studies remain focused on single compounds, and thus may underestimate cumulative exposures and risks arising from coexposures. In addition, the composition of VOC mixtures has not been thoroughly investigated, and mixture components show varying and complex dependencies. Finally, although many factors are known to affect VOC exposures, many personal, environmental, and socioeconomic determinants remain to be identified, and the significance and applicability of the determinants reported in the literature are uncertain. To help answer these unresolved questions and overcome limitations of previous analyses, this project used several novel and powerful statistical modeling and analysis techniques and two large data sets. The overall objectives of this project were (1) to identify and characterize exposure distributions (including extreme values), (2) evaluate mixtures (including dependencies), and (3) identify determinants of VOC exposure. METHODS VOC data were drawn from two large data sets: the Relationships of Indoor, Outdoor, and Personal Air (RIOPA) study (1999-2001) and the National Health and Nutrition Examination Survey (NHANES; 1999-2000). The RIOPA study used a convenience sample to collect outdoor, indoor, and personal exposure measurements in three cities (Elizabeth, NJ; Houston, TX; Los Angeles, CA). In each city, approximately 100 households with adults and children who did not smoke were sampled twice for 18 VOCs. In addition, information about 500 variables associated with exposure was collected. The NHANES used a nationally representative sample and included personal VOC measurements for 851 participants. NHANES sampled 10 VOCs in common with RIOPA. Both studies used similar sampling methods and study periods. Specific Aim 1. To estimate and model extreme value exposures, extreme value distribution models were fitted to the top 10% and 5% of VOC exposures. Health risks were estimated for individual VOCs and for three VOC mixtures. Simulated extreme value data sets, generated for each VOC and for fitted extreme value and lognormal distributions, were compared with measured concentrations (RIOPA observations) to evaluate each model's goodness of fit. Mixture distributions were fitted with the conventional finite mixture of normal distributions and the semi-parametric Dirichlet process mixture (DPM) of normal distributions for three individual VOCs (chloroform, 1,4-DCB, and styrene). Goodness of fit for these full distribution models was also evaluated using simulated data. Specific Aim 2. Mixtures in the RIOPA VOC data set were identified using positive matrix factorization (PMF) and by toxicologic mode of action. Dependency structures of a mixture's components were examined using mixture fractions and were modeled using copulas, which address correlations of multiple components across their entire distributions. Five candidate copulas (Gaussian, t, Gumbel, Clayton, and Frank) were evaluated, and the performance of fitted models was evaluated using simulation and mixture fractions. Cumulative cancer risks were calculated for mixtures, and results from copulas and multivariate lognormal models were compared with risks based on RIOPA observations. Specific Aim 3. Exposure determinants were identified using stepwise regressions and linear mixed-effects models (LMMs). RESULTS: Specific Aim 1. Extreme value exposures in RIOPA typically were best fitted by three parameter generalized extreme value (GEV) distributions, and sometimes by the two parameter Gumbel distribution. In contrast, lognormal distributions significantly underestimated both the level and likelihood of extreme values. Among the VOCs measured in RIOPA, 1,4-dichlorobenzene (1,4-DCB) was associated with the greatest cancer risks; for example, for the highest 10% of measurements of 1,4-DCB, all individuals had risk levels above 10(-4), and 13% of all participants had risk levels above 10(-2). Of the full-distribution models, the finite mixture of normal distributions with two to four clusters and the DPM of normal distributions had superior performance in comparison with the lognormal models. DPM distributions provided slightly better fit than the finite mixture distributions; the advantages of the DPM model were avoiding certain convergence issues associated with the finite mixture distributions, adaptively selecting the number of needed clusters, and providing uncertainty estimates. Although the results apply to the RIOPA data set, GEV distributions and mixture models appear more broadly applicable. These models can be used to simulate VOC distributions, which are neither normally nor lognormally distributed, and they accurately represent the highest exposures, which may have the greatest health significance. Specific Aim 2. Four VOC mixtures were identified and apportioned by PMF; they represented gasoline vapor, vehicle exhaust, chlorinated solvents and disinfection byproducts, and cleaning products and odorants. The last mixture (cleaning products and odorants) accounted for the largest fraction of an individual's total exposure (average of 42% across RIOPA participants). Often, a single compound dominated a mixture but the mixture fractions were heterogeneous; that is, the fractions of the compounds changed with the concentration of the mixture. Three VOC mixtures were identified by toxicologic mode of action and represented VOCs associated with hematopoietic, liver, and renal tumors. Estimated lifetime cumulative cancer risks exceeded 10(-3) for about 10% of RIOPA participants. The dependency structures of the VOC mixtures in the RIOPA data set fitted Gumbel (two mixtures) and t copulas (four mixtures). These copula types emphasize dependencies found in the upper and lower tails of a distribution. The copulas reproduced both risk predictions and exposure fractions with a high degree of accuracy and performed better than multivariate lognormal distributions. Specific Aim 3. In an analysis focused on the home environment and the outdoor (close to home) environment, home VOC concentrations dominated personal exposures (66% to 78% of the total exposure, depending on VOC); this was largely the result of the amount of time participants spent at home and the fact that indoor concentrations were much higher than outdoor concentrations for most VOCs. In a different analysis focused on the sources inside the home and outside (but close to the home), it was assumed that 100% of VOCs from outside sources would penetrate the home. Outdoor VOC sources accounted for 5% (d-limonene) to 81% (carbon tetrachloride [CTC]) of the total exposure. Personal exposure and indoor measurements had similar determinants depending on the VOC. Gasoline related VOCs (e.g., benzene and methyl tert-butyl ether [MTBE]) were associated with city, residences with attached garages, pumping gas, wind speed, and home air exchange rate (AER). Odorant and cleaning-related VOCs (e.g., 1,4-DCB and chloroform) also were associated with city, and a residence's AER, size, and family members showering. Dry-cleaning and industry-related VOCs (e.g., tetrachloroethylene [or perchloroethylene, PERC] and trichloroethylene [TCE]) were associated with city, type of water supply to the home, and visits to the dry cleaner. These and other relationships were significant, they explained from 10% to 40% of the variance in the measurements, and are consistent with known emission sources and those reported in the literature. Outdoor concentrations of VOCs had only two determinants in common: city and wind speed. Overall, personal exposure was dominated by the home setting, although a large fraction of indoor VOC concentrations were due to outdoor sources. City of residence, personal activities, household characteristics, and meteorology were significant determinants. Concentrations in RIOPA were considerably lower than levels in the nationally representative NHANES for all VOCs except MTBE and 1,4-DCB. Differences between RIOPA and NHANES results can be explained by contrasts between the sampling designs and staging in the two studies, and by differences in the demographics, smoking, employment, occupations, and home locations. (ABSTRACT TRUNCATED) PMID- 25145045 TI - Coaching and mentoring modern surgeons. PMID- 25145046 TI - The "bionic" era: exploring the use of advanced technology in surgery. PMID- 25145047 TI - The e-volution of the 21st century surgeon. PMID- 25145048 TI - The five-year general surgery residency: reform or revolution? PMID- 25145049 TI - Statement on peak performance and management of fatigue. PMID- 25145050 TI - Statement on the effects of tobaco use on surgical complications and the utility of smoking cessation counseling. PMID- 25145051 TI - NCDB and ACS-CRP: Working together to develop risk-stratified strategies for surveillance. PMID- 25145052 TI - New draft guideline to prevent SSI. PMID- 25145054 TI - Robin T. Cotton, MD, FACS, FRCSC, receives 2014 ACS Jacobson innovation award. PMID- 25145053 TI - BYOB helmet. PMID- 25145055 TI - In memoriam: C. Barber Mueller, MD, FACS, FRCSC, recognized for contributions to the ACS and academic surgery. PMID- 25145056 TI - ACS commemorates 50-year .anniversary of surgeon general's report on smoking and health. PMID- 25145057 TI - ACS/ANZ traveling scholar reports on trip to Singapore and Australia. PMID- 25145058 TI - Newer diagnostic tools in tuberculosis. AB - Tuberculosis (TB) is a global health problem. Multi Drug Resistant TB (MDR-TB) and Extensively Drug Resistant TB (XDR-TB) cause high mortality. There are obstacles to the diagnosis of TB due to lack of accurate, cost effective and rapid diagnostic tools. The delay in diagnostic process is an unresolved bottleneck impeding access to treatment. Presently available diagnostic tools for TB except some liquid culture and molecular tests take long time. TB culture and drug susceptibility test (DST) need specialized laboratory setup and are also very expensive. The New Diagnostics Working Group (NDWG) on TB is supporting development of new tools and also provides information to World Health Organization (WHO) for endorsement. Globally, TB control programmes need rapid and accurate diagnostic tools, which are to be implemented in peripheral health centers as well. In this review, we describe development of newer diagnostic tools, their endorsement status and usage in TB diagnosis. PMID- 25145059 TI - Prevalence of non-tuberculous mycobacterium in a tertiary care hospital from South India. AB - Tuberculosis is a wide spread infectious disease all over the world as well as in India. Other than tuberculosis complex, more than 30 different non-tuberculous mycobacteria (NTM) are responsible for various diseases, i.e. cervical lymphadelopathy, cutaneous abscess, pulmonary diseases, post-operative infections, etc. These NTMs are resistant to commonly used antimicrobial and anti tubercular agents, jeopardizing the DOTS and DOTS PLUS program in the country. The accurate diagnosis of mycobacteria upto species level is an urgent need to check/control the increasing incidence of tuberculosis in community. A total of 3456 pulmonary and extra-pulmonary samples were subjected to smear examination and culture. The cultures were done in duplicate using Lowenstein Jensen media and examine weekly upto 8 weeks. A total of 33 positive cultures were identified by growth rate, pigment production, niacin test, nitrate test, heat stable catalase test, semiquantitative catalase test, tellurit reduction test, urease test, tween 80 hydrolysis, growth on McConkey media, growth in 5% sodium chloride and susceptibility to para-nitro benzoic acid. The results showed 33.33% were mycobacterium tuberculosis complex and 66.66% were non-tuberculosis mycobacterium. Among the non-tuberculous group, 11 different species of mycobacteria were identified during this study. Identification of mycobacteria is an utmost necessity in every big hospital as it helps clinicians to treat and stop further spread of the disease tuberculosis. This study reveals that NTM are the major group in culture positive pulmonary and extrapulmonary tuberculosis. The importance of NTM can be further evaluated by conducting more studies and need active participation of reference laboratories. PMID- 25145061 TI - Kala-azar--a case series from non endemic area, Uttarakhand. AB - Resurgence of kala azar in India has posed many problems. Apart from endemic areas, cases are being reported from non-endemic area. Other than diagnostic difficulties, resistance to stibogluconate & relapses are common problem in sporadic visceral leishmaniasis (VL). We present one case in detail & give brief description of nine other cases, hailing from non-endemic area, Uttarakhand, during the period from December 2005 to September 2011, diagnosed in our teaching hospital. The patients in our study were diagnosed as VL by clinical findings and confirmed by demonstration of LD bodies in splenic or bone marrow smears. Six cases were treated successfully with amphotericin. One case died during treatment and three cases lost the follow up. Clinician should suspect and investigate for VL in patients with pyrexia of unknown origin even when the disease is not endemic in a specific region for early diagnosis. PMID- 25145060 TI - Is routine medical examination of food handlers enough to ensure food safety in hospitals? AB - Nosocomial food outbreaks due to infected food handlers is primarily due to inadequate knowledge and faulty practices of food handlers during diarrhoeal episodes. The aim of this study was to assess: 1) prevalence of enteropathogen infection among food handlers working in our hospital during 2007 to 2011 and 2) adequacy of precautions taken by them during gastroenteritis episodes. Stool samples submitted by food handlers during 2007 to 2011 were examined for the presence of enteropathogens by standard methodology. For the second part of the study, a questionnaire regarding practices during episodes of diarrhoea in food handlers or their family members was handed out to willing participants. During the years 2007, 2008, 2010 and 2011 respectively, 3.9%, 9.8%, 5.1% and 9.4% food handlers were found infected with enteropathogens. The most common parasite detected was Entamoeba histolytica. Bacterial enteropathogens prevalence was very low during these years. There was high awareness (78.8%) among the food handlers regarding routine testing of faeces. Only 64.7% knew that it was important to report for purpose of treatment and leave. While 9.4% had suffered from diarrhoeal episodes in between intervals of annual microbiological testing, only 4.7% took appropriate treatment and availed medical leave. A regular training programme on food safety should be established and emphasis should be laid on mandatory reporting and stool testing of kitchen personnel as well as abstaining from work till they are medically fit. PMID- 25145062 TI - Incidence of multidrug resistance in Mycobacterium tuberculosis in a tertiary care hospital in South India--a prospective study. AB - Multidrug resistant tuberculosis (MDR-TB) is one worrisome element in this era of pandemic antibiotic resistance. This demands a need for diagnosis, and incidence of primary and acquired resistance to help in better management. Smear positive respiratory samples collected over a period of one year were processed for detection of M. tuberculosis, using biochemical methods and susceptibility to p nitro benzoic acid. Finally, strains detected by the above method were subjected to susceptibility for 2 drugs--Isoniazid and Rifampicin by Absolute concentration method to detect multidrug resistant strains and mono-resistant strains. The study showed primary and acquired resistance for both drugs to be 1.25% and 19% respectively. The data was consistent with the prevalence values available from studies both in India and globally. Finally our study showed MDR-TB to be present more in default patients than new cases. PMID- 25145063 TI - Public health response to the first case of Japanese encephalitis in Delhi, 2011. AB - Japanese Encephalitis (JE) is an acute viral zoonotic infection of the central nervous system. A confirmed case of JE was reported in the MVH, Pooth Khurd, following which the epidemiological investigation was carried out in the study area. Clinical/Syndromic surveillance started in the hospital. The local practitioners and anganwadi workers were contacted and requested to report similar cases in their areas. Serosurveillance to delineate high risk population, animal and vector survey done by taking transect walks through the colony to look for presence of amplifying hosts like pigs, ducks etc. Out of 2328 persons surveyed, 404 persons were found to have/had fever in the preceding one month. Current fever cases were 166, out of which 9 fitted into the criteria of AES. Large water body with vegetations was present within the colony. Piggeries and ducks were found in the colony. In the hospital 9 AES cases were screened. In total only 18 (9 from field, 9 from hospital) cases subjected to testing and found to be negative for IgM specific for JE. In total only 18 (9 from field, 9 from hospital) cases subjected to testing and found to be negative for IgM specific for JE. Most probably the above case of nine year child is the first case of JE indigenous to Delhi. The environmental conditions were conducive for the transmission of the viral agent. Further research is hence recommended to find the missing links and to prevent outbreaks in Delhi. PMID- 25145064 TI - Dengue outbreak in Delhi in 2009: study of laboratory and clinical parameters. AB - Dengue infection is endemic in India with frequent epidemics of Dengue Fever/Dengue Hemorrhagic Fever. The outbreaks vary in the commonest serotype in circulation during that period, predominant laboratory findings and clinical manifestations. This study was carried during the outbreak of dengue in Delhi in 2009. Clinical assessment and laboratory investigations were performed and severity of the disease with clinical, haematological parameters and serotypes were correlated. Of 107 patients included in the study, 64 (59.8%) were positive by ELISA. These 64 patients were tested by RT-PCR and 7 were found to be positive. DEN-2 and DEN-4 serotypes were isolated. There was a decreasing trend in mean age of patients with severity of infection. The outbreak was milder as compared to earlier ones in regards of number of cases presenting with clinical manifestations of bleeding. A considerable number of patients presented with unusual findings, namely, ascites, pleural effusion, myocarditis, cholecystitis and pancreatitis. There was no statistically significant difference either in platelet count between various groups or comparison of bleeding with severity of thrombocytopenia. This study provides an insight into the clinico-laboratory findings of the outbreak of dengue in 2009. PMID- 25145065 TI - Evaluation of indoor residual spray and insecticide treated bed nets in a malaria endemic area of Santhal Pargana, Dumka district (Jharkhand). AB - The study was carried out for evaluation of various activities of malaria control programme in five different tribal and malaria endemic Primary Health Centres of Dumka district (Jharkhand) during 2007-08. A total of 321 houses of 18 villages were surveyed on use of indoor residual spray (IRS) and insecticide-treated bed nets (ITN) and other activities as tool for vector control and interrupting the transmission of malaria. Out of 690 living rooms and 343 verandahs examined, IRS with Dichlorodiphenyl-trichloro-ethane (DDT) was done only in 16.23% living rooms and 64.72% verandahs. Refusal rate of IRS in living rooms was 81.93% due to lack of knowledge regarding the importance of IRS, no prior information to villagers, houses locked, reluctance to remove domestic articles, dislike of smell of DDT spray. Compliance rate of ITN uses was 71.66% during the night, which might be a factor for decline in malaria cases in the study area. Various important components of the programme, viz. surveillance and compliance to treatment activities, use of rapid diagnostic test kits (RDKs), involvement of accredited social health activist (ASHA's) and fever treatment depots (FTDs), laboratory activities, adult mosquito collection, other activities like constitution of village health sanitation committee, information education and communication activities, capacity building, use of larvivorous fishes, supervision of IRS etc. require much strengthening. However, 100% community acceptance was recorded for ITN in the villages surveyed. In addition, an entomological study was carried out for information on prevalence of mosquito species in this area to find out effectiveness of IRS activities. Eleven anopheline species, including three malaria vectors i.e., An. culicifacies, An. stephensi, An. fluviatilis, An. annularis, An. subpictus, An. nigerrimus, An. pallidus, An. aconitus, An. vagus, An. jamsii and An. splendidus were collected from cattle and human dwellings. PMID- 25145066 TI - An unusual presentation of Salmonella typhi bacteriuria in a 10 year old girl from North India. AB - Enteric fever caused mainly by Salmonella typhi (S. typhi), has a high incidence in India. We report a case of enteric fever in a ten year old patient presenting with clinical history of less than one week. Although blood culture, the most important diagnostic modality in early stage of enteric fever was sterile, S. typhi was isolated from culture of urine sample. Serum antibody titres against S. typhi were unusually raised considering that the infection was still in its early stage. Intravenous ceftriaxone therapy was given leading to complete recovery. PMID- 25145067 TI - Tuberculous liver abscess in an immunocompetent adult male--a rare presentation. AB - A 20 year old young male was admitted to our hospital with complaints of pain in upper abdomen right side, anorexia and loss of weight. Ultrasonography of the upper abdomen revealed a hypoechoic area in the left lobe of liver. Entertaining the possibility of pyogenic or amoebic lesion, the patient was started on ofloxacin and metronidazole. Failing to get any response to the therapeutic intervention, ultrasound guided aspiration was undertaken. The aspirated pus did not grow any organism in pyogenic or fungal culture but showed acid fast bacilli in Z.N. stain. The treatment was shifted to four drugs ATT and there was dramatic improvement in the clinical condition. This case is being reported to emphasize that ruling out tuberculosis may avoid unnecessary delays in the initiation of specific anti-tubercular treatment. Also a greater awareness of this rare clinical condition may prevent unwarranted surgical intervention. PMID- 25145068 TI - Rotavirus vaccine: a review. AB - Worldwide, large proportion i.e., 37% of deaths due to diarrhea in young children is attributed to rotavirus. A monovalent P1A[8] G1 vaccine and a pentavalent bovine-human reassortant vaccine human rotavirus vaccine had shown good clinical efficacy without any increase in intussusception among vaccine recipients. WHO recommends that the first dose of rotavirus vaccine should be administered to infants up to age of 6-15 weeks irrespective of the prior history of rotavirus infection and the maximum age for administering the last dose of the vaccine should be 32 weeks. Booster doses are not recommended. The current update reviews the issues related to rotavirus vaccines and their usages like milestones in the development of rotavirus vaccines, concerns regarding their efficacy and cost effectiveness, immunity after natural infection, potential for changes in virus strains, current recommendations, post marketing surveillance, and future challenges and scope for further research regarding rotavirus vaccines. PMID- 25145069 TI - Fecal contamination of drinking water supplies in and around Chandigarh and correlation with acute gastroenteritis. AB - Acute gastroenteritis due to Vibrio cholerae and Enterotoxigenic E. coli is a common problem faced in the hot and humid summer months in north India. The study was undertaken to evaluate drinking water supplies for fecal coliforms, V. cholerae and Enterotoxigenic E. coli in urban, semiurban and rural areas in and around Chandigarh and correlate with occurrence of acute gastroenteritis occurring from the same region. Drinking water sample were collected from various sources from April to October 2004 from a defined area. Samples were tested for fecal coliforms and E. coli count. E. coli were screened for heat labile toxin (LT) also. Stool samples from cases of acute gastroenteritis from the same region and time were collected and processed for V. cholerae, Enterotoxigenic E. coli (ETEC) and others like Salmonella, Shigella and Aeromonas spp. A total of 364 water samples were collected, (251 semi urban, 41 rural and 72 from urban areas). 116 (31.8%) samples were contaminated with fecal coliforms (58.5% rural, 33.4% semiurban and 11.1% of samples from urban areas). E. coli were grown from 58 samples. Ninety two isolates of E. coli were tested for enterotoxins of which 8 and 24 were positive for LT and ST respectively. V. cholerae were isolated from 2 samples during the outbreak investigation. Stored water samples showed a significantly higher level of contamination and most of Enterotoxigenic E. coli were isolated from stored water samples. A total of 780 acute gastroenteritis cases occurred; 445 from semiurban, 265 rural and 70 from urban areas. Out of 189 stool samples submitted, ETEC were the commonest (30%) followed by V. cholerae (19%), Shigellae (8.4%), Salmonellae (2.1%) and Aeromonas (2.6%). ST-ETEC (40/57) were commoner than LT-ETEC (17/57). In the present study, high levels of contamination of drinking water supplies (32.1%) correlated well with cases of acute gastroenteritis. Majority of cases of acute gastroenteritis occurred in the semi urban corresponding with high level of contamination (33.4%). The highest level of water contamination was seen in rural areas (58.5%) but the number of acute gastroenteritis cases were lesser (33.9%) as ponds were infrequently used for drinking purpose. Safer household water storage and treatment is recommended to prevent acute gastroenteritis, together with point-of-use water quality monitoring. PMID- 25145070 TI - Changing antimicrobial resistance observed at a tertiary care hospital in Delhi. AB - Monitoring antimicrobial resistance patterns meticulously and discussing them in multi-speciality forums can guide the usage of and help in judiciously utilising antibiotic resources. This study was done to compare the antimicrobial resistance trends observed over a period of two years at a tertiary care super-speciality hospital in Delhi. Microbiological data was collected for the years 2008 and 2009 and comparisons were made in the number of different isolates received, their antibiograms and changes in their resistance trends. It was observed that resistance to majority of antibiotics increased or remained similar in the following year, exceptions being gentamicin in Pseudomonas which could be attributed to their restricted usage. It was also noticed that whereas resistance increased among non-fermenter gram negative bacilli, nalidixic acid resistant Salmonella, ESBL producing Enterobacteriaceae and vancomycin resistant Enterococcus, it decreased for methicillin resistant S. aureus. This was attributed to teaching programmes emphasizing hand hygiene. Regular monitoring of resistance trends guide us towards making antibiotic policies and helps to influence our practices. PMID- 25145071 TI - School-based health education intervention for prevention of taeniasis and neurocysticercosis: a pilot study. AB - Neurocysticercosis (NC) spreads due to complex socio-cultural and economic conditions prevailing in our country. The up-scaling of the infection among pediatric age group in recent times is related to faulty food preparation and personal hygiene practices, which are amenable to simple preventable measures in daily life. Students are prime targets for educational intervention to change sanitary habits due to their impressionable minds. Further, changing the knowledge, attitudes and practices (KAP) of teachers regarding the disease leads to a multiplier effect as they pass on the message to many generations of students. Our previous studies demonstrated significant lacunae in knowledge about the disease epidemiology and prevention among school students and teachers. A pilot health-education intervention program was undertaken in 24 randomly selected municipal primary schools in Delhi, to increase awareness of students and schoolteachers regarding NC. The content of the program was devised based on the analysis of previous KAP studies done in a similar population. The activities consisted of a slide show, a lecture in vernacular language, demonstration of illustrations, charts and samples of infested pork, and question-answer sessions with the audience. Conducting skits involving role-play by trained child artists was used as a unique mode of passing health education messages. Posters and pamphlets in the local language were prepared and distributed in the school. A total of 200 teachers, 4786 students, 846 parents, 79 sanitary staff, 65 school health nurses and 23 school-health physicians attended the activities. Feedback was collected 3 months after the activity from each school (21 physicians and 70 schoolteachers). All respondents considered the program to be successful in increasing their own and students' awareness about NC and its prevention. There was significant improvement in teachers' knowledge about the impact of changing sanitary habits in prevention of the disease, and the appropriate practices to be adopted. This study demonstrated the feasibility and efficacy of conducting health education intervention in primary schools for changing sanitary practices for prevention of NC. PMID- 25145072 TI - Methicillin and multidrug resistant coagulase negative staphylococcal nasal carriage in medical students. AB - Awareness of the virulence of coagulase negative staphylococcus (CoNS), previously regarded as commensals with minimal pathogenicity has steadily increased. CoNS is one of the most important nosocomial pathogen in blood stream infections and in patients with intravenous catheters and implants. CoNS also acts as a reservoir of drug resistance genes for S.aureus. The present study was done to know the nasal carriage rate of CoNS and methicillin resistant CoNS (MRCoNS) in medical students, the effect of hospital environment and patient exposure on carriage rate in medical students and to know the sensitivity pattern of CoNS and MRCoNS to different drugs. A total of 104 Medical students were the subjects of the study. Nasal swab was collected from each subject and processed without delay on sheep blood agar plates. CoNS isolated were tested for methicillin resistance and resistance to other drugs by Kirby-Bauer disc diffusion method according CLSI 2011 guidelines. Overall CoNS and MRCoNS nasal carriage was seen in 63.46% and 18.26% of medical students. MRCoNS carriage rate was less than 14% in I, II and III phase students where as 29.28% in interns. Drug resistance was very high among MRCoNS isolates when compared to methicillin sensitive CoNS(MSCoNS) isolates. All isolates were susceptible to Linezolid. Nasal carriage rate of CoNS and MRCoNS is very high among medical students. Statistically significant high carriage rate of MRCoNS was seen in students exposed to hospital environment and patients. High level and multi drug resistance is seen in most of MRCoNS isolates. Linezolid has good antiCoNS activity. Continuous surveillance, decolonization of carriers and improvement in hygiene standards in hospitals should be adopted to prevent transmission of MRCoNS. PMID- 25145073 TI - Effect of water storage in silver container on the viability of enteric bacterial pathogens. AB - Silver is one of the heavy metals traditionally played major role in the human life. It is used in the form of ornaments or as containers to store or drink water and other consumable liquids. The study was designed to observe the effect of water storage in silver containers on enteric pathogens. Three sets of sterile silver, stainless steel and glass metal screw capped containers were filled with non-chlorinated sterilized well water. One each of the three sets was inoculated with enteric pathogens viz. Shigella dysenteriae, Vibrio cholerae O1 and Salmonella typhi cultures drawn from the laboratory stock and incubated at 37 degrees C for varying periods. Preliminary findings of this study indicated that silver is bactericidal within an hour to Shigella dysenteriae, Vibrio cholerae O1 and Salmonella typhi which cause life-threatening enteric human diseases. The quantity of silver needed to eliminate these bacteria was found to be less than 2.5 ug/dl at pH 6.5. This study reveals the potential for silver containers to be used to disinfect natural water in areas of poor hygiene and sanitation where groundwater is the main source of drinking water. PMID- 25145074 TI - KAP study conducted to assess the impact of special health education campaign for control of dengue at Vellore in Tamil Nadu. AB - An abnormal increase in the incidence of dengue was reported at Vellore Corporation since September 2012. Intensive control operations supported with health education campaigns were carried out from September to November 2012 till the outbreak situation subsided. During December 2012, a cross sectional survey was conducted at Vellore Corporation to assess the impact of the health education campaigns on the knowledge, attitude and practice in the community and also to assess future needs. A total of 101 families from four different locations at Vellore corporation were interviewed on pre-structured formats. Though 80% of the respondents felt that dengue could be effectively prevented and controlled only with community participation, majority of them lacked awareness on the day time biting behaviour of Aedes mosquitos, their indoor resting and breeding habits and relevance of specific control measures focused on the bionomics of dengue vectors. PMID- 25145075 TI - Impact of mass drug administration on elimination of lymphatic filariasis in Surat city, India. AB - Lymphatic filariasis (LF) is one of the major public health problems in some of the endemic districts in India including Surat city of Gujarat province. Historical data reveals that in 1960s, Surat city had infection rate of about 23% and infectivity rate of 1.6%. Since then, Surat city has been reporting the cases of Lymphoedema and hydrocele. Filaria Control Unit was established under National Filaria Control Programme to detect and provide treatment to the cases. Based on the reports of NFCP, Surat City has been considered as LF endemic. During 2004, the country launched campaign of Elimination of Lymphatic Filariasis through Mass Drug Administration (MDA) with annual single dose of 6 mg/kg body weight of DEC tablets in all LF endemic districts including Surat city. Four rounds of MDA (2004-2007) had shown 41% reduction in mf rate, with drastic reduction in infection rate of 88% and 100% in infectivity rate. Serious adverse effect (SAE) after 4th round of MDA was insignificant (< 0.5%) during 2007. An assessment by surveying 5058 people in different parts of Surat city revealed the drug distribution coverage of more than 95% but actual drug compliance between 70-90%. Analysis of the data revealed that though the overall Microfilaria rate has been reduced due to MDA, higher Microfilaria rate was noticed in North zone of city where the migrant populations influx is higher. The observation and analysis of the data in Surat city towards elimination of Lymphatic filariasis has been discussed in this paper. PMID- 25145076 TI - Time to say enough is enough. PMID- 25145077 TI - Film has impact. 'Coping with crying' is released. PMID- 25145078 TI - Women linked with maternity services. PMID- 25145079 TI - Skull deformity. Helmets have 'no benefit' study claims. PMID- 25145080 TI - Early pregnancy loss. New code to help parents. PMID- 25145081 TI - NMC consultation. Shaping future regulation. PMID- 25145082 TI - Birth spacing. Study looks at influence. PMID- 25145083 TI - Implementing evidence. 'Research is vital for the future'. PMID- 25145085 TI - Woman-centred? Midwifery debate session. PMID- 25145084 TI - Enjoying a record-breaking year. Thousands flock to Prague. PMID- 25145086 TI - Research launch. Landmark series for Lancet. PMID- 25145087 TI - Global report. Research finds 'midwives mean savings'. PMID- 25145088 TI - Breastmilk helps gut bacteria grow. PMID- 25145089 TI - Position doesn't effect DCC. PMID- 25145090 TI - Music in pregnancy. PMID- 25145092 TI - Newborn dialysis. PMID- 25145091 TI - Car crash risk in pregnancy. PMID- 25145094 TI - Midwives and MSWS vote 'yes' in pay consultation. PMID- 25145093 TI - Global midwifery shortage. PMID- 25145096 TI - Event successes. PMID- 25145095 TI - Payroll issues. PMID- 25145097 TI - Protesting for pay. PMID- 25145098 TI - A juggling act. PMID- 25145099 TI - Conference call. PMID- 25145100 TI - When inspiration strikes. PMID- 25145101 TI - Screen test. PMID- 25145102 TI - Meeting the needs of childbearing women. PMID- 25145103 TI - How to ... manage primary postpartum haemorrhage. PMID- 25145104 TI - Closing in on FGM. PMID- 25145105 TI - Making the midwifery voice heard. PMID- 25145106 TI - Postnatal optimism. PMID- 25145107 TI - How will you vote? PMID- 25145109 TI - Providing a voice. PMID- 25145108 TI - Peer review in supervision. PMID- 25145110 TI - Foreword. Maintenance and improvement of the functions of hospitals. PMID- 25145111 TI - Maintenance and improvement of the functions of hospitals. PMID- 25145112 TI - Effects of international accreditation on patient care in a Japanese hospital: nurses' perspectives. PMID- 25145113 TI - FY2014 healthcare system reformation--would we be happier in Japan or Italy? PMID- 25145114 TI - Reduction in the number of hospital beds in a super-aging society: an upsurge in isolation deaths. AB - AIM: This study examines the factors leading to more elderly Japanese patients dying alone, the costs associated with this, and potential solutions. METHOD: This is done through a review of the literature and data concerning Japanese housing policies, elderly households, isolation deaths and the costs of medical care and long-term care (LTC). RESULTS: Due to the decline of the domestic economy, Japanese home ownership has lost its former function of asset-building, and elderly households are overspending. The demand for a final residence for low income, frail, elderly tenants, who have greater risks of isolation deaths, will be increasing, especially in urban areas where there are inadequate postmortem examination systems. Elderly patients requiring a high level of treatment are forcibly discharged from hospitals and LTC costs peak after 90 years of age. CONCLUSIONS: Local governments should do what they can to facilitate the opening of more specialized nursing homes. It is essential to provide hospital beds to elderly patients with the imminent risk of dying to prevent them from isolation deaths because it is a human right to die with dignity. In order to accommodate elderly patients who need extensive medical treatments and to provide an appropriate place for the point of death, more convalescent beds are needed. Collaboration with hospitals, local governments, and integrated community care support centers (ICCSC) is the key to solving this problem. PMID- 25145115 TI - Development of a psoriasis patient assessment sheet. AB - We surveyed 20 psoriasis patients with the goal of creating a convenient psoriasis assessment sheet. The survey focused on symptoms, treatment, exacerbation, concerns regarding the type and cost of treatment, and problems caused by healthcare provider words and attitudes. Using the results of this survey and the available literature, we extracted the following assessment items: treatment (symptoms, efficacy, adverse effects), lifestyle (stress, physical fatigue, colds, diet, drinking, sleeping, bathing, smoking), and concerns regarding type and cost of treatment. PMID- 25145116 TI - The reuse of medical devices intended for single use: the great difference of opinions. PMID- 25145117 TI - [The use of OVD' for enhancement of their use in cataract surgery and complications of surger]. AB - OVD's are pseudoplastic fluids used in anterior segment surgery, their correct use decrease the incidence of complications. Arshinoff classified OVD's according to their properties and described optimal techniques for their use. The three classes are represented by viscoadaptive, cohesinve and dispersive OVD's, used in different steps of the surgery and their behavior is influenced by operating parameters. PMID- 25145118 TI - [When and how we start the treatment in patients with ocular hypertension or in glaucoma suspects?]. AB - The therapeutic decision should be a collaboration between us the doctor and the patient. Patients have different tolerance and education levels, ranging from the highly cautious to the careless one. Treatment initiation in glaucoma is based on intraocular pressure levels, age, race, life expectancy, family history, progression risk, associated pathology. The therapeutic effort is aiming to maintain both quality of life and sight, through sustainable costs. Now we have the proof that intraocular pressure is just another risk factor among many others, lowering-pressure treatment being able to reduce the individual risk of progression. Still, only the high-risk ocular hypertension will be treated, considering other risk factors. There is a fine line between early glaucoma and ocular hypertension, the therapeutic decision and monitoring algorithm varying with the individual risk of progression. PMID- 25145119 TI - [Retinal vascular changes--predictive and prognostic factor in systemic disease]. AB - The retinal circulation represents a unique window for the direct, non invazive in vivo status of the systemic mycrocirculation, but it can also offer scientific support for theories related strictly to ocular diseases, such as glaucoma (vascular theory). The interaction between intraocular pressure, retinal vessels and cerebrospinal fluid pressure located at the retrolaminar part of the optic nerve has been of great interest for both ophthalmologists or neuroscientists, both clinicians and researchers. The retinal vascular bed has structural and functional similarities with other vascular teritories such as Central Nervous System (CNS), kidneys and heart, so as for the ophthalmologist any vascular change in the retina can signalize a systemic disease (diabetes mellitus, stroke, arterial hypertension) that is more or less symptomatic for the patient. The purpose of this meta-analysis was to reviview recent literature data related to the connections between different hemodynamic structures and their impact on the retinal blood flow. PMID- 25145120 TI - [Ocular involvement in spondylarthritis--new mechanisms, new therapies]. AB - Spondyloarthrites (SPA) represent a group of heterogenous rheumatic diseases (ankylosing spondylitis/SA, psoriatic arthritis/PsA, reactive arthritis/ReA, spondyloarthritis in bowel inflammatory diseases/BID, undifferentiated spondyloarthritis/undif SpA) with distinct clinical features and common genetic predisposition (HLA-B27). SpA may also affect other organs, ocular involvement, represented by uveitis and conjunctivitis, being one of the most important extraskeletal manifestations. Pathogenic mechanisms of ocular involment in SpA are not entirely known; nevertheless, the inflammatory process which characterizes the main rheumatic diseases seems to be responsible for this extraskeletal manifestation. SpA treatment targeted at clinical remission has a favourable effect not only on articular but also on ocular involvement. The discovery of new pathogenic mechanisms of both rheumatic and eye disease in SpA have contributed to identification of new pathogenic therapies. The interdisciplinary team work of rheumatologists and ophtalmologists have prove essential for the management of SpA patients with ocular manifestations. PMID- 25145121 TI - [Pathopshysiological mechanisms in macular edema]. AB - The treatment of diabetic macular edema has known a fast development in the last 5 years where the transition from laser monotherapy to intravitreal pharmacotherapy is becoming standard practice. Intravitreal injections therapy is in a continuous development with promising positive results. The use of intratvitreal devices in the treatment of macular edema of vascular cause has become a viable alternative also in treating diabetic macular edema. Several clinical studies have revealed the superiority of intravitreal treatment versus laser monotherapy. This article is evaluating and reviewing present and future treatments used to combat diabetic macular edema. [corrected]. PMID- 25145122 TI - [Congenital toxoplasmosis with ocular involvment--case report]. AB - Two thirds of the congenital toxoplasmosis cases describe minimal or inapparent symptoms present at birth, being diagnosed from a psychomotor retard. The forms of chorioretinitis may be described by repeated outbursts in the first years of life. Chorioretinitis or focal necrotizing retinitis usually develops in a bilateral way, being progressive and leading to blindness. Usually there is only one focal inflammatory beginning at the edge of a pigmented scar and the local inflammatory process may extend through successive spikes in other regions of the retina. Active chorioretinitis is expressed clinically by a blurred misty eyesight, with the advent of scotomas, photophobia, and if the macula is involved, the loss of the central eyesight may occur. In this paper I present the patient R.A., 6 years old from Constanta who is hospitalized in the Clinic of Infectious Diseases for investigations and treatment continuity because positive IgG Toxoplasma was previously found. The child has spastic quadriplegia and profound mental retardation. PMID- 25145123 TI - [Retinal pneumopexy in the treatment of rhegmatogenous retinal detachment]. AB - PURPOSE: To evaluate the efficiency of retinal pneumopexy in patients with rhegmatogenous retinal detachment. METHODS: This clinical prospective study unrolled between november 2010-june 2012 in the Ophthalmology Department of the Military Hospital in Cluj-Napoca and Satu Mare Emergency Hospital included 20 patients (20 eyes) with rhegmatogenous retinal detachment. Patients were treated with retinal pneumopexy followed by laser photocoagulation. RESULTS: Anatomical and functional results were evaluated 1, 3, 6, 12 and 19 months after treatment. In 17 eyes out of 20, we achieved retinal reattachment and visual recovery. Three cases yelded no success, these being further treated with posterior vitrectomy. CONCLUSION: Retinal pneumopexy is a minimally invasive treatment method of rhegmatogenous retinal detachment with very good results in well selected cases. PMID- 25145124 TI - New trends in pesticide residue analysis in various sample matrixes. PMID- 25145125 TI - A review of methods for the analysis of orphan and difficult pesticides: glyphosate, glufosinate, quaternary ammonium and phenoxy acid herbicides, and dithiocarbamate and phthalimide fungicides. AB - This article reviews the chromatography/MS methodologies for analysis of pesticide residues of orphan and difficult chemical classes in a variety of sample matrixes including water, urine, blood, and food. The review focuses on pesticide classes that are not commonly included in multiresidue analysis methods such as highly polar or ionic herbicides including glyphosate, glufosinate, quaternary ammonium, and phenoxy acid herbicides, and some of their major degradation or metabolite products. In addition, dithiocarbamate and phthalimide fungicides, which are thermally unstable and have stability issues in some solvents or sample matrixes, are also examined due to their special needs in residue analysis. PMID- 25145126 TI - Multiresidue analysis of insecticides and other selected environmental contaminants in poultry manure by gas chromatography/mass spectrometry. AB - An analytical method was developed for the simultaneous determination in poultry manure of 41 organic contaminants belonging to different chemical classes: pesticides, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and polybrominated diphenyl ethers. Poultry manure was extracted with a modified QuEChERS method, and the extracts were analyzed by isotope dilution GC/MS. Recovery of these contaminants from samples spiked at levels ranging from 25 to 100 ng/g was satisfactory for all the compounds. The developed procedure provided LODs from 0.8 to 9.6 ng/g. The analysis of poultry manure samples collected on different farms confirmed the presence of some of the studied contaminants. Pyrethroids and polycyclic aromatic hydrocarbons were the main contaminants detected. DDT and its metabolite DDE were also found but at relatively low concentrations. PMID- 25145127 TI - Pesticide multiresidue determination in rice paddy water by gas chromatography coupled with triple quadrupole mass spectrometry. AB - Pollution of water sources by pesticides is a result of intensive use of these compounds, and the establishment of analytical methods for monitoring programs is very important. This paper presents a method for the determination of multiclass pesticide residues in rice paddy water based on SPE and GC/MS/MS. The validation results were satisfactory. All compounds showed adequate linearity (r2 >or= 0.99), and analysis by GC/MS/MS with a triple quadrupole mass spectrometer gave high selectivity and sensitivity. With the proposed SPE step an LOD of 0.06 microg/L was achieved. Recoveries from blank samples spiked at 0.2, 04, and 0.8 microg/L were between 70 and 120% with RSD <20% for most analyzed compounds, despite their different chemical nature, indicating good accuracy and precision. The proposed method is efficient for pesticide residue determination, including some metabolites, and gave good performance when applied to real samples. PMID- 25145128 TI - Electro-oxidation and determination of benomyl by square-wave adsorptive stripping voltammetry. AB - The electro-oxidation of the benomyl fungicide was studied by square-wave adsorptive stripping voltammetry. The voltammetric current at a glassy carbon electrode was acquired within the pH range 1.0-10.0. The quantitation was performed using the peak generated at +1144 mV by scanning the potential from +0.00 to +1600 mV (versus an Ag/AgCI reference electrode, 3 M NaCl). Accumulation potential = 0.0 mV, accumulation time=45 s, frequency=75 Hz, pulse amplitude=-60 mV, and staircase step potential = 7 mV were used as square-wave parameters. The peak current versus concentrations plot were rectilinear over the range from 0.081 to 1.496 microg/mL with an LOD of 0.024 microg/mL. Mean recovery was 99.0% (0.198 +/- 0.011 microg/mL), which was very close to the benomyl content spiked into river water (0.20 microg/mL). The method was efficiently applied for benomyl determination in the pesticide formulation Minelate 50WG, and the average determined content of 49.8 +/- 0.16 (n = 5) was consistent with the 50% benomyl (w/w) quoted by the manufacturer. The benomyl voltammograms recorded between days exhibited a negligible degradation into carbendazim metabolite, and therefore all results were given as the total benomyl concentration. The high recoveries and low RSD gave evidence of good accuracy and precision. PMID- 25145129 TI - Determination of pesticide residues in tea by gas chromatography/triple quadrupole mass spectrometry with solid-phase extraction. AB - An analytical method was developed for determination of multipesticide residues, including organophosphorus, organohalogen, pyrethroid, and organonitrogen, in tea at trace levels by GC coupled with triple quadrupole mass chromatography (QqQ MS/MS). Scan time was selected in order to optimize QqQ-MS/MS conditions. The key parameters for controlling cleanup performance were optimized, including SPE cartridge type and elution solvent volume. Acetonitrile was the extraction solvent, and a novel multilayer SPE cartridge, Cleanert TPT, was used in the cleanup step. The recoveries of the studied pesticides at 5.0, 10.0, and 25.0 microg/kg were in the range of 77.8 to 103.8% with an RSD of less than 14%. Determination coefficient (R2) values between 0.9951 and 0.9998 were obtained for all target compounds. The LOD was between 0.002 and 1.0 microg/kg, and LOQs were 0.0066-3.3 microg/kg, which satisfied the maximum residue limits for pesticides in tea recommended by the European Union and Japan. The optimized method was applied to the analysis of real tea samples obtained from the local market. PMID- 25145130 TI - Chemometric study and optimization of headspace solid-phase microextraction parameters for the determination of multiclass pesticide residues in processed cocoa from Nigeria using gas chromatography/mass spectrometry. AB - Solid-phase microextraction (SPME) is a solventless sample preparation method that combines sample preparation, isolation, concentration, and enrichment into one step. A simple and effective method coupling headspace-SPME to GC/MS was developed for the analysis of chlorpyrifos, fenitrothion, endosulfan I, and endosulfan II pesticide residues in cocoa powder. In this study, multivariate strategy was used to determine the significance of the factors affecting the SPME of the pesticides using a Plackett-Burman design, and the significant factors were optimized using central composite design. The analytes were extracted with 100 microm polydimethylsiloxane fibers according to the factorial design matrix and desorbed into a GC/MS instrument. The developed method was applied for the analysis of a cocoa powder sample, and it exhibited good figures of merit for the analytical methodology. Using the optimized conditions, the linearity ranged from 2.5 to 500 microg/kg (R2> 0.99) using an internal standard calibration method, and the average recoveries were between 75 and 95%, with RSD values between 3.8 and 9.7%. PMID- 25145131 TI - Determination of pesticides in sunflower seeds by high-performance liquid chromatography coupled with a diode array detector. AB - The application of RP-HPLC with a diode array detector for identification and quantitative analysis of pesticides in sunflower seed samples is demonstrated. An HPLC procedure on C18 RP column has been developed for analysis of selected pesticides from different chemical groups: simazine, isoproturon, terbuthylazine, linuron, captan, terbutryn, procymidone, fenitrothion, clofentezine, and bromopropylate. We investigated the possibility of expanding the scope of the four analyte extraction procedures for isolation of pesticides from plant matrixes with high levels of lipids. The following procedures were tested: A, ultrasound-assisted solvent extraction (UAE) and SPE; B, dispersive-SPE (d-SPE); C, UAE and d-SPE; and D, UAE/SPE/d-SPE. Average recoveries from spiked samples at different concentrations in the range from 0.1 to 1.40 microg/g in the plant materials and the SDs for C18 cartridges and solvents by the proposed RP-HPLC-DAD method after the extraction procedures are also presented. The efficiency of procedures A-D was evaluated using real food samples from Hungary, Bulgaria, and Poland. The quantity of terbuthylazine determined was in the range of 7.1-12.7 ng/g (n = 6), whereas the quantity of procymidone determined was in the range of 3.7-5.7 ng/g (n = 3) in plant materials. The quantities of pesticides determined in sunflower seeds were below the maximum residue levels (excluding captan) established in the European Union legislation. The method was validated for precision and accuracy. PMID- 25145132 TI - Determination of quaternary ammonium compounds in oranges and cucumbers using QuEChERS extraction and ultra-performance liquid chromatography/tandem mass spectrometry. AB - A simple and fast method has been developed for determining relevant quaternary ammonium compounds in cucumber and orange samples. The target compounds were benzoalkonium chloride (BAC-10, BAC-12, BAC-14, and BAC-16), didecyldimethylammonium chloride, and benzethonium chloride, all frequently used biocides in the agrifood industry. An extraction based on the buffered Quick, Easy, Cheap, Effective, Rugged, and Safe method and determination by ultra performance LC/MS/MS that eluted the biocides in less than 5 min were used. The method was fully validated and implemented in a UNE-EN-ISO/IEC 17025 accredited laboratory for its application to the analysis of real samples. Performance characteristics of the method are reported, including an estimation of measurement uncertainty. Calibration curves were set between 0.01 and 0.150 mg/kg, LOD values were always between 0.4 and 1.0 microg/kg, LOQ values were in the range 1-4 microg/kg, recovery was between 81 and 115%, intraday and interday precision were always lower than 17% (expressed as RSD), and expanded uncertainty was always lower than 40%. The validation was accomplished for the two studied matrixes at spiking concentrations of 0.011 and 0.050 mg/kg. The method has been applied to the analysis of 30 cucumber and orange samples that were found to contain concentrations of BAC-12 that ranged between 0.015 and 0.210 mg/kg and of BAC-14 between 0.018 and 0.081 mg/kg. PMID- 25145133 TI - QuEChERS approach for the determination of biopesticides in organic and nonorganic vegetables and fruits by ultra-performance liquid chromatography/tandem mass spectrometry. AB - A method for the determination of 14 biopesticides and piperonyl butoxide (PBO), often applied in organic farming, in vegetables and fruits has been developed. Extraction was performed using the Quick, Easy, Cheap, Effective, Rugged, and Safe method, and the determination was carried out by ultra-performance LC/MS/MS in 9 min. Several different food commodities were evaluated as representative matrixes, namely, cucumber, tomato, pepper (high water content), and strawberry and orange (high acid and water content). Biopesticides were quantified using matrix-matched calibration, and the optimized method was validated at three concentration levels, i.e., 10, 50, and 100 microg/kg, for all the compounds, yielding recoveries in the range 70-112%, 71-112%, and 70-109%, respectively, with RSDs <28%. LOQs were <3 microg/kg for all biopesticides. The validated procedure was applied to the analysis of vegetables and fruits, including products from organic farming; PBO was detected in one sample at 8 microg/kg. PMID- 25145134 TI - Sequential extraction procedure for the determination of some trace elements in fertilizer samples. AB - Total concentration of metal ions at trace levels does not give sufficient information about toxicity and biological availability of these elements in fertilizer samples. In the presented work, a sequential extraction procedure modified by the European Community Bureau of Reference (BCR) was applied to fractionate Cd, Cr, Co, Cu, Fe, Pb, Mn, Ni, and Zn levels in two fertilizer samples collected from cooperative agricultural retailers. The fractions extracted were exchangeable/dilute acid soluble, reducible bound to Fe/Mn oxides, oxidizable bound to organic matter and sulfides, and residual. The determination of analyte elements was done by flame atomic absorption spectrometry. The accuracy of the procedure was validated with BCR-701 sediment certified reference material. The RSD of the procedure was less than 10%. PMID- 25145135 TI - Qualitative identification of permitted and non-permitted color additives in cosmetics. AB - Color additives are dyes, pigments, or other substances that can impart color when added or applied to foods, drugs, cosmetics, medical devices, or the human body. These substances must be pre-approved by the U.S. Food and Drug Administration (FDA) and listed in the Code of Federal Regulations before they may be used in FDA-regulated products. Both domestic and imported cosmetic products sold in interstate commerce fall under FDA jurisdiction, and FDA's district laboratories use a combination of analytical methods for identifying or confirming the presence of potentially violative color additives. We have developed a qualitative method for identifying 29 water- and methanol-soluble color additives in various types of cosmetic products. The color additives are extracted with combinations of methylene chloride, methanol, acetic acid, and water and are identified by LC with photodiode array detection. Estimated LOD values ranged from 0.1 to 1.5 mg/L. A survey of lip products, nail polishes, eye products, blushes, body glitter, face paints, bath products, creams, and toothpastes identified permitted and non-permitted color additives. Our new LC method is intended to supplement the visible spectrophotometry and TLC methods currently used by FDA's district laboratories and will help optimize the use of time, labor, and solvents. PMID- 25145136 TI - The accuracy of vitamin D assays of circulating 25-hydroxyvitamin D values: influence of 25-hydroxylated ergocalciferol concentration. AB - Serum samples from 74 obese women were assayed for 25-hydroxyvitamin D [25(OH)D] concentrations using an automated immunoassay [Architect (Abbott)] and ELISA (Alpco Diagnostics), and results were compared with the LC/MS/MS reference method (Quest Diagnostics). The Architect values were significantly lower (mean difference: -13 nmol/L; 95% limits: -54; 28 nmol/L) and the ELISA values were significantly higher (mean difference: 24 nmol/L; 95% limits: -36; 84 nmol/L) than the LC/MSIMS values. The slope of the Passing-Bablok regression line relative to LC/MSIMS was 0.5 [95% confidence interval (CI): 0.41; 0.60] and 1.17 (95% CI: 0.87; 1.56) for Architect and ELISA, respectively, with an intercept of approximately 16 for both assays. Using 50 nmol/L as the cut-point for deficiency, Architect and ELISA misclassified 20 and 27% of the subjects, respectively. In subjects with low circulating 25-hydroxylated ergocalciferol [25(OH)D2] (<10 nmol/L), a Bland-Altman plot and Kappa statistics (Kappa = 0.73; 95% CI: 0.49-0.97) showed good agreement between Architect and LC/MS/MS. However, in subjects with high circulating 25(OH)D2 (>or=10 nmol/L), Architect demonstrated poor agreement (Kappa = 0.40; 95% CI: 0.16-0.65). ELISA demonstrated a higher degree of overestimation in women with minimal 25(OH)D2 than those with high 25(OH)D2, suggesting that ELISA overestimates 25-hydroxylated cholecalciferol [25(OH)D3] but underestimates 25(OH)D2. PMID- 25145137 TI - Parallel microdevice for high throughput analysis of levofloxacin using tris (2,2'-bipyridyl) ruthenium (II) and peroxydisulfate chemiluminescence system. AB - A parallel microdevice has been developed for high throughput analysis using microfluidics. The detection method is based on a chemiluminescence (CL) system based on the oxidation of tris (2,2'-bipyridyl) Ru(ll) [Ru (bipy)3(2+)] by peroxydisulfate. The device consists of a photoreactor chip and two detection chips. The sample throughput can reach up to 720 runs/h with the total reagent consumption of only 2.4 mL. The parallel microdevice was evaluated using levofloxacin (LEVO) in pharmaceutical preparations. The various factors that affect the CL signal were optimized, and the LOD was found to be 30 and 27 microg/L for the two detectors, respectively (S/N = 3), while RSD was 1.1% (n = 15) for 1.0 mg/L LEVO. Two tablet samples that contain LEVO as an active ingredient were successfully analyzed using the proposed parallel microdevice. PMID- 25145138 TI - Determination of flurbiprofen in human plasma by gas chromatography with mass spectrometry and its pharmacokinetics. AB - This paper describes a GCIMS method for the determination of flurbiprofen in human plasma. Flurbiprofen and internal standard ibuprofen were extracted from plasma by using a liquid-liquid extraction method. Derivatization was carried out using N-Methyl-N-(trimethylsilyl)trifluoroacetamide. The calibration curve was linear between the concentration range of 0.10 and 5.0 microg/mL. Intraday and interday precision values for flurbiprofen in plasma were less than 5.49%, and accuracy (relative error) was better than 5.33%. The extraction recoveries of flurbiprofen from human plasma were between 93.6 and 98.6%. The LOD and LOQ of flurbiprofen were 0.03 and 0.10 microg/mL, respectively. This assay was applied to determine the pharmacokinetic parameters of flurbiprofen in healthy Turkish volunteers who had been given 100 mg of flurbiprofen. PMID- 25145139 TI - Immunomagnetic separation and visual fluorescence detection of Salmonella spp., using AOAC approved SAS Molecular Tests. AB - The SAS Molecular Tests method for detection of Salmonella spp. in various food matrixes has been certified by the AOAC Research Institute and designated Performance Tested Method No. 021202. The current method modification includes the optional immunomagnetic separation (IMS) to enrich the bacteria as well as optional visual fluorescence readout without the use of a turbidimeter. The modifications were validated against the U.S. Department of Agriculture/ Food Safety and Inspection Service Microbiology Laboratory Guidebook (MLG) and the U.S. Food and Drug Administration Bacteriological Analytical Manual (BAM) reference methods. Food matrixes (chicken carcass rinse, beef trim, and spinach) were inoculated with low levels of Salmonella spp. (0.2-2 CFU/test portion) to generate fractional positives (5-15) in 20 inoculated samples. Samples were enriched with SAS Enrichment medium and incubated at 42 +/- 1 degree C. Enrichments were tested directly and subjected to anti-Salmonella IMS prior to the SAS Molecular Tests. Results were determined via visual fluorescence and via turbidity using a turbidimeter. All replicates were confirmed using the MLG or BAM reference method procedures, regardless of presumptive result. The SAS Molecular Tests Salmonella Detection modified methods were determined to be equivalent to the reference methods for the detection of Salmonella in chicken carcass rinse, beef trim, and fresh spinach. The inclusion of IMS in the modified method improved the detection rate of Salmonella in chicken carcass rinses and spinach. The optional use of visual fluorescent reagent and heat block either with IMS or without IMS produced results that were comparable to the results obtained from using a real-time turbidimeter. PMID- 25145140 TI - Immunomagnetic separation and visual fluorescence detection of E. coli O157 using AOAC approved SAS Molecular Tests. AB - The SAS Molecular Tests method for the detection of E. coli O157 in various food matrixes has been certified by the AOAC Research Institute and designated Performance Tested Method No. 031203. The current method modification includes the optional immunomagnetic separation (IMS) to enrich the bacteria as well as optional visual fluorescence readout without the use of a turbidimeter. The following study was conducted to validate the proposed modifications against the U.S. Department of Agriculture/Food Safety and Inspection Service Microbiology Laboratory Guidebook (MLG) and the U.S. Food and Drug Administration Bacteriological Analytical Manual (BAM) reference methods. E. coli O157:H7 ATCC 35150 and NM (non-motile) 700377 strains were used to inoculate the ground beef, beef trim, and spinach to obtain 20 low (0.23-2 CFU/test portion) and five high levels (3-5 CFU/test portion) of inoculations. Enriched samples were tested directly and subjected to anti-E. coli IMS prior to the SAS Molecular Tests. Results were determined via visual fluorescence and via turbidity using a turbidimeter. All the replicates, irrespective of the results, were confirmed using MLG 5.05 or BAM Chapter 4A methods. Results indicated that there were no significant differences in the detection of fractional positives (5-15 positives out of 20 replicates) with any of the methods tested above as compared to the reference methods. No false positives or negatives were detected except for two in the ground beef with IMS+Turbidity method. No false-negative samples were detected. Statistical analysis indicated that the modified methods were equivalent to the reference methods in detecting E. coli O157:H7 in the food matrixes tested. SAS Molecular Tests E. coli O157 Detection Kit can be used to detect E. coli O157:H7 in ground beef, beef trim, and spinach. The inclusion of IMS in the modified method improved the detection rate of E. coli O157:H7 in spinach and showed comparable detection rate in ground beef and beef trim. The optional use of visual fluorescent reagent and heat block either with IMS or without IMS produced results that were comparable to the results obtained from using a real-time lurbidimeter. PMID- 25145142 TI - Validation of the Soleris direct yeast and mold method for semiquantitative determination of yeast and mold in a variety of foods. AB - A study was carried out to determine the efficacy of the Soleris Direct Yeast and Mold (DYM) automated growth-based method for semiquantitative detection of yeast and mold in a variety of food products. A probability of detection (POD) statistical model was used to compare Soleris results at multiple test thresholds (dilutions) with plate counts determined using the U.S. Food and Drug Administration Bacteriological Analytical Manual, Chapter 18, dilution plating procedure. Fourteen naturally contaminated food products were tested, with Soleris testing performed at three or more threshold levels for each food. Using the POD model, the majority of Soleris test results were in statistical agreement with the reference plating procedures. The exceptions included a single threshold level in yogurt, black pepper, dried fruit, and dry pet food, and two levels in nonfat dry milk and saw palmetto powder. In all but one of these instances, the exception being pet food, the statistical disagreement was due to Soleris estimating a higher level of contamination than the reference method. Results of ruggedness testing showed that the Soleris method produced accurate results even when significant variances in a critical operating parameter, incubation temperature, were introduced. Results of the internal and independent laboratory validation studies showed that the Soleris DYM method can be used as an accurate alternative to conventional dilution plating procedures for evaluation of yeast and mold counts at threshold levels, while saving as much as 72 h in analysis time. PMID- 25145141 TI - Screening, detection, and serotyping methods for toxin genes and enterotoxins in Staphylococcus strains. AB - Staphylococcus aureus continues to play a significant role in foodborne outbreak investigations, with numerous individuals sickened each year after ingesting assorted foods contaminated with staphylococcal enterotoxins. The purpose of this study was to evaluate the use of several methods for the screening, detection, and enterotoxin serotyping of staphylococcal bacterial strains for classical staphylococcal enterotoxins (SEs; SEA, SEB, SEC, SED, and SEE) and the newly described SE and SE-like enterotoxin genes (seg, seh, sei, sej, sek, sel, sem, sen, seo, sep, seq, ser, ses, set, and seu). Inclusivity and exclusivity panels of staphylococcal strains were tested using a multiplex PCR method in addition to three polyvalent commercially prepared ELISA systems for the detection of SEA-SEE and one monovalent assay for the identification of classical SE serotypes. The results indicate an overall agreement between serological detection methods with a few exceptions, and molecular characterization identified an abundance of SE and SE-like enterotoxin genes including several potentially enterotoxigenic isolates that would have otherwise been missed by ELISA-based methods. These findings demonstrate the significance of PCR for future screening purposes and the use of ELISA systems for the detection and enterotoxin serotyping of staphylococcal bacterial strains. PMID- 25145143 TI - Development of a stir bar sorptive extraction method for analysis of ochratoxin A in beer. AB - A new, simple, and sensitive method was developed for extraction of ochratoxin A (OTA) in beer combined with HPLC-fluorescence detector. Samples were extracted by stir bar sorptive extraction (SBSE) followed by liquid desorption using commercially available Twister EG-Silicone. The main parameters influencing SBSE, including phase ratio, extraction time, stirring speed, ionic strength, organic modifier, pH, temperature, desorption mode, desorption solvent, and desorption time were optimized. Under the optimal conditions, assay was performed on 4 mL of samples acidified at pH 1.5. The samples were extracted for 180 min at a stirring speed of 800 rpm followed by desorption of analyte using 1 mL methanol under sonication for 45 min. The extract was evaporated at 50 degrees C under a gentle nitrogen stream, then redissolved in 200 microL of methanol-water (50 + 50, v/v). After each use, the stir bar was cleaned by sonication in methanol for 30 min three times. The method provided good linearity of the calibration curve with coefficients of determination greater than 0.999. Recoveries of OTA were greater than 83% with RSD lower than 10%, and LOD of OTA in beer was 0.64 ng/L. This method was applied to determine OTA in 19 beer samples. OTA was detected in 12 samples (63%) in the range of 0.01-0.27 ng/mL. PMID- 25145144 TI - Determination of plant stanols and plant sterols in phytosterol enriched foods with a gas chromatographic-flame ionization detection method: NMKL collaborative study. AB - This collaborative study with nine participating laboratories was conducted to determine the total plant sterol and/or plant stanol contents in phytosterol fortified foods with a gas chromatographic method. Four practice and 12 test samples representing mainly commercially available foodstuffs were analyzed as known replicates. Twelve samples were enriched with phytosterols, whereas four samples contained only natural contents of phytosterols. The analytical procedure consisted of two alternative approaches: hot saponification method, and acid hydrolysis treatment prior to hot saponification. As a result, sterol/stanol compositions and contents in the samples were measured. The amounts of total plant sterols and total plant stanols varying from 0.005 to 8.04 g/100 g product were statistically evaluated after outliers were eliminated. The repeatability RSD (RSDr) varied from 1.34 to 17.13%. The reproducibility RSD (RSDR) ranged from 3.03 to 17.70%, with HorRat values ranging from 0.8 to 2.1. When only phytosterol enriched food test samples are considered, the RSDr ranged from 1.48 to 6.13%, the RSD, ranged from 3.03 to 7.74%, and HorRat values ranged from 0.8 to 2.1. Based on the results of this collaborative study, the study coordinator concludes the method is fit for its purpose. PMID- 25145145 TI - Rapid screening of oleuropein from olive leaves using matrix solid-phase dispersion and high-performance liquid chromatography. AB - Matrix solid-phase dispersion (MSPD) methodology as a quick and easy extraction method has been developed to extract oleuropein from Olea europaea leaves. This method has been compared with conventional maceration and Soxhlet extraction (SOXE) methods. Variables affecting MSPD, such as the sorbent material, the ratio of sample to sorbent material, elution solvent, and volume of the elution solvent, have been fully evaluated and optimized. Oleuropein was successfully extracted by silica sorbent with 350 microL of dichloromethane-methanol (70 + 30, v/v) as the elution solvent. The calibration curve showed good linearity (r2 = 0.9985) and precision (RSD <4.5%) in the concentration range of 0.5-100 microg/mL for oleuropein. The LOD and LOQ were 0.14 and 0.5 microg/mL, respectively. The recoveries were in the range of 88.0-94.0% with RSD values ranging from 6.0 to 9.8%. The extraction yields obtained by the MSPD method were comparable with those obtained by the maceration and SOXE methods. The reported MSPD extraction method was revealed to be eco-friendly, simpler, and faster than conventional methods used to quantify oleuropein in O. europaea leaves. PMID- 25145146 TI - Comparison of SNP-based detection assays for food analysis: Coffee authentication. AB - Recently, DNA-based authentication methods were developed to serve as complementary approaches to analytical chemistry techniques. The single nucleotide polymorphism (SNP)-based reaction chemistries, when combined with the existing detection methods, could result in numerous analytical approaches, all with particular advantages and disadvantages. The dual aim of this study was (a) to develop SNP-based analytical assays such as the single-base primer extension (SNaPShot) and pyrosequencing in order to differentiate Arabica and Robusta varieties for the authentication of coffee beans and (b) to compare the performances of SNaPshot, pyrosequencing and the previously developed polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using an Agilent 2100 Bioanalyzer on the basis of linearity (R2) and LOD, expressed as percentage of the adulterant species, using green coffee beans (Arabica and Robusta) as a food model. The results showed that SNaPshot analysis exhibited the best LOD, whereas pyrosequencing revealed the best linearity (R2 = 0.997). The PCR-RFLP assay using the Agilent 2100 Bioanalyzer could prove to be a very useful method for a laboratory that lacks sequencing facilities but it can be used only if a SNP creates/deletes a restriction site. PMID- 25145147 TI - Determination of folate in infant formula and adult/pediatric nutritional formula by ultra-high performance liquid chromatography-tandem mass spectrometry: First Action 2013.13. AB - A UHPLC-MS/MS method for the determination of folate (vitamin B9) in infant formula and adult/pediatric nutritional formula was assessed for compliance with standard method performance requirements set forth by the AOAC INTERNATIONAL Stakeholder Panel for Infant Formula and Adult Nutritionals (SPIFAN). A single laboratory validation (SLV) study was conducted as the first step in the process to validate the method. In the study, 12 matrixes, representing the range of infant and adult nutritional products, were evaluated for folate [the sum of supplemental folic acid plus 5-methyl tetrahydrofolic acid (5-Me THF)]. Method response was linear in the range of 1.0-900 ng/mL, corresponding to 0.33-300 microg/l100 g in reconstituted sample. LOD for folic acid and 5-Me THF, expressed in reconstituted product, were 0.10 microg/100 g and 0.05 microg/100 g, respectively, and LOQ were 0.33 microg/100 g and 0.10 microg/100 g, respectively. Repeatability was <5.3% and intermediate precision was <5.5%. Recovery rates of spiking at 50 and 100% of target values in nonfortified products were within 90 110%. Evaluation of trueness was performed on Certified Reference Material (SRM 1849 Infant/Adult Nutritional Formula) and gave 96.4% of theoretical value. Based on the results of the SLV, the method meets the SPIFAN requirements for AOAC First Action status for the determination of folates in infant formula and adult/pediatric nutritional formula. PMID- 25145148 TI - Detection of Listeria spp. using ACTERO listeria enrichment media. AB - ACTERO Listeria Enrichment Media (ACTERO Listeria) is a selective medium developed for a single-step recovery and enrichment of Listeria spp. from environmental samples. Robustness testing of the ACTERO Listeria medium demonstrated good performance when minor changes were introduced to the incubation temperature and time. All 54 Listeria strains tested, representing the most frequently isolated Listeria species from food (L. monocytogenes, L. ivanovii, L. seeligeri, L. welshimeri, and L. grayi), were successfully enriched in ACTERO Listeria. None of the 30 nontarget strains tested in the exclusivity study was recovered after incubation in ACTERO Listeria. Recovery of Listeria was consistent across three independently produced lots of the ACTERO Listeria, and the prepared medium was stable for 45 days when stored at 4 degrees C in the dark. Matrix studies performed with environmental sponge samples from plastic and stainless steel surfaces demonstrated similar recovery of Listeria spp. in a single-step enrichment using ACTERO Listeria from plastic, and significantly better recovery from stainless steel surfaces when compared to the U.S. Department of Agriculture-Food Safety and Inspection Service reference method. The results of this study prove that ACTERO Listeria Enrichment Media can be effectively used in replacement of the two-step enrichment suggested by the reference method without affecting the recovery of Listeria spp. from environmental samples. PMID- 25145149 TI - Solid-phase extraction of copper(II) in water and food samples using silica gel modified with bis(3-aminopropyl)amine and determination by flame atomic absorption spectrometry. AB - A simple and selective separation and preconcentration method was developed for the determination of Cu(ll) ions. This method is based on adsorption of Cu(ll) ions from aqueous solution on a bis(3-aminopropyl)amine modified silica gel column and flame atomic absorption spectrometric determination after desorption. Various analytical parameters such as pH, type of eluent solution and its volume, flow rate of sample and eluent, and sample volume were optimized. Effects of some cation, anion, and transition metal ions on the recoveries of Cu(ll) ions were also investigated. Cu(ll) ions were quantitatively recovered at pH 6; 5.0 mL of 2 M HCI was used as the eluent. The preconcentration factor was found to be 150. The LOD was 0.12 microg/L for Cu(ll). The accuracy of the method was confirmed by analysis of Tea Leaves (INCT-TL-1) and Fish Protein (DORM-3) certified reference materials. The optimized method was applied to various water and food samples for the determination of Cu(ll). PMID- 25145150 TI - Method validation and proficiency testing for determination of total arsenic in apple juice by inductively coupled plasma/ mass spectrometry. AB - A proficiency test (PT) program for determination of total As in apple juice samples was conducted by the Food Emergency Response Network (FERN) laboratories. An analytical method using inductively coupled plasma (ICP)-MS was validated for this project. The LOD and LOQ were determined to be 0.315 and 2.32 ng/g, respectively. A total of eight apple juice samples were sent to 38 FERN laboratories, and results were statistically evaluated according to ISO 13528:2005. The total As concentrations in the PT samples reported by the participating laboratories were very close to those obtained in the homogeneity and stability tests. The reproducibility, repeatability, interlaboratory, and intralaboratory variability results led to 69% of participating laboratories being rated as satisfactory using the widely accepted Izl score 0.95). PMID- 25145161 TI - Fast and high throughput screening ofamantadine in chicken muscle by extractive derivatization with pentafluorobenzoyl chloride and gas chromatography/negative ion chemical ionization-tandem mass spectrometry. AB - A fast and high throughput screening method for the determination of amantadine (ADA) in chicken muscle is presented. After acidic extraction and extractive derivatization with pentafluorobenzoyl chloride, ADA was analyzed directly without any preconcentration by GC/negative ion chemical ionization-tandem MS/MS. With the selective MS/MS detection, ADA in chicken muscle can be detected at concentrations well below 1 microg/kg. Quantification of ADA in chicken muscle was accomplished by using matrix-matched calibration with memantine as an internal standard. The method was validated with ADA fortified chicken muscle at 1, 2, and 5 microg/kg. The recoveries ranged from 89 to 95%, and RSDs were 90%) capacity of the system for indicator organism and pathogens. It also showed a very good endurance against imposed hydraulic shock load. Tracer study showed that the flow pattern was close to plug flow reactor. Mean HRT was also found to be close to the designed value. PMID- 25145172 TI - Microbial desalination cell for enhanced biodegradation of waste engine oil using a novel bacterial strain Bacillus subtilis moh3. AB - Microbial desalination cell (MDC) is a bioelectrochemical system developed recently from microbial fuel cells (MFCs), for producing green energy from organic wastes along with desalination of saltwater. MDC is proved to be a better performer than MFC in terms of power output and chemical oxygen demand removal, with desalination as an additional feature. This study investigates the application potential of MDC for integrated biodegradation of waste engine oil. This study showed, for the first time, that waste engine oil could be used as an organic substrate in MDC, achieving biodegradation of engine oil along with considerable desalination and power production. Utilization of these wastes in MDC can protect the environment from waste engine oil contamination. Indigenous oil-degrading bacteria were isolated and identified from engine oil contaminated sludge. Degradation of waste engine oil by these novel isolates was studied in batch cultures and optimized the growth conditions. The same cultures when used in MDC, gave enhanced biodegradation (70.1 +/- 0.5%) along with desalination (68.3 +/- 0.6%) and power production (3.1 +/- 0.3 mW/m2). Fourier transform infrared spectroscopy and gas chromatography-mass spectrometry analyses were performed to characterize the degradation metabolites in the anolyte of MDC which clearly indicated the biodegradation of long chain, branched and cyclic hydrocarbons present in waste engine oil. PMID- 25145173 TI - Measurement of biochemical oxygen demand from different wastewater samples using a mediator-less microbial fuel cell biosensor. AB - Microbial fuel cells (MFCs) have attracted considerable attention as potential biosensors. A MFC biosensor for rapid measurement of biochemical oxygen demand (BOD) has been recently studied. However, a standardized bacterial mixture inoculated in the MFC biosensor for BOD measurement is unavailable. Thus, the commercial application of a MFC biosensor is limited. In this study, a mediator less MFC biosensor inoculated with known mixed cultures to quickly determine BOD concentration was tested. Optimal external resistance, operating temperature and measurement time for the MFC biosensor were determined to be 5000 omega, 35 degrees C and 12h, respectively. A good relationship between BOD concentration and voltage output, high reproducibility and long-term stability for the MFC biosensor was observed. The newly developed MFC biosensor was inoculated with a mixture of six bacterial strains (Thermincola carboxydiphila, Pseudomonas aeruginosa, Ochrobactrum intermedium, Shewanella frigidimarina, Citrobacter freundii and Clostridium acetobutylicum) capable of degrading complex organic compounds and surviving toxic conditions. The described MFC biosensor was able to successfully measure BOD concentrations below 240 mg L(-1) in real wastewater samples. PMID- 25145174 TI - Comparison of biomethane production and digestate characterization for selected agricultural substrates in Italy. AB - Starting from (but not limited to) their importance in the Italian context, three agricultural substrates, two of fruit origin (grape seeds and plum stones) and one of herbaceous origin (woad), were comparatively tested for both biomethane production and digestate characterization. The anaerobic digestion tests showed that grape seeds had the highest net methane production of 253.0 NmL g volatile solids (VS)(-1), followed by plum stones, whose best resulting net methane production was 174.7 NmL gVS(-1), and finally by woad with a net methane production of 153.1 NmL gVS(-1). Interestingly, the best methane productions of the fruit substrates were obtained with different substrate to inoculum ratios (on a VS basis), 1:1 for grape seeds but 2:1 for plum stones. On the other hand, a three-month ageing of woad caused a limited reduction of methane production. The estimation of obtained degrees of conversion, carried out on a chemical oxygen demand (COD) basis for the specific tests achieving the respective best methane productions, gave values of 48%, 31%, and 33% for grape seeds, plum stones, and woad, respectively. The estimated degrees of conversion were evaluated along with the respective methane productions and substrate COD/VS ratios. The comparison of Fourier transform infrared (FT-IR) spectra and differential thermal analysis (DTA) profiles, carried out for selected digestates in pairs, revealed some distinctive differences in the relative intensities or presence and absence of particular peaks in the FT-IR spectra and in the relative intensities of the exothermic peaks or horizontal curve shifting of the DTA profiles. PMID- 25145175 TI - Improvement of the coagulation/flocculation process using a combination of Moringa oleifera lam with anionic polymer in water treatment. AB - The objective of this study is to investigate the impacts of anionic polymer as a flocculant aid on the coagulation/flocculation performance with a saline solution of Moringa oleifera as a coagulant to provide larger flocs and decrease the time sedimentation. For the tests, raw water was used from Pirapo River Basin (Maringa, Parana, Brazil). Optimization of coagulation/flocculation tests was initially performed in a jar-test with a dosage of M. oleifera Lam (crude extract -MO, oil-extracted with ethanol--MO (et) and hexane--MO (hex) 1% m/v) as the coagulant that ranged from 10 to 60 mg L(-1) and of the anionic polymer 0.1% as a flocculant aid with a dosage that ranged from 0 to 0.4 mg L(-1). The parameters analysed were colour, turbidity and compounds with absorption in UV254nm. In view of the statistical analysis results, MO (hex) with a dosage of 30 mg L(-1) was chosen as a coagulant for the next tests of coagulation/flocculation. When anionic polymer was used alone (0.0 mg L(-1) of MO (hex)), parameters were not removed and there was no generation of heavy flocs as compared with the combination of MO (hex) with the anionic polymer. Statistical analysis showed that MO (hex) obtained the highest removals of the parameters analysed in lower dosages and no significant increase in parameters removal was observed when the polymer dosage was increased. The efficacy of the coagulant +/- anionic polymer was optimal when 30mg L(-1) of MO (hex) was used as a coagulant and 0.1 mg L(-1) of the anionic polymer was used as a flocculant aid, decreasing the time sedimentation from 1 h to 15 min. PMID- 25145176 TI - Photocatalytic decomposition of humic acids in anoxic aqueous solutions producing hydrogen, oxygen and light hydrocarbons. AB - Photocatalytic water splitting for hydrogen and oxygen production requires sacrificial electron donors, for example, organic compounds. Titanium dioxide catalysts doped with platinum, cobalt, tungsten, copper and iron were experimentally tested for the production of hydrogen, oxygen and low molecular weight hydrocarbons from aqueous solutions of humic substances (HS). Platinum doped catalyst showed the best results in hydrogen generation, also producing methane, ethene and ethane, whereas the best oxygen production was exhibited by P25, followed by copper--and cobalt-containing photocatalysts. Iron-containing photocatalyst produced carbon monoxide as a major product. HS undergoing anoxic photocatalytic degradation produce hydrogen with minor hydrocarbons, and/or oxygen. It appears that better hydrogen yield is achieved when direct HS splitting takes place, as opposed to HS acting as electron donors for water splitting. PMID- 25145177 TI - Comparison of harvesting methods for microalgae Chlorella sp. and its potential use as a biodiesel feedstock. AB - Three methods for harvesting Chlorella sp. biomass were analysed in this paper- centrifugation, membrane microfiltration and coagulation: there was no significant difference between the total amount of biomass obtained by centrifugation and membrane microfiltration, i.e., 0.1174 +/- 0.0308 and 0.1145 +/- 0.0268 g, respectively. Almost the same total lipid content was obtained using both methods, i.e., 27.96 +/- 0.77 and 26.43 +/- 0.67% for centrifugation and microfiltration, respectively. However, harvesting by coagulation resulted in the lowest biomass and lipid content. Similar fatty acid profiles were obtained for all of the harvesting methods, indicating that the main components were palmitic acid (C16:0), oleic acid (C18:1) and linoleic acid (C18:2). However, the amounts of the individual fatty acids were higher for microfiltration than for centrifugation and coagulation; coagulation performed the most poorly in this regard by producing the smallest amount of fatty acids (41.61 +/- 6.49 mg/g dw). The harvesting method should also be selected based on the cost benefit and energy requirements. The membrane filtration method offers the advantages of currently decreasing capital costs, a high efficiency and low maintenance and energy requirements and is thus the most efficient method for microalgae harvesting. PMID- 25145178 TI - Characteristic of fly ash derived-zeolite and its catalytic performance for fast pyrolysis of Jatropha waste. AB - Fly ash from pulp and paper industries was used as a raw material for synthesizing zeolite catalyst. Main compositions of fly ash consisted of 41 wt%SiO2, 20 wt%Al2O3, 14 wt%CaO, and 8 wt% Fe2O3. High content of silica and alumina indicated that this fly ash has potential uses for zeolite synthesis. Fly ash was mixed with 1-3 M NaOH solution. Sodium silicate acting as silica source was added into the solution to obtain the initial SiO2/Al2O3 molar ratio of 23.9. The mixtures were then crystallized at 160 degrees C for 24 and 72 h. Zeolites synthesized after a long synthesis time of 72 h showed superior properties in terms of high crystallinity, less impurity, and small particle size. The catalytic activities of fly ash-derived zeolites were investigated via fast pyrolysis of Jatropha wastes using analytical pyrolysis-gas chromatograph/mass spectrometer (GC/MS). Pyrolysis temperature was set at 500 degrees C with Jatropha wastes to catalyst ratio of 1:1, 1:5, and 1:10. Results showed that higher amounts of catalyst have a positive effect on enhancing aromatic hydrocarbons as well as decreasing in the oxygenated and N-containing compounds. Zeolite Socony Mobil-5 (ZSM-5) treated with 3 M NaOH at 72 h showed the highest hydrocarbon yield of 97.4%. The formation of hydrocarbon led to the high heating value of bio-oils. In addition, the presence of ZSM-5 derived from fly ash contributed to reduce the undesirable oxygenated compounds such as aldehydes, acids, and ketones which cause poor quality of bio-oil to only 0.8% while suppressed N-compounds to 1.7%. Overall, the ZSM-5 synthesized from fly ash proved to be an effective catalyst for catalytic fast pyrolysis application. PMID- 25145179 TI - Relationships between nuclear magnetic resonance parameters used to characterize weathering spilled oil and soil toxicity in central Patagonia. AB - Oil spill in the Central Patagonian zone was studied to evaluate if any relationship exists between the parameters used to characterize weathering spilled oil and soil toxicity for two plant species and to evaluate if the phytotoxicity to local species would be a good index for the soil contamination. Nuclear magnetic resonance (NMR) structural indexes and column chromatography compositional indexes were determined to characterize the oil spill in the soil samples. Bioassays were also carried out using Lactuca sativa L (reference) and Atriplex lampa (native species) as test organisms. Measurements of the total petroleum hydrocarbon (TPH) and the electrical conductivity (EC) of the soil were carried out to evaluate the effect on the bioassays. The principal components analysis of the parameters determined by NMR, compositional indexes, EC, TPH, and toxicology data shows that the first three principal components accounted for the 78% of the total variance (40%, 25%, and 13% for the first, second, and third PC, respectively). A good agreement was found between information obtained by compositional indexes and NMR structural indexes. Soil toxicity increases with the increase of EC and TPH. Other factors, such as, the presence of branched and aromatic hydrocarbons is also significant. The statistical evaluation showed that the Euclidean distances (3D) between the background and each one of the samples might be a better indicator of the soil contamination, compared with chemical criterion of TPH. PMID- 25145180 TI - Hexavalent chromium [Cr(VI)] removal by the electrochemical ion-exchange process. AB - In the present investigation, the performance of a laboratory-scale plate and frame-type electrochemical ion-exchange (EIX) cell on removal ofhexavalent chromium from synthetic wastewater containing 5 mg/l of Cr(VI) was evaluated under varying applied voltages. Ruthenium dioxide-coated titanium plate (RuO2/Ti) was used as anode and stainless steel plates as cathode. The EIX cell was run at different hydraulic retention time (HRT). Before using in the electrochemical cell, the capacity of ion-exchange resin was evaluated through kinetic and isotherm equilibrium tests in batch mode. The batch kinetic study result showed that the equilibrium time for effective ion exchange with resin is 2 h. The isotherm equilibrium data fit well to both Freundlich and Langmuir isotherms. Maximum capacity (qm) of resin calculated from Langmuir isotherm was 71.42 mg/g. Up to 99% of chromium removal was noticed in the EIX cell containing fresh resin at applied voltages of 10 V and higher. Migration of chromium ion to anode chamber was not noticed while performing the experiment with fresh resin. As high as 50% removal of chromium was observed from the middle chamber containing exhausted resin at an applied voltage of 25 V when the influent flow rate was maintained at 45 min of HRT. The performance of the reactor was increased to 72% when the influent flow rate was decreased to maintain at 90 min of HRT. Build-up of chromium in the anode chamber took place when exhausted resin was used in the process. PMID- 25145181 TI - Remediation of hydrocarbon-contaminated soils by ex situ microwave treatment: technical, energy and economic considerations. AB - In this study, the remediation of diesel-polluted soils was investigated by simulating an ex situ microwave (MW) heating treatment under different conditions, including soil moisture, operating power and heating duration. Based on experimental data, a technical, energy and economic assessment for the optimization of full-scale remediation activities was carried out. Main results show that the operating power applied significantly influences the contaminant removal kinetics and the moisture content in soil has a major effect on the final temperature reachable during MW heating. The first-order kinetic model showed an excellent correlation (r2 > 0.976) with the experimental data for residual concentration at all operating powers and for all soil moistures tested. Excellent contaminant removal values up to 94.8% were observed for wet soils at power higher than 600 W for heating duration longer than 30 min. The use of MW heating with respect to a conventional ex situ thermal desorption treatment could significantly decrease the energy consumption needed for the removal of hydrocarbon contaminants from soils. Therefore, the MW treatment could represent a suitable cost-effective alternative to the conventional thermal treatment for the remediation of hydrocarbon-polluted soil. PMID- 25145182 TI - Recovery of struvite via coagulation and flocculation using natural compounds. AB - One of the major setbacks of struvite recovery processes is the difficulty in harvesting struvite crystals. This study evaluates the use of different coagulants to improve precipitation of struvite (MgNH4PO4.6H20) crystals. Chitosan and poly(diallyldimethyl ammonium chloride) (Poly-DADMAC) as a coagulant flocculent and alginate and bentonite as a coagulant aid have been examined in jar tests. Also, a continuous three-phase process, i.e., struvite crystallization, coagulation/flocculation and precipitation process, was set up for real wastewater. Addition of chitosan as the coagulant and bentonite as the coagulant aid was significantly more efficient in forming struvite flocs in comparison to Poly-DADMAC alone or with coagulant aid, which did not show any positive effect. The calculated average settling velocity of struvite with chitosan-bentonite addition in synthetic and in real wastewater increased by approximately 5.3 and 2.8 folds, respectively, compared with that of no coagulant/flocculent addition. Phosphorus recovery of over 70% was achieved by the continuous process. Findings in this study clearly confirmed the possibility of using chitosan and bentonite as an efficient coagulant-flocculent to enhance the recovery of struvite crystals. PMID- 25145183 TI - Effect of solar radiation on the lipid characterization of biomass cultivated in high-rate algal ponds using domestic sewage. AB - The objective of this paper is to compare the lipid content and composition ofbiomass produced by a consortium of microalgae and bacteria, cultivated under different solar radiation intensities and tropical conditions in pilot-scale high rate ponds (HRPs) using domestic sewage as culture medium. The treatment system consisted of an upflow anaerobic sludge blanket reactor followed by UV disinfection and six HRPs covered with shading screens that blocked 9%, 18%, 30%, 60% and 80% of the solar radiation. The total lipid content does not vary significantly among the units, showing a medium value of 9.5%. The results show that blocking over 30% of the solar radiation has a negative effect on the lipid productivity. The units with no shading and with 30% and 60% of solar radiation blocking have statistically significant lipid productivities, varying from 0.92 to 0.96 gm(-2) day(-1). Besides radiation, other variables such as volatile suspended solids and chlorophyll-a are able to explain the lipid accumulation. The lipid profile has a predominance of C16, C18:1 and C18:3 acids. The unsaturation of fatty acids increases with the reduction in solar radiation. On the other hand, the effect of polyunsaturation is not observed, which is probably due to the presence of a complex and diverse biomass. PMID- 25145184 TI - Escherichia coli growth and transport in the presence of nanosilver under variable growth conditions. AB - Nanosilver (silver nanoparticles) has the ability to anchor to the bacterial cell membrane and subsequently penetrate it, thereby causing structural changes (i.e., permeability) in the cell membrane and death of the cell. The bacterial responses to the presence of nanosilver usually vary depending on the concentration of nanosilver particles, exposure time and the bacterial physiological stage. Since bacterial anabolism dependents upon a stoichiometric ratio of carbon and inorganic elements (nutrients), the macronutrient ratio, i.e. carbon to nitrogen ratio (C/N) thus plays an important role of bacterial responses to the exposure of nanosilver. This study investigated the responses of Escherichia coli to the exposure of nanosilver under variable growth conditions. It was discovered that E. coli grown under different growth conditions had different responses to the presence of nanosilver. E. coli had least resistance to the toxicity of nanosilver when cultured under carbon-limited conditions. However, the presence of rhamnolipid, a commonly utilized biosurfactant for soil remediation increased the resistance of E. coli to nanosilver. The transport of E. coli cultured under carbon-limited conditions was further studied in silica sand columns. E. coli adsorption in silica sand increased when cultured in the presence of nanosilver. On the contrary, E. coli adsorption in silica sand was significantly reduced when cultured in the presence of rhamnolipid. PMID- 25145185 TI - Capping hazardous red mud using acidic soil with an embedded layer of zeolite for plant growth. AB - A nearly three-year microcosm experiment was conducted to test the effectiveness of capping red mud using acidic soil with an embedded layer of zeolite in sustaining the growth of a grass species. This 'sandwich-structured' design allowed self-sustaining growth of the plants under rain-fed conditions no matter whether the underlying red mud was neutralized or not. During the initial stage, the plants grew better when the red mud was not neutralized with MgCl2 probably due to pH rise in the root zone. Neutralization of red mud led to salinization and pH decrease in the root zone. However, the difference in plant growth performance between these scenarios became less remarkable over time due to gradual improvement of soil conditions in the neutralized scenarios. Continuous leaching of soluble salts and alkali by rainwater extended the root zone to the red mud layer. As a result of vegetative production, soil organic matter rapidly accumulated. This, combined with increase in pH and decrease in salinity, markedly facilitated microbial activities and consequently improved the supply of nutrients. This study provides abasis for field-scale experimental design that will have implications for effectively establishing vegetative cover in red mud disposal sites to control dust hazards. PMID- 25145186 TI - Studying the demand-side vis-a-vis the supply-side of urban water systems--case study of Oslo, Norway. AB - The research focus of resource consumption and emissions from urban water services has, by and large, been restricted to what comes under the domain of the urban water utilities - the upstream sub-systems of water treatment and supply and the downstream sub-systems of wastewater collection, treatment and disposal. However, the material and energy flows necessitated by activities in the water demand sub-system (households, for instance) are by no means negligible. This paper studies the per-capita material and energy requirements, and the related emissions and life cycle environmental impacts, associated with water consumption in households of the city of Oslo for the year 2009. For example, the per-capita energy consumption in the household consumption phase, at 1.38 MWh per year, is eight times more than the corresponding consumption for the entire water wastewater utility. All findings, taken together, clearly demonstrate the imperativeness of paying more attention to the demand-side management issues. PMID- 25145187 TI - Adsorption of hydrogen sulphide from aqueous solutions using modified nano/micro fibrillated cellulose. AB - In the present study, microfibrillated cellulose (MFC) was modified by aminopropyltriethoxysilane (APS), hydroxy-carbonated apatite (HAP), or epoxy in order to produce novel nanostructured adsorbents for the removal of hydrogen sulphide (H2S) from the aqueous solutions. Structural properties of the modified MFC materials were examined using a scanning electron microscope, Fourier transform infrared spectroscopy and acid/base titration. These methods were used to verify the presence of nanostructures on the adsorbents surfaces as well as functionalities suitable for H2S adsorption. Adsorption of H2S by prepared adsorbents was investigated in batch mode under different experimental conditions, i.e., varying pH and H2S concentrations. H2S uptake was found to be 103.95, 13.38 and 12.73 mg/g by APS/MFC, HAP/MFC and epoxy/MFC, respectively from 80 mg/L H2S solution. The equilibrium data were best described by the Langmuir isotherm for HAP/MFC and APS/MFC and the Sips isotherm for epoxy/MFC. PMID- 25145188 TI - The formation potential of haloacetonitriles in the Dez River water, Iran. AB - The formation potential of haloacetonitriles (HANsFP) from chlorination of raw water of the Dez River in Iran was determined. Samples were collected before treatment at an intake of a water treatment plant. Tests were carried out to determine the effect of the reaction time (5-120 h), water pH (4-10), total organic carbon (TOC) content (2-8 mg L(-1)), chlorine dosage (3-25 mg L(-l)), water temperature (5-30 degrees C) and usual coagulants on HANsFP in the Dez River water. Increasing chlorine reaction time up to 80 h led to the remarkable increase in HANsFP and after that the HANsFP was gradually increased. Over 90% of the HANs was formed during 80 h reaction time. Linear relationships were found between the HANsFP and the chlorine dosage. The result showed that the HANsFP increased by increasing TOC content up to 6 mg L(-1), while further increases in the TOC level did not lead to any significant changes in the HANsFP level. The acidic water pH resulted in the highest HANsFP. An increase in water temperature enhanced the HANsFP; this factor should be considered for tropical waterworks. The ferric chloride had a high efficiency for the removal of HANsFP (72%). Overall, the Dez River water had a high potential for forming the HANs (approximately 17 microg L(-1)). PMID- 25145189 TI - Determination of the mass transfer limiting step of dye adsorption onto commercial adsorbent by using mathematical models. AB - Reactive blue 5G dye removal in a fixed-bed column packed with Dowex Optipore SD 2 adsorbent was modelled. Three mathematical models were tested in order to determine the limiting step of the mass transfer of the dye adsorption process onto the adsorbent. The mass transfer resistance was considered to be a criterion for the determination of the difference between models. The models contained information about the external, internal, or surface adsorption limiting step. In the model development procedure, two hypotheses were applied to describe the internal mass transfer resistance. First, the mass transfer coefficient constant was considered. Second, the mass transfer coefficient was considered as a function of the dye concentration in the adsorbent. The experimental breakthrough curves were obtained for different particle diameters of the adsorbent, flow rates, and feed dye concentrations in order to evaluate the predictive power of the models. The values of the mass transfer parameters of the mathematical models were estimated by using the downhill simplex optimization method. The results showed that the model that considered internal resistance with a variable mass transfer coefficient was more flexible than the other ones and this model described the dynamics of the adsorption process of the dye in the fixed-bed column better. Hence, this model can be used for optimization and column design purposes for the investigated systems and similar ones. PMID- 25145190 TI - Surface rearrangement of nanoscale zerovalent iron: the role of pH and its implications in the kinetics of arsenate sorption. AB - We consider the use of metallic iron nanoparticles for cleaning contaminated water, focusing our study in the sorption of arsenic compounds. In particular, we discuss the results of their sorption process on the surface of zerovalent iron nanoparticles (nZVI) by performing a complete characterization of the surface modifications. Using scanning electron microscopy, X-ray diffraction analysis and high-resolution transmission electron microscopy, spectroscopy diffraction measurements and elemental mapping, we typify the surface reconstruction during the sorption process of As(V) from aqueous solutions using nZVI when it goes into a crystalline parasymplesite structure. The experimental results were correlated to the Freundlich isotherm sorption where the sorption capacity is depleted by the increase in the pH from 4 to 7 and associated with the surface passivation of nZVI. These techniques confirm the dependence of the sorption of arsenic as a function of pH and describe the specific details on the modification of the surface area of the nanoparticles. PMID- 25145191 TI - Acidification of non-medicated and oxytetracycline-medicated cattle manures during anaerobic digestion. AB - Possible adverse effects of a commonly used veterinary antibiotic, oxytetracycline (OTC), on acidogenic phase of anaerobic digestion of cattle manure along with optimum operating conditions were investigated. A standard veterinary practice of 50 ml OTC solution (20 mg/kg cattle weight) was injected into the muscles of cattle and then manure samples were collected for 5 days following the injection. The 5-day samples were equally mixed and used throughout digestion experiments. Preliminary batch tests were conducted to obtain the optimum pH range and observe volatile fatty acids (VFAs) production. In this regard, different sets of batch digesters were operated at pH ranging from 5.2 +/ 0.1 to 5.8 +/- 0.1 at mesophilic conditions with total solids content of 6.0 +/- 0.2%. The pH of 5.5 +/- 0.1 was found to be the optimum value for acidification for both non-medicated and OTC-medicated conditions. Under predetermined conditions, maximum total VFA (VFAtot) of 830 +/- 3 mg (as acetic acid)/L was produced and maximum acidification rate was evaluated as 11% for OTC-medicated cattle manure, whereas they were 900 +/- 6 mg (as acetic acid)/L and 12% for non medicated manure. Digestion studies were further continued in a semi-continuous mode at pH 5.5 +/- 0.1 and SRT/HRT of 5 days. VFAtot concentrations and maximum acidification rate increased up to 2181 +/- 19 mg (as acetic acid)/L and 29% for non-medicated cattle manure. For OTC-medicated cattle manure, lower acidification rate of 18% was observed. PMID- 25145193 TI - Non-selective oxidation of humic acid in heterogeneous aqueous systems: a comparative investigation on the effect of clay minerals. AB - Application of photocatalysis for degradation of natural organic matter (NOM) has received wide interest during the last decades. Besides NOM, model compounds more specifically humic acids (HAs) were also studied. As a continuation of the previous research, TiO2 photocatalytic degradation of HA was investigated in the presence of clay minerals, i.e., montmorillonite (Mt) and kaolinite (Kt). Degradation of HA was expressed by the pseudo-first-order kinetic modelling of dissolved organic carbon (DOC) and UV-VIS parameters (Colour436 and UV254). A slight rate enhancement was attained for Colour436 and UV254 in the presence of either Mt or Kt. The presence of clay particles did not significantly change the DOC degradation rate of HA. The effect of ionic strength (Ca2+ loading from 5 x 10(-4) M to 5 x 1(-3) M) was also assessed for the photocatalytic degradation of sole HA and HA in the presence of either Mt or Kt. Following photocatalytic treatment, molecular size distribution profiles of HA were presented. Besides the effective removal of higher molecular size fractions (100 and 30 kDa fractions), transformation to lower molecular size fractions (<3 kDa) was more pronounced for sole HA rather than HA in the presence of clay minerals. Scanning electron microscopic images with the energy dispersive X-ray analysis confirmed the diversities in surface morphologies of the binary and ternary systems composed of HA, TiO2 and Mt or Kt both prior to and following photocatalysis. This study demonstrated that photocatalysis could be applicable for DOC degradation in the presence of clay minerals in natural waters. PMID- 25145192 TI - Nanofiltration and Fenton's process over iron shavings for surfactants removal. AB - The presence of surfactants in wastewater composition tends to jeopardize the efficiency of the traditional aerobic treatment processes. In this regard, the application of Fenton's reaction and nanofiltration as single processes and integrated (nanofiltration followed by Fenton's process) was investigated on the abatement of a solution containing two surfactants usually found in effluents coming from detergent industry (dodecylbenzene--DDB and sodium lauryl ether sulphate--SLES). The potential of a solid waste (iron shavings) as catalyst in the Fenton's process was evaluated and the reaction system was optimized regarding the key operating parameters (iron and hydrogen peroxide concentration and pH). The highest chemical oxygen demand (COD) degradation (66%) was attained for pH 3, [H2O2] = 32 mM and 50 g/L of iron shavings. Besides, it was concluded that oxidation was due to hydroxyl radicals adsorbed on the metal surface even if bulk interaction between hydrogen peroxide and dissolved iron cannot be neglected. The main variables ruling nanofiltration were evaluated (pH, temperature and cross-flow rate). Eighty-four percent of COD rejection was determined at pH 7.5, cross-flow 14.4 cm3 s(-1), 20 degrees C and 15 bar of pressure drop. Finally, nanofiltration followed by Fenton's process under the best conditions was integrated; however, no significant improvement was attained with 85% of COD being globally removed. PMID- 25145194 TI - Ultrasound-assisted surfactant-enhanced emulsification microextraction for the determination of Cd and Ni in tea and water samples. AB - A microextraction method based on ultrasound-assisted surfactant-enhanced emulsification using solidification of a floating organic droplet (UASEME-SFO) was evaluated for simultaneous determination of Cd and Ni in water and tea samples followed by flame atomic absorption spectrometry. In the UASEME-SFO technique, Triton X-100 was used as an emulsifier to accelerate the emulsification of the extraction solvent into a sample solution and hasten the mass transfer of the analytes. Analytes form a complex and are extracted into 1 dodecanol which was used as an extraction solvent. Some parameters such as type and volume of the extraction solvent, the type and concentration of the surfactant, ultrasound extraction time, reagent concentration, centrifuge conditions and salt concentration were investigated. Under optimum conditions, calibration curves were linear in the range of 0.3-100 and 0.6-180 microg L(-1) with detection limits of 0.11 and 0.20 microg L(-1) for Cd and Ni, respectively. The accuracy of the method was confirmed by parallel analyses using the certified reference material of water and tea samples. The recoveries of the analytes in tea leaves, tea infusions and water samples were in the range of 96.5-105.1%. PMID- 25145195 TI - Bioremoval of Reactive Blue 220 by Gonium sp. biomass. AB - Gonium sp. was tested for the bioremoval of Reactive Blue 220 (RB220) dye at different conditions such as pH values, initial dye concentrations and biomass concentrations to evaluate the possibility of using this microalga in treating wastewaters. According to the data obtained from the experiments, microalgae removed RB220 with the highest yield (54.2%) at pH 8, and could treat the applied dye with the highest removal percentage as 84.2% at the lowest dye concentration (26.2 mg/L RB220). Increasing Gonium sp. biomass concentration from 0.21 to 0.53 g/L stimulated RB220 removal rate from 87.7% to 96.8%. The present study clearly indicated that Gonium sp. biomass could be used as a bioremediation biosorbent in treating RB220 dye in the related wastewaters. PMID- 25145196 TI - Reverse osmosis and nanofiltration of biologically treated leachate. AB - Experiments of nano-filtration (NF) and reverse osmosis (RO) were conducted to remove most pollutants from the biological treated leachate. For example, the purified permeate after reverse osmosis treatment with spiral membranes reached effluent water quality as follows: COD of 57 mg O2/l, BOD7 of 35 mg O2/l, and suspended solid of 1 mg/l which satisfies the discharge standards in Estonia. For both RO and NF, conductivity can be reduced by 91% from 6.06 to 0.371 mS/cm by RO and 99% from 200 to 1 mS/cm by NF. To test the service life of the RO spiral membranes, the process was able to reduce chemical oxygen demand (COD) and biological oxygen demand (BOD) of biologically treated leachate by 97.9% and 93.2% even after 328 and 586 hours, respectively. However, only 39.0% and 21.7% reductions of Ptot and Ntot were achieved. As a result, neither RO (spiral membranes process) nor NF was able to reduce the total nitrogen (TN) to the required discharge limit of 15 mg/l. PMID- 25145197 TI - Impact of crop-manure ratios on energy production and fertilizing characteristics of liquid and solid digestate during codigestion. AB - The influence of maize silage-manure ratios on energy output and digestate characteristics was studied using batch experiments. The methane production, nutrients availability (N and P) and heavy metals' content were followed in multiflask experiments at digestion times 7, 14, 20, 30 and 60 days. In addition, the available nutrient content in the liquid and solid parts of the digestate was evaluated. Aanaerobic digestion favoured the availability of nutrients to plants, after 61 days 20-26% increase in NH4+ and 0-36% increase in PO4(3-) were found in relation to initial concentrations. Digestion time and maize addition increased the availability of PO4(3-). Inorganic nutrients were found to be mainly available in the liquid part of the digestate, i.e. 80-92% NH4+ and 65-74% PO4(3 ). Manure had a positive effect on the methane production rate, whereas maize silage increased the total methane production per unit volatile solids in all treatments. PMID- 25145198 TI - Drawer compacted sand filter: a new and innovative method for on-site grey water treatment. AB - In this paper, results ofa new sand filter design were presented. The drawer compacted sand filter (DCSF) is a modified design for a sand filter in which the sand layer is broken down into several layers, each of which is 10 cm high and placed in a movable drawer separated by a 10 cm space. A lab-scale DCSF was designed and operated for 330 days fed by synthetic grey water. The response of drawer sand filters to variable hydraulic and organic loading rates (HLR and OLR) in terms of biological oxygen demand (BODs), chemical oxygen demand (COD), total suspended solids (TSS), pH, electrical conductivity and Escherichia coli reductions were evaluated. The HLR was studied by increasing from 72 to 142 L m( 2) day(-1) and OLR was studied by increasing it from 23 to 30 g BOD5 m(-2) day( 1) while keeping the HLR constant at 142 L m(-2) day(-1). Each loading regime was applied for 110 days. Results showed that DCSF was able to remove >90% of organic matter and total suspended solids for all doses. No significant difference was noticed in terms of overall filter efficiency between different loads for all parameters. Significant reduction in BOD5 and COD (P < .05) was noticed after water was drained through the third drawer in all tested loads. The paper concludes that DCSF would be appropriate for use in dense urban areas as its footprint is small and is appropriate for a wide range of users because of its convenience and low maintenance requirements. PMID- 25145199 TI - Effects of ageing on elution behaviour of nitrogenous compounds in disposed wastes from landfill sites. AB - Comparative studies of elution and cation exchange capacity (CEC) tests were applied to aged and fresh municipal and industrial solid wastes to examine the effects of ageing on the long-term elution behaviour of nitrogen on leachate in municipal and industrial solid waste landfill sites. Nitrogen in the leachate gradually eluted as organic nitrogen, but not upon transformation of organic nitrogen to elutable inorganic nitrogen compounds in the solid waste. Ammonium in the solid waste, retained similar to its interaction with clay minerals in soil, elutes when exposed to leachate by being replaced with highly concentrated cations or loses its positive charge in high pH in the leachate, which percolates down from the upper layer of the disposed waste. The quantity of ammonium adsorbed into the aged wastes through CEC measurement process by replacement with ammonium acetate was higher than that onto the fresh wastes. That difference in quantities can serve as an index of the ability of the solid waste to withhold ammonium in the leachate that percolates down the landfill layer. Those results demonstrate that ammonification of organic nitrogen in the waste is not the crucial step of the elution of nitrogenous compounds into leachate. PMID- 25145200 TI - Effect of pine bark on the biotransformation of trinitrotoluene and on the bacterial community structure in a batch experiment. AB - Pine bark, a low-cost industrial residue, has been suggested as a promising substitute for granular activated carbon in the on-site treatment of water contaminated with 2,4,6-trinitrotoluene (TNT). However, the complex organic structure and indigenous microbial community of pine bark have thus far not been thoroughly described in the context of TNT-contaminated water treatment. This two week batch study examined the removal efficiency ofTNT from water by (1) adsorption on pine bark and (2) simultaneous adsorption on pine bark and biotransformation by specialized TNT-biotransforming microbial inocula. The bacterial community composition of experimental batches, inocula and pine bark, was profiled by Illumina sequencing of the V6 region of the 16S rRNA gene. The results revealed that the inocula and experimental batches were dominated by phylotypes belonging to the Enterobacteriaceae family and that the tested inocula had good potential for TNT biotransformation. The type of applied inocula had the most profound effect on the TNT-transforming bacterial community structure in the experimental batches. The indigenous microbial community of pine bark harboured phylotypes that also have a potential to degrade TNT. Altogether, the combination of a specialized inoculum and pine bark proved to be the most efficient treatment option for TNT-contaminated water. PMID- 25145201 TI - Optimization of the performance of a thermophilic biotrickling filter for alpha pinene removal from polluted air. AB - Biodegradation of alpha-pinene was investigated in a biological thermophilic trickling filter, using a lava rock and polymer beads mixture as packing material. Partition coefficient (PC) between alpha-pinene and the polymeric material (Hytrel G3548 L) was measured at 50 degrees C. PCs of 57 and 846 were obtained between the polymer and either the water or the gas phase, respectively. BTF experiments were conducted under continuous load feeding. The effect of yeast extract (YE) addition in the recirculating nutrient medium was evaluated. There was a positive relationship between alpha-pinene biodegradation, CO2 production and YE addition. A maximum elimination capacity (ECmax) of 98.9 g m(-3) h(-1) was obtained for an alpha-pinene loading rate of about 121 g m(-3) h(-1) in the presence of 1 g L(-1) YE. The ECmax was reduced by half in the absence of YE. It was also found that a decrease in the liquid flow rate enhances alpha-pinene biodegradation by increasing the ECmax up to 103 gm(-3) h(-1) with a removal efficiency close to 90%. The impact of short-term shock-loads (6 h) was tested under different process conditions. Increasing the pollutant load either 10- or 20-fold resulted in a sudden drop in the BTF's removal capacity, although this effect was attenuated in the presence of YE. PMID- 25145202 TI - The effect of mixed-enzyme addition in anaerobic digestion on methane yield of dairy cattle manure. AB - This study investigates the effect of applying a mixture of enzymes (ME) to dairy cattle manure (DCM) as substrate in anaerobic digestion (AD). The aims of this study were to evaluate different methods of ME application to DCM at different temperatures and to investigate the effect of adding ME during the pre-treatment of the solid fractions of dairy cattle manure (SFDCM). The results showed that there was no positive effect of direct ME addition to substrate at either mesophilic (35 degrees C) or thermophilic (50 degrees C) process temperatures, but there was a significant 4.44% increase in methane yield when DCM, which had been incubated with ME addition at 50 degrees C for three days, was fed to a digester when compared to a control digester operating at the same retention time. Methane production was detected during the pre-treatment incubation, and the total sum methane yield during pre-treatment and digestion was found to be 8.33% higher than in the control. The addition of ME to the SFDCM in a pre incubation stage of 20 h at 35 degrees C gave a significant increase in methane yield by 4.15% in a digester treating a mixed substrate (30% liquid fractions DCM and 70% enzyme-treated SFDCM) when compared with the control digester treating a similar mixed substrate with inactivated enzyme addition. The results indicate that direct physical contact of enzyme molecules and organic material in DCM prior to AD, without the intervention of extracellular enzymes from the indigenous microorganism population, was needed in order to increase methane yields. PMID- 25145203 TI - Comparative removal of commercial diclofenac sodium by electro-oxidation on platinum anode and combined electro-oxidation and electrocoagulation on stainless steel anode. AB - Aqueous solution of diclofenac sodium (DCFNa) from commercial analgesic pill was electro-oxidized on platinum and stainless steel (SS) anodes. On platinum anode, 66% degradation of the parent drug was achieved at pH 4.5 with a corresponding COD reduction of 49% for a specific charge of 4200 Coulombs/L. Degradation and COD reduction were less at higher pHs of 8.5 and 10.9. A number of intermediates were detected with some of them persisting at the end of the treatment. On SS anode, 84% drug removal and 80% COD decline were achieved for a specific charge of 4200 Coulombs/L at pH 10.9, owing to combined electro-oxidation and electrocoagulation. Contrary to platinum anode, here the drug removal and COD reduction were lesser at lower pHs of 8.5 and 4.5. Electrocoagulation was found to proceed with the organics directly forming complex with iron in the matrix of the SS anode with the iron oxidizing to Fe(III) at pH 10.9 and Fe(II) at pHs 8.5 and 4.5. Intermediates detected in residual liquid were much less in number and abundance. PMID- 25145204 TI - Pathogen removal during wastewater treatment by vermifiltration. AB - The study was designed to determine the effect of earthworms and the mechanism behind removal of pathogens during wastewater treatment by vermifiltration. The experimental phase continued for 10 weeks, starting after the initial stabilization phase of one week. Significant organic matter degradation and coliform removal were observed during vermifiltration of domestic wastewater. It was observed that vermifilter (VF) reduced biochemical oxygen demand and chemical oxygen demand by 84.8% and 73.9%, respectively. Significant log removal was observed for total coliforms (TC), faecal coliforms (FC), faecal streptococci (FS) and Escherichia coli with a mean log removal value (K) of 2.92, 2.20, 1.85 and 1.68, respectively. The decay rate constant (k) for indicator organisms (TC, FC and FS) was observed to be high as 8.04, 6.59 and 5.55 m day(-1), respectively. The population of total heterotrophic bacteria, total fungi and actinomycetes reduced remarkably by 3.14, 1.29 and 2.13 log units, respectively. Antibacterial activity of the isolated microorganisms from VF against gram positive Staphylococcus aureus (ATCC 29213) and gram-negative E. coli (ATCC 25922) was observed which indicated the existence of a mechanism that may be responsible for pathogen removal during wastewater treatment. This demonstrated the production of antibacterial substance, from the microorganisms associated with earthworms, that causes inhibition of other microbes, specifying the effect of earthworms for pathogen removal. Overall, the present study contributes to the understanding of mechanism for pathogen removal during vermifiltration through antibacterial action of microflora. PMID- 25145205 TI - Characterization of recycled rubber media for hydrogen sulphide (H2S) control. AB - Hydrogen sulphide (H2S) adsorption capacities on recycled rubber media, tyre derived rubber particle (TDRP), and other rubber material (ORM) have been evaluated. As part of the research, densities, moisture contents, and surface properties of TDRP and ORM have been determined. The research team findings show that TDRP and ORM are more particulate in nature and not highly porous-like activated carbon. The characteristics of surface area, pore size, and moisture content support chemisorption on the macrosurface rather than physical adsorption in micropores. For example, moisture content is essential for H2S adsorption on ORM, and an increase in moisture content results in an increase in adsorption capacity. PMID- 25145206 TI - Improved semi-distributed model for phosphorus losses from Irish catchments. AB - Phosphorus (P) is one of the important limiting elements governing the quality of natural waters in Ireland. Good models that simulate the loss of P from catchments to water bodies are needed to understand the mechanism and transport of P and to assist in formulating appropriate policies and practices to control or manage the problem. In the present study, a new combined model (NCM) is developed as ahybridbetween soil and water assessment tool (SWAT) and Hydrological Simulation Program FORTRAN (HSPF) packages. The developed NCM model was tested, with the data from the Oona catchment in Ireland, and evaluated to insure it is capable of predicting flow and total P loads at the same level or better than SWAT and HSPF packages when used alone. The NCM produced better flow simulation in terms of Nash-Sutcliffe efficiency (R2) than SWAT when used alone for both calibration and validation periods when hourly time steps are used for rainfall and evapotranspiration. In addition, calibration for the total phosphorus load gave better R2 values than previously reported result for either HSPF or SWAT and showed better performance for most of the validation period. Using multi-objective optimization methods for optimizing both flow and total P loads gave better simulated results than using sequential optimization of flow followed by total phosphorus. Hence, the NCM model developed here can be used to improve the prediction of phosphorus loss to water bodies in Ireland. PMID- 25145207 TI - Metagenomic analysis reveals microbial diversity and function in the rhizosphere soil of a constructed wetland. AB - Microbial communities play a critical role in the degradation of effluent contaminants in constructed wetlands. Many questions remain, however, regarding the role ofmicrobial communities in rhizospheric soil. In this study, we used metagenomic analysis to assess microbial community composition and function in a constructed wetland receiving surface water. The diversity of the microbial community of rhizosphere soil was found to be significantly greater than that of the wetland influent water. This enhancement is likely due to the availability of diverse habitats and nutrients provided by the wetland plants. From function annotation of metagenomic data, a number of biodegradation pathways associated with 14 xenobiotic compounds were identified in soil. Nitrogen fixation, nitrification and denitrification genes were semi-quantitatively analysed. By screening of manganese transformation genes, we found that the biological oxidation of Mn2+ (mainly catalysed by multicopper oxidase) in the influent water yielded insoluble Mn4+, which subsequently precipitated and were incorporated into the wetland soil. These data show that the use of metagenomic analysis can provide important new insights for the study of wetland ecosystems and, in particular, how biologically mediated transformation or degradation can be used to reduce contamination of point and non-point source wastewater. PMID- 25145208 TI - Enhanced organic pollutant removal influenced by activated-ferric-sludge. AB - The primary goal of this study was to compare the pollutant removal efficiency of the reactivated activated-ferric-sludge (AFS) with that of the activated sludge (AS). Most tested organic pollutants were preferably removed by reactivated AFS. The optimal reactivated conditions for AFS were a reactivation time of 3 h, pH of 5-9, AFS dose of 5 g/L and dissolved oxygen of 2-6 mg/L. The results revealed a positive correlation between microbial activity and the removal efficiency of organic pollutants, with a higher microbial activity being associated with a better removal efficiency of organic pollutants. Additionally, variations in extracellular polymeric substances were found to be crucial to the microbial activity and adsorption capacity of reactivated AFS. After reactivation, reactivated AFS was superior to AS for the removal ofmost pollutants. Finally, the mechanism of AFS reactivation was investigated. Overall, the results of the present study demonstrate that reactivated AFS has the potential for widespread application in the removal of organic pollutants during the wastewater treatment process. PMID- 25145209 TI - Extracellular polymeric substances and bound water drastically affect bioleached sludge dewaterability at low temperature. AB - It is well documented that bioleaching with the co-inoculation ofAcidithiobacillus ferrooxidans and Acidithiobacillus thiooxidans can drastically enhance sludge dewaterability under ambient temperature condition, but little information on low temperature effect on bioleached sludge dewaterability is available. In this study, the optimum sludge retention time of bioleaching treatment and the mechanisms responsible for the dewaterability enhancement ofbioleached sludge were studied in two bioleaching systems conducted at a low temperature of 10 degrees C and a normal temperature of 28 degrees C, respectively. Results showed that Acidithiobacillus bacteria involved in the bioleaching were still active at 10 degrees C, and sludge capillary suction time (CST) decreased in the first 3 days of bioleaching. Nevertheless, the degree of sludge dewaterability enhancement by bioleaching was much lower at 10 degrees C than that at 28 degrees C. The only slight decreases in the sludge pH value and relative high contents of extracellular polymeric substances (EPS) and bound water at a low temperature were responsible for the relatively lower dewaterability enhancement of bioleached sludge compared to that at the normal temperature. Moreover, statistical results showed that sludge CST had significant positive correlations with the sludge pH value, and EPS and bound water contents in the optimum bioleaching process (from day 0 to day 3). Therefore, reducing medium pH, and/or removing EPS from bioleaching bacteria and bound water ofbioleached sludge through forced physical-chemical approaches prior to mechanical dewatering might be a good method to greatly improve sludge dewatering at a low temperature. PMID- 25145210 TI - Removal of road deposited sediments by sweeping and its contribution to highway runoff quality in Korea. AB - Highway runoff is known to be an important non-point source (NPS), increasing the load of pollutants in receiving water. For reducing NPS pollutants in runoff, removal of road deposited sediment (RDS) by sweeping is considered effective. However, the contribution of sweeping to the improvement of runoff quality has not been clearly and quantitatively demonstrated so far. In this study, a field test was carried out on a section of operating highway in Korea to investigate the effectiveness of sweeping on improving the quality of highway runoff. Results showed that the average reduction in the load of RDS by sweeping was 61.10% with a standard deviation of 1.74%. RDS removal efficiency decreased when the sweeping speed increased from 4-8 to 20 km h(-1), the load decreased from 12.5 to 1.25 g m(-2) and particle size decreased from sand to silt/clay size ranges. Runoff was induced by applying a 15 mm h(-1) artificial rainfall to both swept and non-swept sections. Analysis of runoff quality showed that the event mean concentrations of total suspended solid, biological oxygen demand, chemical oxygen demand, nutrients and most of the heavy metals were reduced by 31-87% after sweeping. In addition, field tests for RDS build-up indicated a sweeping frequency of once every four or five days to prevent re-suspension of RDS. The results of this study suggest that sweeping can be the best management practice for effectively reducing RDS on highways and improving the quality of highway runoff. PMID- 25145211 TI - Characterization of a cetyltrimethyl ammonium bromide-modified sorbent for removal of perfluorooctane sulphonate from water. AB - This study was carried out to develop a cost-effective and practicable sorbent for application in abrupt perfluorooctane sulphonate (PFOS) pollution accidents. The main merit of this work was that a waste material, namely construction and demolition (C&D) waste, was employed as a raw base material for the sorbent synthesis. The waste material underwent alkaline fusion-hydrothermal synthesis and a cationic surfactant cetyltrimethyl ammonium bromide (CTAB) modification process to form a CTAB-modified sorbent (CMCDSS). Experimental results showed that PFOS concentrations and solution pH had significant effect on the PFOS sorption on construction and demolition waste synthesized sorbent (CDSS) and CMCDSS (using 0.2CMCDSS as representative). PFOS could be effectively and rapidly adsorbed on CMCDSS, and sorption equilibrium was achieved within 2.5 h. The sorption amounts of PFOS on CMCDSSs enhanced along with the increase in CTAB loading amounts. Moreover, the CMCDSS can be applied effectively under acidic condition at pH 2-6 and various removal mechanisms were clarified at different sorption conditions. Accordingly, this work developed a novel and applicable material for dealing with abrupt environmental PFOS contamination accidents. PMID- 25145212 TI - Thermophilic co-digestion feasibility of distillers grains and swine manure: effect of C/N ratio and organic loading rate during high solid anaerobic digestion (HSAD). AB - Anaerobic co-digestion of high solids containing distillers grains and swine manure (total solids, 27 +/- 2% and 18 +/- 2%, respectively) was evaluated in this study to assess the effect of C/N ratio and organic loading rate (OLR). Feed mixture was balanced to achieve a C/N ratio of 30/1 by mixing distillers grains and swine manure. Pilot-scale co-digestion of distillers grains and swine manure was carried out under thermophilic conditions in the continuous mode for seven different OLRs from R1 to R7 (3.5, 5, 6, 8, 10, 12 and 14 kg VS/m3 day) under high solid anaerobic digestion. The methane yield and volatile solid (VS) removal were consistent; ranging from 0.33 to 0.34 m3CH4/kg VS day and 50-53%, respectively, until OLR 8 kg VS/m3 day. After which methane yield and VS removal significantly decreased to 0.26 m3 CH4/kg VS day and 42%, respectively, when OLR was increased to 14 kg VS/m3 day. However, during operation, at OLR of 10 kg VS/m3 day, the methane yield and VS removal increased after the 19th day to 0.33 m3 CH4/kg VS day and 46%, respectively, indicating that a longer acclimatization period is required by methanogens at a higher loading rate. PMID- 25145213 TI - Effect of activator on the structure and desulphurization efficiency of sludge activated carbon. AB - Sludge-activated carbons (SACs) prepared with excess of activated sludge are used to solve the problems of sludge disposal and odour pollution in a sewage treatment plant. For the preparation, ZnCl2, KOH and H2SO4 are used as activators, respectively. The structure of the SACs are characterized by scanning electron microscope, X-ray photoelectron spectrometer, specific surface area and pore structure technologies, and the adsorption performance of H2S is investigated. Results indicate that the desulphurization activity of SACs, whose activators are ZnCl2 and KOH (SACZ and SACK), is better than that of carbon with H2SO4 as the activator (SACH). The breakthrough time of SACZ and SACK is up to 86 min, the sulphur capacity is 7.7 mg/cm3, and the maximal iodine value is 409.95 mg/g. While the breakthrough time of SACH is only 26 min with the sulphur capacity of 2.3 mg/cm3. A large percentage of pore volume with a diameter of 2-5 nm in the total pore volume is conductive to the desulphurization reaction. The large amount of surface acid functional groups is also helpful to the adsorption of H2S. The desulphurization activity of SACZ and SACK is superior over that of commercial-activated carbon. PMID- 25145214 TI - Calculating specific denitrification rates in pre-denitrification by assessing the influence of dissolved oxygen, sludge loading and mixed-liquor recycle. AB - This article presents the results of an experimental study on the correlation among the specific denitrification rate (SDNR), the dissolved oxygen concentration (DO), the F:M ratio (F:M) and the mixed-liquor (ML) recycle in the pre-denitrification reactors fed by domestic sewage. The experimental curves reveal a 28.8-32.0% reduction in the SDNR at 20 degrees C (SDNR(20 degrees C)) with DO equal to 0.1 mgO2 L(-1) and F:M in the range 0.2-0.4 kgBOD5 kgMLVSS(-1) d(-1). The SDNR reduction increases to 50.0-55.9% with DO = 0.3 mgO2 L(-1). A mathematical correlation of these results and an equation for calculating SDNR(20 degrees C) as function of the F:M as well as the average DO and BOD5 in the total flow rate fed in the denitrification stage are proposed. The conducted experience gives useful suggestions for practical usage, in particular regarding the denitrification reactor design, and represents a good starting point for future applications with the aim to optimize the biological process in domestic sewage treatment plants. PMID- 25145215 TI - Pseudomonas fluorescens JH 70-4 promotes pb stabilization and early seedling growth of sudan grass in contaminated mining site soil. AB - A bacterial strain (JH 70-4) exhibiting plant growth promoting characteristics (indoleacetic acid production and 1-aminocyclopropane-1-carboxylate deaminase activity), as well as heavy metal(loid) (HM) tolerance and Pb precipitation, was isolated from HM-contaminated soil at an abandoned mine site. The bacterium was identified as Pseudomonas fluorescens based on 16S rDNA sequencing. The JH 70-4 strain induced precipitation of Pb as PbS nanoparticles, confirmed by X-ray diffraction. Solution pH, incubation time, and Pb concentration influenced removal and PbS formation. Inoculating contaminated soil with JH 70-4 decreased Pb availability; exchangeable Pb decreased while organic- and sulphide-bound Pb increased. The toxicity characteristic leaching procedure showed a 65% decrease in Pb in leachate 60 d after inoculating soil with JH 70-4. Shoot and root lengths of Sudan grass grown in the inoculated soil were greater than in the uninoculated soil. Findings suggest that microbial Pb fixation is a viable strategy for remediating soil and promoting plant growth for phytostabilization of contaminated sites. PMID- 25145216 TI - Isolating lignin from spent liquor of thermomechanical pulping process via adsorption. AB - Wood chips are pretreated with steam prior to refining in the thermomechanical pulping process. The steam treatment dissolves part of lignin of wood chips in the spent liquor (SL) of this process, and subsequently the SL is sent to the wastewater system of the process. However, the lignin of SL can be used in the production of value-added chemicals, but it should first be separated from the SL in order to have a feasible downstream process. In this study, activated carbon (AC) was considered as an adsorbent to isolate lignin from SL. The results showed that the maximum adsorption of lignin on AC was 166 mg/g under the optimal conditions of pH 5.2, 30 degrees C and 3 h treatment. Furthermore, the separation of lignin from SL was improved from 45% to 60% by having a two-stage adsorption process at pH 5.2, which also reduced the turbidity and chemical oxygen demand of SL by 39% and 32%, respectively. PMID- 25145217 TI - Improving biomass resource recycling capacity of Rubrivivax gelatinosus cultivated in wastewater through regulating the generation and use of energy. AB - This paper investigated Mg2+ enhancement of biomass production through regulating the generation and use of energy in Rubrivivax gelatinosus wastewater treatment. Results showed that proper Mg2+ dosage range was 1.5-15 mg/L. With optimal Mg2+ dosage (10 mg/L), biomass production (5010 mg/L) was improved by 60%. Both protein and chemical oxygen demand (COD) removals reached above 90%. Biomass yield improved by 38%. Hydraulic retention time was shortened by 25%. Mechanism analysis indicated that as activator, Mg2+ promoted specifically isocitrate dehydrogenase (IDH) and Ca2+ / Mg2+ -ATPase activities in energy metabolism, and then improved the generation of adenosine triphosphate (ATP) and the use of ATP. This enhanced the secretion and activity of protease, protein and COD removals, and then led to more biomass production. With 10 mg/L Mg2+, IDH and Ca2+ / Mg2+ ATPase activities, ATP production, protease activity were improved by 43.8%, 40.6%, 39.4% and 46.5%, respectively. PMID- 25145218 TI - Impacts of tilling and covering treatments on the biosolids solar drying conversion from class B to class A. AB - The objective of this study was to evaluate the effects of tillage and cover treatments of solar drying on the conversion of class B treated sewage sludge to a class A product. The experiments were performed over two years at Green Valley, Arizona in steel-constructed sand-filled drying beds of 1.0 m (width) x 3.0 m (length) x 0.6 m (depth). Freshly produced aerobically and anaerobically digested biosolids from nearby wastewater treatment plants received tillage and cover treatments for expediting solar drying and microbial inactivation. During the summer drying, covered drying bed increased faecal inactivation rate by 26% over other treatments and automated rain shield abated faecal coliform regrowth from summer rains. Tilling accelerated evaporation of moisture from the biosolids and increased the inactivation rate of faecal coliforms during the summer season. An automated retractable roof to protect the biosolids from rain aided in maintaining class A criteria by preventing dried biosolids from re-wetting by rainfall. However, results from tilling and passive solar heating during the cold winter seasons did not improve the faecal coliform inactivation rate due mainly to lower ambient temperatures. Thus, tilling and cover treatments can be effective in accelerating biosolids solar drying and thus enhancing pathogen inactivation during the summer season. Investigation on the effects of tillage depth and frequency is recommended to determine optimal tilling practice. PMID- 25145219 TI - Simultaneous removal of multiple pesticides from water: effect of organically modified clays as coagulant aid and adsorbent in coagulation-flocculation process. AB - Contamination of drinking water sources with agrochemical residues became a major concern in the twenty-first century. Coagulation-flocculation is the most widely used water-treatment process, but the efficiency to remove pesticides and other organic pollutants are limited compared to adsorption process. Thus, simultaneous action of adsorption on normal bentonite or organo-modified montmorillonite clays [modified with octadecylamine (ODA-M) and octadecylamine + amino propyltriethoxysilane (ODAAPS-M)] followed by coagulation-flocculation by alum and poly aluminium chloride has been evaluated for removal of 10 different pesticides, namely atrazine, lindane, metribuzin, aldrin, chlorpyriphos, pendimethalin, alpha-endosulphan, beta-endosulphan, p,p'-DDT, cypermethrin and two of its metabolites, endosulphan sulphate and p,p'-DDE, from water. The coagulation without integration of adsorption was less effective (removal % varies from 12 to 49) than the adsorption-coagulation integrated system (removal % varies from 71 to 100). Further, coagulation integrated with adsorption was more effective when organically modified montmorillonite was used as adsorbent compared to normal bentonite. The removal efficiency of organic clay depends upon the concentration of pesticides, doses of clay minerals, and efficiency was more for ODAAPS-M as compared to ODA-M. The combination of ODAAPS-M-clay with coagulants was also used efficiently for the removal of pesticides from natural and fortified natural water collected and the results exhibit the usefulness of this remediation technique for application in water decontamination and in treatment of industrial and agricultural waste waters. PMID- 25145220 TI - Simultaneous removal of nitrogen, phosphorus and COD in an integrated OCO reactor. AB - An integrated OCO reactor with two side-ditch separators based on the anaerobic/anoxic/oxic (A2/O) process was developed for municipal wastewater treatment in this study. The effects of dissolved oxygen (DO) concentration, hydraulic retention time (HRT) and the ratio of chemical oxygen demand (COD) to total nitrogen (C/N) in the influent were investigated for optimization, in order to achieve the removal of total nitrogen (TN), total phosphorus (TP) and COD in the reactor simultaneously. When the DO concentration of 2.0 mg/L in the aerobic zone, HRT of 12 h and C/N ratio of 8:1 were applied in the reactor, the superior removal efficiencies of COD, TN and TP reached 96%, 81% and 92%, respectively. The modification in integrated OCO system was characterized by the mixing of the liquid refluxed from anoxic and aerobic zones with the influent in the anaerobic zone. And the risk of activated sludge bulking was decreased successfully by enhancing phosphorus removal without any chemical auxiliary methods. Quite precise prediction results with the correlation coefficients (R) of 0.9584-0.9948 were forecasted by the back-propagation neural network model. All the results indicated that the integrated OCO process is able to remove TN, TP and COD in a reactor simultaneously. PMID- 25145221 TI - Effect of solids retention time on membrane fouling intensity in two-stage submerged anaerobic membrane bioreactors treating palm oil mill effluent. AB - Submerged anaerobic membrane bioreactors (SAnMBRs) treating palm oil mill effluent were analysed in terms of membrane fouling dynamics when working at three different sludge retention times (SRTs of 15, 30 and 60 d). The average permeate flux was fixed at 2.4 L x m(-2) x h(-1). During operation, the membrane was regenerated by using two steps: membrane wiping during each experiment as soon as trans-membrane pressure reached 125-130 mbars, and complete membrane cleaning including backwash and chemical cleaning at the end of each experiment when analysing the membrane surface and foulant material. Whatever the SRT, the cake formation was the dominant effect on membrane fouling dynamics. The concentration of suspended solids in the SAnMBRs, depending on the SRT, was then a determining criterion. Scanning electron microscopy, energy dispersive X-ray spectroscopy, atomic force microscopy, Fourier transform infrared spectroscopy indicated that fouled membrane surfaces were covered with a cake layer containing organic and inorganic elements whose concentrations were higher when working at a higher SRT; the higher concentrations of such elements gave to the cake layer a denser and more compact structure. In these experiments, the soluble fractions played a secondary role because of the dominant effect of cake layer structuring. PMID- 25145222 TI - Challenges and advances in pesticide application technology. PMID- 25145223 TI - High-speed imaging use to predict spray retention on barley leaves. AB - Measuring spray retention by plant leaves was the aim of many experiments in plant protection researches. Different methods have been used to measure spray proportion retained on vegetative surfaces, such as chemical methods using dyes and other methods using image analysis. We conducted Laboratory studies in order to validate the effectiveness of using high-speed imaging method developed by Massinon and Lebeau (2012a) to replace chemical analysis by spectrofluorometry. Measurements were performed with a high speed camera coupled with a retro-LED lighting. Sizes and velocities of the drops were extracted by image analysis and drop impact behaviours were determined by the operator. Drops were produced with a flat-fan nozzle mounted on a movable ramp. Two surfactants (Break Thru 5240 and Li700) were sprayed to highlight the effect of the reduction of surface tension. Sprays contained a fluorescent tracer for the chemical analysis, fluorescein. Relative volume proportions were computed within of an energy scale based on the Weber number. Results of high-speed imaging were compared to those of the chemical analysis by spectrofluorometry. PMID- 25145224 TI - Decision support tools for environmentally safe use of pesticides. AB - Prevention of environmental risk due to pesticide application is demanded by EU legislation regarding water and crop protection issues. The pesticide users are required to take responsibility for the environmental consequences of applications. Therefore they need to make responsible decisions at both strategic and tactical level. The first one is a long term decision on selection of equipment, and the other applies to decisions on use of equipment in actual meteorological and environmental situation at any time when treatment is needed. In order to assist the user to make proper decisions the decision support tools were developed in form of web-based applications: EOS - Environmentally Optimised Sprayer; DET--Drift Evaluation Tool. EOS performs evaluation of the sprayer in terms of its risk mitigation potential based on the technical solutions present on the sprayer and selected by the user. EOS has been designed as a stepwise structured questionnaire, divided in sections representing different sources of pollution, i.e. RISK AREAS (step 1): Inside contamination; outside contamination; Filling; Spray Loss (Drift); Remnants. Within each RISK AREA there were identified PROBLEMS (step 2) to be solved by different TECHNOLOGIES (step 3), evaluated in different ASPECTS (step 4) when the user selects TECHNICAL SOLUTION (step 5) used on the sprayer. The items of steps 1-4 were assigned weights (%) and the items of TECHNICAL SOLUTIONs were scored from 0 to 10 (10 = best in class). This stepwise approach and valuation of items allows for calculating the effective score of each individual TECHNICAL SOLUTION in terms of its risk mitigation potential. The sum of these individual scores related to the final score of environmentally optimised sprayer gives the evaluated sprayer's EOS index (%) expressing the environmental value of the sprayer. DET performs evaluation of drift risk in actual situation, and proposes measures to mitigate this risk, helping the operator to make better tactical decisions. It consists of three sections: (I) SPRAY APPLICATION SITE; (II) METEO and FIELD CONDITIONS; (III) DRIFT RISK MITIGATION. Within the sections (I) and (II) the user makes selection of options defining the distance between application site and sensitive areas, as well as weather and field/crop conditions. The selected items describe the actual and objective situation, for which DET calculates the Drift Risk Value [%] followed by appropriate recommendation. In section (III) the user can simulate and check the effect of drift mitigation measures by selecting one of the classified spray drift reduction technologies or key application parameters affecting risk of drift. Based on the user's selection the tool appropriately modifies the Drift Risk Value and gives the final recommendation. Simple and practical EOS and DET tools are meant to be used by pesticide users and advisors as they also have educative and awareness raising value. PMID- 25145226 TI - A novel device for the study of antimicrobial activity by vapor-contact of volatile substances on food products. AB - A novel device for the study of antimicrobial activity by vapour contact of volatile substances have been designed. This "big size" system, made up in inert acrylic material, is furnished with a fan and a hot plate with the aim to have a quick evaporation of volatile substances. It is able to contain fruits or other food products under controlled atmosphere and it can simulate real condition of storage or as well real condition of food pre-treatment by antimicrobial volatile substances. Such system is suitable to perform both in vitro (disk diffusion test) and in vivo (exposure and testing of food products) experiments. To shed light on the behaviour of this chamber the concentration in the head space of several substances have been monitored by GC-MS analysis during the time. Both single (mono-terpene compounds) and mixture of terpenoids have been studied. Different behaviours have been founds depending on the starting molecules studied. Limonene, myrcene and eucalyptol, in single standard experiment, show a similar shape of head space concentration curve versus the time: the concentration increases at the beginning, then reaches a maximum and decreases until it reaches a plateau. In contrast linalool shows a head space concentration curve constant during the time, whereas mixtures of terpenes like myrcene and linalool show a concentration curve of vapour phase in agreement with Raloult's Law. The experiments carried out with Essential Oils (EOs) shows that in our system only more volatile fraction of EOs compose the vapour phase. PMID- 25145225 TI - Quality changes of 'Sanguinello' oranges wrapped with different plastic films under simulated marketing conditions. AB - Chemical and eating quality of citrus fruit changes slowly after harvest, and quality alteration is mainly due to shrinkage, loss of firmness, excessive weight loss and decay rather than a reduction of nutritional value and taste features. Film wrapping may be a suitable means to reduce transpiration and preserve market quality provided film permeability to gases does not lead to: 1) a reduction of in-package O2 partial pressure at a point that would induce anaerobic respiration; 2) an increase of CO2 concentration to toxic levels. This experiment was carried out to study quality changes of 'Sanguinello' oranges treated or not treated with 500 mg/L imazalil (IMZ) and wrapped with continuous, macro- or micro perforated polyolefinic films. Wrapped and no-wrapped fruit were stored at 20 degrees C and 60% RH for 20 or 30 days. In-package gas composition of the macro perforated film showed no significant difference compared to air composition, while in-package partial pressure of CO2 and O2 ranged between 4 (continuous film) and 9.8 kPa (micro-perforated films), and 14.8 (continuous film) and 5 kPa (micro-perforated films), respectively. After 30 days of storage weight loss in fruit wrapped with the macro-perforated film was (4.3%) slightly lowerthan un packed fruit (5%), while in all other packages weight loss never exceeded 0.7%.Quality changes were quite stable over storage in all treatments, although slight but significantly lower levels of total soluble solids and ascorbic acid were detected in micro-perforated films with the lowest degree of perforation. However, the sensory analysis denoted a remarkable decrease of firmness in un wrapped or wrapped fruit with macro-perforated film, while a moderate build-up of off-flavour, which reduced the eating quality, developed in micro-perforated films. Decay ranged between 6 and 12% in not treated fruit, with the lowest incidence detected in un-wrapped fruit, whereas differences among the different films were not significant. No decay was detected in fruit treated with IMZ. 'Sanguinello' oranges can be stored under retail conditions for a month by the only means of film wrapping without important changes in chemical, eating and marketing quality provided fruit are treated with an effective fungicide to prevent decay and that in-package gas composition is not markedly changed with respect to air. PMID- 25145227 TI - Effect of different film packaging on microbial growth in minimally processed cactus pear (Opuntia ficus-indica). AB - Microorganisms are natural contaminants of fresh produce and minimally processed products, and contamination arises from a number of sources, including the environment, postharvest handling and processing. Fresh-cut products are particularly susceptible to microbial contaminations because of the changes occurring in the tissues during processing. In package gas composition of modified atmosphere packaging (MAP) in combination with low storage temperatures besides reducing physiological activity of packaged produce, can also delay pathogen growth. Present study investigated on the effect of MAPs, achieved with different plastic films, on microbial growth of minimally processed cactus pear (Opuntio ficus-indica) fruit. Five different plastic materials were used for packaging the manually peeled fruit. That is: a) polypropylene film (Termoplast MY 40 micron thickness, O2 transmission rate 300 cc/m2/24h); b) polyethylene film (Bolphane BHE, 11 micron thickness, O2 transmission rate 19000 cc/m2/24h); c) polypropylene laser-perforated films (Mach Packaging) with 8, 16 or 32 100-micron holes. Total aerobic psychrophilic, mesophilic microorganisms, Enterobacteriaceae, yeast, mould populations and in-package CO2, O2 and C2H4 were determined at each storage time. Different final gas compositions, ranging from 7.8 KPa to 17.1 KPa O2, and 12.7 KPa to 2.6 KPa CO2, were achieved with MY and micro perforated films, respectively. Differences were detected in the mesophilic, Enterobacteriaceae and yeast loads, while no difference was detected in psychrophilic microorganisms. At the end of storage, microbial load in fruits sealed with MY film was significantly lower than in those sealed with BHE and micro perforated films. Furthermore, fruits packed with micro-perforated films showed the highest microbial load. This occurrence may in part be related to in package gas composition and in part to a continuous contamination of microorganisms through micro-holes. PMID- 25145228 TI - Effect of heat treatments on biomolecular profile of Sardinian apple cultivars. AB - Postharvest heat treatments (hot water or hot air treatment) may be applied to horticultural crops to control fungal diseases, insect infestation and to reduce chilling injury in cultivars susceptible to low storage temperatures. The present study investigated the influence of hot water (53 degrees C for 60s) and hot air treatment (38 degrees C for 24h) applied to two typical Sardinian apple varieties, cvs. Miali and Caddina, on the composition of the lipophilic extracts of the peel as well as on the antioxidant activity of ethanolic extracts of both peel and pulp. The lipophilic extracts of the peel of the two varieties were almost similar and resulted to be dominated by the presence of triterpenes being ursolic and oleanoic acids the main metabolites in both analysed fruits. The chemical analysis of the extracts obtained from the different heat-treated samples for each variety revealed no significant difference in the relative distribution of triterpene components with respect to untreated control samples. This strongly suggested that heat treatment does not affect the composition of terpene metabolite profile of the fruit peel. On the other hand, the antioxidant activity of the ethanolic extracts of the peel and the pulp of heat treated was significantly different from that of control In particular, on Caddina variety the antioxidant activity levels of the peel were consistently higher than in the pulp and were affected by storage conditions. Differently, on Miali variety the antioxidant activity of heat-treated samples was higher than control sample in both peel and pulp. PMID- 25145229 TI - Postharvest decay control of citrus fruit by preharvest pyrimethanil spray. AB - Preharvest infections or conidia load on fruit surface by Penicillium digitatum, P. italicum, Alternaria citri and other filamentous fungi can cause important postharvest losses of citrus fruit. Reduction in pruning frequency occurred in the last decade together with un-picked yield that eventually rots on the trees have increased the risk of postharvest decay especially when environmental conditions at picking time are favourable to pathogens' development. Sanitation procedures in the packinghouses, alternate use of postharvest fungicides with different modes of action, along with fungicide application before harvest could be an effective approach to minimize postharvest decay in citrus fruit. The present study investigated the effectiveness of a preharvest treatment with pyrimethanil (PYR), a broad spectrum fungicide, recently registered in different citrus-producing countries for postharvest treatments of citrus fruit and widely used worldwide as a preharvest treatment to control various diseases in different crops. PYR (750 mg/L) was sprayed by a hand-back sprayer at run-off on 'Fremont' mandarins. The day after the treatment, half of the trees were sprayed with a 10(4) conidial suspension of P. digitatum at run-off. Fruit were harvested following 2 or 4 weeks from treatments. Sound or either wounded 2-mm-deep and 2 mm-wide or superficial wound-scratched fruit were stored at 20 degrees C and 90% RH and inspected for decay after 1, 2 or 3 weeks of storage. In fruit harvested after 2 weeks from field treatment, PYR remarkably reduced decay development during two weeks of storage in sound fruit and in wound-scratched fruit and was fairly effective even after 4 weeks from treatment, but was ineffective in fruit wounded 2 mm deep and 2 mm wide. PYR was also effective in reducing preharvest decay incited by P. digitatum, P. italicum and Botrytis cinerea, but not by other pathogens. Results show that preharvest treatment with PYR could be a feasible approach to reduce postharvest chemical control of decay of citrus fruit. PMID- 25145230 TI - Secondary metabolites: applications on cultural heritage. AB - Biological sciences and related bio-technology play a very important role in research projects concerning protection and preservation of cultural heritage for future generations. In this work secondary metabolites of Burkholderia gladioli pv. agaricicola (Bga) ICMP 11096 strain and crude extract of glycoalkaloids from Solanaceae plants, were tested against a panel of microorganisms isolated from calcarenite stones of two historical bridges located in Potenza and in Campomaggiore (Southern Italy). The isolated bacteria belong to Bacillus cereus and Arthrobacter agilis species, while fungi belong to Aspergillus, Penicillium, Coprinellus, Fusarium, Rhizoctonio and Stemphylium genera. Bga broth (unfiltered) and glycoalkaloids extracts were able to inhibit the growth of all bacterial isolates. Bga culture was active against fungal colonies, while Solanaceae extract exerted bio-activity against Fusarium and Rhizoctonia genera. PMID- 25145231 TI - Pest select database: a new tool to use selective pesticides for IPM. AB - Crop pests can be naturally controlled by a set of beneficial arthropods, as entomophagous predators or parasites, leading to a global reduction of pest occurrence and insecticide use. The selectivity of plant protection products for these beneficial arthropods is a key factor in the success of IPM strategies. An abundant scientific literature concerning this subject exists, but for the final pesticide users, the information is not always easily accessible or understood. The IOBC working group "Pesticides and Beneficial Organisms" (PBO) has developed a new database to compile all data concerning pesticide selectivity on beneficial arthropods, obtained with methods that followed the IOBC test standard characteristics. These standards have been developed since the 70's by the Working group Pesticide and Beneficial Organisms, in the context of IPM. This database includes a first set of data previously published, coming from the different Joint Pesticide Testing Programs, with the addition of results published later in the IOBC Bulletin. The second set of data has been extracted from the Public verse of the Draft Assessment Report (DAR), established by the different EU member' states in the context of the registration process at the European Level and available online on the EFSA website. As nearly all active ingredients have to be tested on at least 2 to 4 selected beneficial arthropod species with methods that followed the IOBC standard characteristics, these DAR represent an important source of information for pesticide users dealing with beneficial arthropods and selectivity, with about 50% of the actual records. This source was previously only exploited for registration purposes and not accessible to a large public, but a lot of results, mainly from the first tier testing, have been compiled and interpreted for IPM. The new database is available online on the area restricted to the IOBC-members (http:// www.iobc wprs.org/restricted_member/toolbox.cfm). This database will be updated regularly on basis of the new IOBC publications, EFSA Draft Assessment Report and scientific publication results that followed IOBC standard characteristics. PMID- 25145232 TI - Vegephy: impact of vegetable oils used as extemporaneous additives on pesticide residues and their crop protection potential. AB - Within the framework of the VEGEPHY project set up to assess the effect of refined oils used as extemporaneous additives, both alone and in combination with oligosaccharides (guar, xanthan and carboxymethyl cellulose), on the quality of plant protection treatments for wheat, a study was conducted on the effect of combinations of additives on the level of pesticide residues in wheat plants and grain and their impact on treatment efficiency. The use of some of these additives gave efficiency results that were comparable with those obtained with additives that are currently used but are not bio-based. The use of refined oils as extemporaneous additives, both alone and combined with oligosaccharides, led to better penetration by the pesticide as well as longer persistence of its activity. The experiments were conducted with fungicides, herbicides, plant growth regulators and various types of formulation (EC, SC and WG). The results obtained were conclusive, but they did depend on the physico-chemical properties of the active substance. The risk of exceeding the maximum residue levels (MRLs) of pesticides was also evaluated. Even where the MRLs had not been not exceeded, the experiments showed that in some cases the treatment with these additives could lead to pesticide residues up to two times higher than those measured for the treatment without additives. It would be necessary, therefore, to reduce the treatment dose associated with the additive and/or have a long enough pre-harvest interval to avoid exceeding the MRLs. The use of green additives could be a useful and easy way to attain the European Union (EU) goal of reducing pesticide use by improving the retention of active substances on the plant and reducing the number of treatments. PMID- 25145233 TI - Pesticide residue free fruits: the aim of Trentino apple production system. AB - Chemical analyses performed in 2011 on the 575 samples of apples in Trentino (Italy), there are in average 3.24 active ingredient per sample. Moreover, in 98% of the samples with detectable residues, the level did not exceed 30% of the official MRL This result is achieved thanks to the implementation of the guide lines for integrated production by the 8000 fruit growers, to an extension service which justifies the need of the treatment and gives advice on which pesticide fit better for the time-pest combination, to the systematic check up of the sprayers, to the correct sizing of mix volumes to spray according to the size of the canopy, to the selection of active ingredients based on their residual activity in field tests, and to the systematic monitoring of the level of residues found on representative samples of the product at harvest. With these assumptions, the next goal is to eliminate all traces of insecticides and acaricides now present only in 30% of the samples. This aim could be achieved by extending the use of pheromone mating disruption to control fruit feeding Lepidoptera, as well as by promoting the use of short persistent residue products during the final part of the season. Results of some of the experimental field trials are presented and discussed. PMID- 25145234 TI - Residue levels, persistence and effectiveness of imazalil against a resistant strain of penicillium digitatum when applied in combination with heat and sodium bicarbonate. AB - Green and blue molds, respectively caused by Penicillium digitatum Sacc., and P. italicum Wehmer, are the most important postharvest diseases of citrus fruit Postharvest management of these pathogens is mainly based on the application of thiabendazole (TBZ) or imazalil (IMZ) fungicides. However, their intensive and prolonged use has led to the selection of TBZ- IMZ-resistant strains of these pathogens and to a reduction of TBZ and IMZ effectiveness to control postharvest decay. However, while TBZ may become completely ineffective against TBZ-resistant strains of P. digitatum, reduction of IMZ efficacy is only partial, and an effective control of decay can still be achieved by increasing its concentration, heating the treatment-solution and/or combining IMZ with sodium bicarbonate (SBC) or other food additives or natural salts. In this study, 'Desiderio' and 'Nova' mandarins were inoculated with spores of a sensitive strain of P. digitatum to IMZ and TBZ (PDs) or with a strain of P. digitatum with double resistance to both fungicides (PDr) and immersed in IMZ or TBZ emulsions at increasing concentrations up to 1000 mg/L or in IMZ (25, 200 or 400 mg/L), SBC (0.5, 1 or 2%) or IMZ + SBC emulsions either at 20 or 40 degrees C. IMZ was superior to TBZ to control decay of 'Desiderio' mandarins incited by PDs and was also effective to control decay in fruit inoculated with PDr, while TBZ even at the highest rate was completely ineffective. In 'Desiderio' mandarins inoculated with PDs, a complete control of decay was achieved with 25 mg/L IMZ but in fruit inoculated with PDr, 25 mg/L IMZ were ineffective to control decay despite in combination with SBC at 2% a synergistic effect was detected. In contrast, a good control of decay was achieved with 400 mg/L IMZ. In 'Nova' mandarins after 1 week of incubation at 20 degrees C decay incidence in fruit dipped in 400 mg/L at 20 degrees C or 200 mg/L IMZ at 40 degrees C was almost completely inhibited, while the addition of SBC at 0.5, 1 or 2% did not improve treatments performance in fruit inoculated with PDs. However, when 'Nova' mandarins were inoculated with PDr, SBC showed a modest but significant control of decay and in combination with IMZ either at 400 mg/L and 20 degrees C or 200 mg/L and 40 degrees C, significantly improved decay control. SBC did not affect IMZ residue load in 'Valencia' oranges, whereas dipping the fruit in 400 mg/L IMZ at 20 degrees C produced similar IMZ residue load as dips at 200 mg/L IMZ at 40 degrees C. In all cases, residue levels of IMZ never exceeded 2 mg/kg, which is about 40% of the maximum residue limits (MRLs) allowed in European countries. Thus, despite the selection of IMZ-resistant strains of P. digitatum, IMZ continues to be highly effective to control green mold of citrus fruit at concentrations leaving on fruit surface residue levels below the MRLs. PMID- 25145235 TI - Chlorpyrifos residues in food plant in the region of Setif-Algeria. AB - The epidemiological studies demonstrate that the residues of pesticides in plant food, increases the impact of cancers on the professionally populations. The effect of the residues of pesticides can also be at the origin of dysfunction of the reproductive systems, endocrinal and immune systems, ague attack and column of the nervous system and the deterioration of lungs. In this study, Chlorpyrifos residues in the samples were detected and quantified by employing high performance liquid chromatography (HPLC). The presence of these wastes in fruits and vegetables are confirmed. Acquired results revealed concentration in residue of chlorpyrifos in the apples, tomatoes, green and red pepper cultivated in the country as well as at the level of the cucumber. Our results showed that 61% of the analyzed samples introduce stocks of residues of pesticides which are broadly superior to the accepted maximum limit. PMID- 25145236 TI - The impact of mesotrione on several microbiological activity of chernozem soil. AB - The effect of mesotrione on microbiological activity in soil was investigated. Trials were set up in laboratory on chernozem soil (pH 7.0, organic matter 3.5%, sand 26%, silt 45%, clay 29%) at Surcin, Serbia. Mesotrione was added at rates 0.5 (field rate), 5, 25 i 50 mg/kg soil. Untreated soil served as control. Samples were collected for analysis 5, 20, 40 and 60 days after mesotrione application. The effects were assessed on bacteria abundance, fungi abundance, and dehydrogenase activity. Mesotrione was found to cause different effects on the soil microbial activity in soil and its influence depended on the rate of application and duration of activity. Mesotrione applied at 0.5 and 5 mg/kg soil did not have any effect on microbial activity. The higher herbicide doses (25 and 50 mg/kg) induced increasing activity from the 5th to 60th day. These experimental data indicated that mesotrione affected soil microbial activity, but the effects were only detected at higher doses far exceeding the recommended field rate. PMID- 25145237 TI - Essential oil compounds as stress reducing agents in rats. AB - Essential oil compounds were studied to demonstrate their potential as stress reducing agents against rats. Rats were intraperitoneal administered with Linalool, Cineole and Thymol, respectively. Anxiety-related behaviors were determined by open field test and elevated plus maze test. Thymol reduced anxiety related behavior of the animals. Linalool had no effect in both sexes of rats in the open field test. Thus, the results suggested that Thymol and Linalool are safe to control pets without harming non-target mammals PMID- 25145238 TI - Toxicity of pendimethalin containing formulation and copper sulphate to chicken embryos. AB - The aim of this study was to determine the individual and combined toxic effects of STOMP 330 EC herbicide (33% pendimethalin) and copper sulphate on the development of chicken embryos. On the first day of incubation chicken eggs were dipped in the solution or emulsion of the test materials for 30 minutes. Applied concentration of copper sulphate was 0.01% and of herbicide STOMP 330 EC was 1.25%. The chicken embryos were examined for the followings: rate of embryo mortality, body weight, type of developmental anomalies, macroscopic examination. Our teratogenicity study revealed that, the individual toxic effect of copper sulphate and pendimethalin containing herbicide formulation (STOMP 330 EC) were embryotoxic but not teratogenic in chicken. The combined administration of STOMP 330 EC and copper sulphate did not increase the embryotoxic effect. PMID- 25145239 TI - In vitro eye corrosion study of agrochemicals on isolated chicken eye. AB - Agrochemicals must undergo numberless toxicological tests before marketing. The eye irritation test is part of this test packet. Nowadays, OECD 405 can be used to classify the irritation potential of substances, the base of the OECD 405 guideline is the Draize test, which is one of the most criticized in vivo methods because of the injuries of the test animals and subjective nature of the test in recording the results. Therefore, several in vitro tests have been developed to replace totally or partly the in vivo eye irritation testing. The isolated chicken eye test method (OECD 438), which was used, is one of these alternative methods. Five different agrochemicals were examined in the following way: All test compounds were applied in a single dose onto the cornea of isolated chicken eyes in order to potentially classify the test compounds as ocular corrosive and/or severe irritant. The damages caused by the test substances were assessed by the determination of corneal swelling, opacity, fluorescein retention and morphological effects. These parameters were evaluated pre-treatment and starting at approximately 30, 75, 120, 180, and 240 minutes after the post-treatment rinse. The endpoints evaluated were corneal opacity, swelling, fluorescein retention and morphological effects. All of the endpoints, with the exception of fluorescein retention (which was determined only at pre-treatment and 30 minutes after test substance exposure) were determined at each of the above time points. Positive and negative controls were used and they showed the expected results in each study. In these in vitro eye corrosives and severe irritants studies, using the Isolated Chicken Eye model with five different products, no ocular corrosion or severe irritation potential were observed. These results correspond to the available information about the tested agrochemicals, so these studies with isolated chicken eye are considered to be successful. PMID- 25145240 TI - Biology of rice bug Leptocorisa oratorius (Fabricius) (Hemiptera: Alydidae), population change and alternative host plants. AB - Leptocorisa oratorius (Fabricius) (Hemiptera: Alydidae) is a major rice pest which feeds on the sap of stems and rice seeds. Some graminaceous weed species serve as an alternative host of L. oratorius causing outbreaks throughout the rice growing season. Population changes of L. oratorius during both rice growing seasons - wet-season rice and dry-season rice - including the influence of alternative host, barnyard grass Echinochloa crus-galli (Graminaceae) on the development of L. oratorius was studied. Results presented that L. oratorius was the dominant pest species during the late phase of rice growth. Adults of L. oratorius started their migrations to wet-season rice at the vegetative stage of rice growth, while they migrated to dry-season rice at the repropuctive stage of rice growth. Leptocorisa oratorius breds rapidly in rice fields. Meanwhile, other adults migrated to the rice field. The population of adults and nymphs significantly increased from the reproductive stage to grain formation and ripening stage in both rice growing seasons. The population of nymphs was greater than adults but not significantly different in their number of individuals. Leptocorisa oratorius had one generation in each rice growing season. The results of the host plant study indicated that L oratorius developed completely in barnyard grass E. crus-galli as well as rice Oriza sativa (Graminaceae). However, L. oratorius preferred rice to barnyard grass for feeding and oviposition. PMID- 25145241 TI - Some ecological aspects on olive parlatoria scale, Parlatoria oleae (Colvee) infested plum and olive trees under irrigation system at Burg El-Arab area, Alexandria, Egypt. AB - Field studies were conducted under irrigation system at Burg El-Arab area (50 K.m. west of Alexandria city) to study some ecological aspects of Parlatoria oleae (Colvee) and its parasitoid, Aphytis maculicornis (Masi) that infested olive and plum trees during the two successive years of 2010 and 2011. Field observations revealed that the most of the inspected individuals occurred mainly on the branches of plum trees as compared with those found on leaves, but on olive the insect occurred on all the plant parts including fruits. On plum trees, the obtained data showed that the population of P. oleae reached the maximum during April, November and January in the first year, but in the second one it had four peaks of high population levels during March, August, November and January. The maximal percent as adult females was observed during March, September and January, whereas the adult males appeared only during October and November. The parasitized individuals by A. maculicornis represented higher rate of parasitization from March to August in the first year that extended to September in the second year. On olive trees under irrigation the population of Parlatoria scale and its parasitoid was relatively low. It had three high peaks, during March, December and February in the first year, while in the second one the population reached the maximum during March, December and February. The parasitoid Aphytis maculicormis appeared in March and April marking high percentage levels in the first year, noticeably it was nearly parasitized the scale insect all the year round. PMID- 25145242 TI - Cultural diabrotica containment strategy in Switzerland: until now a convincing success story. AB - Ever since 2000 Switzerland belongs to the 22 European countries where the quarantine pest Diabrotica virgifera virgifera LeConte, Western corn rootworm (WCR), has been detected. It is reported to be the most important maizepest worldwide with an economic damage reaching 1.5 billion US$. In Switzerland it is constantly present in the southern part of the Alps while only few beetles are sporadically found in the northern part. Observations from 2000 up to 2012 support the hypothesis that the populations in the southern part of the Alps are generated by yearly migrations from principal foci situated in neighbouring Italian areas of Lombardy. Neither the tight correlation between travel distance and time of first arrival at various points from South to North, nor the steady decline of population along the route can be explained otherwise. Control measures enacted by Swiss authorities were principally based on a tightly enforced crop rotation scheme without chemical inputs as usually practiced in parts of the European Union. The effectiveness of crop rotation has been tested in a 5 year field trial comparing a continuous maize cropping system with a croprotation system and a maximum of one year of maizewithin a two year period (1:1). Population density was measured using synthetic pheromone baited traps and observations of root damage. Results showed that no economically relevant population built up during this period in the crop rotation treatment, whereas in the statistical evaluation of continuous maizecropping root damages could be detected after 4 years. One to one (1:1) year crop rotations are a common practice since 2001 in Southern Switzerland and are well accepted by farmers. Consequently, not a gram of pesticide has been employed against WCR in Switzerland up to now. The low level population density also helped to avoid the introduction of WCR populations into Cantons north of the Alps and thus prevented further spreading towards the state territories of northern neighbours. PMID- 25145243 TI - Screening Rhododendron spp. for broad mite (polyphagotarsonemus latus) resistance. PMID- 25145244 TI - Pheromone dispensers, including organic polymer fibers, described in the crop protection literature: comparison of their innovation potential. AB - Pheromone dispensers, although known in a variety of different designs, are one of the few remaining technical bottlenecks along the way to a sustainable pheromone based strategy in integrated pest management (IPM). Mating disruption with synthetic pheromones is a viable pest management approach. Suitable pheromone dispensers for these mating disruption schemes, however, are lagging behind the general availability of pheromones. Specifically, there is a need for matching the properties of the synthetic pheromones, the release rates suitable for certain insect species, and the environmental requirements of specific crop management. The "ideal" dispenser should release pheromones at a constant but pre adjustable rate, should be mechanically applicable, completely biodegradable and thus save the costs for recovering spent dispensers. These should be made from renewable, cheap organic material, be economically inexpensive, and be toxicologically and eco-toxicologically inert to provide satisfactory solutions for the needs of practicing growers. In favourable cases, they will be economically competitive with conventional pesticide treatments and by far superior in terms of environmental and eco-toxicological suitability. In the course of the last 40 years, mating disruption, a non-toxicological approach, provided proof for its potential in dozens of pest insects of various orders and families. Applications for IPM in many countries of the industrialized and developing world have been reported. While some dispensers have reached wide circulation, only few of the key performing parameters fit the above requirements ideally and must be approximated with some sacrifice in performance. A fair comparison of the innovation potential of currently available pheromone dispensers is attempted. The authors advance here the use of innovative electrospun organic fibers with dimensions in the "meso" (high nano- to low micrometer) region. Due to their unique multitude of adjustable parameters, they hold considerable promise for future pest control against a variety of pest insects. In combination with well known synthetic sex pheromones, they can be used for communication disruption studies. One example, the pheromone of the European grape vine moth Lobesia botrana (Lepidoptera: Tortricidae), in combination with Ecoflex fibers, has been thoroughly tested in vineyards of Freiburg, Southwest Germany, with promising results. Seven weeks of communication disruption have been achieved, long enough to cover any one of several flights of this multivoltine grape pest. Disruption effects of around 95% have been achieved which are statistically indistinguishable from positive controls tested simultaneously with Isonet LE fibers, while an untreated negative control is significantly different. Ecoflex is a cheap organic co-polyester and completely biodegradable within half a year. Thus, an extra recovery step as with some other dispensers is unnecessary. This co-polyester is also of proven non-toxicity. The extension of the seven week disruption period towards half a year (the entire duration of all 3 Lobesia flights combined) is desirable and is under additional investigation in the near future. The discovery of suitable mesofibers is protected by European and US patents. The pheromone literature appearing between 1959 and today contains more than 25,000 references. This wealth of information is immediately applicable to pest management. It has major impacts on chemical ecology and IPM. In this paper, an attempt is made to compare the systems described in the literature and to derive some predictions about their prospective innovation potential. Special emphasis is given to the new development of organic biodegradable microfibers. To this end, a new electronic searching algorithm is introduced for reviewing the entries to be found in 4 specific databases. Its prominent features will be described. Surprisingly we found no previous entries in the literature linking pheromones with biodegradable organic polymer fibers whose diameters are in the dimension range of low micrometers and in the upper nanometer scale. In conclusion, the microfiber pheromone combination must be considered as a novel approach whose virtues should be further explored for IPM in the near future. PMID- 25145245 TI - Lobesia botrana IPM: electrospun polyester microfibers serve as biodegradable sex pheromone dispensers. AB - Modern insect pest management is faced with an increasingly sophisticated set of requirements. Control agent/dispenser combinations must be at the same time safe, nontoxic, inexpensive, reproducibly efficacious, environmentally compatible, biodegradable, and sustainable, and should be based on renewable resources. The methods employed preferably should be suitable for the growing and tightly controlled organic growing sector as well. All this calls for a level of sophistication and reproducibility previously unknown. Only very few systems can offer this kind of performance, but fortunately can be found in the area of suitable pheromone/dispenser combinations. This report is an attempt to adapt electrospun Ecoflex polyester micro fibers of the Greiner-Wendorff type to the very specific needs of the grape growing industry. Specifically required are "semi-intelligent" dispenser materials. On a weight basis, the electrospun product should achieve as high a proportion as possible of "retainable" sex pheromone (E,Z)-7,9-dodecadienyl acetate of Lobesia botrana (Lep.: Tortricidae) and should release it as uniformly as possible into the surrounding airspace. Using the Doye bioassay, some progress indeed has recently been achieved with electrospun Ecoflex microfibers of 0.5-3.5 microm diameter. They were employed as dispensers for programmed sex pheromone release with an effective mating disruption duration of up to seven weeks. With one microfiber/pheromone treatment, this covers one entire flight period of the trivoltine L. botrana. Mechanical application of this microfiber/pheromone preparation (with the option of automation) is possible. Disruption effects are comparable with those of commercially available dispensers of the Isonet type. Exposed under vineyard conditions, Ecoflex polyester fibers are a spider silk like material which is biodegradable within half a year. Thus, after releasing its pheromone load, it does not need removal, which saves one cultivation step. The fibers are under rigorous quantitative pretesting by analytical lab methods such as scanning EM, CLSA, timed weight loss curves in isothermal wind tunnels, and by thermogravimetry. Grapes produced under protection with these pheromone-charged biodegradable and mechanically deployable Ecoflex microfibers are completely free of pesticide residues. PMID- 25145246 TI - Evaluation of an aerosol emitter for mating disruption of Cydia pomonella in Italy. AB - Some techniques have been developed to disrupt mating (MD) of codling moth (CM) by treating orchards with pheromone. Synthetic pheromone is applied to the crop as a formulation that is designed to protect these generally labile compounds from degradation while gradually releasing pheromone into the atmosphere. In Trentino South Tyrol MD has been adopted successfully (24,500 ha, i.e. 73% of the apple area) to control CM in heavily infested areas; while in areas with low pest pressure, less pesticides are usually applied (2-3 per year) and as a consequence, pheromone mating disruption is not considered economically convenient. Hand applied sealed plastic tubes and plastic ampoules are the two pheromone formulations more widely used. A new pheromone-based control technique, called Puffer, has been recently proposed. Puffers are battery-powered devices that release pheromone from pressurized aerosol cans every 15 minutes for 12 hours or 30 min for 24 hours. During each puff a quantity of 6.95 mg a.i. is emitted. The high release rate of pheromone per puff from aerosol dispensers is thought to compensate for their low application densities (2-2.5 puffer/hectare). Results of three year field trials carried out in Trentino-South Tyrol demonstrated the potential of Puffer as effective tool to control the moth. PMID- 25145247 TI - Study on the sensitivity of three oat varieties to the saddle gall midge, haplodiplosis margina ta (von Roser) (Diptera: cecidomyiidae). AB - The saddle gall midge, Haplodiplosis marginota (von Roser, 1840) is a univoltine pest of cereals which occurs in Europe. The larvae feed on stems and attractive saddle-shaped depressions, driving to important yield losses when the galls are numerous. After 40 years without any reporting, large populations of H. marginata and important damage have been observed since 2010 in wheat crops in Belgium, especially in the Flemish Polders where clay soils and intensive farming of cereals favour heavy infestations. According to some research conducted in the 1960s during the last outbreak, oat (Avena sativa L.) is known to be one of the less favourable hosts to the saddle gall midge. Our study was performed in order to assess the host sensitivity of three oat varieties currently grown in Belgium: EVITA, EFFEKTIv and FREDDY. Therefore, oat varieties were sown on infested soil in two separate enclosures in a glasshouse. In the first enclosure, only the three oat varieties were grown; in the second one, these three oat varieties were grown together with two varieties of spring wheat: GRANNY and KWS CHAMSIN. TWO parameters were measured: the percentage of leaves with laid eggs, and the number of galls per stem. The percentage of leaves with eggs showed that the infestation was significantly lower on oats when they were in presence of wheat. The egg infestation was also significantly higher on wheat than on oat, which means oat is a much less favourable host plant than spring wheat for egg laying. Oat varieties were significantly different from each other regarding the number of galls per stem, but with very little damage compared to wheat. The FREDDY variety even seemed to be completely resistant to saddle gall midge, as no galls were observed although there was a similar percentage of leaves with eggs for the three oat varieties. Cropping oat could thus contribute to reduce infestations of H. morginato. PMID- 25145248 TI - Control of sawflies in apple and pear in Belgium. AB - In the Belgian fruit growing area, sawflies are generally common but minor pests in pome fruit. Though, intensity and frequency of sawfly damage in apple and pear is increasing the last years in IPM and especially in organic orchards. The main species are apple sawfly (Hoplocampa testudinea Klug) and pear sawfly (Hoplocaompa brevis Klug) and recently also pear shoot sawfly (Janus compressus Fabricius). Here we report efficacy results on all three sawfly species fromtrial of three consecutive years (2011, 2012, and 2013). Flights and embryonic development were monitored and small plot efficacy trials were executed. Control of apple sawfly was complete (97.6% Abbott -trial 2011) when thiacloprid at 120 g/ha LWA was applied at the moment embryos are visible in the sawfly eggs. In 2012, a trial was executed on pear sawfly. Applications with thiacloprid were executed when the embryo was visible in the pear sawfly eggs and earlier at the start of egg laying. At both application timings, 100% Abbott efficacy was reached. A number of other active ingredients were tested at the moment embryos are visible in the sawfly eggs and very interesting efficacy results were reached for thiofanate-methyl, indoxacarb, spinosad, pyrethrins + piperonyl butoxide (PBO) and acetamiprid. In 2013, a preflowering application with pyrethrins + PBO reached the highest control against this pest. The most effective active ingredients of the pear sawfly trial were applied also in a trial on pear shoot sawfly. Efficacies were low or lacking, except for thiacloprid. Thiacloprid is in pear growing in Belgium only registered before flowering and after harvest. Therefore further research is needed to test the effect of earlier applications against this pest. This is a valuable efficacy study on occasionally occurring pests that are able to cause considerable economic losses. PMID- 25145249 TI - Biological activity of three alkyl cinnamates on young larvae of Tuta absoluta. AB - The "tomato moth," Tuto absoluta (Meyrick) (Lepidoptera: Gelechiidae), is a neotropical oligophagous insect considered a key pest of tomato crops. It was detected in Europe seven years ago and quickly spread to several regions of Asia and North Africa. In Argentina, its control is done by chemical pesticides mainly. The indiscriminate use of chemical broad spectrum pesticides have caused several problems in the control of this pest due to resistance mechanism involved to several insecticides including pyrethroids, organophosphates and biopesticides. In this context, the searching and evaluation of new compounds- compatible with integrated pest management programs- has become relevant. Within the phenylpropanoids, alkyl cinnamates, whether natural or synthetic, have been reported with biological activity: repellence, antifeedant and insecticide. Therefore, the cinnamates could be a valuable alternative to replace the conventional insecticides. The aim of this work was to study the antifeedant effect of three alkyl cinnamates (methyl, ethyl and propyl cinnamate) on the consumption rate patterns of second instar larvae of T. absoluta. A series of concentrations of each compound (100, 250 and 500 micrograms/milliliter) were prepared using acetone (analytical grade) - distilled water as solvent and a surfactant (Tween 80) was added to each solution to improve the wet of leaves. Tomato leaf disks of 2 cm diameter were treated by immersion in each solution during 15 seconds. Afterward, the treated discs were dried under fume hood and each disk was placed in a plastic capsule. A larva with 6-8 hours of starvation was added to each experimental unit. Each treatment was replicated between 24-30 times. The area consumed by each larva was measured after 24, 48 and 72 hours post-treatment. We also evaluated development time, weight of the pupa, adult emergence, fecundity and fertility as sublethal effects. The results were analyzed using ANOVA test. None of the compounds tested at the aforementioned concentrations exhibited insecticidal effect. However, ethyl cinnamate showed a strong antifeedant effect. The results observed on the leaf consumption and other sublethal effects assessed will be discussed. According to these preliminary results, further studies are needed to complete its toxicological profile by other exposure methods. PMID- 25145252 TI - Effect of eucalyptus wood vinegar on rubberwood infestation by Asian subterranean termite, Coptotermes gestroi Isoptera: Rhinotermitidae). AB - Wood degradation caused by fungi, termites, and insects, is a major problem for the rubberwood industry. The potential of wood vinegar as rubberwood preservative was studied. The infestation rates of Coptotermes gestroi (Wasmann) (Isoptera: Rhinotermitidae) on rubberwood samples treated with 25%, 50% and 100% eucalyptus wood vinegar for 24 hours were observed in laboratory conditions. Both non-choice and choice experiments were included. The effects of eucalyptus wood vinegar treatment depended on its concentration. In the non-choice experiments, rubberwood samples treated with 100% eucalyptus wood vinegar had the highest resistance to C. gestroi infestation, with the lowest relative loss of mass, followed in rank order by 50% and 25% treatments. However, in the choice experiments the relative loss of mass did not differ significantly between the treatments with varied wood vinegar concentration. Untreated control samples were distinctly infested by C. gestroi in both non-choice and choice experiments, but their relative loss of mass in the non-choice experiments was not significantly different from samples treated with 25% eucalyptus wood vinegar. Hence, 25% eucalyptus wood vinegar was not effective as rubberwood preservative against C. gestroi attack. The results suggest that eucalyptus wood vinegar acts as a rubberwood preservative against termites, provided the treatment is done without dilution. About 50% dilution still has some efficacy, while lower concentrations are not effective. PMID- 25145250 TI - Bio efficacy of some piperaceae plant extracts against Plutella xylostella L. (Lepidoptera: Plutellidae). AB - The extracts of Piper sarmentosum Roxb., Piper retrofractum Vahl, Piper interruptum Opiz and Piper nigrum plants belonging to the family Piperaceae were evaluated for their efficacy against diamondback moth, Plutello xylostella L. third instars under laboratory conditions. Comparative toxicity of various extracts prepared in hexane, dichloromethane, ethyl acetate and ethanol following sequential extraction procedure were applied topically to the larvae. The hexane extract of Piper retrofractum was most active (LD = 237 ppm). The toxicity was dose dependant and correlated to duration of exposure. The hexane extract of P. nigrum was least active with an LD50 of 18,435 ppm. The mode of action of these extracts and effect on other developmental parameters is in progress. PMID- 25145251 TI - Effect of thymol on reproductive biology of Helicoverpa armigera Hubner (Lepidoptera: Noctuidae). AB - The objective of this study was to determine the possibilities for use of thymol, a common compound in essential oils of Thymus and Origanum plants, as an alternative biopesticidal compound to control Helicoverpa armigera. Thymol was applied to Helicoverpa armigera larvae topically and also administered orally at sublethal levels to determine the effects on their reproduction and development. Thymol did affect egg development and oviposition was reduced by 9.42 and 38.86% under two different applications, respectively. Growth inhibition was also observed and 6.7% of insects were dead as larvae, 42.4% as pupae and 6.6% as pupal-adult intermediates. The present studies clearly indicate that thymol used at sublethal levels can alternatively control bollworms by altering reproductive mechanisms. PMID- 25145253 TI - Hot palm oil treatment to confer rubberwood resistance against the pest Sinoxylonanale Lesne (Coleoptera: Bostrichidae). AB - This work evaluated the potential of hot oil treatments, at various temperatures and durations, to give rubberwood resistance against Sinoxylon anale Lesne (Coleoptera: Bostrichidae) attack. Rubberwood samples were treated with hot palm oil, at 170 degrees C or 180 degrees C for three or five hours, before testing with S. anole and comparison with untreated control samples. The relative loss of mass was lowest with treatment at 180 degrees C for five hours. The relative loss of mass did not significantly differ between the control and treatment at 170 degrees C for three hours. Appropriate treatment with hot palm oil reduced S anale infestation in rubberwood. PMID- 25145254 TI - Gall midges and their parasitoids on common reed in Kis-Balaton area, Hungary. PMID- 25145255 TI - What do tiger-fly larvae (Diptera: Muscidae) eat? AB - Coenosia attenuata, usually known as tiger-fly, is a generalist predator of agricultural and forest pests in both larval and adult stages; it has potential to be an effective biocontrol agent in protected crops. To contribute for the knowledge of which prey this predator larvae potentially consumes, and of the occurrence and the conditions that promote cannibalism by tiger-fly larvae, intact alive specimens and portions of the earthworm Lumbricus terrestris were tested as prey and the cannibalism was evaluated in the presence or in absence of fungus gnat larvae. The tiger-fly larvae fed on the bisected earthworm portions but seem to have difficulty to penetrate in the cuticle of the alive and moving L. terrestris. However, the time to start feeding on the portions of L terrestris was shorter than on fungus gnats. Cannibalism by C. attenuato was not detected, but mortality occurred in several modalities. Nevertheless, escaping from the Petri dishes was the dominant behaviour of the larvae in the cannibalism evaluation assay. PMID- 25145256 TI - Toxicity of cypermethrin on the neotropical lacewing Chrysoperla externa (Neuroptera: Chrysopidae). AB - The generalist predator Chrysoperla externa (Neuroptera: Chrysopidae) is distributed in the Neotropical Region and presents a strong potential as a biological control agent due to its easily rearing, high voracity and tolerance to several pesticides. This species feeds on relevant pests such as aphids, whiteflies, trips and various lepidopterans. In Argentina, an indiscriminate chemical control with broad spectrum pesticides is still the first option for controlling pests causing resistance problems and reduction of beneficial organisms. Therefore, it would be desirable that predators or parasitoids develop tolerance or resistance as phytophagous pests for their maintenance in the agricultural ecosystems. The objective of this work was to evaluate the tolerance of C. externo to the pyrethroid cypermethrin by topical exposure in laboratory conditions. The symptoms evaluated were tremors, movement, knockdown, inability to walk due to being glued. Recovery from poisoning symptoms was also evaluated. Six different concentrations of the pesticide, including the full field one, were tested. The exposure method was by topical applications on third larval instar. A low toxicity on larvae at 24 h post-treatment was observed, even at the highest concentration evaluated. Most of treated individuals looked normal at 24 h post treatment; those who were knocked down showed a complete recovery between 48 and 72 h post-treatment. C externa demonstrated a high tolerance to pyrethroids. This could be due to the activity involved in pyrethroids biotransformation (for example, esterases and mixed-function oxidases), or to a low sensitivity of the molecular target. Future studies should be addressed at biochemical and molecular levels to complete our knowledge about insecticide effects on this predator. PMID- 25145257 TI - Preliminary results on the ability of pentatomidae to transfer fire blight Erwinia amylovora under controlled conditions. AB - With their piercing-sucking mouthparts stink bugs (Heteroptera: Pentatomidae), a major pest in especially organic orchards, create wounds in fruit of pear trees. As Erwinia amylovora (Burrill, Winslow et al.), a wide spread bacterial disease affecting many rosaceous plants including pome fruit trees and hawthorn, enters through openings in flowers, leaves, shoots and fruit, feeding punctures caused by these bugs might be inoculated with Erwinia bacteria. In order to investigate the ability of the bugs Pentotoma rufipes L. and Polomena prasina L. to transmit fire blight, insects were caught in an organically managed orchard without fire blight, brought into contact with artificially inoculated immature pear fruit/slices and transferred to healthy, mechanically wounded pear fruit/slices. After an incubation period potential transmission of bacteria was examined by evaluation of symptom expression (necrosis, ooze production). To assess the presence of bacteria on the exoskeleton of the tested bugs, all bugs were forced to walk on a semiselective nutrient agar medium. In another experiment the viability of Ea on the exoskeleton was tested -after previous contact with ooze- through washing and plating of the wash water. All experiments were conducted under optimal climatological conditions and according to quarantine standards. Results demonstrated the ability of stink bugs to transfer E. amylovora to fruit and the viability of bacteria on stink bugs externally - both under lab conditions. PMID- 25145259 TI - Headspace collection of grapevine volatiles in a Hungarian vineyard. AB - L. botrana is a major pest of the grapevine, the larvae is feeding on the flower buds and the berries. Because of the damage of the larvae, secondary fungal infection can be evolved by the grey mold (Botrytis cinerea). A special blend of plant volatiles are emitted by the host plant. Mated L. botrana females use olfactory cues to find their host plant and oviposition sites. Grapevine volatiles were collected in 2012 and the blend was analyzed with GC, numerous compounds were present in the collected blend. More grapevine volatiles will be collected in 2013, in several phenological stadia of different grapevine varieties. PMID- 25145258 TI - Biological efficacy evaluation of mating disruption against the grape berry moth, Lobesia botrana, in grape in glasshouses. AB - The grape berry moth, Lobesia botrana, is an important pest of grapes. In Belgium, severe losses of production appeared due to the presence of L. botrona in grapes commercially grown in glasshouses. In 2010 mating disruption became a key pest management tactic in Flemish pip fruit orchards after being tested for several years. In other (European) countries, mating disruption is already applied in grapes but there is no registration in Belgium for use in grapes. Searching for an interesting residue free technique for application in small glasshouses, we evaluated the effect of mating disruption for control of L. botrana under protected conditions (glasshouse trials) during three consecutive years (2010-2012). A prerequisite for successful mating disruption is the treatment of large contiguous areas, as the pheromone product will not remain in sufficient quantities on narrow sites and, moreover, a larger portion of the crop remains at risk from migrating mated females. The glasshouses are rather small, however, we hypothesized that these so called border effects are not present due to the secluded spaces of the glasshouses. Pheromone dispensers were deployed and flights of L botrano moths were monitored (pheromone traps/UV-traps) during the whole time period of the trials. In the mating disrupted glasshouses hardly any moth was caught anymore in pheromone traps, in contrast to UV-traps or catches by pheromone traps in comparable non-mating disrupted glasshouse compartments. This indicates the incapability of the males to localize sex pheromone sources, and hence, the inability of finding females for mating. In line with these flight monitoring data, the nearly absence or strongly decreased L. botrana caused damage symptoms in the mating disrupted glasshouses demonstrates the benefits of the mating disruption technique under protected conditions of grape growing in glasshouses. PMID- 25145260 TI - Assessment of genetic relatedness in the honeybee Apis mellifera L. (Hymenoptera: apidae) colonies by using microsatellite loci. AB - In this study the relatedness was estimated between mother queen's colony and her daughters' queens' colonies, by extracting DNA from their individual workers offspring (N= 20) and using five microsatellite loci. Locus As indicated more diversity in the length of alleles from 130 to 162 PB with frequency from 0.05 to 0.1, followed by locus A76 that showed alleles lengths 210 to 340 PB with frequency 0.05 to 0.2 that means big diversity in the colonies individuals due to the numbers of drones mated with mother queen. On the other hand, A107 illustrated the weight of alleles from 179 to 205 PB with frequency 0.05 to 0.25. Loci B124 and ACOO6 also showed high frequency of 0.25 and indicated more relatedness. Through locus 8124 the Correlation coefficient was 1.00 between P.Q and F,.QO and 0.87 for P.Q and F1.Q1 and F,.Q3. A43 indicated relatedness through the correlation coefficient (0.968) between F.Q1.and F2.Q2. The microsatellites demonstrated that there was a genetic diversity within and between colonies. PMID- 25145261 TI - Association between vitamin C intake and lung cancer: a dose-response meta analysis. AB - Epidemiological studies evaluating the association between the intake of vitamin C and lung cancer risk have produced inconsistent results. We conducted a meta analysis to assess the association between them. Pertinent studies were identified by a search of PubMed, Web of Knowledge and Wan Fang Med Online through December of 2013. Random-effect model was used to combine the data for analysis. Publication bias was estimated using Begg's funnel plot and Egger's regression asymmetry test. Eighteen articles reporting 21 studies involving 8938 lung cancer cases were included in this meta-analysis. Pooled results suggested that highest vitamin C intake level versus lowest level was significantly associated with the risk of lung cancer [summary relative risk (RR) = 0.829, 95%CI = 0.734-0.937, I(2) = 57.8%], especially in the United States and in prospective studies. A linear dose-response relationship was found, with the risk of lung cancer decreasing by 7% for every 100 mg/day increase in the intake of vitamin C [summary RR = 0.93, 95%CI = 0.88-0.98]. No publication bias was found. Our analysis suggested that the higher intake of vitamin C might have a protective effect against lung cancer, especially in the United States, although this conclusion needs to be confirmed. PMID- 25145263 TI - Pharmacological inhibition of coronary restenosis: systemic and local approaches. AB - INTRODUCTION: Percutaneous coronary intervention (PCI) with stent implantation has revolutionized the treatment of obstructive coronary artery disease. However, the main limitation of this therapy is stent failure, which is usually caused by in-stent restenosis. AREAS COVERED: The aim of this article is to critically review the literature on the prevention of in-stent restenosis focusing on drug compounds that have reached clinical testing. EXPERT OPINION: The pathophysiological response following PCI includes many possible targets for antirestenosis treatment. Most notable success is seen with sirolimus (and its analogs) and paclitaxel, both of which target vascular smooth muscular cell proliferation. In view of the systemic side effects of both drugs, the high efficacy of local drug delivery methods reduced enthusiasm for systemic therapy. Cilastazol has shown benefit in restenosis reduction particularly in patients at high risk for stent failure, though further study in broader populations is warranted. Probucol showed variable results, but local drug delivery in combination with sirolimus seems promising. A hypothesized independent antirestenotic effect of pioglitazone in patients with diabetes has not been clearly demonstrated. Initial encouraging results with tranilast have not been replicated in a recent large-scale randomized trial. Colchicine and prednisone have shown promising results but require further investigation in larger clinical trials. PMID- 25145262 TI - Chiari-like malformation and syringomyelia in American Brussels Griffon dogs. AB - BACKGROUND: Although Chiari-like malformation (CM) and syringomyelia (SM) have been described in many small breed dogs, the prevalence and clinical manifestations of this complex have not been documented in a large cohort of American Brussels Griffon (ABG) dogs. OBJECTIVES: To characterize the clinical and magnetic resonance imaging (MRI) features of CM and SM in the ABG breed. ANIMALS: Eighty-four American Kennel Club registered ABG dogs were recruited. METHODS: Prospective study. Complete histories and neurologic examinations were obtained before MRI. Images were blindly reviewed and calculations were made by using OsiriX. All analyses were performed by Student's t-test, Spearman's correlation, ANOVA, and chi-square test where appropriate. RESULTS: Chiari-like malformation and SM were present in 65% and 52% of dogs, respectively. Twenty eight percent of dogs had neurologic deficits and 20% had neck pain. Mean central canal (CC) transverse height was 2.5 mm with a mean length of 3.6 cervical vertebrae. Neurologic deficits were significantly associated with a larger syrinx (P = .04, P = .08) and syrinx size increased with age (P = .027). SM was associated with a smaller craniocervical junction (CCJ) height (P = .04) and larger ventricles (P = .0001; P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Syringomyelia and CM are prevalent in American Brussels Griffon dogs. Syrinx size is associated with neurologic deficits, CM, larger ventricles, a smaller craniocervical junction height, neurologic deficits, and cerebellar herniation. Fifty-two percent of dogs with a SM were clinically normal. PMID- 25145265 TI - MPK6 controls H2 O2-induced root elongation by mediating Ca2+ influx across the plasma membrane of root cells in Arabidopsis seedlings. AB - Mitogen-activated protein kinases (MPKs) play critical roles in signalling and growth, and Ca(2+) and H2 O2 control plant growth processes associated with abscisic acid (ABA). However, it remains unclear how MPKs are involved in H2 O2 - and Ca(2+) -mediated root elongation. Root elongation in seedlings of the loss-of function mutant Atmpk6 (Arabidopsis thaliana MPK6) was less sensitive to moderate H2 O2 or ABA than that in wild-type (WT) plants. The enhanced elongation was a result of root cell expansion. This effect disappeared when ABA-induced H2 O2 accumulation or the cytosolic Ca(2+) increase were defective. Molecular and biochemical evidence showed that increased expression of the cell wall peroxidase PRX34 in Atmpk6 root cells enhanced apoplastic H2 O2 generation; this promoted a cytosolic Ca(2+) increase and Ca(2+) influx across the plasma membrane. The plasma membrane damage caused by high levels of H2 O2 was ameliorated in a Ca(2+) -dependent manner. These results suggested that there was intensified PRX34 mediated H2 O2 generation in the apoplast and increased Ca(2+) flux into the cytosol of Atmpk6 root cells; that is, the spatial separation of apoplastic H2 O2 from cytosolic Ca(2+) in root cells prevented H2 O2 -induced inhibition of root elongation in Atmpk6 seedlings. PMID- 25145264 TI - Formation of nuclear bodies by the lncRNA Gomafu-associating proteins Celf3 and SF1. AB - Gomafu/MIAT/Rncr2 is a long noncoding RNA that has been proposed to control retinal cell specification, stem cell differentiation and alternative splicing of schizophrenia-related genes. However, how Gomafu controls these biological processes at the molecular level has remained largely unknown. In this study, we identified the RNA-binding protein Celf3 as a novel Gomafu-associating protein. Knockdown of Celf3 led to the down-regulation of Gomafu, and cross-link RNA precipitation analysis confirmed specific binding between Celf3 and Gomafu. In the neuroblastoma cell line Neuro2A, Celf3 formed novel nuclear bodies (named CS bodies) that colocalized with SF1, another Gomafu-binding protein. Gomafu, however, was not enriched in the CS bodies; instead, it formed distinct nuclear bodies in separate regions in the nucleus. These observations suggest that Gomafu indirectly modulates the function of the splicing factors SF1 and Celf3 by sequestering these proteins into separate nuclear bodies. PMID- 25145266 TI - Evaluation of antioxidant activity and total phenol in different varieties of Lantana camara leaves. AB - BACKGROUND: Phytochemicals like carotenoids, tocopherols, ascorbates and phenols present in the plants are strong antioxidants and have an important role in the health care system. There is growing interest in correlating the phytochemical constituents of a plant with its pharmacological activity. Therefore, the present study investigates the content of total phenolics, flavonoids and the antioxidant activity of four different varieties of Lantana camara L. (Verbenaceae) leaves by using in vitro antioxidant models. METHODS: The leaves of Chandigarh purple variety (CPV), Palampur red variety (PRV), Chandigarh yellow turning pink variety (YTPV) and Chandigarh yellow variety (CYV) Lantana camara were collected and the total phenolic, flavonoid content, antioxidant and free radical scavenging activities were determined in their methanolic extracts. RESULTS: The phenolic content was found to be highest in the CYV extract (232.99 +/- 15.97 mg GAE/ g extract). The content of the flavonoids are in the order of YTPV, PRV, CPV and CYV. The IC50 values for the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging test were in the order of CYV (33.30 +/- 2.39) < PRV (40.32 +/- 2.94) < YTPV (475.33 +/- 5.20) < CPV (927.16 +/- 2.88 MUg/mL). The highest total antioxidant capacity was observed in CYV (222.20 +/- 5.05 mg AAE/ g). The Ferric ion reducing antioxidant potential (FRAP) value of the extracts were in the order of CYV > PRV > YTPV > CPV. The IC50 values of 2, 2'-azino-bis-(3 ethylbenzothiazoline-6-sulfonate) (ABTS) scavenging assay for CYV, PRV, YTPV, CPV were 18.25 +/- 0.19, 18.24 +/- 1.82, 50.43 +/- 9.49, 52.84 +/- 1.82 MUg/mL respectively. PRV extract showed the maximum in vitro lipid peroxidation inhibition effect with an IC50 value of 68.50 MUg/mL which is even stronger as compared to the standard Rutin (79.69 MUg/mL). The extracts showed a strong correlation between the phenolic content and their antioxidant activities. The highest correlation (r = 0.998, R2 = 0.997) was found between total phenolic content and ABTS scavenging assay. CONCLUSION: Among the four varieties investigated, CYV and PRV extracts showed strong antioxidant activities and may be used as a potential source of natural antioxidant against free radical associated diseases. PMID- 25145267 TI - Complications of central venous stenosis due to permanent central venous catheters in children on hemodialysis. AB - BACKGROUND: Central venous catheters are frequently used as access for hemodialysis (HD) in children. One of the known complications is central venous stenosis. Although this complication is not rare, it is often asymptomatic and therefore unacknowledged. Superior vena cava (SVC) stenosis is obviously suspected in the presence of upper body edema, but several other signs and symptoms are often unrecognized as being part of this syndrome. CASE DIAGNOSIS/TREATMENT: We describe four patients with various manifestations of central venous stenosis and SVC syndrome. These sometimes life- or organ threatening conditions include obstructive sleep apnea, unresolving stridor, increased intracranial pressure, increased intraocular pressure, right-sided pleural effusion, protein-losing enteropathy and lymphadenopathy. The temporal relationship of these complications associated with the use of central venous catheters and documentation of venous stenosis, together with their resolution after alleviation of high venous pressure, points to a causal role. We suggest pathophysiological mechanisms for the formation of each of these complications. CONCLUSIONS: In patients with occlusion of the SVC, various unexpected clinical entities can be caused by high central venous pressure. As often the etiology is not obvious, a high index of suspicion is needed as in some cases prompt alleviation of the high pressure is mandatory. PMID- 25145268 TI - Proteinuria in a Crohn's disease patient: Questions and Answers. PMID- 25145270 TI - Early life obesity and chronic kidney disease in later life. AB - The prevalence of chronic kidney disease (CKD) has increased considerably with a parallel rise in the prevalence of obesity. It is now recognized that early life nutrition has life-long effects on the susceptibility of an individual to develop obesity, diabetes, cardiovascular disease and CKD. The kidney can be programmed by a number of intrauterine and neonatal insults. Low birth weight (LBW) is one of the most identifiable markers of a suboptimal prenatal environment, and the important intrarenal factors sensitive to programming events include decreased nephron number and altered control of the renin-angiotensin system (RAS). LBW complicated by accelerated catch-up growth is associated with an increased risk of obesity, hypertension and CKD in later life. High birth weight and exposure to maternal diabetes or obesity can enhance the risk for developing CKD in later life. Rapid postnatal growth per se may also contribute to the subsequent development of obesity and CKD regardless of birth weight and prenatal nutrition. Although the mechanisms of renal risks due to early life nutritional programming remain largely unknown, experimental and clinical studies suggest the burdening role of early life obesity in longstanding cardiovascular and renal diseases. PMID- 25145271 TI - Should all nephrotics with thyroid dysfunction be treated with levothyroxine? PMID- 25145272 TI - Jasplakinolide reduces actin and tropomyosin dynamics during myofibrillogenesis. AB - The premyofibril model proposes a three-stage process for the de novo assembly of myofibrils in cardiac and skeletal muscles: premyofibrils to nascent myofibrils to mature myofibrils. FRAP experiments and jasplakinolide, a drug that stabilizes F-actin, permitted us to determine how decreasing the dynamics of actin filaments affected the dynamics of tropomyosin, troponin-T, troponin-C, and two Z-Band proteins (alpha-actinin, FATZ) in premyofibrils versus mature myofibrils. Jasplakinolide reduced markedly the dynamics of actin in premyofibrils and in mature myofibrils in skeletal muscles. Two isoforms of tropomyosin-1 (TPM1alpha, TPM1kappa) are more dynamic in premyofibrils than in mature myofibrils in control skeletal muscles. Jasplakinolide reduced the exchange rates of tropomyosins in premyofibrils but not in mature myofibrils. The reduced tropomyosin recoveries did not match the YFP-actin recoveries in premyofibrils in jasplakinolide. There were no significant differences in the effects of jasplakinolide on the dynamics of troponins in the thin filaments or of two Z-band proteins in premyofibrils or skeletal mature myofibrils. Cardiac control mature myofibrils lack nebulin, and small decreases in actin (~5%) and two tropomyosin isoforms (~10-15%) dynamics are detected in premyofibril to mature myofibril transformations compared with skeletal muscle. In contrast to skeletal muscle, jasplakinolide lowered the dynamics of actin and tropomyosin isoforms in the cardiac mature myofibrils. These results suggest that the dynamics of tropomyosins in control muscle cells are related to actin exchange. These results also suggest a stabilizing role for nebulin, an actin and tropomyosin-binding protein, present in mature myofibrils but not in premyofibrils of skeletal muscles. PMID- 25145274 TI - Oxygen modulates human embryonic stem cell metabolism in the absence of changes in self-renewal. AB - Human embryonic stem (ES) cells are routinely cultured under atmospheric oxygen (~20%), a concentration that is known to impair embryo development in vitro and is likely to be suboptimal for maintaining human ES cells compared with physiological (~5%) oxygen conditions. Conflicting reports exist on the effect of oxygen during human ES cell culture and studies have been largely limited to characterisation of typical stem cell markers or analysis of global expression changes. This study aimed to identify physiological markers that could be used to evaluate the metabolic impact of oxygen on the MEL-2 human ES cell line after adaptation to either 5% or 20% oxygen in extended culture. ES cells cultured under atmospheric oxygen displayed decreased glucose consumption and lactate production when compared with those cultured under 5% oxygen, indicating an overall higher flux of glucose through glycolysis under physiological conditions. Higher glucose utilisation at 5% oxygen was accompanied by significantly increased expression of all glycolytic genes analysed. Analysis of amino acid turnover highlighted differences in the consumption of glutamine and threonine and in the production of proline. The expression of pluripotency and differentiation markers was, however, unaltered by oxygen and no observable difference in proliferation between cells cultured in 5% and 20% oxygen was seen. Apoptosis was elevated under 5% oxygen conditions. Collectively these data suggest that culture conditions, including oxygen concentration, can significantly alter human ES cell physiology with coordinated changes in gene expression, in the absence of detectable alterations in undifferentiated marker expression. PMID- 25145273 TI - Parameterization of highly charged metal ions using the 12-6-4 LJ-type nonbonded model in explicit water. AB - Highly charged metal ions act as catalytic centers and structural elements in a broad range of chemical complexes. The nonbonded model for metal ions is extensively used in molecular simulations due to its simple form, computational speed, and transferability. We have proposed and parametrized a 12-6-4 LJ (Lennard-Jones)-type nonbonded model for divalent metal ions in previous work, which showed a marked improvement over the 12-6 LJ nonbonded model. In the present study, by treating the experimental hydration free energies and ion oxygen distances of the first solvation shell as targets for our parametrization, we evaluated 12-6 LJ parameters for 18 M(III) and 6 M(IV) metal ions for three widely used water models (TIP3P, SPC/E, and TIP4PEW). As expected, the interaction energy underestimation of the 12-6 LJ nonbonded model increases dramatically for the highly charged metal ions. We then parametrized the 12-6-4 LJ-type nonbonded model for these metal ions with the three water models. The final parameters reproduced the target values with good accuracy, which is consistent with our previous experience using this potential. Finally, tests were performed on a protein system, and the obtained results validate the transferability of these nonbonded model parameters. PMID- 25145275 TI - Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors. AB - Neglected tropical diseases remain a serious global health concern. Here, a series of novel bis-tetrahydropyran 1,4-triazole analogues based on the framework of chamuvarinin, a polyketide natural product isolated from the annonaceae plant species are detailed. The analogues synthesized display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness, also known as Human African Trypanosomiasis (HAT). A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure-activity relationship studies. Together, the biological potency and calculated lipophilicity values indicate that while there is room for improvement, these derivatives may represent a promising novel class of anti-HAT agents. PMID- 25145276 TI - Transgenic rodent assay for quantifying male germ cell mutant frequency. AB - De novo mutations arise mostly in the male germline and may contribute to adverse health outcomes in subsequent generations. Traditional methods for assessing the induction of germ cell mutations require the use of large numbers of animals, making them impractical. As such, germ cell mutagenicity is rarely assessed during chemical testing and risk assessment. Herein, we describe an in vivo male germ cell mutation assay using a transgenic rodent model that is based on a recently approved Organisation for Economic Co-operation and Development (OECD) test guideline. This method uses an in vitro positive selection assay to measure in vivo mutations induced in a transgenic lambdagt10 vector bearing a reporter gene directly in the germ cells of exposed males. We further describe how the detection of mutations in the transgene recovered from germ cells can be used to characterize the stage-specific sensitivity of the various spermatogenic cell types to mutagen exposure by controlling three experimental parameters: the duration of exposure (administration time), the time between exposure and sample collection (sampling time), and the cell population collected for analysis. Because a large number of germ cells can be assayed from a single male, this method has superior sensitivity compared with traditional methods, requires fewer animals and therefore much less time and resources. PMID- 25145278 TI - Urinary excretion of arsenic following rice consumption. AB - Patterns of arsenic excretion were followed in a cohort (n = 6) eating a defined rice diet, 300 g per day d.wt. where arsenic speciation was characterized in cooked rice, following a period of abstinence from rice, and other high arsenic containing foods. A control group who did not consume rice were also monitored. The rice consumed in the study contained inorganic arsenic and dimethylarsinic acid (DMA) at a ratio of 1:1, yet the urine speciation was dominated by DMA (90%). At steady state (rice consumption/urinary excretion) ~40% of rice derived arsenic was excreted via urine. By monitoring of each urine pass throughout the day it was observed that there was considerable variation (up to 13-fold) for an individual's total arsenic urine content, and that there was a time dependent variation in urinary total arsenic content. This calls into question the robustness of routinely used first pass/spot check urine sampling for arsenic analysis. PMID- 25145279 TI - The epigenetic regulation of SOX9 by miR-145 in human chondrosarcoma. AB - Chondrosarcoma is the most common primary bone malignancy in the adult population with a high rate of pulmonary metastasis. Chondrosarcoma is managed with surgical excision as the tumors do not respond well to conventional chemotherapy or radiation therapy. Thus, there exists a dire need to develop systemic treatment options to target chondrosarcoma cells for metastatic spread. We hypothesized that the expression of miR-145 is low in chondrosarcoma, leading to decreased transcriptional control of SOX9 (the master regulator of chondrogenesis), and downstream activation of the transcription factor ETV5. We have previously shown that ETV5 activates MMP-2 expression in chondrosarcoma, which in turn increases local bone matrix resorption. In this study, we confirm high expression of SOX9 in human chondrosarcoma using real-time PCR, Western blotting, and immunofluorescence. An ETV5 promoter-reporter plasmid was transfected into chondrosarcoma cells to determine if SOX9 directly regulates the expression of ETV5. Co-transfection of the ETV5 promoter-plasmid with SOX9 lentivirus significantly increased the luciferase activity derived from the ETV5 promoter, from which the regulatory relationship between SOX9 and ETV5 is established. MiR 145 was found to be down-regulated in chondrosarcoma cell lines, patient samples, and further confirmed with a public sarcoma database. After stable miR-145 lentiviral transfection, the subsequent mRNA expression levels of SOX9, ETV5, and MMP-2 were significantly decreased in chondrosarcoma cells. The results generated by this study may have important clinical significance in the treatment of patients with chondrosarcoma in that targeted miRNA may have the potential to downregulate the upstream activators of proteases such as MMP-2. PMID- 25145282 TI - Establishment of a structural equation model for ground-level ozone: a case study at an urban roadside site. AB - This study established a cause-effect relationship between ground-level ozone and latent variables employing partial least-squares analysis at an urban roadside site in four distinct seasons. Two multivariate analytic methods, factor analysis, and cluster analysis were adopted to cite and identify suitable latent variables from 14 observed variables (i.e., meteorological factors, wind and primary air pollutants) in 2008-2010. Analytical results showed that the first six components explained 80.3 % of the variance, and eigenvalues of the first four components were greater than 1. The effectiveness of this model was empirically confirmed with three indicators. Except for surface pressure, factor loadings of observed variables were 0.303-0.910 and reached statistical significance at the 5 % level. Composite reliabilities for latent variables were 0.672-0.812 and average variances were 0.404-0.547, except for latent variable "primary" in spring; thus, discriminant validity and convergent validity were marginally accepted. The developed model is suitable for the assessment of urban roadside surface ozone, considering interactions among meteorological factors, wind factors, and primary air pollutants in each season. PMID- 25145280 TI - Hepatic transcriptomic profiling reveals early toxicological mechanisms of uranium in Atlantic salmon (Salmo salar). AB - BACKGROUND: Uranium (U) is a naturally occurring radionuclide that has been found in the aquatic environment due to anthropogenic activities. Exposure to U may pose risk to aquatic organisms due to its radiological and chemical toxicity. The present study aimed to characterize the chemical toxicity of U in Atlantic salmon (Salmo salar) using depleted uranium (DU) as a test model. The fish were exposed to three environmentally relevant concentrations of DU (0.25, 0.5 and 1.0 mg U/L) for 48 h. Hepatic transcriptional responses were studied using microarrays in combination with quantitative real-time reverse transcription polymerase chain reaction (qPCR). Plasma variables and chromosomal damages were also studied to link transcriptional responses to potential physiological changes at higher levels. RESULTS: The microarray gene expression analysis identified 847, 891 and 766 differentially expressed genes (DEGs) in the liver of salmon after 48 h exposure to 0.25, 0.5 and 1.0 mg/L DU, respectively. These DEGs were associated with known gene ontology functions such as generation of precursor metabolites and energy, carbohydrate metabolic process and cellular homeostasis. The salmon DEGs were then mapped to mammalian orthologs and subjected to protein-protein network and pathway analysis. The results showed that various toxicity pathways involved in mitochondrial functions, oxidative stress, nuclear receptor signaling, organ damage were commonly affected by all DU concentrations. Eight genes representative of several key pathways were further verified using qPCR No significant formation of micronuclei in the red blood cells or alterations of plasma stress variables were identified. CONCLUSION: The current study suggested that the mitochondrion may be a key target of U chemical toxicity in salmon. The induction of oxidative stress and uncoupling of oxidative phosphorylation may be two potential modes of action (MoA) of DU. These MoAs may subsequently lead to downstream events such as apoptosis, DNA repair, hypoxia signaling and immune response. The early toxicological mechanisms of U chemical toxicity in salmon has for the first time been systematically profiled. However, no other physiological changes were observed. Future efforts to link transcriptional responses to adverse effects have been outlined as important for understanding of potential risk to aquatic organisms. PMID- 25145281 TI - Using ecological memory as an indicator to monitor the ecological restoration of four forest plantations in subtropical China. AB - A large area of plantations has been established worldwide and especially in China. Evaluating the restoration status of these plantations is essential for their long-term management. Based on our previous work, we used an ecological memory (EM) approach to evaluate four 26-year-old plantations that represent four common kinds of plantations in subtropical China, i.e., mixed broad-leaved plantation (MBP), mixed coniferous plantation (MCP), eucalyptus plantation (EP), and mixed legume plantation (MLP). Comparing them with the regional climax community, i.e., monsoon evergreen broad-leaved forest (BF), all four plantations accumulated nearly the same pattern of EM during succession. EM was >50 % for soil minerals, light conditions, soil age, soil animals, and soil microbes. EM was about 25 % for soil pollen and 10 % for birds, soil seed bank, and plant species. The total EM value of the four plantations ranged from 50.96 to 52.54, which indicated that all four plantations were in the regional, natural trajectory of succession and between the early and medium successional stages. The results indicated that natural succession processes are unlikely to be accelerated by planting late-stage tree species without sufficient EM. The results also demonstrated that all four plantations were in positive successional trajectories, and the positive succession dynamics were greater in the MLP and MCP. We suggest that the entire natural succession trajectory be used to evaluate the restoration of a site and that the ultimate restoration target be divided into several milestones along the reference trajectory to monitor progress. Forest restoration may be accelerated by starting with a minimum dynamic unit supporting sufficient EM. PMID- 25145283 TI - Efficacy and drug survival of anti-tumour necrosis factor-alpha therapies in patients with non-radiographic axial spondyloarthritis: an observational cohort study from Southern Sweden. AB - OBJECTIVES: To evaluate the efficacy and drug survival of anti-tumour necrosis factor (anti-TNF) therapy in non-radiographic axial spondyloarthritis (nr-axSpA) patients treated in clinical practice in Southern Sweden. METHOD: In this cohort study we prospectively included 112 patients with nr-axSpA and high disease activity as well as inadequate response or intolerance to non-steroidal anti inflammatory drugs (NSAIDs) receiving their first course of anti-TNF therapy. Patients fulfilling modified New York criteria for ankylosing spondylitis (AS) were excluded. The Assessment of SpondyloArthritis International Society (ASAS) criteria for axial SpA were fulfilled by 77% (n = 86) of the included patients. RESULTS: At baseline, the median age of the cohort was 38 years, 59% were males, 79% of the patients had imaging suggestive of sacroiliitis (primarily inflammation on magnetic resonance imaging, MRI), 71% were HLA-B27 positive, and the median disease duration was 6 years and 10 months. At 6 months of follow-up, the median Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) decreased from 5.6 to 3.2 (p = 0.002), the Bath Ankylosing Spondylitis Functional Index (BASFI) decreased from 3.9 to 1.8 (p = 0.005), and C-reactive protein (CRP) level decreased from 4.4 to 1.7 mg/L (p = 0.001). After 1 year of treatment the Kaplan Meier estimated drug survival was 76%, and at 2 years of follow-up this value decreased to 65%. Patients with inflammatory MRI findings at baseline had significantly better drug survival [hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.10-0.55, p = 0.001]. Male sex was also associated with higher drug survival (HR 0.45, 95% CI 0.24-0.85, p = 0.011). CRP level at baseline was not associated with drug survival. CONCLUSIONS: Anti-TNF treatment of patients with nr-axSpA in clinical practice resulted in reduced BASDAI and BASFI scores and good drug survival. The results from this study suggest that male gender and positive imaging at baseline are associated with a favourable treatment course. PMID- 25145284 TI - A conformation-equilibrium model captures ligand-ligand interactions and ligand biased signalling by G-protein coupled receptors. AB - G-protein coupled receptors (GPCRs) are a versatile, important class of cell surface receptors. GPCRs occur in different conformations that exist in a dynamic ligand-sensitive equilibrium. These conformations vary in their affinities for intracellular signalling proteins and initiate signalling via different intracellular routes. The binding of extracellular ligands and allosteric ligand ligand interactions shift conformation equilibria to cause biased signalling. Here, we present a mathematical model that describes the effects of ligands on the conformation equilibria of GPCRs. Our extended Monod-Wyman-Changeux model describes the receptor as shifting between active and inactive receptor conformations under the influence of extracellular ligands. For each receptor conformation, the intracellular domain of the receptor can attain alternative domain conformations that differ in their affinity for intracellular signalling proteins. At the extracellular domain, the model can accommodate different mechanisms for allosteric ligand-ligand interactions that induce shifts in receptor and domain conformation equilibria. We use the model to study ligand biased signalling and how ligand affinity, ligand sensitivity and maximal signalling output depend on allosteric ligand-ligand interactions. PMID- 25145285 TI - Synthesis, novel luminescence properties, and surface-enhanced Raman scattering of Au/Y2O3:Eu(3+) composite nanotubes. AB - Y(OH)3:Eu(3+) nanotubes were synthesized by a facile hydrothermal method first, and then Au particles were grown on the surface of Y2O3:Eu(3+) nanotubes by combining the vacuum extraction method and the annealing process. The composite nanotubes were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). The effects of the Au content on the photoluminescence properties of the Au/Y2O3:Eu(3+) composite nanotubes were investigated in detail. In the excitation spectra of Au/Y2O3:Eu(3+) monitored at 614 nm, the (7)F0->(5)H3 transition from Eu(3+) increased with increasing Au content, while the other sharp lines originating from Eu(3+) f-f electron transitions almost vanished. In the emission spectra, the spectral configurations of Eu(3+) in Au/Y2O3:Eu(3+) composite nanotubes varied with the excitation wavelengths. When the excitation wavelength was 256 nm, the (5)D4->(7)F0, (5)D7->(7)F0, (5)G2->(7)F0, (5)L6->(7)F0, (5)D0->(7)F0, (5)D0->(7)F1, (5)D0->(7)F2, (5)D0->(7)F3, and (5)D0->(7)F4 transitions from Eu(3+) ions in Au/Y2O3:Eu(3+) were observed. When the excitation wavelength was 378 nm, the plasmon resonance peak from Au nanoparticles was observed. In addition, 4-ATP was chosen as the model molecule to examine the performance of the Au/Y2O3:Eu(3+) composite nanotubes as SERS substrates. The relative intensities of the SERS spectra enhanced with the increase of Au(+) : Ln(3+) ratio. PMID- 25145286 TI - Myeloid-specific disruption of recombination signal binding protein Jkappa ameliorates hepatic fibrosis by attenuating inflammation through cylindromatosis in mice. AB - Macrophages play multidimensional roles in hepatic fibrosis, but their control has not been fully understood. The Notch pathway mediated by recombination signal binding protein Jkappa (RBP-J), the transcription factor transactivated by signals from four mammalian Notch receptors, is implicated in macrophage activation and plasticity. In this study, by using mouse hepatic fibrosis models, we show that myeloid-specific disruption of RBP-J resulted in attenuated fibrosis. The activation of hepatic stellate cells and production of profibrotic factors including platelet-derived growth factor (PDGF)-B and transforming growth factor beta1 (TGF-beta1) reduced significantly in myeloid-specific RBP-J deficient mice. The infiltration of inflammatory cells and production of proinflammatory factors were reduced in liver of myeloid-specific RBP-J-deficient mice during fibrosis. In RBP-J-deficient macrophages, the nuclear factor kappa B (NF-kappaB) activation was remarkably attenuated as compared with the control. This could be attributed to the up-regulation of cylindromatosis (CYLD), a negative regulator of NF-kappaB, in Notch signal-compromised macrophages, because the knockdown of CYLD in RBP-J-deficient macrophages or overexpression of p65 in RBP-J knockdown cells both restored NF-kappaB activation and the production of proinflammatory and/or profibrotic factors by macrophages. In human hepatic fibrosis biopsies, stronger Notch activation is correlated with more severe fibrosis, which is accompanied by a lower level of CYLD but irrespective of etiological reasons. CONCLUSION: RBP-J-mediated Notch signaling is required for macrophages to promote hepatic fibrosis by up-regulation of NF-kappaB activation through CYLD. PMID- 25145287 TI - Hydrogen-bond-directed-linking solving transparence-efficiency tradeoff in nonlinear optical molecule. AB - It is well known that settling transparency-efficiency tradeoff is important to design nonlinear optical (NLO) materials. In this work, we constructed one dimensional polymeric cyanoacetylene (NCCCH)n by hydrogen-bond-directed-linking to understand this tradeoff from molecular level. Results show that the first hyperpolarizability of (NCCCH)n (n=2-8) gradually increased with the increase of n, and what is more important is that the red-shifts, associated with the increase of n, were very little. It is proposed that these polymeric structures possess double-degenerated charge transitions, which contribute to the hyperpolarizability in an additive fashion, and that the coupled oscillators are gradually improved, which lead to the increase of the first hyperpolarizability. Therefore, we propose the hydrogen-bond-directed-linking idea is helpful to develop the potential high-performance NLO materials. PMID- 25145288 TI - Development and validation of a parent report measure for detection of cognitive delay in infancy. PMID- 25145291 TI - Engineering functionality gradients by dip coating process in acceleration mode. AB - In this work, unique functional devices exhibiting controlled gradients of properties are fabricated by dip-coating process in acceleration mode. Through this new approach, thin films with "on-demand" thickness graded profiles at the submillimeter scale are prepared in an easy and versatile way, compatible for large-scale production. The technique is adapted to several relevant materials, including sol-gel dense and mesoporous metal oxides, block copolymers, metal organic framework colloids, and commercial photoresists. In the first part of the Article, an investigation on the effect of the dip coating speed variation on the thickness profiles is reported together with the critical roles played by the evaporation rate and by the viscosity on the fluid draining-induced film formation. In the second part, dip-coating in acceleration mode is used to induce controlled variation of functionalities by playing on structural, chemical, or dimensional variations in nano- and microsystems. In order to demonstrate the full potentiality and versatility of the technique, original graded functional devices are made including optical interferometry mirrors with bidirectional gradients, one-dimensional photonic crystals with a stop-band gradient, graded microfluidic channels, and wetting gradient to induce droplet motion. PMID- 25145289 TI - MicroRNA-378 controls classical brown fat expansion to counteract obesity. AB - Both classical brown adipocytes and brown-like beige adipocytes are considered as promising therapeutic targets for obesity; however, their development, relative importance and functional coordination are not well understood. Here we show that a modest expression of miR-378/378* in adipose tissue specifically increases classical brown fat (BAT) mass, but not white fat (WAT) mass. Remarkably, BAT expansion, rather than miR-378 per se, suppresses formation of beige adipocytes in subcutaneous WAT. Despite this negative feedback, the expanded BAT depot is sufficient to prevent both genetic and high-fat diet-induced obesity. At the molecular level, we find that miR-378 targets phosphodiesterase Pde1b in BAT but not in WAT. Indeed, miR-378 and Pde1b inversely regulate brown adipogenesis in vitro in the absence of phosphodiesterase inhibitor isobutylmethylxanthine. Our work identifies miR-378 as a key regulatory component underlying classical BAT specific expansion and obesity resistance, and adds novel insights into the physiological crosstalk between BAT and WAT. PMID- 25145292 TI - [Computed tomography in multiple trauma patients: technical aspects, work flow, and dose reduction]. AB - CLINICAL/METHODICAL ISSUE: Patients with severe, life-threatening trauma require a fast and accurate clinical and imaging diagnostic workup during the first phase of trauma management. STANDARD RADIOLOGICAL METHODS: Early whole-body computed tomography has clearly been proven to be the current standard of care of these patients. METHODICAL INNOVATIONS: A similar imaging quality can be achieved in the multiple trauma setting compared with routine imaging especially using rapid, latest generation computed tomography (CT) scanners. PERFORMANCE: This article encompasses a detailed view on the use of CT in patients with life-threatening trauma. A special focus is placed on radiological procedures in trauma units and on the methods for CT workup in routine cases and in challenging situations. Another focus discusses the potential of dose reduction of CT scans in multiple trauma as well as the examination of children with severe trauma. ACHIEVEMENTS: Various studies have demonstrated that early whole-body CT positively correlates with low morbidity and mortality and is clearly superior to the use of other imaging modalities. PRACTICAL RECOMMENDATIONS: Optimal trauma unit management means a close cooperation between trauma surgeons, anesthesiologists and radiologists, whereby the radiologist is responsible for a rapid and accurate radiological workup and the rapid communication of imaging findings. However, even in the trauma setting, aspects of patient radiation doses should be kept in mind. PMID- 25145290 TI - Bedside ultrasonography (US), Echoscopy and US point of care as a new kind of stethoscope for Internal Medicine Departments: the training program of the Italian Internal Medicine Society (SIMI). AB - In recent years, thanks to the development of miniaturized ultrasound devices, comparable to personal computers, tablets and even to smart phones, we have seen an increasing use of bedside ultrasound in internal medicine departments as a novel kind of ultrasound stethoscope. The clinical ultrasound-assisted approach has proved to be particularly useful in assessing patients with nodules of the neck, dyspnoea, abdominal pain, and with limb edema. In several cases, it has allowed a simple, rapid and precise diagnosis. Since 2005, the Italian Society of Internal Medicine and its Ultrasound Study Group has been holding a Summer School and training courses in ultrasound for residents in internal medicine. A national network of schools in bedside ultrasound was then organized for internal medicine specialists who want to learn this technique. Because bedside ultrasound is a user-dependent diagnostic method, it is important to define the limits and advantages of different new ultrasound devices, to classify them (i.e. Echoscopy and Point of Care Ultrasound), to establish appropriate different levels of competence and to ensure their specific training. In this review, we describe the point of view of the Italian Internal Medicine Society on these topics. PMID- 25145295 TI - Guest modulation of spin-crossover transition temperature in a porous iron(II) metal-organic framework: experimental and periodic DFT studies. AB - The synthesis, structure, and magnetic properties of three clathrate derivatives of the spin-crossover porous coordination polymer {Fe(pyrazine)[Pt(CN)4]} (1) with five-membered aromatic molecules furan, pyrrole, and thiophene is reported. The three derivatives have a cooperative spin-crossover transition with hysteresis loops 14-29 K wide and average critical temperatures Tc =201 K (1?fur), 167 K (1?pyr), and 114.6 K (1?thio) well below that of the parent compound 1 (Tc =295 K), confirming stabilization of the HS state. The transition is complete and takes place in two steps for 1?fur, while 1?pyr and 1?thio show 50 % spin transition. For 1?fur the transformation between the HS and IS (middle of the plateau) phases occurs concomitantly with a crystallographic phase transition between the tetragonal space groups P4/mmm and I4/mmm, respectively. The latter space group is retained in the subsequent transformation involving the IS and the LS phases. 1?pyr and 1?thio display the tetragonal P4/mmm and orthorhombic Fmmm space groups, respectively, in both HS and IM phases. Periodic calculations using density functional methods for 1?fur, 1?pyr, 1?thio, and previously reported derivatives 1?CS2 , 1?I, 1?bz(benzene), and 1?pz(pyrazine) have been carried out to investigate the electronic structure and nature of the host-guest interactions as well as their relationship with the changes in the LS HS transition temperatures of 1?Guest. Geometry-optimized lattice parameters and bond distances in the empty host 1 and 1?Guest clathrates are in general agreement with the X-ray diffraction data. The concordance between the theoretical results and the experimental data also comprises the guest molecule orientation inside the host and intermolecular distances. Furthermore, a general correlation between experimental Tc and calculated LS-HS electronic energy gap was observed. Finally, specific host-guest interactions were studied through interaction energy calculations and crystal orbital displacement (COD) curve analysis. PMID- 25145293 TI - Comparison of effectiveness and cost between perventricular device occlusion and minimally invasive surgical repair for perimembranous ventricular septal defect. AB - Perventricular device occlusion and minimally invasive surgical repair for perimembranous ventricular septal defect (pmVSD) are two typical methods to reduce the invasiveness of the conventional operation through median sternotomy. However, few comparative studies have been made between them in terms of effectiveness and cost. A review was made of the inpatients with isolated pmVSD, who had undergone perventricular device occlusion or minimally invasive surgical repair from June 2011 and January 2013 for a comparative investigation between the two procedures. The two treatment groups had similar baseline characteristics. Procedural success was achieved in 163 (94.8%) of the perventricular and 137 (98.6%) of the surgical (P = 0.136). Major complications occurred in 2 (1.2%) of the perventricular and 4 (2.9 %) of the surgical (P = 0.497), and minor complications, in 57 (33%) of the percutaneous and 49 (35.2%) of the surgical (P = 0.696). In cost, the surgical repair was 30.5% cheaper than the device occlusion (Yuan 20139 +/- 3760 vs. 28970 +/- 3343, P < 0.001), where most of the cost was attributed to the occluder in the amount of Yuan 19,500. Compared with perventricular device closure, minimally invasive surgical repair can provide comparable efficacy and complication rates, without the potential for developing atrioventricular block at long-term follow-up. In addition, it is 30.5% cheaper than hybrid procedure. In the low-income countries where health care resources are limited the medical resources must be judiciously allocated to the treatment that allows for effective treatment of the largest number of patients. PMID- 25145294 TI - Fibrinolytic therapy for mechanical pulmonary valve thrombosis. AB - Treatment of prosthetic heart valve thrombosis using intravenous thrombolytics, although an acceptable alternative to surgery, is not complication free, and the literature has a dearth of data on the subject. This study analyzed the results of fibrinolytic treatment (FT) among a single-center group of patients with mechanical pulmonary valve thrombosis. Between 2000 and 2013, 23 consecutive patients with 25 episodes of pulmonary valve thrombosis received FT. The diagnosis of mechanical pulmonary valve thrombosis was established by fluoroscopy and echocardiography. Streptokinase (SK) was used in 24 cases and alteplase in 1 case. The FT was continued a second day for 14 patients (58.3%), a third day for 1 patient, and a fourth day for 1 patient. Echocardiography and fluoroscopy were performed every day until improvement of malfunction was achieved. Of the 23 patients, 19 had complete resolution of hemodynamic abnormalities after FT, 1 had partial resolution, and 2 showed no change. No patient had major complications. Five minor complications were detected, namely, fever, nausea, thrombophlebitis, epistaxi, and pain. Seven patients (30%) experienced recurrence of thrombosis, whereas four patients had surgery (biological pulmonary valve replacement) without re-thrombolytic therapy, one patient was treated with Alteplase, one patient received SK, and one patient received intense anticoagulation using heparin and warfarin. Overall, FT had a success rate of 84%. The results indicate that regardless of the time to pulmonary valve replacement and echocardiographic and fluoroscopic findings, FT was effective in most cases of mechanical pulmonary valve thrombosis. The efficacy increased with second-day thrombolytic therapy. Major complications were not common after lytic therapy for mechanical pulmonary valve thrombosis. PMID- 25145297 TI - A 3-D diamondoid MOF catalyst based on in situ generated [Cu(L)2] N-heterocyclic carbene (NHC) linkers: hydroboration of CO2. AB - A new MOF, [Zn4O{Cu(L)2}2] (1), with a 4-fold interpenetrated 3D diamondoid structure was synthesised from in situ generated [Cu(L)2] NHC linkers. MOF 1 possesses tetrahedral Zn4O nodes, which are unusually coordinated by four pairs of carboxylates from four [Cu(L)2] linkers, and 14 A 1-D pore channels lined with [Cu(L)2] moieties that catalyse the hydroboration of CO2. PMID- 25145296 TI - Concise stereoselective synthesis of oxaspirocycles with 1-tosyl-1,2,3-triazoles: application to the total syntheses of (+/-)-Tuberostemospiroline and (+/-) stemona-lactam R. AB - A 4-substituted-1-tosyl-1,2,3-triazole-based stereoselective synthesis of structurally diverse oxaspirocycles is reported. The synthesis involves Rh catalyzed loss of nitrogen from 4-substituted-1-tosyl-1,2,3-triazoles, Grignard reaction, and a ring-closing metathesis reaction as key steps. By employing readily available and stable 4-substituted-1-tosyl-1,2,3-triazoles as surrogates of diazo compounds and nitrogen sources, two types of oxaspirocycles were obtained. The latter compounds, which contain adjacent nitrogen stereocenters, could serve as the core structures of many natural products. This chemistry has been successfully applied to the total syntheses of (+/-)-tuberostemospiroline and (+/-)-stemona-lactam R. PMID- 25145300 TI - A country left behind: folic acid food fortification policy in New Zealand. PMID- 25145299 TI - CXCR4 promotes GSK3beta expression in pancreatic cancer cells via the Akt pathway. AB - BACKGROUND: CXCR4 and glycogen synthase kinase-3beta (GSK3beta) promote proliferation and invasion of pancreatic cancer. Inhibition of CXCR4 suppresses GSK3beta expression. However, the molecular mechanism by which CXCR4 contributes to human pancreatic cancer metastasis is not completely understood. In this study, therefore, we analyzed the effect of CXCR4 on GSK3beta expression and its molecular mechanism. METHODS: PANC-1 and SW-1990 cells were used in this study. PANC-1 and SW-1990 cell lines which stably expressed upregulated or downregulated CXCR4 were used for further study. Western blotting was employed to detected the expression of CXCR4, GSK3beta and MMP-2. Cell invasion assay was used to detect the effect of the Akt pathway on CXCR4-induced GSK3beta expression. RESULTS: Overexpression of CXCR4 promoted GSK3beta expression and silencing of CXCR4 suppressed GSK3beta expression. Overexpression of CXCR4 activated cyclin D1 and p Akt expression, but inhibited p21 expression. Silencing of CXCR4 had the reverse effect. CXCR4 promoted GSK3beta expression and PANC-1 invasion by Akt signaling. CXCR4 upregulated GSK3beta expression, at least in part, at the level of transcription. CONCLUSIONS: CXCR4 promotes GSK3beta expression via the Akt cell signaling pathway in pancreatic cancer cells. PMID- 25145298 TI - Optimizing biopsy procedures during colposcopy for women with abnormal cervical cancer screening results: a multicenter prospective study. AB - BACKGROUND: In cervical cancer screening programs, women with abnormal cytology results are referred to colposcopy for histological diagnosis. This study was designed to evaluate the sensitivity of colposcopic procedures for detecting cervical cancer and its precursor, cervical intraepithelial neoplasia (CIN). METHODS: Women referred to colposcopy for abnormal cytology were enrolled from four hospitals. Gynecologists were required to take a colposcopy-guided biopsy from the worst of the abnormal-looking areas as a first biopsy. They were also asked to take >= 3 cervical specimens including by endocervical curettage (ECC). Random biopsies were performed at the gynecologist's discretion. We analyzed 827 biopsy results from 255 women who were diagnosed by central pathologists as having histology of CIN or cancer. RESULTS: In this study, 78.1% of diagnoses of CIN grade 2 or worse (CIN2+) (the threshold that would trigger intensive management) were obtained from a first colposcopy-guided biopsy. The additional diagnostic utility of second and third colposcopy-guided biopsies was 16.4 and 1.8%, respectively. The combined sensitivity of two colposcopy-directed biopsies for CIN2+ detection was >90%, regardless of the colposcopist. Random biopsies and ECC increased the diagnostic yield of CIN2+ lesions otherwise missed by colposcopy-guided biopsies alone, but only by 1.2 and 2.4%, respectively. Random biopsies were more useful for women referred after low-grade abnormal cytology (P = 0.01). The utility of ECC was greatest among women with unsatisfactory colposcopy (P = 0.03) or aged >= 40 years (P = 0.02). CONCLUSIONS: Our data suggest that at least two colposcopy-directed biopsies should be taken for histological diagnosis. Random biopsies and ECC are recommended for special populations. PMID- 25145301 TI - Unmet need or medicalising distress? PMID- 25145302 TI - Sleep disorders, depression, anxiety and satisfaction with life among young adults: a survey of university students in Auckland, New Zealand. AB - AIM: Sleep symptoms, depression and anxiety often coexist and tertiary students are a population group that are increasingly recognised to be at risk. However the rates of these conditions in the New Zealand population are poorly understood. The aim of this study was to determine the rates of sleep disorders, depression and anxiety, and identify correlations between satisfactions with life among university students in Auckland. METHOD: Auckland Sleep Questionnaire (ASQ) was administered to undergraduate students from six schools of The University of Auckland. The different types of sleep disorders were calculated for the students who reported a significant sleep problem lasting more than 1 month. The rate of depression, anxiety and substance use as well as the satisfaction with life scale scores were also calculated for the whole cohort. RESULTS: A total of 1933 students were invited to participate and 66.8% completed the questionnaire. The median age was 20 years (range 16-38) and women represented 63.9% of the total group. A total of 39.4% of the students surveyed reported having significant sleep symptoms lasting longer than 1 month. The most prevalent causes for sleep symptoms were depression and anxiety. Delayed sleep phase disorder was found in 24.9% of students and parasomnias were reported by 12.4%. Depression and anxiety were present in 17.3% and 19.7% of the total group respectively, and 7.3% of students had thoughts of "being better off dead" or self-harm. A total of 15.5% students were found to have a CAGE score greater than or equal to 2 and 9.3% reported using recreational drugs in the last 3 months. Moderate negative correlations between SWLS scores and depression and anxiety were found (r=-0.45 and r=-0.37 respectively). CONCLUSION: A large number of university students are suffering from significant sleep symptoms. Mood disorders, substance use, and circadian rhythm disorders can greatly contribute to sleep difficulties in this population group. The study also showed that harmful alcohol and drug use was common among this population group and is associated with clinically significant depression and anxiety. Accurate diagnosis using defined criteria will enable effective treatment for these conditions that impact greatly on the quality of life. PMID- 25145303 TI - Coming to work sick: a survey of hospital doctors in New Zealand. AB - AIM: To estimate the rate of sickness presenteeism in hospital doctors in a New Zealand tertiary hospital and to also identify reasons for why doctors continue to work whilst sick. METHODS: An anonymous online survey about sickness presenteeism for all hospital doctors at one tertiary care hospital in New Zealand RESULTS: The response rate for the survey was 328/685 (47.8%). Sickness presenteeism was reported by 269/328 (82%) of respondents. The main reasons for sickness presenteeism were: not wanting to burden co-workers and the desire to ensure care for patients. CONCLUSIONS: Sickness presenteeism is highly prevalent in this survey. It is likely a change in attitudes by doctors towards their illnesses, and better allocation of staff resources are necessary to prevent this to avoid potential harm to patients and health care workers. PMID- 25145304 TI - Progress of successful New Zealand Registration Examination (NZREX Clinical) candidates during their first year of supervised clinical practice in New Zealand. AB - AIM: To determine the frequency and nature of clinical difficulties faced in the first year of supervised clinical practice by international medical graduates (IMGs) who have successfully passed NZREX Clinical in order to be able to practise in New Zealand. METHOD: All doctors who successfully passed NZREX Clinical and who registered with the Medical Council of New Zealand (the Council) from 2005 to 2013 were identified. Supervisor reports for each of the four runs in the first year of practice were obtained and reports where concerns were raised over clinical performance analysed. RESULTS: Of 353 IMGs successful in NZREX Clinical, 316 (89.6%) completed the subsequent clinical year with no adverse reports. Those requiring more than one attempt to pass NZREX Clinical had an incremental increase in number of unsatisfactory reports, where areas of the IMGs' performance were rated as 'below the expected standard'. Less than 2% of IMGs had more than one unsatisfactory report. The majority of unsatisfactory reports were generated in the first half of the clinical year. Areas of concerns found were Clinical Knowledge and Skills (28%), Clinical Judgment (35%), Patient Communication (28%) and Professional Attitudes and Behaviour (9%). CONCLUSION: Most IMGs who were successful in NZREX Clinical performed well in the subsequent year of clinical practice. NZREX Clinical would appear to have acceptable criterion validity. PMID- 25145305 TI - Adoption of endovenous laser treatment as the primary treatment modality for varicose veins: the Auckland City Hospital experience. AB - AIM: To assess the effectiveness of adopting endovenous laser treatment (EVLT) as the primary treatment modality for varicose veins at Auckland City Hospital (Auckland, New Zealand). METHODS: The outcomes of 354 consecutive EVLT procedures performed between 2007 and 2013 were reviewed. Data was collected from a prospectively maintained procedural database and by retrospective chart review. RESULTS: Of the 319 patients who had an ultrasound, at 1 month post-procedure there was a saphenous vein occlusion rate of 96%. Side effects were minimal with no cases of DVT or skin burns and one case of self-limiting neuralgia. The procedure was well tolerated with a median pain score of 3. Since the adoption of EVLT there has been a large increase in the number of patients treated for varicose veins (28 in 2007 compared to 176 in 2013). CONCLUSIONS: EVLT is a safe and effective treatment for varicose veins and its adoption has allowed a large increase in the number of varicose vein patients treated at Auckland City Hospital. PMID- 25145306 TI - Acute surgical treatment of cutaneous abscesses: cost savings from prioritisation in theatre. AB - INTRODUCTION: Treatment of cutaneous abscesses is an important part of the acute surgical workload and most are treated with incision and drainage. Traditionally most are treated after major cases in theatre prioritisation and remain in hospital overnight. AIM: To examine the cost saved in patients after drainage of skin abscesses according to the time of surgery ('am' versus 'pm'). METHODS: The clinical records of all patients who underwent acute incision and drainage of cutaneous abscesses at North Shore Hospital (Takapuna, Auckland, New Zealand) between 1 June-31 December 2011 were reviewed with respect to the time of day when surgery was performed [am (defined as 0730-12 noon of the day of surgery)] versus pm). Costs were calculated using standard tariffs set by our hospital. RESULTS: 339 patients (median age 34 yr, 164 female) were admitted for acute drainage of cutaneous abscesses with 149 operated in "am". There was no difference in patients undergoing am versus pm drainage in terms of age, sex, race, Charlson comorbidity score or smoking status although diabetic patients were more likely to undergo a pm drainage (p=0.008). The median cost per discharge was NZ$2397.39. The cost of the 'am' group was significantly less compared to the cost of the 'pm' group with NZ$2236.63 compared to NZ$2531.70 (p=0.0034) and saved a median of NZ$295.07 per patient. This amounted to the cost of an overnight bed stay. CONCLUSIONS: Prioritisation of abscess drainage in acute theatre management is safe and associated with significant cost savings. PMID- 25145307 TI - A review of the Christchurch Hospital Breast Cancer Service in 2012: meeting the new Tumour Standards. AB - AIMS: To determine whether patients diagnosed with breast cancer in 2012 received timely access to services at Christchurch Hospital when audited against Ministry of Health Tumour Standards of Service Provision (TS) (2013) and the Faster Cancer Treatment (FCT) indicators, and to discover factors which impeded patient pathways, and which would need to be addressed in order to meet the standards. METHODS: Data on referrals, dates and treatment for patients diagnosed with breast cancer at Christchurch Hospital was extracted from the Christchurch Breast Cancer Patient Register and other hospital databases. RESULTS: In 2012, 288 breast cancer patients were treated at Christchurch Hospital, 60% referred by general practitioners, and 40% via the national screening programme. Some 2013 Tumour Standards were achieved. The FCT indicator 1 (TS 2.4) and 3 (TS 2.5) were met, with 87% (greater than or equal to 80%) receiving their first treatment within 62 days of referral, and 89% (greater than or equal to 80%) within 31 days of decision-to-treat. However, FCT indicator 2 (TS 2.1), requiring first specialist assessment within 14 days of referral, was met in 61% (greater than or equal to 90% required). Only 64% of women started adjuvant chemotherapy within 42 days of their surgery (TS 2.6, greater than or equal to 90%). CONCLUSION: The management of breast cancer patients by a multidisciplinary team is crucial to ensure patients receive timely and appropriate care. However, waiting for weekly multidisciplinary meetings and adequate anatomical pathology resource, together with other factors, were identified as delaying the patient pathway and solutions to resolve these are discussed. PMID- 25145308 TI - Where does New Zealand stand on permitting research on human embryos? AB - In many respects New Zealand has responded to the assisted reproductive technologies (ARTs) as positively as many comparable societies, such as Australia and the UK. Consequently, in vitro fertilisation (IVF) and pre-implantation genetic diagnosis (PGD) are widely available, as is non-commercial surrogacy utilising IVF. These developments have been made possible by the Human Assisted Reproductive Technology (HART) Act 2004, overseen by its two committees, the Advisory Committee on Assisted Reproductive Technology (ACART) and the Ethics Committee (ECART). However, New Zealand stands apart from many of these other societies by the lack of permission for scientists to conduct research using human embryos. There is no doubt this reflects strongly held viewpoints on the part of some that embryos should be protected and not exploited. Legitimate as this stance is, the resulting situation is problematic when IVF is already designated as an established procedure. This is because the development of IVF involved embryo research, and continuing improvements in procedures depend upon ongoing embryo research. While prohibition of research on human embryos gives the impression of protecting embryos, it fails to do this and also fails to enhance the health and wellbeing of children born using IVF. This situation will not be rectified until research is allowed on human embryos. PMID- 25145309 TI - When enough is not enough: folic acid fortification in New Zealand. PMID- 25145310 TI - Possible impact of the Tick Programme in New Zealand on selected nutrient intakes: tentative estimates and methodological complexities. PMID- 25145312 TI - Medical cost impact of intrathecal baclofen therapy for severe spasticity. AB - OBJECTIVES: To evaluate the economic effects of intrathecal baclofen (ITB) for patients with severe spasticity based on costs of care before and after implantation of an intrathecal drug delivery system. MATERIALS AND METHODS: An actuarial projection of post-implant experience in the absence of ITB intervention was used to simulate a continued conventional medical management protocol (ITB-free) by assuming a reasonable trend rate based on health-care industry standards. Cost projections were developed over a 30-year time horizon at various reimplantation rates. The model was informed by retrospective analysis of commercial administrative claims data from 409 pediatric and adult spasticity patients who received a pump implant (ITB-experienced) within a 3-year service period (January 2006 to January 2009). Common indications associated with pump implant included multiple sclerosis (N = 124), cerebral palsy (N = 131), and spinal cord injury (N = 40). RESULTS: ITB was less costly than the conventional protocol over our baseline implantation cycle. Costs in the month of implant and in the year following were cumulatively $26,375 more than with the conventional protocol. However, ITB financial break-even occurs between the second and third years post-implant. The lifetime analysis indicates that savings for ITB are $8009 per patient per year compared with conventional therapy. Most of the savings are derived from reductions in inpatient admissions, physician office visits, and outpatient physiotherapy. CONCLUSIONS: The results suggest that spasticity patients receiving ITB would expect to experience a reduction in cumulative future medical costs relative to anticipated costs in the absence of a pump implant. This finding complements the existing literature on the cost effectiveness of ITB. PMID- 25145311 TI - MicroRNA-mediated multi-tissue detargeting of oncolytic measles virus. AB - Precise oncotropism is required for successful systemic administration of next generation oncolytic measles viruses (MVs). We have previously established a system for efficient post-entry targeting by insertion of synthetic microRNA target sites (miRTS) into the MV genome, thereby repressing replication in the presence of cognate microRNAs. Thus, differential expression of microRNAs, as frequently observed in normal compared with malignant tissues, can be exploited to increase vector specificity and safety. Here we report the combination of miRTS for different microRNAs in a single vector to detarget pivotal organs at risk during systemic administration (liver, brain, gastrointestinal tract). Accordingly, miRTS for miR-122, miR-7 and miR-148a that are enriched in these tissues were inserted to create multi-tissue-detargeted MV (MV-EGFP(mtd)). Replication of MV-EGFP(mtd) is repressed in cell lines as well as in non transformed primary human hepatocytes and liver slices expressing cognate microRNAs. Oncolytic potency of MV-EGFP(mtd) is retained in a model of pancreatic cancer in vitro and in vivo. This work is a proof-of-concept that favorable expression profiles of multiple microRNAs can be exploited concomitantly to reshape the tropism of MV without compromising oncolytic efficacy. This strategy can be adapted to different vectors and cancer entities for safe and efficient high-dose systemic administration in clinical trials. PMID- 25145313 TI - MRI model-based non-invasive differential diagnosis in pulmonary hypertension. AB - Pulmonary hypertension(PH) is a disorder characterised by increased mean pulmonary arterial pressure. Currently, the diagnosis of PH relies upon measurements taken during invasive right heart catheterisation (RHC). This paper describes a process to derive diagnostic parameters using only non-invasive methods based upon MRI imaging alone. Simultaneous measurements of main pulmonary artery (MPA) anatomy and flow are interpreted by 0D and 1D mathematical models, in order to infer the physiological status of the pulmonary circulation. Results are reported for 35 subjects, 27 of whom were patients clinically investigated for PH and eight of whom were healthy volunteers. The patients were divided into 3 sub-groups according to the severity of the disease state, one of which represented a negative diagnosis (NoPH), depending on the results of the clinical investigation, which included RHC and complementary MR imaging. Diagnostic indices are derived from two independent mathematical models, one based on the 1D wave equation and one based on an RCR Windkessel model. Using the first model it is shown that there is an increase in the ratio of the power in the reflected wave to that in the incident wave (Wpb/Wptotal) according to the classification of the disease state. Similarly, the second model shows an increase in the distal resistance with the disease status. The results of this pilot study demonstrate that there are statistically significant differences in the parameters derived from the proposed models depending on disease status, and thus suggest the potential for development of a non-invasive, image-based diagnostic test for pulmonary hypertension. PMID- 25145314 TI - Quantification of plantar soft tissue changes due to aging in various metatarsophalangeal joint angles with realistic tissue deformation. AB - The nonlinearity of plantar soft tissue is seldom examined because of the small extent of deformation induced during indentation for measurement purposes. Furthermore, in most indentation experiments, the metatarsophalangeal joint (MTPJ) angle is not well controlled, although it has been proven to have a significant stiffening effect on sub-metatarsal head (MTH) pads. Hence, the study aims to quantify changes in the mechanical properties of plantar soft tissue due to aging under an experimental condition which is similar to walking. This is done by subjecting the tissue to an appropriate level of deformation at various MTPJ angles. A custom-made in vivo tissue indenter was used to measure directly the force-indentation response of the plantar tissue of two healthy groups: "Young" (n=25, mean age 22) and "Elderly" (n=25, mean age 67) subjects. Tests were performed on the 2nd sub-MTH pad at angles of 0 degrees , 20 degrees , 40 degrees MTPJ dorsiflexion, as well as at the hallux and heel pad at 0 degrees MTPJ angle. At all three plantar sites tested, elderly subjects showed significantly higher tissue stiffness than the young (p<0.05). However, the stiffening effect of MTPJ angle was not notably influenced by aging. In this work, tissue stiffness is quantified in stiffness constant (K) based on the proposed indentation technique. It is hypothesized that the increase in stiffness with age observed is probably due to compositional change in the plantar soft tissue. PMID- 25145315 TI - Lower-limb amputee recovery response to an imposed error in mediolateral foot placement. AB - Despite walking with a wider step width, amputees remain 20% more likely to fall than non-amputees. Since mediolateral (ML) balance is critical for ambulation and contingent on ML foot placement, we used a ML disturbance to perturb walking balance and explore the influence of prosthetic foot stiffness on balance recovery. Ten transtibial amputees were fit with two commonly prescribed prosthetic feet with differing stiffness characteristics; 12 non-amputees also participated. A perturbation device that released an air burst just before heel strike imposed a repeatable medial or lateral disturbance in foot placement. After a medial disturbance, the first recovery step width was narrowed (p<0.0001) for the prosthetic limb (-103%), the sound limb (-51%) and non-amputees (-41%) and more than twice as variable. The ML inclination angle remained reduced ( 109%) for the prosthetic limb, while the sound limb and non-amputees approached undisturbed levels (p<0.0004). Amputees required five steps to return to undisturbed step width after a prosthetic medial disturbance versus two steps for the sound limb and for non-amputees. After a lateral disturbance, the first recovery step was widened for the prosthetic limb (+82%), sound limb (+75%), and wider than non-amputees (+51%; p<0.0001), with all participants requiring three steps to return to undisturbed step width. Amputees also exhibited a similar upper torso response compared to the non-amputees for both disturbances. Prosthetic feet with different stiffness properties did not have a significant effect. In conclusion, amputee balance was particularly challenged by medial disturbances to the prosthetic limb implying a need for improved interventions that address these balance deficits. PMID- 25145316 TI - Modeling stroke in mice: permanent coagulation of the distal middle cerebral artery. AB - Stroke is the third most common cause of death and a main cause of acquired adult disability in developed countries. Only very limited therapeutical options are available for a small proportion of stroke patients in the acute phase. Current research is intensively searching for novel therapeutic strategies and is increasingly focusing on the sub-acute and chronic phase after stroke because more patients might be eligible for therapeutic interventions in a prolonged time window. These delayed mechanisms include important pathophysiological pathways such as post-stroke inflammation, angiogenesis, neuronal plasticity and regeneration. In order to analyze these mechanisms and to subsequently evaluate novel drug targets, experimental stroke models with clinical relevance, low mortality and high reproducibility are sought after. Moreover, mice are the smallest mammals in which a focal stroke lesion can be induced and for which a broad spectrum of transgenic models are available. Therefore, we describe here the mouse model of transcranial, permanent coagulation of the middle cerebral artery via electrocoagulation distal of the lenticulostriatal arteries, the so called "coagulation model". The resulting infarct in this model is located mainly in the cortex; the relative infarct volume in relation to brain size corresponds to the majority of human strokes. Moreover, the model fulfills the above mentioned criteria of reproducibility and low mortality. In this video we demonstrate the surgical methods of stroke induction in the "coagulation model" and report histological and functional analysis tools. PMID- 25145318 TI - Are patient preferences for end-of-life care socially influenced? Examining racial disparities in advance care planning. PMID- 25145317 TI - The impact of transmural multiprofessional simulation-based obstetric team training on perinatal outcome and quality of care in the Netherlands. AB - BACKGROUND: Perinatal mortality and morbidity in the Netherlands is relatively high compared to other European countries. Our country has a unique system with an independent primary care providing care to low-risk pregnancies and a secondary/tertiary care responsible for high-risk pregnancies. About 65% of pregnant women in the Netherlands will be referred from primary to secondary care implicating multiple medical handovers. Dutch audits concluded that in the entire obstetric collaborative network process parameters could be improved. Studies have shown that obstetric team training improves perinatal outcome and that simulation-based obstetric team training implementing crew resource management (CRM) improves team performance. In addition, deliberate practice (DP) improves medical skills. The aim of this study is to analyse whether transmural multiprofessional simulation-based obstetric team training improves perinatal outcome. METHODS/DESIGN: The study will be implemented in the south-eastern part of the Netherlands with an annual delivery rate of over 9,000. In this area secondary care is provided by four hospitals. Each hospital with referring primary care practices will form a cluster (study group). Within each cluster, teams will be formed of different care providers representing the obstetric collaborative network. CRM and elements of DP will be implemented in the training. To analyse the quality of care as perceived by patients, the Pregnancy and Childbirth Questionnaire (PCQ) will be used. Furthermore, self-reported collaboration between care providers will be assessed. Team performance will be measured by the Clinical Teamwork Scale (CTS). We employ a stepped-wedge trial design with a sequential roll-out of the trainings for the different study groups.Primary outcome will be perinatal mortality and/or admission to a NICU. Secondary outcome will be team performance, quality of care as perceived by patients, and collaboration among care providers. CONCLUSION: The effect of transmural multiprofessional simulation-based obstetric team training on perinatal outcome has never been studied. We hypothesise that this training will improve perinatal outcome, team performance, and quality of care as perceived by patients and care providers. TRIAL REGISTRATION: The Netherlands National Trial Register, http://www.trialregister.nl/NTR4576, registered June 1, 2014. PMID- 25145319 TI - An aptamer intrinsically comprising 5-fluoro-2'-deoxyuridine for targeted chemotherapy. AB - An aptamer specifically binding the interleukin-6 receptor and intrinsically comprising multiple units of the nucleoside analogue 5-fluoro-2'-deoxyuridine can exert a cytostatic effect direcly on certain cells presenting the receptor. Thus the modified aptamer fulfils the requirements for active drug targeting in an unprecedented manner. It can easily be synthesized in a single enzymatic step and it binds to a cell surface receptor that is conveyed into the lysosome. Upon degradation of the aptamer by intracellular nucleases the active drug is released within the targeted cells exclusively. In this way the aptamer acts as a prodrug meeting two major prerequisites of a drug delivery system: specific cell targeting and the controlled release of the drug triggered by an endogenous stimulus. PMID- 25145320 TI - Sleep apnea-hypopnea syndrome and type 2 diabetes. A reciprocal relationship? AB - Epidemiological data suggest that sleep apnea-hypopnea syndrome (SAHS) is independently associated with the development of insulin resistance and glucose intolerance. Moreover, despite significant methodological limitations, some studies report a high prevalence of SAHS in patients with type 2 diabetes mellitus (DM2). A recent meta-analysis shows that moderate-severe SAHS is associated with an increased risk of DM2 (relative risk=1.63 [1.09 to 2.45]), compared to the absence of apneas and hypopneas. Common alterations in various pathogenic pathways add biological plausibility to this relationship. Intermittent hypoxia and sleep fragmentation, caused by successive apnea-hypopnea episodes, induce several intermediate disorders, such as activation of the sympathetic nervous system, oxidative stress, systemic inflammation, alterations in appetite-regulating hormones and activation of the hypothalamic-pituitary adrenal axis which, in turn, favor the development of insulin resistance, its progression to glucose intolerance and, ultimately, to DM2. Concomitant SAHS seems to increase DM2 severity, since it worsens glycemic control and enhances the effects of atherosclerosis on the development of macrovascular complications. Furthermore, SAHS may be associated with the development of microvascular complications: retinopathy, nephropathy or diabetic neuropathy in particular. Data are still scant, but it seems that DM2 may also worsen SAHS progression, by increasing the collapsibility of the upper airway and the development of central apneas and hypopneas. PMID- 25145321 TI - Pulmonologists, mechanical ventilation and complementary techniques. PMID- 25145322 TI - Severe community acquired pneumonia due to Legionella maceachernii infection. PMID- 25145323 TI - Nighttime aircraft noise impairs endothelial function and increases blood pressure in patients with or at high risk for coronary artery disease. AB - AIMS: Epidemiological studies suggest the existence of a relationship between aircraft noise exposure and increased risk for myocardial infarction and stroke. Patients with established coronary artery disease and endothelial dysfunction are known to have more future cardiovascular events. We therefore tested the effects of nocturnal aircraft noise on endothelial function in patients with or at high risk for coronary artery disease. METHODS: 60 Patients (50p 1-3 vessels disease; 10p with a high Framingham Score of 23%) were exposed in random and blinded order to aircraft noise and no noise conditions. Noise was simulated in the patients' bedroom and consisted of 60 events during one night. Polygraphy was recorded during study nights, endothelial function (flow-mediated dilation of the brachial artery), questionnaires and blood sampling were performed on the morning after each study night. RESULTS: The mean sound pressure levels L eq(3) measured were 46.9 +/- 2.0 dB(A) in the Noise 60 nights and 39.2 +/- 3.1 dB(A) in the control nights. Subjective sleep quality was markedly reduced by noise from 5.8 +/- 2.0 to 3.7 +/- 2.2 (p < 0.001). FMD was significantly reduced (from 9.6 +/- 4.3 to 7.9 +/- 3.7%; p < 0.001) and systolic blood pressure was increased (from 129.5 +/ 16.5 to 133.6 +/- 17.9 mmHg; p = 0.030) by noise. The adverse vascular effects of noise were independent from sleep quality and self-reported noise sensitivity. CONCLUSIONS: Nighttime aircraft noise markedly impairs endothelial function in patients with or at risk for cardiovascular disease. These vascular effects appear to be independent from annoyance and attitude towards noise and may explain in part the cardiovascular side effects of nighttime aircraft noise. PMID- 25145324 TI - The role of iron in gray matter degeneration in Huntington's disease: a magnetic resonance imaging study. AB - In Huntington's disease, iron accumulation in basal ganglia accompanies neuronal loss. However, if iron content changes with disease progression and how it relates to gray matter atrophy is not clear yet. We explored iron content in basal ganglia and cortex and its relationship with gray matter volume in 77 mutation carriers [19 presymptomatic, 8 with soft symptoms (SS), and 50 early stage patients) and 73 matched-controls by T2*relaxometry and T1-weighted imaging on a 3T scanner. The ANCOVA model showed that iron accumulates in the caudate in presymptomatic subjects (P = 0.004) and remains relatively stable along disease stages in this nucleus; while increases in putamen and globus pallidus (P < 0.05). Volume instead decreases in basal ganglia, starting from the caudate (P < 0.0001) and extending to the putamen and globus pallidus (P <= 0.001). The longer the disease duration and the higher the CAG repeats, the higher the iron accumulation and the smaller the volume. In the cortex, iron decreases in parieto occipital areas in SS (P < 0.027); extending to premotor and parieto-temporo occipital areas in patients (P < 0.003); while volume declines in frontoparietal and temporal areas in presymptomatic (P < 0.023) and SS (P < 0.045), and extends throughout the cortex, with the exception of anterior frontal regions, in patients (P < 0.023). There is an inverse correlation between volume and iron levels in putamen, globus pallidus and the anterior cingulate; and a direct correlation in cortical structures (SMA-sensoriomotor and temporo-occipital). Iron homeostasis is affected in the disease; however, there appear to be differences in the role played by iron in basal ganglia and in cortex. PMID- 25145325 TI - Beyond transmission: intergenerational patterns of family formation among middle class American families. AB - Research about parental effects on family behavior focuses on intergenerational transmission: that is, whether children show the same family behavior as their parents. This focus potentially over emphasizes similarity and obscures heterogeneity in parental effects on family behavior. In this study, we make two contributions. First, instead of focusing on isolated focal events, we conceptualize parents' and their children's family formation holistically as the process of union formation and childbearing between ages 15 and 40. We then discuss mechanisms likely to shape these intergenerational patterns. Second, beyond estimating average transmission effects, we innovatively apply multichannel sequence analysis to dyadic sequence data on middle-class American families from the Longitudinal Study of Generations (LSOG; N = 461 parent-child dyads). The results show three salient intergenerational family formation patterns among this population: a strong transmission, a moderated transmission, and an intergenerational contrast pattern. We examine what determines parents' and children's likelihood to sort into a specific intergenerational pattern. For middle-class American families, educational upward mobility is a strong predictor of moderated intergenerational transmission, whereas close emotional bonds between parents and children foster strong intergenerational transmission. We conclude that intergenerational patterns of family formation are generated at the intersection of macro-structural change and family internal psychological dynamics. PMID- 25145327 TI - RNA isolation from mouse pancreas: a ribonuclease-rich tissue. AB - Isolation of high-quality RNA from ribonuclease-rich tissue such as mouse pancreas presents a challenge. As a primary function of the pancreas is to aid in digestion, mouse pancreas may contain as much a 75 mg of ribonuclease. We report modifications of standard phenol/guanidine thiocyanate lysis reagent protocols to isolate RNA from mouse pancreas. Guanidine thiocyanate is a strong protein denaturant and will effectively disrupt the activity of ribonuclease under most conditions. However, critical modifications to standard protocols are necessary to successfully isolate RNA from ribonuclease-rich tissues. Key steps include a high lysis reagent to tissue ratio, removal of undigested tissue prior to phase separation and inclusion of a ribonuclease inhibitor to the RNA solution. Using these and other modifications, we routinely isolate RNA with RNA Integrity Number (RIN) greater than 7. The isolated RNA is of suitable quality for routine gene expression analysis. Adaptation of this protocol to isolate RNA from ribonuclease rich tissues besides the pancreas should be readily achievable. PMID- 25145328 TI - Fast reversibility of dimeriser system enables quantification of signal molecule turnover. AB - The design of a brake: Chemical induced dimerisation systems have revolutionised signal transduction research by allowing fast activation of specific proteins. A recent report describes the design of tools that enable the rapid switching off of the induced signal, thereby enabling quantification of signal molecule turnover. PMID- 25145326 TI - Rural-to-urban migration and sexual debut in Thailand. AB - Migration from one's parents' home and sexual debut are common features of the transition to adulthood. Although many studies have described both of these features independently, few have examined the relationship between migration and sexual debut in a systematic manner. In this study, we explore this link for young adults in Thailand. With relatively high rates of internal migration, rapid modernization, a moderate HIV epidemic, and a declining average age of sexual debut, Thailand presents an instructive environment in which to examine migration and sexual debut. We use two waves of a longitudinal data set (2005 and 2007) that includes a subsample of young adults who migrated to urban areas during that period. We identify characteristics and behaviors associated with sexual debut and examine the role of migration on debut. Our approach reduces several common sources of bias that hamper existing work on both migration and sexual debut: (1) the longitudinal nature of the data enables us to examine the effects of characteristics that predate both behaviors of interest; (2) the survey on sexual behavior employed a technique that reduces response bias; and (3) we examine differences in debut by marital status. We find that migrants have a higher likelihood of sexual debut than nonmigrants. PMID- 25145329 TI - Patent prospects toward therapeutics and diagnostics of anthrax. AB - Anthrax is one of the deadly infectious disease as documented in the CDC website. In spite of the availability of appropriate antimicrobial agents, the mortality related with the anthrax remains high. The pathogenicity of B. anthracis is mainly accredited to the two foremost components: toxins and capsule. Virulence component of B. anthracis includes protective antigen (PA) which plays a vital role in pathogenesis, virulence protein edema factor (EF) and lethal factor (LF). This search for novel therapeutic strategies that attack the proteins involved in the pathogenesis of anthrax and may potentially supplement antimicrobials being investigated. Currently, extensive attempts are in progress to develop novel helpful therapies to all of the virulence components: lethal factor, protective antigen, edema factor and the capsule of B. anthracis. This review discusses the potential anthrax therapeutic, prophylactic measures and diagnostic applications based on recent patents' prospects. PMID- 25145331 TI - First evidence of chitin in calcified coralline algae: new insights into the calcification process of Clathromorphum compactum. AB - Interest in calcifying coralline algae has been increasing over the past years due to the discovery of extensive coralline algal dominated ecosystems in Arctic and Subarctic latitudes, their projected sensitivity to ocean acidification and their utility as palaeoenvironmental proxies. Thus, it is crucial to obtain a detailed understanding of their calcification process. We here extracted calcified skeletal organic matrix components including soluble and insoluble fractions from the widely-distributed Subarctic and Arctic coralline alga Clathromorphum compactum. The lyophilized skeletal organic matrix fractions showed comparatively high concentrations of soluble and insoluble organic matrices comprising 0.9% and 4.5% of skeletal weight, respectively. This is significantly higher than in other skeletal marine calcifiers. Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy (ATR-FTIR) and X-Ray Diffraction (XRD) results indicate that chitin is present in the skeletal organic matrices of C. compactum. This polymer exhibits similar hierarchical structural organizations with collagen present in the matrix and serves as a template for nucleation and controls the location and orientation of mineral phases. Chitin contributes to significantly increasing skeletal strength, making C. compactum highly adapted for living in a shallow high-latitude benthic environment. Furthermore, chitin containing polysaccharides can increase resistance of calcifiers to negative effects of ocean acidification. PMID- 25145330 TI - Development and characterization of siRNA lipoplexes: Effect of different lipids, in vitro evaluation in cancerous cell lines and in vivo toxicity study. AB - Cationic liposomes have long been used as non-viral vectors for small interfering RNA (siRNA) delivery but are associated with high toxicity, less transfection efficiency, and in vivo instability. In this investigation, we have developed siRNA targeted to RRM1 that is responsible for development of resistance to gemcitabine in cancer cells. Effect of different lipid compositions has been evaluated on formation of stable and less toxic lipoplexes. Optimized cationic lipoplex (D2CH) system was comprised of dioleoyl-trimethylammoniumpropane (DOTAP), dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), hydrogenated soya phosphocholine (HSPC), cholesterol, and methoxy(polyethyleneglycol)2000-1,2 distearoyl-sn-glycero-3-phosphoethanolamine (mPEG2000-DSPE). D2CH lipoplexes have shown particle size (147.5 +/- 2.89 nm) and zeta potential (12.26 +/- 0.54 mV) characteristics essential for their in vivo use. In vitro cytotoxicity study has shown low toxicity of developed lipoplexes as compared with lipofectamine-2000 up to N/P ratio as high as 7.5. Cell uptake studies and gene expression studies have confirmed intracellular availability of siRNA. In addition, developed lipoplexes also showed ~3 times less hemolytic potential as compared with DOTAP/DOPE lipoplexes at lipid concentration of 5 mg/mL. Lipoplexes also maintained particle size less than 200 nm on exposure to high electrolyte concentration and showed >70% siRNA retention in presence of serum showing siRNA protection conferred by lipoplexes. Furthermore, in vivo acute toxicity studies in mice showed that formulation was non-toxic up to a dosage of 0.75 mg of siRNA/kg as lipoplexes and 300 mg lipid/kg as blank liposomes indicating tolerability of lipoplexes at a dose much higher than required for therapeutic use. Promising results of this study warrant further investigation of developed siRNA lipoplexes for cancer treatment. PMID- 25145332 TI - Relation of D-dimer and troponin I in patients with new-onset atrial fibrillation. PMID- 25145333 TI - Meta-analysis of revascularization versus medical therapy for atherosclerotic renal artery stenosis. AB - The aim of the study was to compare the efficacy of revascularization versus medical therapy in patients with atherosclerotic renal artery stenosis (ARAS). ARAS is the most common cause of secondary hypertension and is associated with several complications, such as renal failure, coronary artery disease, cardiac destabilization, and stroke. Medical therapy is the cornerstone for management of ARAS; however, numerous trials have compared medical therapy with revascularization in the form of percutaneous renal artery angioplasty (PTRA) or percutaneous renal artery angioplasty with stent placement (PTRAS). Medline (PubMed and Ovid SP), Embase, Cochrane Central Register of Controlled Clinical Trials (CENTRAL), and Cochrane Database of Systematic Review (CDSR) were searched till present (November 2013) to identify clinical trials where medical therapy was compared with revascularization (PTRA or PTRAS). We performed a meta-analysis using a random effects model. The heterogeneity was assessed using I2 values. The initial database search identified 540 studies and 7 randomized controlled trials, and 2,139 patients were included in the final analysis. Angioplasty with or without stenting was not superior to medical therapy with respect to any outcome. The incidence of nonfatal myocardial infarction was 6.74% in both the stenting and medical therapy group (odds ratio=0.998, 95% confidence interval 0.698 to 1.427, p=0.992), and incidence of renal events in stenting population was found to be 19.58% versus 20.53% in medical therapy (odds ratio=0.945, 95% confidence interval 0.755 to 1.182, p=0.620). In conclusion, PTRA or PTRAS does not improve outcomes compared with medical therapy in patients with ARAS. Future studies should investigate to identify patient subgroups that may benefit from such an intervention. PMID- 25145334 TI - The role of assessment packages for diagnostic consultations: A conversation analytic perspective. AB - This article reports a conversation analysis of assessment package consultations. Healthcare delivery packages belong to a highly structured mode of healthcare delivery, in which specific courses of healthcare interventions related to assessment and treatment are predefined, both as to timing and content. Assessment packages are widely used in an increasing number of medical specialities; however, there is a lack of knowledge about how packaged assessment influences the interaction between doctor and patient. In this study, we investigate the final consultation in assessment packages, which is when the final clarification of the patient's symptoms takes place. The primary data of the study were eight audio recordings of consultations, and the secondary data were ethnographic field descriptions. In most consultations, packaged assessment was a resource as it provided fast and efficient clarification. In most cases, clarification was treated as good news since it either confirmed the absence of a serious disease or resulted in a diagnosis leading to relevant treatment offers. However, in some cases, clarification was not perceived as good news. This was the case in consultations with patients whose goal was to leave the consultation with clarification in the form of a definite diagnosis, but who were not offered such clarification. These patients negotiated the outcome of the consultation by applying implicit and explicit pressure, which induced the doctors to disregard the boundaries of the package and offer the patient more tests. The study highlights some of the problems related to introducing narrow, specialized package assessment. PMID- 25145335 TI - Salt stability--effect of particle size, relative humidity, temperature and composition on salt to free base conversion. AB - PURPOSE: The aim of this study was to investigate how factors such as temperature, relative humidity and particle size impact the extent of disproportionation (salt to free base conversion) in powder blends of miconazole, benzocaine or sertraline mesylate salts mixed with a basic additive. METHOD: Raman spectroscopy was used to quantitate the extent of disproportionation. The data was further analyzed by multivariate analysis with partial least squares (PLS) modeling. RESULTS: It was found that salt disproportionation was significantly influenced by % weight gain due to moisture sorption both in terms of the kinetics and the conversion extent, suggesting a solution-mediated reaction. Temperature plays an important role in impacting the value of pHmax which in turn has a significant correlation to the amount of free base formed. The particle size and drug: additive ratio were also found to influence the extent of disproportionation. CONCLUSIONS: This study shows that the extent of salt disproportionation is influenced by multiple factors and the application of PLS modeling demonstrated the feasibility of utilizing multivariate analysis to generate a predictive model for estimating the extent of conversion and thus may serve as a tool for risk assessment. PMID- 25145336 TI - Interaction studies between indomethacin nanocrystals and PEO/PPO copolymer stabilizers. AB - PURPOSE: The lack of effective screening methods and systemic understanding of interaction mechanisms complicates the stabilizer selection process for nanocrystallization. This study focuses on the efficiency of stabilizers with various molecular compositions and structures to stabilize drug nanocrystals. METHODS: Five structurally different polymers were chosen as stabilizers for indomethacin nanocrystals. The affinity of polymers onto drug surfaces was measured using surface plasmon resonance (SPR) and contact angle techniques. Nanosuspensions were prepared using the wet-ball milling technique and their physico-chemical properties were thoroughly characterized. RESULTS: SPR and contact angle measurements correlated very well with each other and showed that the binding efficiency decreased in the order L64 > 17R4 > F68 ~ T908 ~ T1107, which is attributed to the reduced PPO/PEO ratio and different polymer structures. The electrostatic interactions between the protonated amine of poloxamines and ionized indomethacin enhanced neither the affinity nor the properties of nanosuspensions, such as particle size and physical stability. CONCLUSIONS: A good stabilizer should have high binding efficiency, full coverage, and optimal hydrophobic/hydrophilic balance. A high affinity combined with short PEO chains (L64, 17R4) caused poor physical stability of nanosuspensions, whereas moderate binding efficiencies (F68, T908, T1107) with longer PEO chains produced physically stable nanosuspensions. PMID- 25145337 TI - The characterization of the human nasal epithelial cell line RPMI 2650 under different culture conditions and their optimization for an appropriate in vitro nasal model. AB - PURPOSE: The further characterization of the cell line RPMI 2650 and the evaluation of different culture conditions for an in vitro model for nasal mucosa. METHODS: Cells were cultured in media MEM or A-MEM at air-liquid (A-L) or liquid-liquid (L-L) interfaces for 1 or 3 weeks. Different cryopreservation methods and cell culture techniques were evaluated with immunolabelling of junctional proteins, ultrastructural analysis using electron microscopy, transepithelial electrical resistance (TEER) measurements, permeation studies with dextran and jacalin, and gene expression profiling of 84 drug transporters. RESULTS: Cell proliferation and differentiation depended on the used medium. The established epithelia expressed occludin, claudin-1, and E-cadherin under all conditions. Cells grown at the A-L interface formed more layers and exhibited a higher TEER and lower dextran and jacalin permeability than at the L-L interface, where cells morphologically exhibited a more differentiated phenotype. The expression of ABC and SLC transporters depended on culture duration and interface. CONCLUSIONS: The RPMI 2650 cells form a polarized epithelium resembling nasal mucosa. However, different culture conditions have a significant effect on cell ultrastructure, barrier integrity, and gene expression, and should be considered when using this cell line as an in vitro model for drug permeability studies and screening of nasal drug candidates. PMID- 25145338 TI - Acute respiratory distress syndrome in a pregnant woman with systemic lupus erythematosus: a case report. AB - When the disease activity of systemic lupus erythematosus (SLE) is controlled appropriately, a pregnant woman who has lupus is able to carry safely to term and deliver a healthy infant. While the physiology of a healthy pregnancy itself influences ventilatory function, acute pulmonary distress may decrease oxygenation and influence both mother and fetus. Though respiratory failure in pregnancy is relatively rare, it remains one of the leading conditions requiring intensive care unit admission in pregnancy and carries a high risk of maternal and fetal morbidity and mortality, not to mention the complexity caused by lupus flare. We report a case of SLE complicated with lupus pneumonitis and followed by acute respiratory distress during pregnancy. Though there is a high risk of maternal and fetal morbidity and mortality, maternal respiratory function improved after cesarean section and treatment of the underlying causes. The newborn had an extremely low birth weight but was well at discharge. PMID- 25145339 TI - Labelled leucocyte scintigraphy in an infected externalized Riata lead. PMID- 25145341 TI - Dominant negative mutant of Plasmodium Rad51 causes reduced parasite burden in host by abrogating DNA double-strand break repair. AB - Malaria parasites survive through repairing a plethora of DNA double-stranded breaks (DSBs) experienced during their asexual growth. In Plasmodium Rad51 mediated homologous recombination (HR) mechanism and homology-independent alternative end-joining mechanism have been identified. Here we address whether loss of HR activity can be compensated by other DSB repair mechanisms. Creating a transgenic Plasmodium line defective in HR function, we demonstrate that HR is the most important DSB repair pathway in malarial parasite. Using mouse malaria model we have characterized the dominant negative effect of PfRad51(K143R) mutant on Plasmodium DSB repair and host-parasite interaction. Our work illustrates that Plasmodium berghei harbouring the mutant protein (PfRad51(K143R)) failed to repair DSBs as evidenced by hypersensitivity to DNA-damaging agent. Mice infected with mutant parasites lived significantly longer with markedly reduced parasite burden. To better understand the effect of mutant PfRad51(K143R) on HR, we used yeast as a surrogate model and established that the presence of PfRad51(K143R) completely inhibited DNA repair, gene conversion and gene targeting. Biochemical experiment confirmed that very low level of mutant protein was sufficient for complete disruption of wild-type PfRad51 activity. Hence our work provides evidence that HR pathway of Plasmodium could be efficiently targeted to curb malaria. PMID- 25145340 TI - Mouse IDGenes: a reference database for genetic interactions in the developing mouse brain. AB - The study of developmental processes in the mouse and other vertebrates includes the understanding of patterning along the anterior-posterior, dorsal-ventral and medial- lateral axis. Specifically, neural development is also of great clinical relevance because several human neuropsychiatric disorders such as schizophrenia, autism disorders or drug addiction and also brain malformations are thought to have neurodevelopmental origins, i.e. pathogenesis initiates during childhood and adolescence. Impacts during early neurodevelopment might also predispose to late onset neurodegenerative disorders, such as Parkinson's disease. The neural tube develops from its precursor tissue, the neural plate, in a patterning process that is determined by compartmentalization into morphogenetic units, the action of local signaling centers and a well-defined and locally restricted expression of genes and their interactions. While public databases provide gene expression data with spatio-temporal resolution, they usually neglect the genetic interactions that govern neural development. Here, we introduce Mouse IDGenes, a reference database for genetic interactions in the developing mouse brain. The database is highly curated and offers detailed information about gene expressions and the genetic interactions at the developing mid-/hindbrain boundary. To showcase the predictive power of interaction data, we infer new Wnt/beta-catenin target genes by machine learning and validate one of them experimentally. The database is updated regularly. Moreover, it can easily be extended by the research community. Mouse IDGenes will contribute as an important resource to the research on mouse brain development, not exclusively by offering data retrieval, but also by allowing data input. DATABASE URL: http://mouseidgenes.helmholtz muenchen.de. PMID- 25145342 TI - Modelling the implications of regular increases in tobacco taxation in the tobacco endgame. AB - OBJECTIVE: We examine the potential role for taxation in the tobacco endgame in New Zealand, where the goal is to become 'smokefree' (less than 5% smoking prevalence) by 2025. DESIGN: Modelling study using a dynamic population model. SETTING AND PARTICIPANTS: New Zealand, Maori and non-Maori men and women. INTERVENTIONS: Annual increases in tobacco excise tax of 5%, 10%, 15% and 20% (with 10% reflecting the annual increase recently legislated by the New Zealand Government to 2016). RESULTS: With a continued commitment to annual 10% increases in tobacco excise tax, in addition to on-going Quitline and cessation support, New Zealand's smoking prevalence is projected to fall from 15.1% in 2013 to 8.7% (95% uncertainty interval 8.6% to 8.9%) by 2025. This is compared to 9.9% without any further tax rises. With annual tax increases of 20%, the prevalence is projected to fall to 7.6% (7.5% to 7.7%) by 2025. The potential reductions in smoking prevalence are substantial for both Maori and non-Maori populations, although annual tax increases as high as 20% will still only see Maori smoking prevalence in 2025 approaching the non-Maori smoking levels for 2013. Scenario analyses did not suggest that growth of the illicit tobacco market would substantively undermine the impact of tobacco tax rises. Nevertheless, unknown factors such as the gradual denormalisation of smoking and changes to the 'nicotine market' may influence sensitivity to changes in tobacco prices in the future. CONCLUSIONS: Regular increases in tobacco taxation could play an important role in helping to achieve tobacco endgames. However, this modelling in New Zealand suggests that a wider range of tobacco endgame strategies will be needed to achieve a smoke-free goal of less than 5% prevalence for all social groups--a conclusion that could also apply in other countries. PMID- 25145343 TI - NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report. AB - NUP98/NSD1 has recently been reported in association with poor outcome in acute myeloid leukemia (AML). Previous studies also observed a high overlap between NUP98/NSD1 and FLT3/ITD, raising the question as to whether the reported poor outcome is due to NUP98/NSD1 or caused by the co-occurrence of these 2 genetic lesions. We aimed to determine the prognostic significance of NUP98/NSD1 in the context of FLT3/ITD AML. A total of 1421 patients enrolled in 5 consecutive Children's Oncology Group/Children's Cancer Group and SWOG trials were evaluated. NUP98/NSD1 was found in 15% of FLT3/ITD and 7% of cytogenetically normal (CN) AML. Those with dual FLT3/ITD and NUP98/NSD1 (82% of NUP98/NSD1 patients) had a complete remission rate of 27% vs 69% in FLT3/ITD without NUP98/NSD1 (P < .001). The corresponding 3-year overall survival was 31% vs 48% (P = .011), respectively. In CN-AML, patients with concomitant NUP98/NSD1 and FLT3/ITD had a worse outcome than those harboring NUP98/NSD1 only. In multivariate analysis, the dual NUP98/NSD1 and FLT3/ITD remained an independent predictor of poor outcome, and NUP98/NSD1 without FLT3/ITD lost its prognostic significance. Our study demonstrates that it is the interaction between NUP98/NSD1 and FLT3/ITD that determines the poor outcome of patients with NUP98/NSD1 disease. PMID- 25145344 TI - BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. AB - Myelosuppression, graft-versus-host disease (GVHD), and relapse remain major causes of morbidity after stem cell transplantation for relapsed lymphoma. In this phase 1/2 study, we tested the safety and efficacy of escalating doses of bendamustine (70, 90, 110, and 130 mg/m2 per day for 3 days), coupled with our historical fixed doses of fludarabine and rituximab (BFR), as a nonmyeloablative allogeneic conditioning regimen for patients with relapsed lymphoma (n = 41) and chronic lymphocytic leukemia (CLL) (n = 15). Ten patients entered the phase 1 study; none experienced a dose-limiting toxicity. Forty-six additional patients were then treated in the phase 2 study at the maximum dose of 130 mg/m2 per day for 3 days. The proportions of transplants from matched siblings or unrelated donors were 54% and 46%. Remarkably, 55% of patients did not experience severe neutropenia. Forty-nine patients (88%) did not require platelet transfusion. The incidence of acute grade II-IV GVHD was 11%. The 2-year rate of extensive chronic GVHD was 26%. After a median follow-up duration of 26 months (range, 6-50 months), the 2-year overall and progression-free survival rates were 90% and 75%. In conclusion, our new BFR regimen is safe and effective for relapsed CLL and lymphoma patients. PMID- 25145346 TI - Ethical issues in genomic research on the African continent: experiences and challenges to ethics review committees. AB - This is a report on a workshop titled 'Ethics for genomic research across five African countries: Guidelines, experiences and challenges', University of the Witwatersrand, Johannesburg, South Africa, 10 and 11 December 2012. The workshop was hosted by the Wits-INDEPTH partnership, AWI-Gen, as part of the H3Africa Consortium. PMID- 25145345 TI - Gene discovery and differential expression analysis of humoral immune response elements in female Culicoides sonorensis (Diptera: Ceratopogonidae). AB - BACKGROUND: Female Culicoides sonorensis midges (Diptera: Ceratopogonidae) are vectors of pathogens that impact livestock and wildlife in the United States. Little is known about their biology on a molecular-genetic level, including components of their immune system. Because the insect immune response is involved with important processes such as gut microbial homeostasis and vector competence, our aims were to identify components of the midge innate immune system and examine their expression profiles in response to diet across time. METHODS: In our previous work, we de novo sequenced and analyzed the transcriptional landscape of female midges under several feeding states including teneral (unfed) and early and late time points after blood and sucrose. Here, those transcriptomes were further analyzed to identify insect innate immune orthologs, particularly humoral immune response elements. Additionally, we examined immune gene expression profiles in response to diet over time, on both a transcriptome wide, whole-midge level and more specifically via qRTPCR analysis of antimicrobial peptide (AMP) expression in the alimentary canal. RESULTS: We identified functional units comprising the immune deficiency (Imd), Toll and JAK/STAT pathways, including humoral factors, transmembrane receptors, signaling components, transcription factors/regulators and effectors such as AMPs. Feeding altered the expression of receptors, regulators, AMPs, prophenoloxidase and thioester-containing proteins, where blood had a greater effect than sucrose on the expression profiles of most innate immune components. qRTPCR of AMP genes showed that all five were significantly upregulated in the alimentary canal after blood feeding, possibly in response to proliferating populations of gut bacteria. CONCLUSIONS: Identification and functional insight of humoral/innate immune components in female C. sonorensis updates our knowledge of the molecular biology of this important vector. Because diet alone influenced the expression of immune pathway components, including their effectors, subsequent study of the role of innate immunity in biological processes such as gut homeostasis and life history are being pursued. Furthermore, since the humoral response is a key contributor in gut immunity, manipulating immune gene expression will help in uncovering genetic components of vector competence, including midgut barriers to infection. The results of such studies will serve as a platform for designing novel transmission-blocking strategies. PMID- 25145348 TI - Role of linker histone H1c during the reprogramming of Chinese swamp buffalo (Bubalus Bubalis) embryos produced by somatic cell nuclear transfer. AB - During reprogramming, there is exchange of histone H1c and the oocyte-specific linker histone, and H1c may play a critically important role in the reprogramming process of somatic cell nuclear transfer (SCNT). The aim of the present study was to investigate the role of the H1c gene in SCNT reprogramming in Chinese swamp buffalo (Bubalus bubalis) using RNA interference (RNAi). Chinese swamp buffalo H1c gene sequences were obtained and H1c-RNAi vectors were designed, synthesised and then transfected into a buffalo fetal skin fibroblast cell line. Expression of H1c was determined by real-time polymerase chain reaction to examine the efficiency of vector interference. These cells were then used as a nuclear donor for SCNT so as to observe the further development of SCNT embryos. Inhibition of H1c gene expression in donor cells significantly improved the developmental speed of embryos from the 1-cell to 8-cell stage. Furthermore, compared with the control group, inhibition of H1c gene expression significantly reduced the blastocyst formation rate. It is concluded that linker histone H1c is very important in SCNT reprogramming in Chinese swamp buffalo. Correct expression of the H1c gene plays a significant role in preimplantation embryonic development in B. bubalis. PMID- 25145347 TI - An evolutionary preserved intergenic spacer in gadiform mitogenomes generates a long noncoding RNA. AB - BACKGROUND: Vertebrate mitogenomes are economically organized and usually lack intergenic sequences other than the control region. Intergenic spacers located between the tRNA(Thr) and tRNA(Pro) genes ("T-P spacers") have been observed in several taxa, including gadiform species, but information about their biological roles and putative functions is still lacking. RESULTS: Sequence characterization of the complete European hake Merluccius merluccius mitogenome identified a complex T-P spacer ranging in size from 223-532 bp. Further analyses of 32 gadiform species, representing 8 families and 28 genera, revealed the evolutionary preserved presence of T-P spacers across all taxa. Molecular complexity of the T-P spacers was found to be coherent with the phylogenetic relationships, supporting a common ancestral origin and gain of function during codfish evolution. Intraspecific variation of T-P spacer sequences was assessed in 225 Atlantic cod specimens and revealed 26 haplotypes. Pyrosequencing data representing the mito-transcriptome poly (A) fraction in Atlantic cod identified an abundant H-strand specific long noncoding RNA of about 375 nt. The T-P spacer corresponded to the 5' part of this transcript, which terminated within the control region in a tail-to-tail configuration with the L-strand specific transcript (the 7S RNA). CONCLUSIONS: The T-P spacer is inferred to be evolutionary preserved in gadiform mitogenomes due to gain of function through a long noncoding RNA. We suggest that the T-P spacer adds stability to the H-strand specific long noncoding RNA by forming stable hairpin structures and additional protein binding sites. PMID- 25145349 TI - Construction and characterization of a novel vocal fold bioreactor. AB - In vitro engineering of mechanically active tissues requires the presentation of physiologically relevant mechanical conditions to cultured cells. To emulate the dynamic environment of vocal folds, a novel vocal fold bioreactor capable of producing vibratory stimulations at fundamental phonation frequencies is constructed and characterized. The device is composed of a function generator, a power amplifier, a speaker selector and parallel vibration chambers. Individual vibration chambers are created by sandwiching a custom-made silicone membrane between a pair of acrylic blocks. The silicone membrane not only serves as the bottom of the chamber but also provides a mechanism for securing the cell-laden scaffold. Vibration signals, generated by a speaker mounted underneath the bottom acrylic block, are transmitted to the membrane aerodynamically by the oscillating air. Eight identical vibration modules, fixed on two stationary metal bars, are housed in an anti-humidity chamber for long-term operation in a cell culture incubator. The vibration characteristics of the vocal fold bioreactor are analyzed non-destructively using a Laser Doppler Vibrometer (LDV). The utility of the dynamic culture device is demonstrated by culturing cellular constructs in the presence of 200-Hz sinusoidal vibrations with a mid-membrane displacement of 40 um. Mesenchymal stem cells cultured in the bioreactor respond to the vibratory signals by altering the synthesis and degradation of vocal fold-relevant, extracellular matrix components. The novel bioreactor system presented herein offers an excellent in vitro platform for studying vibration-induced mechanotransduction and for the engineering of functional vocal fold tissues. PMID- 25145350 TI - Toxicity evaluation of manufactured CeO2 nanoparticles before and after alteration: combined physicochemical and whole-genome expression analysis in Caco 2 cells. AB - BACKGROUND: Engineered nanomaterials may release nanosized residues, by degradation, throughout their life cycle. These residues may be a threat for living organisms. They may be ingested by humans through food and water. Although the toxicity of pristine CeO2 nanoparticles (NPs) has been documented, there is a lack of studies on manufactured nanoparticles, which are often surface modified. Here, we investigated the potential adverse effects of CeO2 Nanobyk 3810TM NPs, used in wood care, and their residues, altered by light or acid. RESULTS: Human intestinal Caco-2 cells were exposed to residues degraded by daylight or in a medium simulating gastric acidity. Size and zeta potential were determined by dynamic light scattering. The surface structure and redox state of cerium were analyzed by transmission electronic microscopy (TEM) and X-ray absorption spectroscopy, respectively. Viability tests were performed in Caco-2 cells exposed to NPs. Cell morphology was imaged with scanning electronic microscopy. Gene expression profiles obtained from cells exposed to NPs before and after their alteration were compared, to highlight differences in cellular functions.No change in the cerium redox state was observed for altered NPs. All CeO2 NPs suspended in the culture medium became microsized. Cytotoxicity tests showed no toxicity after Caco-2 cell exposure to these various NPs up to 170 MUg/mL (24 h and 72 h). Nevertheless, a more-sensitive whole-gene-expression study, based on a pathway-driven analysis, highlighted a modification of metabolic activity, especially mitochondrial function, by altered Nanobyk 3810TM. The down-regulation of key genes of this pathway was validated by qRT-PCR. Conversely, Nanobyk 3810TM coated with ammonium citrate did not display any adverse effect at the same concentration. CONCLUSION: The degraded nanoparticles were more toxic than their coated counterparts. Desorption of the outside layer was the most likely cause of this discrepancy in toxicity. It can be assumed that the safe design of engineered nanoparticles could include robust protective layers conferring on them greater resistance to alteration during their life cycle. PMID- 25145352 TI - Grail controls Th2 cell development by targeting STAT6 for degradation. AB - T helper (Th)-2 cells are the major players in allergic asthma; however, the mechanisms that control Th2-mediated inflammation are poorly understood. Here we find that enhanced expression of Grail, an E3 ubiquitin ligase, in Th2 cells depends on interleukin (IL)-4-signalling components, signal transducer and activator of transcription 6 (Stat6) and Gata3, that bind to and transactivate the Grail promoter. Grail deficiency in T cells leads to increased expression of Th2 effector cytokines in vitro and in vivo and Grail-deficient mice are more susceptible to allergic asthma. Mechanistically, the enhanced effector function of Grail-deficient Th2 cells is mediated by increased expression of Stat6 and IL 4 receptor alpha-chain. Grail interacts with Stat6 and targets it for ubiquitination and degradation. Thus, our results indicate that Grail plays a critical role in controlling Th2 development through a negative feedback loop. PMID- 25145354 TI - Bone cement implantation syndrome and proximal femoral fracture. PMID- 25145355 TI - Anaesthesiology and perioperative medicine around the world: different names, same goals. PMID- 25145353 TI - Effects of early and late diabetic neuropathy on sciatic nerve block duration and neurotoxicity in Zucker diabetic fatty rats. AB - BACKGROUND: The neuropathy of type II diabetes mellitus (DM) is increasing in prevalence worldwide. We aimed to test the hypothesis that in a rodent model of type II DM, neuropathy would lead to increased neurotoxicity and block duration after lidocaine-induced sciatic nerve block when compared with control animals. METHODS: Experiments were carried out in Zucker diabetic fatty rats aged 10 weeks (early diabetic) or 18 weeks (late diabetic, with or without insulin 3 units per day), and age-matched healthy controls. Left sciatic nerve block was performed using 0.2 ml lidocaine 2%. Nerve conduction velocity (NCV) and F-wave latency were used to quantify nerve function before, and 1 week after nerve block, after which sciatic nerves were used for neurohistopathology. RESULTS: Early diabetic animals did not show increased signs of nerve dysfunction after nerve block. In late diabetic animals without insulin vs control animals, NCV was 34.8 (5.0) vs 41.1 (4.1) ms s(-1) (P<0.01), and F-wave latency was 7.7 (0.5) vs 7.0 (0.2) ms (P<0.01), respectively. Motor nerve block duration was prolonged in late diabetic animals, but neurotoxicity was not. Late diabetic animals receiving insulin showed intermediate results. CONCLUSIONS: In a rodent type II DM model, nerves have increased sensitivity for short-acting local anaesthetics without adjuvants in vivo, as evidenced by prolonged block duration. This sensitivity appears to increase with the progression of neuropathy. Our results do not support the hypothesis that neuropathy due to type II DM increases the risk of nerve injury after nerve block. PMID- 25145357 TI - Backseat drivers: Regulation of dynein motility. AB - Control of the activity of the microtubule motor cytoplasmic dynein 1 is essential for its function in intracellular transport. A recent paper by McKenney et al. published in Science shows that activation of processive dynein motility requires the formation of cargo adaptor-dynein-dynactin complexes. PMID- 25145358 TI - Mixed messages: Re-initiation factors regulate translation of animal mRNAs. AB - When ribosomes encounter upstream open reading frames (uORFs) during scanning of the 5' untranslated region (5' UTR), translation of the downstream ORF requires re-initiation. In a recent paper in Nature, Schleich et al. describe metazoan factors which specifically promote re-initiation. PMID- 25145356 TI - Blocking autocrine VEGF signaling by sunitinib, an anti-cancer drug, promotes embryonic stem cell self-renewal and somatic cell reprogramming. AB - Maintaining the self-renewal of embryonic stem cells (ESCs) could be achieved by activating the extrinsic signaling, i.e., the use of leukemia inhibitory factor (LIF), or blocking the intrinsic differentiation pathways, i.e., the use of GSK3 and MEK inhibitors (2i). Here we found that even in medium supplemented with LIF, mESCs still tend to differentiate toward meso-endoderm lineages after long-term culture and the culture spontaneously secretes vascular endothelial growth factors (VEGFs). Blocking VEGF signaling with sunitinib, an anti-cancer drug and a receptor tyrosine kinase (RTK) inhibitor mainly targeting VEGF receptors (VEGFRs), is capable of maintaining the mESCs in the undifferentiated state without the need for feeder cells or LIF. Sunitinib facilitates the derivation of mESCs from blastocysts, and the mESCs maintained in sunitinib-containing medium remain pluripotent and are able to contribute to chimeric mice. Sunitinib also promotes iPSC generation from MEFs with only Oct4. Knocking down VEGFR2 or blocking it with neutralizing antibody mimicks the effect of sunitinib, indicating that blocking VEGF/VEGFR signaling is indeed beneficial to the self renewal of mESCs. We also found that hypoxia-inducible factor alpha (HIF1alpha) and endoplasmic reticulum (ER) stress are involved in the production of VEGF in mESCs. Blocking both pathways inhibits the expression of VEGF and prevents spontaneous differentiation of mESCs. Interestingly, LIF may also exert its effect by downregulating HIF1alpha and ER stress pathways and subsequent VEGF expression. These results indicate the existence of an intrinsic differentiation pathway in mESCs by activating the autocrine VEGF signaling. Blocking VEGF signaling with sunitinib or other small molecules help to maintain the mESCs in the ground state of pluripotency. PMID- 25145360 TI - Rbpj links uterine transformation and embryo orientation. AB - Implantation involves complex signaling networks, which direct morphological and molecular transformation of the embryo and the uterus and establish the trajectory of normal pregnancy. The recent work by Zhang et al. published in Cell Research, identifies the transcriptional regulator, Rbpj, as essential for uterine closure and proper embryo alignment during implantation in the mouse, raising the possibility that aberrant Rbpj signaling could contribute to infertility in humans. PMID- 25145362 TI - Charting progress in the battle against cancer. PMID- 25145359 TI - Baf250a orchestrates an epigenetic pathway to repress the Nkx2.5-directed contractile cardiomyocyte program in the sinoatrial node. AB - The sinoatrial node (SAN) is essential for rhythmic beating of the heart; however, our understanding of what controls proper functioning of the SAN remains primitive. To explore molecular control of SAN function, we specifically deleted Baf250a, a key regulatory component of the ATP-dependent chromatin remodeling complex SWI/SNF, in the SAN. Deletion of Baf250a in the SAN led to sinus bradycardia. Time series analysis of dysregulated genes after deletion of Baf250a reveals a transcriptional hierarchy maintaining pacemaker cell identity, i.e., Baf250a activates the expression of Tbx3, and Baf250a, Tbx3 and histone deacetylase 3 coordinately repress the expression of Nkx2.5. Disruption of this repressive pathway switches on expression of Nkx2.5, which stimulates expression of Gata4 and Tbx5. These three cardiac transcription factors further turn on a contractile cardiomyocyte program in the SAN, which eventually leads to sick sinus disease (SSD). Our study suggests that disruption of key genetic pathways regulating cardiac lineage segregation may cause SSD and cardiac arrhythmias in general. PMID- 25145363 TI - Cancer mortality and incidence trends comparing New Zealand and Australia for the period 2000-2007. AB - BACKGROUND AND AIMS: A previous study showed that cancer mortality in New Zealand in 1996-97 was substantially higher than that expected from Australian rates. This study compared cancer mortality and incidence in New Zealand for 2000-2007 with rates in Australia, to assess if any differences had persisted or changed. METHODS: The numbers of cancer deaths in New Zealand, by type of cancer, year, sex, and 5 year age group, were compared to the numbers that would have occurred if NZ rates had been the same as those in Australia. Trends over time, and also cancer incidence, were assessed. RESULTS: From 2000-2007, there were each year an average of 586 (15.1% of the total) more deaths from cancer in New Zealand women than expected from Australian rates; and 197 (4.7%) more deaths in men. There was no significant change over time in these differentials. Higher cancer mortality was seen for most common sites; the greatest excesses were for colorectal cancer in both men and women. Cancer incidence in New Zealand women was 3.3% higher, and incidence in men was 4.7% lower, than in Australia over this period; thus the higher cancer deaths in New Zealand are not due simply to higher incidence. Over this time period, cancer mortality has fallen substantially in both countries; in New Zealand, it fell from 1990 to 2007 by 20% in women and 24% in men. CONCLUSION: Cancer mortality remains substantially higher in New Zealand than in Australia, especially for women, although mortality has reduced in both countries. While the differences in 2000-07 were slightly smaller than in 1996 97, there has been little change since 2000. The greater differences in deaths than in incidence suggest that patient survival is lower in New Zealand. PMID- 25145361 TI - Osteogenic fate of hypertrophic chondrocytes. PMID- 25145364 TI - A comparison of cancer statistics in New Zealand and Australia: 1996-2007. AB - AIM: To compare the burden and outcomes of cancer in New Zealand with those in Australia. METHODS: For the years 1996-1997 and 2006-2007, the incidence and mortality of cancer in New Zealand and Australia was compared to determine if differences between the two countries had changed over the decade under study. Summarised cancer data from New Zealand and Australia, age standardised to the 2002 World Health Organisation's standard population, were used to make the comparisons. RESULTS: For the 11 year timeframe of this study, total rates of cancer incidence reduced in New Zealand and increased in Australia. The incidence of cancer in New Zealand, relative to Australia, changed from an excess of +10.3 to a deficit of -27.5 per 100,000 people. When considering the excess in terms of gender, the annual excess of cancer registrations for New Zealand females fell from +19.9 to +0.9 per 100,000, and male cancer registration fell from an excess of +3.7 to a deficit of -58.0 per 100,000, due almost entirely to a surge in prostate cancer registration in Australia. Over the same 11-year timeframe, cancer-specific mortality rates decreased in both countries, but there was no change in the difference between New Zealand and Australian rates, which remained 10% higher in New Zealand. Similar to findings on 1996/7 data, the main cancer sites responsible for the overall excess mortality in 2006/7 were colorectal cancer in both sexes, and lung and breast cancer in females. CONCLUSION: The persisting different cancer mortality rates between the two countries is likely to have been partly due to lifestyle and ethnic differences in the populations, and partly due to New Zealanders presenting with more advanced cancers and having less easy access to some treatments. Until we know the relative contributions of these factors, it will be difficult for New Zealand to plan interventions in the future which have a good chance of lifting our cancer survival rates to those of our closest neighbour. The collection of clinical stage on all new cancer registrations would provide the base information required. PMID- 25145365 TI - Screening for pulmonary arterial hypertension in patients with scleroderma--a New Zealand perspective. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) in scleroderma (SSc) patients is a devastating complication with high mortality if untreated. Early recognition and specific treatment of PAH may improve outcome. Regular interval screening for PAH is generally recommended in scleroderma patients especially with the availability of emerging new therapies. The aim of this study is to determine the self-reported screening and treatment practices for SSc-PAH amongst rheumatologists in New Zealand (NZ). METHODS: An anonymous online questionnaire survey was emailed to all rheumatologists in New Zealand. RESULTS: Responses were received from 65% (39/60) of rheumatologists. The majority of patients had limited SSc (lcSSc) (57%) versus diffuse SSc (dcSSc) (34%). Twelve percent of patients had PAH. Eighty-two percent of rheumatologists screened for PAH in all SSc patients regardless of symptoms. The most commonly used screening modalities were pulmonary function tests (PFT) (97%) followed by clinical examination (95%) and echocardiogram (TTE) (92%). The majority of rheumatologists performed screening tests on a yearly basis (80% used PFT and 64% used TTE). A right heart catheter was used to confirm PAH in 70% of patients. Sixty-four percent of rheumatologists extend screening interval time if their patients were clinically stable. The most common PAH-specific therapy used was sildenafil (57%) followed by bosentan (19%). Sixty-four percent of rheumatologists supported a national PAH SSc screening guideline. CONCLUSION: This study has shown a wide variability of how NZ rheumatologists screen for PAH in scleroderma patients. The development of a PAH-SSc guideline for screening and diagnosis may help standardise treatment practices in NZ. PMID- 25145367 TI - Construction and use of mapping techniques to describe the geographical distribution of medication dispensing for the secondary prevention of atherosclerotic CVD in New Zealand: VIEW-2. AB - BACKGROUND: The Health Quality and Safety Commission (HQSC) is developing Atlases of Healthcare Variation in New Zealand. We were invited to create and map the sociogeographic distribution of medication dispensing patterns among people with atherosclerotic cardiovascular disease (CVD). METHODS: We developed two interactive online atlas 'templates' demonstrating geographical variations in CVD medication dispensing using InstantAtlas. Each template provides stratified results in tabular, graphical and map format. In the 'Standard' template proportions were mapped according to standard deviations from the mean, while the 'Advanced' template used a 'heat-map' classification to show DHB-level variations. Furthermore, we added commentaries describing the variations present and provided questions of potential interest for users. RESULTS: The Standard template was best suited for DHB-level variations relative to a specific age, gender, or ethnic group but less effective for showing comparisons between two groups (e.g. Maori and Pacific). By contrast, the fixed legend and 'radar plot' in the Advanced template highlighted variations in medication dispensing rates geographically and sociodemographically more effectively. CONCLUSIONS: Geographical mapping of unwarranted variations in effective care requires careful consideration. Our experience from developing this CVD atlas is documented here for developers of other components of the Atlas of Healthcare Variation in New Zealand. PMID- 25145366 TI - Effect of age, gender, ethnicity, socioeconomic status and region on dispensing of CVD secondary prevention medication in New Zealand: the Atlas of Health Care Variation CVD cohort (VIEW-1). AB - BACKGROUND: Triple therapy with anti-platelet/anti-coagulant, blood pressure (BP) lowering, and statin medications improves outcomes in atherosclerotic cardiovascular disease (CVD). However, in practice there is often a substantial evidence-practice gap, with sub-optimal initiation and longer-term adherence. Our aim was to enumerate a contemporary national cohort of people with significant CVD and report the variation in CVD secondary prevention dispensing by demographic variables. METHODS: Using anonymised linkage of national data sets, we identified 86,256 individuals, alive and residing in New Zealand at the end of 2010, aged 30-79 years who were hospitalised for an atherosclerotic CVD event or procedure in the previous10 years. This cohort was linked to the national pharmaceutical dispensing dataset to assess dispensing of CVD prevention medications during the 2011 calendar year. Adequate dispensing was defined as being dispensed a drug in at least 3 of the 4 quarters of the year. Multivariate regression was used to identify independent predictors of adequate dispensing. RESULTS: 59% were maintained on triple therapy, 77% on BP-lowering medication, 75% on anti-platelet/anti-coagulants and 70% on statins. From multivariate analysis, patients less than 50 years were about 20% less likely than older patients and women were 10% less likely than men to be maintained on triple therapy. Indian patients were about 10% more likely to be maintained on triple therapy than NZ European/Others. Those living in the Southern Cardiac Network region of New Zealand had slightly higher rates of triple therapy than National Cardiac Regions further north. CONCLUSIONS: The significant under-utilisation of safe and inexpensive secondary prevention medication, particularly in younger people and women, provides an opportunity to improve CVD outcomes in this easily identifiable high-risk population. PMID- 25145368 TI - Stakeholder engagement for the New Zealand Atlas of Healthcare Variation: cardiovascular disease secondary prevention: VIEW-3. AB - AIMS: As part of the Health Quality and Safety Commission's Atlas of Healthcare Variation in New Zealand, sociodemographic and regional differences in drug management for people with cardiovascular disease (CVD) were mapped. The aim of stakeholder engagement was to obtain feedback regarding interpretation, presentation and use of the Atlas data. METHODS: Feedback was obtained through surveys, one-on-one interviews and presentations at various meetings of clinicians, managers and researchers with an interest in CVD. Presentation and utility of the Atlas data for frontline quality improvement was explored. RESULTS: 28 stakeholders completed one-on-one feedback and over 100 attended meetings where the Atlas data were presented. Differences in dispensing by medication type, age, gender and ethnicity were thought to be related to diagnostic accuracy or the behaviour of prescribers or patients. Stakeholders found a funnel plot of the variation in triple therapy dispensing among general practices to be the most useful method of presentation, as it enabled practitioners to benchmark against peers, highlight areas for improvement, and monitor their progress over time. CONCLUSION: Stakeholder engagement has informed the interpretation of findings and the formatting of the Atlas data in a way that would potentially lead to improvements in the quality of patient care. PMID- 25145369 TI - Why are we failing with the epidemic of obesity and other chronic diseases? A further look at aetiopathogenesis. AB - It is timely to be addressing this question: in some respects medicine and the delivery of healthcare has driven itself slowly to an impasse, whilst the biological sciences that should underpin our understanding of healthcare are undergoing a revolution. That there could now be seriously conflicting scientific opinion over the role of saturated fats in the aetiopathogenesis of coronary heart disease is a terrifying indictment of our limited understanding of the role of the modern diet in disease. Currently there remains a substantial disconnect between the new directions indicated by the biological sciences, and our entrenched views concerning treatment of the epidemic chronic diseases such as obesity. As the new knowledge unfolds it seems likely that a better understanding of diet in all respects will move to centre stage as we endeavour to solve these problems. PMID- 25145370 TI - Cephalic tetanus complicating geriatric fall. AB - We report a case of cephalic tetanus which initially presented with acute lower motor neurone facial weakness. Tetanus is a rare diagnosis in the developed world but sporadic cases do occur. People born before 1960 in New Zealand are less likely to be immune. Judicious use of human tetanus immunoglobulin (TIG) and immunisation prevents the development of tetanus following injury and should always be considered in the elderly who are less likely to have immunity. PMID- 25145371 TI - Medical image. An unusual case of painful ophthalmoplegia. Tolosa-Hunt syndrome. PMID- 25145372 TI - Response to Professor Richmond's viewpoint article on the End of Life Choice Bill. PMID- 25145373 TI - Falling through the cracks: New Zealand prostate cancer survivors' experiences and views regarding PSA testing. PMID- 25145374 TI - High-resolution spatiotemporal analysis of receptor dynamics by single-molecule fluorescence microscopy. AB - Single-molecule microscopy is emerging as a powerful approach to analyze the behavior of signaling molecules, in particular concerning those aspect (e.g., kinetics, coexistence of different states and populations, transient interactions), which are typically hidden in ensemble measurements, such as those obtained with standard biochemical or microscopy methods. Thus, dynamic events, such as receptor-receptor interactions, can be followed in real time in a living cell with high spatiotemporal resolution. This protocol describes a method based on labeling with small and bright organic fluorophores and total internal reflection fluorescence (TIRF) microscopy to directly visualize single receptors on the surface of living cells. This approach allows one to precisely localize receptors, measure the size of receptor complexes, and capture dynamic events such as transient receptor-receptor interactions. The protocol provides a detailed description of how to perform a single-molecule experiment, including sample preparation, image acquisition and image analysis. As an example, the application of this method to analyze two G-protein-coupled receptors, i.e., beta2-adrenergic and gamma-aminobutyric acid type B (GABAB) receptor, is reported. The protocol can be adapted to other membrane proteins and different cell models, transfection methods and labeling strategies. PMID- 25145375 TI - Alternative tobacco product use and smoking cessation among homeless youth in los angeles county. AB - INTRODUCTION: Approximately 70% of homeless youth smoke cigarettes, but their use of alternative tobacco products (ATPs) is unknown. This paper reports on ATP use among past-month smokers in Los Angeles County, including whether it differs by demographic characteristics, homelessness severity, past-year quit attempts, and readiness to quit smoking. Given the growing popularity of e-cigarettes, we also report on perceptions of harm and reasons for using this product. METHODS: We surveyed 292 unaccompanied homeless youth who were randomly sampled from street sites. Participants had smoked at least 100 cigarettes during their lifetime and 1 cigarette during the past month. RESULTS: Seventy-two percent of youth reported past-month ATP use (e-cigarettes = 51%; little cigars/cigarillos = 46%; hookah = 31%; other smokeless tobacco product = 24%; chewing tobacco/moist snuff = 19%). Current ATP use was unrelated to most demographic characteristics or having a past-year quit attempt. However, youth who planned to quit smoking in the next 30 days were significantly less likely to report current use of hookahs, other smokeless tobacco products, or e-cigarettes. Among lifetime e-cigarette users, the most common reasons for use included not having to go outside to smoke (38%) and being able to deal with situations or places where they cannot smoke (36%); it was less common to report using e-cigarettes to quit smoking (17%-18%). DISCUSSION: Dual use of ATPs among homeless youth smokers is common and is more likely among those who have no immediate plans to quit smoking. Effective and easily disseminable strategies for reducing all forms of tobacco use among homeless youth are urgently needed. PMID- 25145376 TI - Water pipe steam stones: familiarity and use among US young adults. AB - INTRODUCTION: Water pipe tobacco smoking (WTS) is associated with substantial toxicant exposure. Water pipe steam stones (WSS) are marketed as a healthier alternative. The purpose of this study was to determine, in a nationally representative sample, young adults' familiarity with, perceptions regarding, and use of WSS. METHODS: A survey about WTS was completed by 3,253 members of an online nonvolunteer access panel. Four items specifically addressed WSS. RESULTS: Of the 228 individuals who had heard of WSS, 17% (n = 41) reported using them. Use was associated with ever (adjusted odds ratio [AOR] = 7.7, 95% confidence interval [CI] = 2.7-21.8) and current (AOR = 16.1, 95% CI = 5.1-51.5) WTS. Compared with those who thought that WSS had about the same harm as WTS, those who thought that WSS was "a lot less harmful" to a person's health had substantially higher odds of having tried WSS (AOR = 6.8, 95% CI = 2.0-23.1). CONCLUSIONS: Approximately 1 in 6 young adults who have heard of WSS used them. WSS use is associated with the perception of reduced harm. PMID- 25145377 TI - Pharmacokinetic-pharmacodynamic modeling of the effect of varenicline on nicotine craving in adult smokers. AB - INTRODUCTION: Varenicline has been shown to significantly reduce craving and several aspects of smoking reinforcement in clinical trials, compared with placebo. This is the first report describing the concentration-effect relationship of varenicline on relief of craving. METHODS: The pharmacokinetics (PK) and pharmacodynamics (PD) of a single 2mg dose of varenicline were investigated in 40 smokers in a randomized, crossover study comparing the effect of varenicline with placebo on ameliorating abstinence-and cue-induced craving and withdrawal symptoms. Subjects were asked to complete self-reported questionnaires (Smoking Urges Scale and Minnesota Nicotine Withdrawal Scale [MNWS]) and blood samples were simultaneously collected for measurement of varenicline concentrations. Only the data from the 4-hr postdose abstinence period (just prior to the cue session) were analyzed. Data were described by a 2 compartment PK model and a linear PD model with first-order onset/offset rate constants describing the placebo response "kinetics." Response was described as the net effect of the baseline, placebo, and drug responses. RESULTS: Varenicline significantly decreased mean craving score when compared with placebo and the magnitude of this response was related to varenicline concentration. The time course and magnitude of both placebo and varenicline craving response were characterized by a large degree of unexplained variability. Simulations were used to illustrate the expected craving response over time and its associated random variability after chronic dosing. CONCLUSIONS: Craving reduction is associated with increased varenicline concentrations. The relatively rapid onset of this effect within 4 hr postdose suggests that, smokers may experience some craving relief after acute administration of varenicline. PMID- 25145379 TI - Intra-abdominal desmoid tumor after resection for gastrointestinal stromal tumor of the small intestine: case report. AB - Mesenchymal tumors are thought to constitute only 1% of primary gastrointestinal malignancies. Both gastrointestinal stromal tumor and desmoid tumor are rare. The case of a 56-year-old male with a desmoid tumor 1 year after surgical removal of a gastrointestinal stromal tumor near the ligament of Treitz is described. Although he received adjuvant therapy of imatinib mesylate for 1 year after the surgery, a small nodule was found 1 year and 3 months after the surgery. The nodule was considered to be a recurrent tumor of gastrointestinal stromal tumor, and a wedge resection of the duodenum including the tumor was done. Histopathological examination by immunohistochemical staining revealed that it was a desmoid tumor. It would be useful to be aware of the possibility of desmoid tumor after removal of gastrointestinal stromal tumor. To accumulate further information on these rare diseases, a central database that includes rare diseases will be necessary. PMID- 25145378 TI - Tobacco use pattern among a national firefighter cohort. AB - INTRODUCTION: To date, there have been no large-scale, national epidemiological studies of tobacco use patterns among firefighters, particularly with a focus on smokeless tobacco (SLT) and dual use with cigarettes. While rates of firefighters' smoking are relatively low compared to the general population, SLT use typically is substantially higher than the populations they protect. In the current study, we systemically examine tobacco use, including SLT and dual use, and the health-related profiles of various tobacco use groups in a national sample of career firefighters. METHODS: Data are from a national cohort study of career departments (N = 20) comprised of 947 male firefighters. RESULTS: Among 947 participants, 197 (21%) were tobacco users, of which, 34.5% used cigarettes, 53.2% used SLT, and 12.2% used both cigarettes and SLT. Adjusted rates of smoking, SLT use, and dual use were 13.2%, 10.5%, and 12.2%, respectively. Tobacco users of all types were significantly younger and had served fewer years in fire service and were significantly more likely to engage in heavy and binge drinking, as well as more likely to show signs of depressive symptoms compared to nontobacco users. CONCLUSIONS: Detailed information on tobacco use pattern will aid in better understanding what factors are contributing to the high rates of SLT and dual use among firefighters in order to guide and develop an appropriate treatment program for the fire service. PMID- 25145380 TI - Using drawing tests to explore the multidimensional psychological aspects of children with cancer. AB - In seeking to understand how life-threatening illness affects children psychologically, projective testing may be beneficial, particularly when attempting to identify psychological problems in younger adolescents. The advantages of projective testing are that it does not depend on patients' verbal ability and is not invasive. Three cancer inpatients from Kyoto Prefectural University of Medicine, aged between 10 and 16 years old, participated in the study. Projective testing was used to measure the depth of participants' distress and included a tree-drawing test, a person-drawing test and a free drawing test. Results from the tree- and person-drawing tests indicated energy loss, anxiety and a sense of emptiness. However, results from the free drawing test suggested that the children had hope and a desire to recover from their illness. The combination of drawing tests in this study may increase the understanding of the internal psychological difficulties faced by children hospitalized with cancer. PMID- 25145381 TI - Gastrostomy dependence in head and neck carcinoma patient receiving post operative therapy. AB - OBJECTIVE: Post-operative concurrent chemoradiotherapy significantly improves the rates of locoregional control and disease-free survival in high-risk patients but has significant adverse effects. Percutaneous endoscopic gastrostomy and opioid based pain control increase treatment completion rates but can result in dysphagia. METHODS: The rate and duration of use of prophylactically placed percutaneous endoscopic gastrostomies were evaluated in 43 patients who underwent post-operative radiotherapy or chemoradiotherapy from April 2007 through March 2010. All patients completed treatment and received 60 Gy or more of radiotherapy. RESULTS: Thirty four of 43 patients (79.1%) used percutaneous endoscopic gastrostomies, which could later be removed in 25 of 34 patients. The median period of use was 108 days. Only one disease-free patient was permanently dependent on percutaneous endoscopic gastrostomy feeding. The frequency of percutaneous endoscopic gastrostomy use among patients with oral, oropharyngeal and hypopharyngeal cancer was 91.7, 100 and 54.5%, respectively. CONCLUSIONS: Prolonged percutaneous endoscopic gastrostomy use is not required in patients receiving post-operative chemoradiotherapy and will not lead to dysphagia. PMID- 25145382 TI - Glutathione S-transferase gene polymorphisms and susceptibility to acute myeloid leukemia: meta-analyses. AB - OBJECTIVE: A large body of evidence has shown the possible relevance of polymorphisms of the genes that encode glutathione S-transferase MU, pi and theta (GSTM1, GSTP1 and GST1, respectively) to the susceptibility of acute myeloid leukemia, but the exact association still remains uncertain. Therefore, we performed a meta-analysis to derive a more precise estimation of the relationship. METHODS: A comprehensive literature search of PubMed and Web of Knowledge electronic databases was conducted to collect relevant studies until 20 February 2014. References of the retrieved articles were also screened. The extracted data were statistically analyzed, and pooled odds ratios with 95% confidence intervals were calculated to estimate the association strength using Review Manager version 5.2. RESULTS: Twenty-nine studies were included in the meta-analysis. The pooled analyses revealed that the GSTM1-null genotype was associated with an increased risk of acute myeloid leukemia in East Asians (P = 0.01; odds ratio = 1.22; 95% confidence interval = 1.05-1.42), and GSTT1-null genotype in Caucasians (P < 0.0001; odds ratio = 1.48; 95% confidence interval = 1.29-1.69). There was also a predilection towards the female gender for both of these polymorphisms. For GSTP1 Ile105Val polymorphism, no significant association was found under any contrast model. In addition, the presence of the double-null genotypes increased the risk of acute myeloid leukemia in both Caucasians and East Asians. CONCLUSIONS: This meta-analysis suggested that heritable GST status could influence the risk of developing acute myeloid leukemia. PMID- 25145383 TI - Socio-economic and demographic determinants of under-five mortality in rural northern Ghana. AB - BACKGROUND: In spite of global decline in under-five mortality, the goal of achieving MDG 4 still remains largely unattained in low and middle income countries as the year 2015 closes-in. To accelerate the pace of mortality decline, proven interventions with high impact need to be implemented to help achieve the goal of drastically reducing childhood mortality. This paper explores the association between socio-economic and demographic factors and under-five mortality in an impoverished region in rural northern Ghana. METHODS: We used survey data on 3975 women aged 15-49 who have ever given birth. First, chi-square test was used to test the association of social, economic and demographic characteristics of mothers with the experience of under-five death. Subsequently, we ran a logistic regression model to estimate the relative association of factors that influence childhood mortality after excluding variables that were not significant at the bivariate level. RESULTS: Factors that significantly predict under-five mortality included mothers' educational level, presence of co wives, age and marital status. Mothers who have achieved primary or junior high school education were 45% less likely to experience under-five death than mothers with no formal education at all (OR = 0.55, p < 0.001). Monogamous women were 22% less likely to experience under-five deaths than mothers in polygamous marriages (OR = 0.78, p = 0.01). Similarly, mothers who were between the ages of 35 and 49 were about eleven times more likely to experience under-five deaths than those below the age of 20 years (OR = 11.44, p < 0.001). Also, women who were married had a 27% less likelihood (OR = 0.73, p = 0.01) of experiencing an under-five death than those who were single, divorced or widowed. CONCLUSION: Taken independently, maternal education, age, marital status and presence of co-wives are associated with childhood mortality. The relationship of these indicators with women's autonomy, health seeking behavior, and other factors that affect child survival merit further investigation so that interventions could be designed to foster reductions in child mortality by considering the needs and welfare of women including the need for female education, autonomy and socioeconomic well-being. PMID- 25145384 TI - Isolation, identification, and purification of murine thymic epithelial cells. AB - The thymus is a vital organ for T lymphocyte development. Of thymic stromal cells, thymic epithelial cells (TECs) are particularly crucial at multiple stages of T cell development: T cell commitment, positive selection and negative selection. However, the function of TECs in the thymus remains incompletely understood. In the article, we provide a method to isolate TEC subsets from fresh mouse thymus using a combination of mechanical disruption and enzymatic digestion. The method allows thymic stromal cells and thymocytes to be efficiently released from cell-cell and cell-extracellular matrix connections and to form a single-cell suspension. Using the isolated cells, multiparameter flow cytometry can be applied to identification and characterization of TECs and dendritic cells. Because TECs are a rare cell population in the thymus, we also describe an effective way to enrich and purify TECs by depleting thymocytes, the most abundant cell type in the thymus. Following the enrichment, cell sorting time can be decreased so that loss of cell viability can be minimized during purification of TECs. Purified cells are suitable for various downstream analyses like Real Time-PCR, Western blot and gene expression profiling. The protocol will promote research of TEC function and as well as the development of in vitro T cell reconstitution. PMID- 25145385 TI - Probing transport mechanisms of BaFe2As2 superconducting films and grain boundary junctions by noise spectroscopy. AB - An important step forward for the understanding of high-temperature superconductivity has been the discovery of iron-based superconductors. Among these compounds, iron pnictides could be used for high-field magnet applications, resulting more advantageous over conventional superconductors, due to a high upper critical field as well as its low anisotropy at low temperatures. However, the principal obstacle in fabricating high quality superconducting wires and tapes is given by grain boundaries. In order to study these effects, the dc transport and voltage-noise properties of Co-doped BaFe2As2 superconducting films with artificial grain boundary junctions have been investigated. A specific procedure allows the separation of the film noise from that of the junction. While the former shows a standard 1/f behaviour, the latter is characterized by an unconventional temperature-dependent multi-Lorentzian voltage-spectral density. Moreover, below the film superconducting critical temperature, a peculiar noise spectrum is found for the grain boundary junction. Possible theoretical interpretation of these phenomena is proposed. PMID- 25145386 TI - MondoA deficiency enhances sprint performance in mice. AB - MondoA is a basic helix-loop-helix (bHLH)/leucine zipper (ZIP) transcription factor that is expressed predominantly in skeletal muscle. Studies in vitro suggest that the Max-like protein X (MondoA:Mlx) heterodimer senses the intracellular energy status and directly targets the promoter region of thioredoxin interacting protein (Txnip) and possibly glycolytic enzymes. We generated MondoA-inactivated (MondoA-/-) mice by gene targeting. MondoA-/- mice had normal body weight at birth, exhibited normal growth and appeared to be healthy. However, they exhibited unique metabolic characteristics. MondoA-/- mice built up serum lactate and alanine levels and utilized fatty acids for fuel during exercise. Gene expression and promoter analysis suggested that MondoA functionally represses peroxisome-proliferator-activated receptor gamma co activator-1alpha (PGC-1alpha)-mediated activation of pyruvate dehydrogenase kinase 4 (PDK-4) transcription. PDK4 normally down-regulates the activity of pyruvate dehydrogenase, an enzyme complex that catalyses the decarboxylation of pyruvate to acetyl-CoA for entry into the Krebs cycle; in the absence of MondoA, pyruvate is diverted towards lactate and alanine, both products of glycolysis. Dynamic testing revealed that MondoA-/- mice excel in sprinting as their skeletal muscles display an enhanced glycolytic capacity. Our studies uncover a hitherto unappreciated function of MondoA in fuel selection in vivo. Lack of MondoA results in enhanced exercise capacity with sprinting. PMID- 25145388 TI - Long noncoding RNAs in liver cancer: what we know in 2014. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer with an estimated over half a million new cases diagnosed annually. Due to the difficulty in early diagnosis and lack of effective treatment options, HCC is currently ranked as the second highest neoplastic-related mortality in the world, with an extremely low 5-year survival rate of between 6 and 11%. Long noncoding RNAs (lncRNAs), are genes lacking protein coding ability, have recently emerged as pivotal participants in biological processes, often dysregulated in a range of cancers, including HCC. AREAS COVERED: In this review, we highlight the recent findings of lncRNAs in HCC pathogenesis, with particular attention on epigenetic events. In silico analysis was utilized to emphasize intrinsic linkages within the ncRNA families associated with hepatocarcinogenesis. EXPERT OPINION: While our understanding of lncRNAs in the onset and progression of HCC is still in its infancy, there is no doubt that understanding the activities of ncRNAs will certainly secure strong biomarkers and improve treatment options for HCC patients. PMID- 25145387 TI - Congenital methemoglobinemia in a dog with a promoter deletion and a nonsynonymous coding variant in the gene encoding cytochrome b5. PMID- 25145390 TI - The role of general practitioners in the pre hospital setting, as experienced by emergency medicine technicians: a qualitative study. AB - BACKGROUND: Together with the ambulances staffed with emergency medical technicians (EMTs), general practitioners (GPs) on call are the primary resources for handling emergencies outside hospitals in Norway. The benefit of the GP accompanying the ambulance to pre-hospital calls is a matter of controversy in Norway. The purpose of the present study was to gain better insight into the EMT's experiences with the role of the GPs in the care for critically ill patients in the pre-hospital setting. METHODS: We conducted four focus group interviews with EMTs at four different ambulance stations in Norway. Three of the stations were located at least 2 hours driving distance from the nearest hospital. The interviews were transcribed and analyzed using systematic text condensation. RESULTS: The EMTs described increasing confidence in emergency medicine during the last few years. However, they felt the need for GP participation in the ambulance when responding to a critically ill patient. The presence of GPs made the EMTs feel more confident, especially in unclear and difficult cases that did not fit into EMT guidelines. The main contributions of the GPs were described as diagnosis and decision-making. Bringing the physician to the patient shortened transportation time to the hospital and important medication could be started earlier. Several examples of sub-optimal treatment in the absence of the GP were given. The EMTs described discomfort with GPs not responding to the calls. They also experienced GPs responding to calls that did not function in the pre-hospital emergency setting. The EMTs reported a need for professional requirements for GPs taking part in out-of-hours work and mandatory interdisciplinary training on a regular basis. CONCLUSIONS: EMTs want GPs to be present in challenging pre-hospital emergency settings. The presence of GPs is perceived as improving patient care. However, professional requirements are needed for GPs taking part in out-of-hours work, and the informants suggested a formalized area for training between EMTs and GPs on call. PMID- 25145389 TI - Malaria in school-age children in Africa: an increasingly important challenge. AB - School-age children have attracted relatively little attention as a group in need of special measures to protect them against malaria. However, increasing success in lowering the level of malaria transmission in many previously highly endemic areas will result in children acquiring immunity to malaria later in life than has been the case in the past. Thus, it can be anticipated that in the coming years there will be an increase in the incidence of both uncomplicated and severe malaria in school-age children in many previously highly endemic areas. In this review, which focuses primarily on Africa, recent data on the prevalence of malaria parasitaemia and on the incidence of clinical malaria in African school age children are presented and evidence that malaria adversely effects school performance is reviewed. Long-lasting insecticide treated bednets (LLIN) are an effective method of malaria control but several studies have shown that school age children use LLINs less frequently than other population groups. Antimalarial drugs are being used in different ways to control malaria in school-age children including screening and treatment and intermittent preventive treatment. Some studies of chemoprevention in school-age children have shown reductions in anaemia and improved school performance but this has not been the case in all trials and more research is needed to identify the situations in which chemoprevention is likely to be most effective and, in these situations, which type of intervention should be used. In the longer term, malaria vaccines may have an important role in protecting this important section of the community from malaria. Regardless of the control approach selected, it is important this is incorporated into the overall programme of measures being undertaken to enhance the health of African school-age children. PMID- 25145391 TI - Therapeutic effect of hepatocyte growth factor-secreting mesenchymal stem cells in a rat model of liver fibrosis. AB - Bone marrow-derived mesenchymal stromal cells (MSCs) have been reported to be beneficial for the treatment of liver fibrosis. Here, we investigated the use of genetically engineered MSCs that overexpress hepatocyte growth factor (HGF) as a means to improve their therapeutic effect in liver fibrosis. Liver fibrosis was induced by intraperitoneal injection of dimethylnitrosamine. HGF-secreting MSCs (MSCs/HGF) were prepared by transducing MSCs with an adenovirus carrying HGF encoding cDNA. MSCs or MSCs/HGF were injected directly into the spleen of fibrotic rats. Tissue fibrosis was assessed by histological analysis 12 days after stem cell injection. Although treatment with MSCs reduced fibrosis, treatment with MSCs/HGF produced a more significant reduction and was associated with elevated HGF levels in the portal vein. Collagen levels in the liver extract were decreased after MSC/HGF therapy, suggesting recovery from fibrosis. Furthermore, liver function was improved in animals receiving MSCs/HGF, indicating that MSC/HGF therapy resulted not only in reduction of liver fibrosis but also in improvement of hepatocyte function. Assessment of cell and biochemical parameters revealed that mRNA levels of the fibrogenic cytokines PDGF bb and TGF-beta1 were significantly decreased after MSC/HGF therapy. Subsequent to the decrease in collagen, expression of matrix metalloprotease-9 (MMP-9), MMP 13, MMP-14 and urokinase-type plasminogen activator was augmented following MSC/HGF, whereas tissue inhibitor of metalloprotease-1 (TIMP-1) expression was reduced. In conclusion, therapy with MSCs/HGF resulted in an improved therapeutic effect compared with MSCs alone, probably because of the anti-fibrotic activity of HGF. Thus, MSC/HGF represents a promising approach toward a cell therapy for liver fibrosis. PMID- 25145393 TI - Octaphlorethol A: a potent alpha-glucosidase inhibitor isolated from Ishige foliacea shows an anti-hyperglycemic effect in mice with streptozotocin-induced diabetes. AB - alpha-Glucosidase inhibitors are important agents for decreasing postprandial hyperglycemia. The current study examined the inhibitory effects of octaphlorethol A (OPA) isolated from Ishige foliacea, a brown alga, on alpha glucosidase, and analyzed the inhibitor's binding modes using the crystal structure of alpha-glucosidase. The effects of OPA on postprandial blood glucose levels after meals were also investigated. The IC50 value of OPA against alpha glucosidase was 0.11 mM, which is higher than that of the commercial inhibitor acarbose. For further insights, we predicted the 3D structure of alpha glucosidase and used a docking algorithm to simulate binding between alpha glucosidase and OPA. These molecular modeling studies were successful, and indicated that OPA interacts with Phe575, His600, Arg526, Met444, Asp542, Tyr605, Ser448, Asp203, Lys480, and Phe450. Furthermore, increases in postprandial blood glucose levels were significantly suppressed in the OPA-treated group compared with those in the streptozotocin-induced diabetic or normal mice. Additionally, the area under the curve was significantly reduced following OPA administration (907 versus 1034 mg h dL(-1)) in the diabetic mice, along with a delay in the absorption of dietary carbohydrates. Collectively, these results indicated that OPA is a potent inhibitor of alpha-glucosidase, and shows potential to be used as an anti-diabetic agent. PMID- 25145394 TI - Highly sensitive protein detection by combination of atomic force microscopy fishing with charge generation and mass spectrometry analysis. AB - An approach combining atomic force microscopy (AFM) fishing and mass spectrometry (MS) analysis to detect proteins at ultra-low concentrations is proposed. Fishing out protein molecules onto a highly oriented pyrolytic graphite surface coated with polytetrafluoroethylene film was carried out with and without application of an external electric field. After that they were visualized by AFM and identified by MS. It was found that injection of solution leads to charge generation in the solution, and an electric potential within the measuring cell is induced. It was demonstrated that without an external electric field in the rapid injection input of diluted protein solution the fishing is efficient, as opposed to slow fluid input. The high sensitivity of this method was demonstrated by detection of human serum albumin and human cytochrome b5 in 10(-17) -10(-18) m water solutions. It was shown that an external negative voltage applied to highly oriented pyrolytic graphite hinders the protein fishing. The efficiency of fishing with an external positive voltage was similar to that obtained without applying any voltage. PMID- 25145392 TI - Mindfulness-based interventions in multiple sclerosis: beneficial effects of Tai Chi on balance, coordination, fatigue and depression. AB - BACKGROUND: Patients suffering from Multiple Sclerosis (MS) experience a wide array of symptoms, including balance problems, mobility impairment, fatigue and depression. Physical exercise has recently been acknowledged as a treatment option complementary to medication. However, information regarding putative effects of structured exercise programs on neurological symptoms is sparse. Tai Chi, a Chinese martial art incorporating physical exercise and mindfulness training, has been shown to yield health benefits in various neurological groups. It seems particularly suitable for patients with motoric deficits as it challenges coordination and balance. The purpose of the current study was to explore the therapeutic value of structured Tai Chi training for coordination, balance, fatigue and depression in mildly disabled MS patients. METHODS: A sample of 32 MS patients (Expanded Disability Status Scale, EDSS < 5) was examined. A structured Tai Chi course was devised and a Tai Chi group participated in two weekly sessions of 90 minutes duration for six months, while a comparison group received treatment as usual (TAU). Both groups were examined prior to and following the six-months interval with regards to balance and coordination performance as well as measures of fatigue, depression and life satisfaction. RESULTS: Following the intervention, the Tai Chi group showed significant, consistent improvements in balance, coordination, and depression, relative to the TAU group (range of effect-sizes: partial eta2 = 0.16 - 0.20). Additionally, life satisfaction improved (partial eta2 = 0.31). Fatigue deteriorated in the comparison group, whereas it remained relatively stable in the Tai Chi group (partial eta2 = 0.24). CONCLUSIONS: The consistent pattern of results confirms that Tai Chi holds therapeutic potential for MS patients. Further research is needed to determine underlying working mechanisms, and to verify the results in a larger sample and different MS subgroups. PMID- 25145396 TI - Structural and permeability characterization of biosynthetic PVA hydrogels designed for cell-based therapy. AB - Incorporation of extracellular matrix (ECM) components to synthetic hydrogels has been shown to be the key for successful cell encapsulation devices, by providing a biofunctional microenvironment for the encapsulated cells. However, the influence of adding ECM components into synthetic hydrogels on the permeability as well as the physical and mechanical properties of the hydrogel has had little attention. Therefore, the aim of this study was to investigate the effect of incorporated ECM analogues on the permeability performance of permselective synthetic poly(vinyl alcohol) (PVA) hydrogels in addition to examining the physico-mechanical characteristics. PVA was functionalized with a systematically increased number of methacrylate functional groups per chain (FG/c) to tailor the permselectivity of UV photopolymerized hydrogel network. Heparin and gelatin were successfully incorporated into PVA network at low percentage (1%), and co hydrogels were characterized for network properties and permeability to bovine serum albumin (BSA) and immunoglobulin G (IgG) proteins. Incorporation of these ECM analogues did not interfere with the base PVA network characteristics, as the controlled hydrogel mesh sizes, swelling and compressive modulii remained unchanged. While the permeation profiles of both BSA and IgG were not affected by the addition of heparin and gelatin as compared with pure PVA, increasing the FG/c from 7 to 20 significantly limited the diffusion of the larger IgG. Consequently, biosynthetic hydrogels composed of PVA with high FG/c and low percent ECM analogues show promise in their ability to be permselective for various biomedical applications. PMID- 25145395 TI - Distinct subclades of Aux/IAA genes are direct targets of ARF5/MP transcriptional regulation. AB - The regulatory interactions between AUXIN RESPONSE FACTORS (ARFs) and Aux/IAA repressors play a central role in auxin signal transduction. Yet, the systems properties of this regulatory network are not well established. We generated a steroid-inducible ARF5/MONOPTEROS (MP) transgenic background to survey the involvement of this factor in the transcriptional regulation of the entire Aux/IAA family in Arabidopsis thaliana. Target genes of ARF5/MP identified by this approach were confirmed by chromatin immunoprecipitation, in vitro gel retardation assays and gene expression analyses. Our study shows that ARF5/MP is indispensable for the correct regulation of nearly one-half of all Aux/IAA genes, and that these targets coincide with distinct subclades. Further, genetic analyses demonstrate that the protein products of multiple Aux/IAA targets negatively feed back onto ARF5/MP activity. This work indicates that ARF5/MP broadly influences the expression of the Aux/IAA gene family, and suggests that such regulation involves the activation of specific subsets of redundantly functioning factors. These groups of factors may then act together to control various processes within the plant through negative feedback on ARF5. Similar detailed analyses of other Aux/IAA-ARF regulatory modules will be required to fully understand how auxin signal transduction influences virtually every aspect of plant growth and development. PMID- 25145397 TI - HemR is an OmpR/PhoB-like response regulator from Leptospira, which simultaneously effects transcriptional activation and repression of key haem metabolism genes. AB - Several Leptospira species cause leptospirosis, the most extended zoonosis worldwide. In bacteria, two-component systems constitute key signalling pathways, some of which are involved in pathogenesis. The physiological roles of two component systems in Leptospira are largely unknown, despite identifying several dozens within their genomes. Biochemical confirmation of an operative phosphorelaying two-component system has been obtained so far only for the Hklep/Rrlep pair. It is known that hklep/rrlep knockout strains of Leptospira biflexa result in haem auxotrophy, although their de novo biosynthesis machinery remains fully functional. Haem is essential for Leptospira, but information about Hklep/Rrlep effector function(s) and target(s) is still lacking. We are now reporting a thorough molecular characterization of this system, which we rename HemK/HemR. The DNA HemR-binding motif was determined, and found within the genomes of saprophyte and pathogenic Leptospira. In this way, putative HemR regulated genes were pinpointed, including haem catabolism-related (hmuO - haem oxygenase) and biosynthesis-related (the hemA/C/D/B/L/E/N/G operon). Specific HemR binding to these two promoters was quantified, and a dual function was observed in vivo, inversely repressing the hmuO, while activating the hemA operon transcription. The crystal structure of HemR receiver domain was determined, leading to a mechanistic model for its dual regulatory role. PMID- 25145398 TI - Analysis of nephron composition and function in the adult zebrafish kidney. AB - The zebrafish model has emerged as a relevant system to study kidney development, regeneration and disease. Both the embryonic and adult zebrafish kidneys are composed of functional units known as nephrons, which are highly conserved with other vertebrates, including mammals. Research in zebrafish has recently demonstrated that two distinctive phenomena transpire after adult nephrons incur damage: first, there is robust regeneration within existing nephrons that replaces the destroyed tubule epithelial cells; second, entirely new nephrons are produced from renal progenitors in a process known as neonephrogenesis. In contrast, humans and other mammals seem to have only a limited ability for nephron epithelial regeneration. To date, the mechanisms responsible for these kidney regeneration phenomena remain poorly understood. Since adult zebrafish kidneys undergo both nephron epithelial regeneration and neonephrogenesis, they provide an outstanding experimental paradigm to study these events. Further, there is a wide range of genetic and pharmacological tools available in the zebrafish model that can be used to delineate the cellular and molecular mechanisms that regulate renal regeneration. One essential aspect of such research is the evaluation of nephron structure and function. This protocol describes a set of labeling techniques that can be used to gauge renal composition and test nephron functionality in the adult zebrafish kidney. Thus, these methods are widely applicable to the future phenotypic characterization of adult zebrafish kidney injury paradigms, which include but are not limited to, nephrotoxicant exposure regimes or genetic methods of targeted cell death such as the nitroreductase mediated cell ablation technique. Further, these methods could be used to study genetic perturbations in adult kidney formation and could also be applied to assess renal status during chronic disease modeling. PMID- 25145400 TI - Stimulation parameters define the effectiveness of burst spinal cord stimulation in a rat model of neuropathic pain. AB - INTRODUCTION: Although burst spinal cord stimulation (SCS) has been reported to reduce neuropathic pain, no study has explicitly investigated how the different parameters that define burst SCS may modulate its efficacy. The effectiveness of burst SCS to reduce neuronal responses to noxious stimuli by altering stimulation parameters was evaluated in a rat model of cervical radiculopathy. METHODS: Neuronal firing was recorded in the spinal dorsal horn before and after burst SCS on day 7 following painful cervical nerve root compression (N = 8 rats). The parameters defining the stimulation (number of pulses per burst, pulse frequency, pulse width, burst frequency, amplitude) were individually varied in separate stimulation trials while holding the remaining parameters constant. The percent reduction of firing of wide-dynamic-range (WDR) and high-threshold neurons after SCS and the percentage of neurons responding to SCS were quantified for each parameter and correlated to the charge per burst delivered during stimulation. RESULTS: Pulse number, pulse width, and amplitude each were significantly correlated (p <0.009) to suppression of neuronal firing after SCS. Pulse frequency and amplitude significantly affected (p <0.05) the percentage of responsive neurons. Charge per burst was correlated to a reduction of WDR neuronal firing (p <0.03) and had a nonlinear effect on the percentage of neurons responding to burst SCS. CONCLUSIONS: Burst SCS can be optimized by adjusting relevant stimulation parameters to modulate the charge delivered to the spinal cord during stimulation. The efficacy of burst SCS is dependent on the charge per burst. PMID- 25145401 TI - An ultracompact X-ray source based on a laser-plasma undulator. AB - The capability of plasmas to sustain ultrahigh electric fields has attracted considerable interest over the last decades and has given rise to laser-plasma engineering. Today, plasmas are commonly used for accelerating and collimating relativistic electrons, or to manipulate intense laser pulses. Here we propose an ultracompact plasma undulator that combines plasma technology and nanoengineering. When coupled with a laser-plasma accelerator, this undulator constitutes a millimetre-sized synchrotron radiation source of X-rays. The undulator consists of an array of nanowires, which are ionized by the laser pulse exiting from the accelerator. The strong charge-separation field, arising around the wires, efficiently wiggles the laser-accelerated electrons. We demonstrate that this system can produce bright, collimated and tunable beams of photons with 10-100 keV energies. This concept opens a path towards a new generation of compact synchrotron sources based on nanostructured plasmas. PMID- 25145402 TI - Extra-powerful on the visuo-perceptual space, but variable on the number space: Different effects of optokinetic stimulation in neglect patients. AB - We studied the effects of optokinetic stimulation (OKS; leftward, rightward, control) on the visuo-perceptual and number space, in the same sample, during line bisection and mental number interval bisection tasks. To this end, we tested six patients with right-hemisphere damage and neglect, six patients with right hemisphere damage but without neglect, and six neurologically healthy participants. In patients with neglect, we found a strong effect of leftward OKS on line bisection, but not on mental number interval bisection. We suggest that OKS influences the number space only under specific conditions. PMID- 25145399 TI - Gene silencing via DNA methylation in naturally occurring Tragopogon miscellus (Asteraceae) allopolyploids. AB - BACKGROUND: Hybridization coupled with whole-genome duplication (allopolyploidy) leads to a variety of genetic and epigenetic modifications in the resultant merged genomes. In particular, gene loss and gene silencing are commonly observed post-polyploidization. Here, we investigated DNA methylation as a potential mechanism for gene silencing in Tragopogon miscellus (Asteraceae), a recent and recurrently formed allopolyploid. This species, which also exhibits extensive gene loss, was formed from the diploids T. dubius and T. pratensis. RESULTS: Comparative bisulfite sequencing revealed CG methylation of parental homeologs for three loci (S2, S18 and TDF-44) that were previously identified as silenced in T. miscellus individuals relative to the diploid progenitors. One other locus (S3) examined did not show methylation, indicating that other transcriptional and post-transcriptional mechanisms are likely responsible for silencing that homeologous locus. CONCLUSIONS: These results indicate that Tragopogon miscellus allopolyploids employ diverse mechanisms, including DNA methylation, to respond to the potential shock of genome merger and doubling. PMID- 25145403 TI - Silver-catalyzed cyclization of 2-pyridyl alkynyl carbinols with isocyanides: divergent synthesis of indolizines and pyrroles. AB - Divergent syntheses of indolizines and 2,4-disubstituted pyrroles by the silver catalyzed cyclization of 2-pyridyl alkynyl carbinols with isocyanides are reported. These methods provide an effective route to highly functionalized indolizines and 2,4-disubstituted pyrroles in good to excellent yields. The 2,4 disubstituted pyrroles are synthesized by an unprecedented regioselective [3+2] cycloaddition of terminal alkynes with isocyanides. PMID- 25145404 TI - There is still insufficient data to recommend screening twin pregnancies with transvaginal ultrasound cervical length, but this might change soon! PMID- 25145405 TI - Drug resistance to EGFR tyrosine kinase inhibitors for non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) harboring an activating mutation within the epidermal growth factor receptor (EGFR) was defined as a clinically distinct molecular group. These lesions show oncogene addiction to EGFR and dramatic responses to the EGFR tyrosine kinase inhibitors (TKIs). Several large Phase III trials have shown that EGFR-TKIs improved the progression-free survival of patients with EGFR mutant NSCLC compared to conventional chemotherapy. However, the long-term effectiveness of EGFR-TKIs is usually limited because of acquired drug resistance. To overcome this resistance to EGFR-TKIs, it will be essential to identify the specific mechanisms underlying the resistance. Many investigators have attempted to identify the mechanisms using preclinical models and drug resistant clinical samples. As a result, several mechanisms have been showed to be responsible for the resistance, but not all of the relevant mechanisms have been uncovered. In this review, we provide an overview of mechanisms underlying drug-resistance to EGFR-TKIs, focusing on results obtained with preclinical models, and we present some possible strategies to overcome the EGFR-TKI resistance. PMID- 25145406 TI - Two-directional arthrographic assessment for treating bilateral development dislocation of the hips in children after walking age. AB - We reviewed the treatment outcome in 14 hips of 7 patients who were diagnosed as having bilateral developmental dislocation of the hip (DDH) after walking age and could be followed up until they were at least 14 years of age. Based on the results of two-directional arthrography of the hip, closed reduction was performed in 2 hips, and open reduction was performed without osteotomy in 12 hips. The final radiographic evaluations were made according to the Kalamchi and MacEwen classification and Severin classification. The mean age at the initial visit was 1 year and 9 months (range, 1 year and 5 months to 3 years). The outcome was satisfactory for one hip in Group I and 2 hips in Group II according to the Kalamchi and MacEwen classification, and in 83% of the Severin Class I and II hips. Arthrography was useful for identifying asymmetry, demonstrating the usefulness of a treatment strategy based on arthrography of the hip. PMID- 25145407 TI - A questionnaire study on attitudes toward birth and child-rearing of university students in Japan, China, and South Korea. AB - This study examines the attitudes of young Japanese, Chinese, and South Koreans toward birth and child-rearing. The survey targeted four-year university students (n=1,668) who responded to an anonymous survey using self-report questionnaires between December 2012 and April 2013. The collection rates were 72.5%, 94.7%, and 96.5% for the Japanese, Chinese, and South Korean students, respectively. Correlations among the respondents' attributes, medical and scientific literacy levels, and views of preferred qualities of children were analyzed using chi square test, supplemented by residual analysis (significance level set at p<0.05). Participants were asked whether they were willing to use the following methods for obtaining preferred qualities in their children:(1) choosing a spouse (43.2%, 72.6%, and 85.1% of the Japanese, Chinese, and South Koreans, respectively, agreed);(2) using a sperm bank (cryobank) (5.8%, 60.1%, and 81.7% of the Japanese, Chines, and South Koreans, respectively, agreed);and (3) using an egg cell bank (ova bank or cryobank) (5.3%, 47.2%, and 70.3% of the Japanese, Chinese, and South Koreans, respectively, agreed). The proportion of affirmative responses (indicating "eugenic inclination") to these statements was significantly higher among the Chinese and South Korean participants than their Japanese counterparts (p<0.001). Significant differences were also found in the attitudes of the 3 groups toward methods for obtaining the preferred qualities for their children:prenatal diagnosis, pre-implantation diagnosis, the environment during pregnancy, and child-rearing. PMID- 25145408 TI - Renal distribution of Vasohibin-1 in patients with chronic kidney disease. AB - Experimental studies have demonstrated the involvement of angiogenesis-related factors in the progression of chronic kidney disease (CKD). There have so far been no reports investigating the distribution and clinical roles of Vasohibin-1 (VASH-1), a negative feedback regulator of angiogenesis, in CKD. We recruited 54 Japanese CKD patients and 6 patients who had normal renal tissues excised due to localized renal cell carcinoma. We evaluated the correlations between the renal expression level of VASH-1 and the clinical/histological parameters. VASH-1 was observed in renal endothelial/mesangial cells, crescentic lesions and interstitial inflammatory cells. Significant positive correlations were observed between 1) crescent formation and the number of VASH-1+ cells in the glomerulus (r=0.48, p=0.001) or cortex (r=0.64, p<0.0001), 2) interstitial cell infiltration and the number of VASH-1+ cells in the cortex (r=0.34, p=0.02), 3) the glomerular VEGFR-2+ area and the number of VASH-1+ cells in the glomerulus (r=0.44, p=0.01) or medulla (r=0.63, p=0.01). These results suggest that the renal levels of VASH 1 may be affected by local inflammation, crescentic lesions and VEGFR-2. PMID- 25145409 TI - Factors associated with remission and/or regression of microalbuminuria in type 2 diabetes mellitus. AB - The aim of this study was to clarify the factors associated with the remission and/or regression of microalbuminuria in Japanese patients with type 2 diabetes mellitus. We retrospectively analyzed the data of 130 patients with type 2 diabetes mellitus with microalbuminuria for 2-6 years (3.39+/-1.31 years). Remission was defined as improving from microalbuminuria to normoalbuminuria using the albumin/creatinine ratio (ACR), and regression of microalbuminuria was defined as a decrease in ACR of 50% or more from baseline. Progression of microalbuminuria was defined as progressing from microalbuminuria to overt proteinuria during the follow-up period. Among 130 patients with type 2 diabetes mellitus with microalbuminuria, 57 and 13 patients were defined as having remission and regression, respectively, while 26 patients progressed to overt proteinuria. Sex (female), higher HDL cholesterol and lower HbA1c were determinant factors associated with remission/regression of microalbuminuria by logistic regression analysis. Lower systolic blood pressure (SBP) was also correlated with remission/regression, but not at a significant level. These results suggest that proper control of blood glucose, BP and lipid profiles may be associated with remission and/or regression of type 2 diabetes mellitus with microalbuminuria in clinical practice. PMID- 25145410 TI - Prevalence and outcomes of acute hepatitis B in Okayama, Japan, 2006-2010. AB - Hepatitis B virus (HBV) is one of the major viruses causing acute hepatitis. Recently, the incidence of acute hepatitis with genotype A has been increasing in Japan. The aim of this study was to investigate acute hepatitis B (AHB) in Okayama prefecture, with special attention to HBV genotype A. AHB patients who visited one of 12 general hospitals in Okayama prefecture between 2006 and 2010 were retrospectively analyzed. Over the course of the study period, 128 patients were diagnosed with AHB. Sexual transmission was supposed in the majority of patients (78 patients, 61%), including 59 (76%) having sex with heterosexual partners. The genotypes of HBV were assessed in 90 patients (70%), of whom 27 patients were infected with genotype A, 5 with genotype B, and 58 with genotype C. The prevalence of genotype A was significantly higher among male patients (28.7%), aged 20-29 (35.6%, p<0.01), among men who had sex with men (100%, p<0.005), and among patients having sex with unspecified partners (44.8%, p<0.005). Genotype A was not a significant factor associated with delayed HBsAg disappearance. Caution should be exercised with regard to sexually transmissible diseases in order to slow the pandemic spread of AHB due to genotype A. PMID- 25145411 TI - Tracheal stenosis caused by unnoticed foreign bodies. AB - We describe an extremely rare case of tracheal stenosis caused by unnoticed microscopic fiber-like foreign bodies. A 66-year-old woman complained of dyspnea with inspiratory stridor. Magnifying electroendoscopy and computed tomography revealed stenosis involving the entire circumference of the tracheal lumen. Tracheotomy and biopsy were performed. Histologically, the lesion showed chronic inflammation with a deposition of fiber-like foreign bodies. The patient had no history of trauma or inhalation injury, but had undergone intratracheal intubation on 4 occasions. The lesion was incised using semiconductor laser photoresection, and the postoperative course was good. To the best of our knowledge, this represents the first report in the English literature of tracheal stenosis caused by unnoticed foreign bodies. The origin of these fiber-like foreign bodies remains unclear but might be related to chronic inflammation resulting from intratracheal intubations. PMID- 25145413 TI - In vitro antiplasmodial activity of cepharanthine. AB - BACKGROUND: New classes of anti-malarial drugs are needed to control the alarming Plasmodium falciparum resistance toward current anti-malarial therapy. The ethnopharmacological approach allows the discovery of original chemical structures from the vegetable biodiversity. Previous studies led to the selection of a bisbenzylisoquinoline, called cepharanthine and isolated from a Cambodian plant: Stephania rotunda. Cepharanthine could exert a mechanism of action different from commonly used drugs. Potential plasmodial targets are reported here. METHODS: To study the mechanism of action of cepharanthine, a combined approach using phenotypic and transcriptomic techniques was undertaken. RESULTS: Cepharanthine blocked P. falciparum development in ring stage. On a culture of synchronized ring stage, the comparisons of expression profiles showed that the samples treated with 5 MUM of cepharanthine (IC90) were significantly closer to the initial controls than to the final ones. After a two-way ANOVA (p-value < 0.05) on the microarray results, 1,141 probes among 9,722 presented a significant differential expression.A gene ontology analysis showed that the Maurer's clefts seem particularly down-regulated by cepharanthine. The analysis of metabolic pathways showed an impact on cell-cell interactions (cytoadherence and rosetting), glycolysis and isoprenoid pathways. Organellar functions, more particularly constituted by apicoplast and mitochondrion, are targeted too. CONCLUSION: The blockage at the ring stage by cepharanthine is described for the first time. Transcriptomic approach confirmed that cepharanthine might have a potential innovative antiplasmodial mechanism of action. Thus, cepharanthine might play an ongoing role in the progress on anti-malarial drug discovery efforts. PMID- 25145414 TI - Long-term effect on in vitro cloning efficiency after treatment of somatic cells with Xenopus egg extract in the pig. AB - In somatic cell nuclear transfer (SCNT), donor cell reprogramming is considered as a biologically important and vulnerable event. Various donor cell pre treatments with Xenopus egg extracts can promote reprogramming. Here we investigated if the reprogramming effect of one treatment with Xenopus egg extract on donor cells was maintained for several cell passages. The extract treatment resulted in increased cell-colony formation from early passages in treated porcine fibroblasts (ExTES), and increased development of cloned embryos. Partial dedifferentiation was observed in ExTES cells, shown as a tendency towards upregulation of NANOG, c-MYC and KLF-4 and downregulation of DESMIM compared with ExTES at Passage 2. Compared with our routine SCNT, continuously increased development of cloned embryos was observed in the ExTES group, and ExTES cloned blastocysts displayed hypermethylated DNA patterns and hypermethylation of H3K4me3 and H3K27me3 in ICM compared with TE. All seven recipients became pregnant after transferral of ExTES cloned embryos and gave birth to 7-22 piglets per litter (average 12). In conclusion, our results demonstrate that one treatment of porcine fibroblasts with Xenopus egg extract can result in long-term increased ability of the cells to promote their in vitro function in subsequent SCNT. Finally these cells can also result in successful development of cloned embryos to term. PMID- 25145415 TI - Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study. AB - AIM: The aim of this study was to examine whether vigabatrin treatment had caused visual field defects (VFDs) in children of school age who had received the drug in infancy. METHOD: In total, 35 children (14 males, 21 females; median age 11y, SD 3.4y, range 8-23y) were examined by static Humphrey perimetry, Goldmann kinetic perimetry, or Octopus perimetry. The aetiologies of infantile spasms identified were tuberous sclerosis (n=10), other symptomatic causes (n=3), or cryptogenic (n=22). RESULTS: Typical vigabatrin-attributed VFDs were found in 11 out of 32 (34%) children: in one out of 11 children (9%) who received vigabatrin for <1 year (group 1), in three out of 10 children (30%) who received vigabatrin for 12 to 24 months (group 2), and in seven out of 11 children (63%) who received vigabatrin treatment for longer than 2 years (group 3). VFDs were mild in five and severe in six children. Patients with tuberous sclerosis were at higher risk of VFDs (six out of 10 children). The mean cumulative doses of vigabatrin were 140.5, 758.8, and 2712g in group 1, 2, and 3, respectively. INTERPRETATION: VFDs were found in 34% of the cohort of children in this study. The rate of VFD increased from 9% to 63% as duration of treatment increased. The results of this study showed that the risk-benefit ratio should always be considered when using vigabatrin. PMID- 25145416 TI - Quantitative detection of trace explosive vapors by programmed temperature desorption gas chromatography-electron capture detector. AB - The direct liquid deposition of solution standards onto sorbent-filled thermal desorption tubes is used for the quantitative analysis of trace explosive vapor samples. The direct liquid deposition method yields a higher fidelity between the analysis of vapor samples and the analysis of solution standards than using separate injection methods for vapors and solutions, i.e., samples collected on vapor collection tubes and standards prepared in solution vials. Additionally, the method can account for instrumentation losses, which makes it ideal for minimizing variability and quantitative trace chemical detection. Gas chromatography with an electron capture detector is an instrumentation configuration sensitive to nitro-energetics, such as TNT and RDX, due to their relatively high electron affinity. However, vapor quantitation of these compounds is difficult without viable vapor standards. Thus, we eliminate the requirement for vapor standards by combining the sensitivity of the instrumentation with a direct liquid deposition protocol to analyze trace explosive vapor samples. PMID- 25145417 TI - Controlled cortical impact model for traumatic brain injury. AB - Every year over a million Americans suffer a traumatic brain injury (TBI). Combined with the incidence of TBIs worldwide, the physical, emotional, social, and economical effects are staggering. Therefore, further research into the effects of TBI and effective treatments is necessary. The controlled cortical impact (CCI) model induces traumatic brain injuries ranging from mild to severe. This method uses a rigid impactor to deliver mechanical energy to an intact dura exposed following a craniectomy. Impact is made under precise parameters at a set velocity to achieve a pre-determined deformation depth. Although other TBI models, such as weight drop and fluid percussion, exist, CCI is more accurate, easier to control, and most importantly, produces traumatic brain injuries similar to those seen in humans. However, no TBI model is currently able to reproduce pathological changes identical to those seen in human patients. The CCI model allows investigation into the short-term and long-term effects of TBI, such as neuronal death, memory deficits, and cerebral edema, as well as potential therapeutic treatments for TBI. PMID- 25145418 TI - Carbon dioxide emissions from estuaries of northern and northeastern Brazil. AB - The carbon dioxide flux through the air-water interface of coastal estuarine systems must be quantified to understand the regional balance of carbon and its transport through adjacent coastal regions. We estimated and calculated the emissions of carbon dioxide (FCO2) and the partial pressure of CO2 (pCO2) values in 28 estuarine environments at a variety of spatial scales in the northern and northeastern regions of Brazil. The results showed a mean FCO2 (water to air) of 55 +/- 45 mmol.m(-2).d(-1). Additionally, a negative correlation between dissolved oxygen saturation and pCO2 was observed, indicating a control by biological processes and especially by organic matter degradation. This leads to increased dissolved CO2 concentration in estuarine waters which results in a pCO2 that reached 8,638 MUatm. Our study suggests that northern and northeastern Brazilian estuaries act as sources of atmospheric CO2. The range of pCO2 observed were similar to those found in inner estuaries in other places around the world, with the exception of a few semi-arid estuaries (Koppen climate classification - BSh) in which record low levels of pCO2 have been detected. PMID- 25145419 TI - Inflammatory, insulin resistance metabolic markers and pancreatic cancer: quo vadis? [corrected]. PMID- 25145420 TI - Dietary supplementation in cancer patients: a personal view of current status and future perspectives. PMID- 25145421 TI - Proneural-mesenchymal transformation of glioma stem cells: do therapies cause evolution of target in glioblastoma? PMID- 25145423 TI - Advancing treatment of metastatic cancers: from research to communication--where do we need to go? AB - Bruce Zetter* speaks to Francesca Lake, Managing Commissioning Editor: Bruce Zetter is the Charles Nowiszewski Professor of Cancer Biology at Harvard Medical School in Boston (MA, USA). Dr Zetter received a BA degree in anthropology from Brandeis University in Waltham (MA, USA) and a PhD from the University of Rhode Island in Kingston (RI, USA). He completed fellowships at Massachusetts Institute of Technology in Cambridge (MA, USA) and at the Salk Institute in San Diego (CA, USA). Subsequently, he was an assistant research biochemist at the University of California in San Francisco (CA, USA) before joining the faculty at Harvard Medical School. At Harvard, he directed the course in human physiology taken by all medical students. He further served as the Chief Scientific Officer at Boston Children's Hospital (MA, USA), where he directed the research efforts for the hospital. Dr Zetter has made major discoveries on the mechanisms underlying tumor metastasis and on the detection and treatment of late-stage tumors. As an internationally recognized expert in the field of tumor metastasis, Dr Zetter has chaired multiple international research conferences and grant review panels for agencies such as the US NIH and the US Department of Defense. He also chaired the NASA committee that selects scientific projects for the space shuttle. Dr Zetter has a strong interest in the interactions of academic and corporate institutions and has served as an advisor to more than 30 biotechnology and pharmaceutical companies, as well as to venture firms and investment companies. PMID- 25145424 TI - Promising new developments in cervical cancer. AB - Mary McCormack* speaks to Francesca Lake, Managing Commissioning Editor: Dr McCormack qualified as a doctor from Guy's and St Thomas's Hospital (London, UK) in 1993. She has worked in a variety of London cancer centers and was appointed as a consultant at University College London Hospitals (London, UK) in 2002. She is a clinical oncologist, offering chemotherapy and radiotherapy for gynecological and breast cancers. She is a member of the National Cancer Research Institute Gynecological Clinical Studies Group and the Gynecologic Cancer InterGroup, and is a major contributor to national and international clinical trials. She is also a medical advisor to Jo's Trust and a founding member of Debbie Fund, a University College London-based charity dedicated to raising funds for cervical cancer research. PMID- 25145425 TI - Rethinking cancer clinical trials for the future. PMID- 25145426 TI - Ramucirumab for metastatic gastric or gastroesophageal junction cancer: results and implications of the REGARD trial. AB - Gastric cancer is a highly aggressive disease. In metastatic setting, median overall survival, even with modern chemotherapy regimens, generally does not exceed 1 year and toxicity is a major concern. Angiogenesis plays a crucial role in cancer development and progression, and VEGF is one of the most important mediators of this process. Ramucirumab, an anti-VEGFR-2 antibody, has been recently evaluated in the large Phase III REGARD trial, demonstrating a significant survival benefit in second-line treatment of patients with advanced gastric or gastro-eosophageal junction adenocarcinoma. Unlike traditional chemotherapy, treatment with ramucirumab was associated with very few toxic effects. This article will review the main findings of the REGARD trial and discuss their potential impact on future treatment of metastatic gastric cancer. PMID- 25145427 TI - Role of the MEK inhibitor trametinib in the treatment of metastatic melanoma. AB - Approximately 50% of patients with cutaneous metastatic melanoma harbor a somatic BRAF mutation. BRAF inhibitors are now established in the treatment paradigm of BRAF mutant melanoma, following the approval of vemurafenib by the US FDA in 2011. The vast majority of patients obtain some degree of tumor shrinkage with oral BRAF inhibitors, and responses are often rapid. However, resistance inevitably develops, with a median progression-free survival of 5-7 months. The oral MEK inhibitor trametinib has also shown activity in BRAF mutant melanoma in Phase III trials. We review the rationale for treating BRAF mutant melanoma with trametinib, as single-agent therapy and in combination with BRAF inhibitors, as well as the clinical data to date. PMID- 25145429 TI - Regorafenib in gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the GI tract and constitute less than 1% of all digestive tract tumors--the stomach is the most common site. Regorafenib is a multi-tyrosine kinase inhibitor with regulatory approvals granted for colorectal cancers and GIST. The US FDA granted approval for the use of regorafenib in February 2013 in patients with advanced GIST for those who had failed on imatinib and sunitinib. This was based on a pivotal Phase III double-blind placebo controlled randomized trial that showed that there was a significant improvement in progression-free survival for patients on regorafenib. PMID- 25145430 TI - Cost savings from anemia management with biosimilar epoetin alfa and increased access to targeted antineoplastic treatment: a simulation for the EU G5 countries. AB - AIM: We simulated the budget impact of biosimilar erythropoiesis-stimulating agent (ESA) in EU G5 countries. MATERIALS & METHODS: Three models were built to estimate the number of patients who could be provided with antineoplastic therapy with rituximab, bevacizumab or trastuzumab from cost savings of biosimilar erythropoietin use in a hypothetical panel of 100,000 patients. The associated number of patients needed to convert to biosimilar ESA to provide such treatments was also calculated. RESULTS: Under fixed dosing, the savings from 100% conversion were ?110,592,159, translating into an additional 9770 rituximab, 3912 bevacizumab, or 3713 trastuzumab treatments. Under weight-based dosing, the savings from 100% conversion were ?146,170,333, corresponding to an additional 12,913 rituximab, 5171 bevacizumab or 4908 trastuzumab treatments. The number of patients needed to convert ranged from four to 51. CONCLUSION: Using biosimilar ESA for supportive cancer care yields significant savings and increases accessibility to primary antineoplastic therapy in a budget neutral way. PMID- 25145428 TI - Quizartinib for the treatment of FLT3/ITD acute myeloid leukemia. AB - FLT3/ITD acute myeloid leukemia is a poor prognosis disease driven by a constitutively activated receptor tyrosine kinase, making it an obvious target for drug development. The development of clinically effective FLT3 inhibitors has been slow, in part because many are multi-targeted inhibitors that are not selective or specific for FLT3. Quizartinib is the first small molecule FLT3 tyrosine kinase inhibitor expressly developed as a FLT3 inhibitor. It is potent, selective and has ideal pharmacokinetics in comparison to other compounds previously tested. This article summarizes its advantages and limitations, and details the insights into the biology of the disease that have been uncovered through the laboratory and clinical use of quizartinib. PMID- 25145432 TI - Large germline copy number variations as predisposing factor in childhood neoplasms. AB - AIMS: Constitutive genetic factors are believed to predispose to cancer in children. This study investigated the role of rare germline copy number variations (CNVs) in pediatric cancer predisposition. PATIENTS & METHODS: A total of 54 patients who developed cancer in infancy were screened by array-CGH for germline CNVs. RESULTS: In total, 12 rare CNVs were detected, including a Xq27.2 triplication, and two >1.8 Mb deletions: one of them at 13q31, containing only RNA genes, and another at 3q26.33-q27.1, in a patient with congenital malformations. Detected rare CNVs are significantly larger than those identified in controls, and encompass genes never implicated in cancer predisposition. CONCLUSION: Our results suggest that constitutive CNVs contribute to the etiology of pediatric neoplasms, revealing new candidate genes for tumorigenesis. PMID- 25145433 TI - A historical account of breast cancer surgery: beware of local recurrence but be not radical. AB - In the late 19th century, William Halsted proposed the radical mastectomy, which became the standard surgical treatment of breast cancer for nearly 100 years. Later in this period, theories suggesting that breast cancer was a systemic disease at inception were championed by Bernard Fisher. This alternative hypothesis of biological predeterminism was based upon results of randomized clinical trials comparing breast conserving therapy with mastectomy, which showed similar overall survival outcomes. Nonetheless, data from meta-analyses suggest that inadequate local therapy can increase risk of local recurrence, which can subsequently increase mortality. In this review, the authors provide an historical account of how local therapy of breast cancer has evolved in the face of improved adjuvant therapies and better understanding of disease biology. PMID- 25145431 TI - Safety profile and treatment response of everolimus in different solid tumors: an observational study. AB - AIM: Only few efforts have been taken to investigate the potential existence of disease-specific differences in the safety profile of everolimus. We analyze here the correlation between different patient and tumor characteristics on the safety profile of this molecule. Information on treatment response is also provided. METHODS: Consecutive patients with metastatic renal cell carcinoma (mRCC), pancreatic neuroendocrine tumors (pNET) or biliary tract cancer were included in this retrospective study. All patients received everolimus 10 mg/day or 5 mg/day. Clinical assessments were performed every 3 weeks. RESULTS: In total, 98 patients were enrolled: 51 with mRCC, 25 with pNET and 22 with biliary tract cancer. The incidence of toxicities (any grade) was 76% with mRCC, 64% with pNET and 95% with biliary tract cancer. Patients with biliary tract cancer also presented a higher frequency of severe toxicities: 64 versus 18% with mRCC and 32% with pNET. Multivariate analysis disclosed that biliary tract cancer (odds ratio [OR]: 23.8; 95% CI: 6.0-117.8; p < 0.0001) is a predictive factor for the development of toxicities during everolimus treatment. No correlations between liver metastasis and toxicities were identified. Disease control rate (DCR) was 45% in mRCC patients, 96% in pNET and 50% for biliary tract cancer patients. pNET tumors were associated with a higher DCR than the mRCC and biliary tract cancer (OR vs mRCC: 66.7; 95% CI: 6.2-276.5; p = 0.004; OR vs biliary tract cancer: 2.6; 95% CI: 0.5 14.2; p = 0.025). CONCLUSION: This study suggests that the safety profile of everolimus is acceptable in patients with either mRCC or pNET. In addition, the onset of toxicities is associated with an improved DCR. In patients with biliary tract cancer, everolimus is safe but associated with a higher incidence of adverse events. PMID- 25145435 TI - Translating genetic risk factors for prostate cancer to the clinic: 2013 and beyond. AB - Prostate cancer (PrCa) is the most commonly diagnosed cancer in the male UK population, with over 40,000 new cases per year. PrCa has a complex, polygenic predisposition, due to rare variants such as BRCA and common variants such as single nucleotide polymorphisms (SNPs). With the introduction of genome-wide association studies, 78 susceptibility loci (SNPs) associated with PrCa risk have been identified. Genetic profiling could risk-stratify a population, leading to the discovery of a higher proportion of clinically significant disease and a reduction in the morbidity related to age-based prostate-specific antigen screening. Based on the combined risk of the 78 SNPs identified so far, the top 1% of the risk distribution has a 4.7-times higher risk of developing PrCa compared with the average of the general population. PMID- 25145437 TI - Lysyl oxidase in cancer research. AB - Metastasis is the main reason for cancer-associated deaths and therapies are desperately needed to target the progression of cancer. Lysyl oxidase (LOX) plays a pivotal role in cancer progression, including metastasis, and is therefore is an attractive therapeutic target. In this review we will breakdown the process of cancer progression and the various roles that LOX plays has in the advancement of cancer. We will highlight why LOX is an exciting therapeutic target for the future. PMID- 25145436 TI - PDGF receptors in tumor biology: prognostic and predictive potential. AB - PDGF receptors (PDGFRs) exert cell type-specific effects in many different tumor types. They are emerging as key regulators of mesenchymal cells of the tumor microenvironment, and of many common malignancies, such as cancer of the breast, colon and prostate. In some tumor types PDGFRs are genetically activated and are thus directly involved in stimulation of malignant cell growth. Recent studies have uncovered clinically relevant variations in stromal PDGFR expression. High stromal PDGFRbeta expression or activation is associated with poor prognosis in breast and prostate cancer. Indications of prognostic significance of stromal PDGFRbeta expression in various GI tract tumor types also exist. The prognostic significance of PDGFRalpha and beta in malignant cells of common epithelial tumor types should be further studied. Collectively data suggest that continued characterization of PDGFR expression in human tumors should present opportunities for improved accuracy in prognosis and also allow novel biomarker-based clinical studies exploring the efficacy of PDGFR-directed tumor therapies. PMID- 25145434 TI - Immunotherapy in pediatric malignancies: current status and future perspectives. AB - Novel immune-based therapies are becoming available as additions to, and in some cases as alternatives to, the traditional treatment modalities such as chemotherapy, surgery and radiation that have improved outcomes for childhood cancer for decades. In this article, we will discuss what immunotherapies are being tested in the clinic, barriers to widespread application, and the future of immuno-oncology for childhood cancer. While in many cases, these therapies have shown dramatic responses in the setting of refractory or relapsed cancer, much remains to be learned about how to integrate these therapies into existing upfront regimens. The progress and challenges of developing immunotherapies for childhood cancer in a timely and cost-effective fashion will be discussed. PMID- 25145441 TI - Clearance of serum solutes by hemofiltration in dogs with severe heat stroke. AB - BACKGROUND: We have previously reported that hemofiltration (HF) may be an effective additional means of treating heat stroke when rapid cooling is not effective. METHODS: Dogs were assigned to a heat stroke (control) or heat stroke + hemofiltration (HF) group (n = 8 each group). After heat stroke induction, dogs in the HF group received HF for 3 h. Serum concentrations of interleukin (IL)-10, tumor necrosis factor (TNF)-alpha, IL-6, blood urea nitrogen (BUN) and creatinine were measured at baseline and 1, 2, and 3 h after heat stroke. Clearance rates of solutes were determined 1, 2, and 3 h after the start of HF. RESULTS: Serum concentrations of all solutes tended to increase with time after heat stroke in the control group, but decreased (BUN, creatinine) or remained relatively unchanged (TNF-alpha, IL-6, IL-10) with time in the HF group. Concentrations of all solutes were significantly lower in the HF group compared with the control group at 2 and 3 h (P < 0.05). Clearance rates for small molecular weight solutes were high, while those for larger molecular weight solutes were low. CONCLUSION: HF prevents heat stroke-induced increases in serum cytokine concentrations and is effective for clearing small molecular weight solutes from serum, but less effective for clearing larger molecular weight solutes, including TNF-alpha, IL 6, and IL-10. PMID- 25145438 TI - Chromatin and oxygen sensing in the context of JmjC histone demethylases. AB - Responding appropriately to changes in oxygen availability is essential for multicellular organism survival. Molecularly, cells have evolved intricate gene expression programmes to handle this stressful condition. Although it is appreciated that gene expression is co-ordinated by changes in transcription and translation in hypoxia, much less is known about how chromatin changes allow for transcription to take place. The missing link between co-ordinating chromatin structure and the hypoxia-induced transcriptional programme could be in the form of a class of dioxygenases called JmjC (Jumonji C) enzymes, the majority of which are histone demethylases. In the present review, we will focus on the function of JmjC histone demethylases, and how these could act as oxygen sensors for chromatin in hypoxia. The current knowledge concerning the role of JmjC histone demethylases in the process of organism development and human disease will also be reviewed. PMID- 25145442 TI - Cold exposure inhibits hypothalamic Kiss-1 gene expression, serum leptin concentration, and delays reproductive development in male Brandt's vole (Lasiopodomys brandtii). AB - Cold commonly affects growth and reproductive development in small mammals. Here, we test the hypothesis that low ambient temperature will affect growth and puberty onset, associated with altered hypothalamic Kiss-1 gene expression and serum leptin concentration in wild rodents. Male Brandt's voles (Lasiopodomys brandtii) were exposed to cold (4 +/- 1 degrees C) and warm (23 +/- 1 degrees C) conditions from the birth and sacrificed on different developmental stages (day 26, day 40, day 60, and day 90, respectively). Brandt's voles increased the thermogenic capacity of brown adipose tissue, mobilized body fat, decreased serum leptin levels, and delayed the reproductive development especially on day 40 in the cold condition. They increased food intake to compensate for the high energy demands in the cold. The hypothalamic Kiss-1 gene expression on day 26 was decreased, associated with lower wet testis mass and testis testosterone concentration on day 40, in the cold-exposed voles compared to that in the warm. Serum leptin was positively correlated with body fat, testis mass, and testosterone concentration. These data suggested that cold exposure inhibited hypothalamic Kiss-1 gene expression during the early stage of development, decreased serum leptin concentration, and delayed reproductive development in male Brandt's voles. PMID- 25145443 TI - The association between weather conditions and stroke admissions in Turkey. AB - Although several factors such as cigarette smoking, blood pressure, diabetes, obesity, hypercholesterolemia, physical inactivity and dietary factors have been well documented to increase the risk for stroke, there are conflicting data about the role of meteorological variables in the etiology of stroke. We conducted a retrospective study to investigate the association between weather patterns, including daily temperature, humidity, wind speed, and air pressure, and stroke admissions to the Emergency Department of Ataturk Training and Research Hospital in Ankara, Turkey, between January 2009 and April 2010. Generalized additive models with logistic link function were used to investigate the relationship between predictors and days with and without stroke admission at lags 0-4. A total of 373 stroke patients were admitted to the emergency department (ED) between January 2009 and April 2010. Of patients, 297 had ischemic stroke (IS), 34 hemorrhagic stroke (HS), and 42 subarachnoidal hemorrhage (SAH). Although we did not find any association between overall admissions due to stroke and meteorological parameters, univariable analysis indicated that there were significantly more SAH cases on days with lower daily mean temperatures of 8.79 +/- 8.75 degrees C as compared to relatively mild days with higher temperatures (mean temperature = 11.89 +/- 7.94 degrees C, p = 0.021). The multivariable analysis demonstrated that admissions due to SAH increased on days with lower daily mean temperatures for the same day (lag 0; odds ratio (OR) [95% confidence interval (95% CI)] = 0.93 [0.89-0.98], p = 0.004) and lag 1 (OR [95% CI] =0.76 [0.67-0.86], p = 0.001). Furthermore, the wind speed at both lag 1 (OR [95% CI] = 1.63 [1.27-2.09], p = 0.001) and lag 3 (OR [95% CI] = 1.43 [1.12-1.81], p = 0.004) increased admissions due to HS, respectively. In conclusion, our study demonstrated that there was an association between ED admissions due to SAH and HS and weather conditions suggesting that meteorological variables may, at least in part, play as risk factors for intracranial hemorrhages. PMID- 25145444 TI - Enhanced biotransformation of dehydroepiandrosterone to 3beta,7alpha,15alpha trihydroxy-5-androsten-17-one with Gibberella intermedia CA3-1 by natural oils addition. AB - Dihydroxylation of dehydroepiandrosterone (DHEA) is an essential step in the synthesis of many important pharmaceutical intermediates. However, the solution to the problem of low biohydroxylation conversion in the biotransformation of DHEA has yet to be found. The effects of natural oils on the course of dihydroxylation of DHEA to 3beta,7alpha,15alpha-trihydroxy-5-androsten-17-one (7alpha,15alpha-diOH-DHEA) were studied. With rapeseed oil (2 %, v/v) addition, the bioconversion efficiency was improved, and the 7alpha,15alpha-diOH-DHEA yield was increased by 40.8 % compared with that of the control at DHEA concentration of 8.0 g/L. Meantime, the ratio of 7alpha,15alpha-diOH-DHEA to 7alpha-OH-DHEA was also increased by 4.5 times in the rapeseed oil-containing system. To explain the mechanism underlying the increase of 7alpha,15alpha-diOH-DHEA yield, the effects of rapeseed oil on the pH of the bioconversion system, the cell growth and integrity of Gibberella intermedia CA3-1, as well as the membrane composition were systematically studied. The addition of rapeseed oil enhanced the substrate dispersion and maintained the pH of the system during bioconversion. Cells grew better with favorable integrity. The fatty acid profile of G. intermedia cells revealed that rapeseed oil changed the cell membrane composition and improved cell membrane permeability for lipophilic substrates. PMID- 25145445 TI - Non-endemic cases of lymphatic filariasis. AB - OBJECTIVE: Several cases of lymphatic filariasis (LF) have been reported in non endemic countries due to travellers, military personnel and expatriates spending time in and returning from endemic areas, as well as immigrants coming from these regions. These cases are reviewed to assess the scale and context of non-endemic presentations and to consider the biological factors underlying their relative paucity. METHODS: Cases reported in the English, French, Spanish and Portuguese literature during the last 30 years were examined through a search of the PubMed, ProMED-mail and TropNet resources. RESULTS: The literature research revealed 11 cases of lymphatic filariasis being reported in non-endemic areas. The extent of further infections in recent migrants to non-endemic countries was also revealed through the published literature. CONCLUSIONS: The life-cycle requirements of Wuchereria and Brugia species limit the extent of transmission of LF outside of tropical regions. However, until elimination, programmes are successful in managing the disease, there remains a possibility of low rates of infection being reported in non-endemic areas, and increased international travel can only contribute to this phenomenon. Physicians need to be aware of the signs and symptoms of lymphatic filariasis, and infection should be considered in the differential diagnosis of people with a relevant travel history. PMID- 25145446 TI - Inheritance and QTL mapping of related root traits in soybean at the seedling stage. AB - KEY MESSAGE: This study provides a foundation for further research on root genetic regulation and molecular breeding with emphasis on correlations among root traits to ensure robust root growth and well-developed root systems. A set of 447 recombinant inbred lines (RILs) derived from a cross between Jingdou23 (cultivar, female parent) and ZDD2315 (semi-wild, male parent) were used to analyze inheritance and detect QTLs related to root traits at the seedling stage using major gene plus polygene mixed inheritance analysis and composite interval mapping. The results showed that maximum root length (MRL) was controlled by three equivalent major genes, lateral root number (LRN) was controlled by two overlapping major genes, root weight (RW) and volume (RV) were controlled by four equivalent major genes. Hypocotyl length (HL) was controlled by four additive main genes, and hypocotyl weight (HW) was controlled by four additive and additive * additive epistatic, major genes; however, polygene effects were not detected in these traits. Shoot weight (SW) was controlled by multi-gene effects, but major gene effects were not detected. Twenty-four QTLs for MRL, LRN, RW, RV, SW, HL, HW were mapped on LG A1 (chromosome 5), LG A2 (chromosome 8), LG B1 (chromosome 11), LG B2 (chromosome 14), LG C2 (chromosome 6), LG D1b (chromosome 2), LG F_1 (chromosome 13), LG G (chromosome 18), LG H_1 (chromosome 12), LG H_2 (chromosome 12), LG I (chromosome 20), LG K_2 (chromosome 9), LG L (chromosome 19), LG M (chromosome 7), LG N (chromosome 3), LG O (chromosome 10), separately. Root traits were shown to have complex genetic mechanisms at the seedling stage, SW was controlled by multi-gene effects, and the other six traits were controlled by major gene effects. It is concluded that correlations among root traits must be considered to improve the development of beneficial root traits. PMID- 25145447 TI - Factor analytic and reduced animal models for the investigation of additive genotype-by-environment interaction in outcrossing plant species with application to a Pinus radiata breeding programme. AB - KEY MESSAGE: Modelling additive genotype-by-environment interaction is best achieved with the use of factor analytic models. With numerous environments and for outcrossing plant species, computation is facilitated using reduced animal models. The development of efficient plant breeding strategies requires a knowledge of the magnitude and structure of genotype-by-environment interaction. This information can be obtained from appropriate linear mixed model analyses of phenotypic data from multi-environment trials. The use of factor analytic models for genotype-by-environment effects is known to provide a reliable, parsimonious and holistic approach for obtaining estimates of genetic correlations between all pairs of trials. When breeding for outcrossing species the focus is on estimating additive genetic correlations and effects which is achieved by including pedigree information in the analysis. The use of factor analytic models in this setting may be computationally prohibitive when the number of environments is moderate to large. In this paper, we present an approach that uses an approximate reduced animal model to overcome the computational issues associated with factor analytic models for additive genotype-by-environment effects. The approach is illustrated using a Pinus radiata breeding dataset involving 77 trials, located in environments across New Zealand and south eastern Australia, and with pedigree information on 315,581 trees. Using this approach we demonstrate the existence of substantial additive genotype-by-environment interaction for the trait of stem diameter measured at breast height. This finding has potentially significant implications for both breeding and deployment strategies. Although our approach has been developed for forest tree breeding programmes, it is directly applicable for other outcrossing plant species, including sugarcane, maize and numerous horticultural crops. PMID- 25145439 TI - Controlling gene networks and cell fate with precision-targeted DNA-binding proteins and small-molecule-based genome readers. AB - Transcription factors control the fate of a cell by regulating the expression of genes and regulatory networks. Recent successes in inducing pluripotency in terminally differentiated cells as well as directing differentiation with natural transcription factors has lent credence to the efforts that aim to direct cell fate with rationally designed transcription factors. Because DNA-binding factors are modular in design, they can be engineered to target specific genomic sequences and perform pre-programmed regulatory functions upon binding. Such precision-tailored factors can serve as molecular tools to reprogramme or differentiate cells in a targeted manner. Using different types of engineered DNA binders, both regulatory transcriptional controls of gene networks, as well as permanent alteration of genomic content, can be implemented to study cell fate decisions. In the present review, we describe the current state of the art in artificial transcription factor design and the exciting prospect of employing artificial DNA-binding factors to manipulate the transcriptional networks as well as epigenetic landscapes that govern cell fate. PMID- 25145448 TI - Effects of leukemia inhibitory receptor gene mutations on human hypothalamo pituitary-adrenal function. AB - BACKGROUND: Stuve-Wiedemann syndrome (STWS) (MIM #601559) is a rare autosomal recessive disorder caused by mutations in the leukemia inhibitory factor receptor (LIFR) gene. STWS has a diverse range of clinical features involving hematopoietic, skeletal, neuronal and immune systems. STWS manifests a high mortality due to increased risk of sudden death. Heterodimerization of the LIFR mediates leukemia inhibitory factor (LIF) signalling through the intracellular Janus kinase (JAK)/STAT3 signalling cascade. The LIF/LIFR system is highly expressed in and regulates the hypothalamo-pituitary-adrenal (HPA) axis. OBJECTIVES: HPA function was investigated in three STWS patients to characterise consequences of impaired LIF/LIFR signalling on adrenal function. DESIGN: Six genetically proven STWS patients from four unrelated Turkish families were included in the study. Sudden death occurred in three before 2 years of age. Basal adrenal function tests were performed by measurement of early morning serum cortisol and plasma ACTH concentrations on at least two different occasions. Low dose synacthen stimulation test and glucagon stimulation tests were performed to explore adrenal function in three patients who survived. RESULTS: All patients carried the same LIFR (p.Arg692X) mutation. Our oldest patient had attenuated morning serum cortisol and plasma ACTH levels at repeated measurements. Two of three patients had attenuated cortisol response (<18 MUg/dl) to glucagon, one of whom also had borderline cortisol response to low dose (1 MUg) ACTH stimulation consistent with central adrenal insufficiency. CONCLUSIONS: STWS patients may develop central adrenal insufficiency due to impaired LIF/LIFR signalling. LIF/LIFR system plays a role in human HPA axis regulation. PMID- 25145449 TI - Biological properties of Indian walking catfish (Clarias batrachus) (L.) gonadotropins in female reproduction. AB - The biological activities of catfish LH-like (semi-purified: s200a and purified Qa) and FSH-like (semi-purified: s200b and purified: Qb) were compared in intact and hypophysectomized female catfish, Clarias batrachus, during preparatory and the pre-spawning periods on vitellogenesis and ovarian maintenance, as well as in vitro final maturation of oocytes, germinal vesicle breakdown (GVBD). During preparatory period, in intact catfish, semi-purified FSH-like induced complete vitellogenesis through the production of estradiol-17beta (E2) and vitellogenin (Vg) accompanied by the formation of SIII yolky oocytes. On the other hand, semi purified LH-like had induced the formation of only SII (characterized by the appearance of cortical alveoli in cytoplasm) oocytes, which indicates the initiation of vitellogenesis. In hypophysectomized female catfish, purified LH like but not FSH-like induced the formation of SII oocytes in the ovaries. Treatment with semi-purified LH- and FSH-like at the dose level of 5 ug/fish/day for 7 days significantly maintained the yolky oocytes in gravid catfish after hypophysectomy with a significant reduction in plasma Vg, but not E2 levels, indicating some unknown GtH-induced factor doing the job. In in vitro oocytes culture, both LH- and FSH-like induced GVBD, but the response was significantly more with LH-like than FSH-like. All these findings revealed that both LH-like and FSH-like have overlapping physiological functions, but their responses differ depending on the physiological status of the catfish. PMID- 25145451 TI - Modelling the outside-xylem hydraulic conductance: towards a new understanding of leaf water relations. PMID- 25145450 TI - Lantana camara Induces Apoptosis by Bcl-2 Family and Caspases Activation. AB - Breast cancer is one of the most common cancers worldwide, and the second most fatal cancer in women after lung cancer. Because there are instances of cancer resistance to existing therapies, studies focused on the identification of novel therapeutic drugs are very important. In this study, we identified a natural anticancer agent from Lantana camara, a flowering plant species of the genus Verbena. The extract obtained from the L. camara exhibited cell death properties in the human breast cancer cell line, MCF-7. We found that the apoptosis induced by treatment with the L. camara extract was regulated by the Bcl-2 family. Bid and Bax was increased and Bcl-2 was decreased by L. camara extract. L. camara extract modulated cleavage of caspase-8, and caspase-9, as well as poly (ADP ribose) polymerase (PARP). Our results support the potential use of the L. camara extract as an anti-breast cancer drug. PMID- 25145452 TI - Retained surgical stents as a cause of biliary obstruction in pediatric liver transplants. AB - BACKGROUND: Small-caliber plastic stents are sometimes placed across the hepaticojejunostomy in liver transplant recipients at the time of biliary reconstruction. These stents usually pass spontaneously, but they can be retained and, rarely, this may cause biliary obstruction. OBJECTIVE: The purpose of this paper is twofold: to describe the appearance of biliary tract obstruction caused by retained surgical stents in pediatric liver transplants, and to report how these stents can be removed using interventional radiology techniques. MATERIALS AND METHODS: Three pediatric patients presenting with biochemical and imaging evidence of biliary obstruction were encountered over a 6-month period. At percutaneous cholangiography all patients were found to have retained surgical stents which appeared to be causing biliary tract obstruction. Percutaneous snaring of the stents was undertaken. RESULTS: All stents were successfully removed using interventional radiology techniques, and follow-up showed no evidence of recurrent obstruction. CONCLUSION: Surgical stents in children undergoing hepaticojejunostomy may be retained and cause biliary obstruction. Radiologists involved with imaging these patients should be aware of this potential cause of biliary obstruction. This complication is amenable to interventional radiology techniques with good long-term results. There is no easy endoscopic or surgical treatment option in these patients. PMID- 25145453 TI - Evaluation of the effect of multiple doses of lansoprazole on the pharmacokinetics and safety of ponatinib in healthy subjects. AB - BACKGROUND: In vitro studies have demonstrated that the aqueous solubility of the tyrosine kinase inhibitor ponatinib decreases as pH increases. OBJECTIVES: The primary aim of this study was to assess the effects of the gastric proton pump inhibitor lansoprazole on the pharmacokinetics of ponatinib. The single-dose safety profile of ponatinib with and without coadministration of lansoprazole was also characterized. METHODS: This was a phase I, open-label, non-randomized, two period crossover study in 20 healthy subjects aged 18-55 years. Subjects received a single oral dose of ponatinib 45 mg alone on day 1, an oral dose of lansoprazole 60 mg on day 14, and ponatinib 45 mg plus lansoprazole 60 mg on day 15. RESULTS: Lansoprazole coadministration resulted in a 1-h increase in the time to maximum plasma concentration (t max) of ponatinib (6 vs. 5 h post-dose; P < 0.001). A corresponding 25 % decrease in the geometric mean maximum plasma concentration (C max) of ponatinib was observed for ponatinib + lansoprazole versus ponatinib alone (40.67 vs. 53.96 ng/mL). Importantly, lansoprazole did not decrease the overall ponatinib systemic exposure as assessed by the ponatinib area under the plasma concentration-time curve from time zero to infinity (AUCinfinity 1,153 ng.h/mL for lansoprazole + ponatinib vs. 1,222 ng.h/mL for ponatinib alone). The safety profile was considered acceptable when ponatinib was administered alone or with lansoprazole. CONCLUSIONS: Although coadministration of lansoprazole led to a modest, albeit statistically significant, reduction in ponatinib C max, overall systemic exposure to ponatinib did not change. The findings suggest that no dose adjustment is necessary when ponatinib is administered with drugs that increase gastric pH. PMID- 25145454 TI - Comparative phosphoproteome analysis of the developing grains in bread wheat (Triticum aestivum L.) under well-watered and water-deficit conditions. AB - Wheat (Triticum aestivum), one of the most important cereal crops, is often threatened by drought. In this study, water deficit significantly reduced the height of plants and yield of grains. To explore further the effect of drought stress on the development and yield of grains, we first performed a large scale phosphoproteome analysis of developing grains in wheat. A total of 590 unique phosphopeptides, representing 471 phosphoproteins, were identified under well watered conditions. Motif-X analysis showed that four motifs were enriched, including [sP], [Rxxs], [sDxE], and [sxD]. Through comparative phosphoproteome analysis between well-watered and water-deficit conditions, we found that 63 unique phosphopeptides, corresponding to 61 phosphoproteins, showed significant changes in phosphorylation level (>=2-fold intensities). Functional analysis suggested that some of these proteins may be involved in signal transduction, embryo and endosperm development of grains, and drought response and defense under water-deficit conditions. Moreover, we also found that some chaperones may play important roles in protein refolding or degradation when the plant is subjected to water stress. These results provide a detailed insight into the stress response and defense mechanisms of developmental grains at the phosphoproteome level. They also suggested some potential candidates for further study of transgenosis and drought stress as well as incorporation into molecular breeding for drought resistance. PMID- 25145455 TI - An increasing opine carbon bias in artificial exudation systems and genetically modified plant rhizospheres leads to an increasing reshaping of bacterial populations. AB - To investigate how exudation shapes root-associated bacterial populations, transgenic Arabidopsis thaliana plants that exuded the xenotopic compound octopine at low and high rates were grown in a nonsterile soil. Enumerations of both cultivable and octopine-degrading bacteria demonstrated that the ratios of octopine degraders increased along with octopine concentration. An artificial exudation system was also set up in which octopine was brought at four ratios. The density of octopine-degrading bacteria directly correlated with the input of octopine. Bacterial diversity was analysed by rrs amplicon pyrosequencing. Ensifer and Pseudomonas were significantly more frequently detected in soil amended with artificial exudates. However, the density of Pseudomonas increased as a response to carbon supplementation while that of Ensifer only correlated with octopine concentrations possibly in relation to two opposed colonization strategies of rhizosphere bacteria, that is, copiotrophy and oligotrophy. PMID- 25145457 TI - Liquid crystal size selection of large-size graphene oxide for size-dependent N doping and oxygen reduction catalysis. AB - Graphene oxide (GO) is aqueous-dispersible oxygenated graphene, which shows colloidal discotic liquid crystallinity. Many properties of GO-based materials, including electrical conductivity and mechanical properties, are limited by the small flake size of GO. Unfortunately, typical sonochemical exfoliation of GO from graphite generally leads to a broad size and shape distribution. Here, we introduce a facile size selection of large-size GO exploiting liquid crystallinity and investigate the size-dependent N-doping and oxygen reduction catalysis. In the biphasic GO dispersion where both isotropic and liquid crystalline phases are equilibrated, large-size GO flakes (>20 MUm) are spontaneously concentrated within the liquid crystalline phase. N-Doping and reduction of the size-selected GO exhibit that N-dopant type is highly dependent on GO flake size. Large-size GO demonstrates quaternary dominant N-doping and the lowest onset potential (-0.08 V) for oxygen reduction catalysis, signifying that quaternary N-dopants serve as principal catalytic sites in N-doped graphene. PMID- 25145458 TI - Commentary on "a nationwide survey of knowledge of and compliance with cancer pain management guidelines by korean physicians". PMID- 25145456 TI - Association of retinal vessel calibre and visual outcome in eyes with diabetic macular oedema treated with ranibizumab. AB - PURPOSE: The study aims to identify the association between the baseline retinal vascular calibre and visual outcome of patients with diabetic macular oedema (DMO) treated with intravitreal ranibizumab. METHODS: The 1-M field (as defined in the ETDRS study) of the digital colour fundus photographs of DMO patients who had been treated primarily with ranibizumab in a clinical trial was assessed. Of the 84 patients, 25 had gradable retinal photographs that could be subjected to analyses by the Interactive Vessel Analysis (IVAN) software at baseline. The average retinal vascular calibre of the six largest venules (CRVE) and the six largest arterioles (CRAE) in the peripapillary area (0.5 and 1 disc diameter from the optic disc margin) was measured. The relationship between CRVE and CRAE at baseline and the change in visual acuity at month 12 was assessed using the Mann Whitney U test. RESULTS: Ten eyes from 10 patients who had shown an improvement of >=2 lines of best corrected visual acuity (BCVA) at month 12 had a wider baseline CRVE (248.3+/-24.5 MUm) compared with the 15 eyes from 15 patients who did not show the improvement of >=2 lines (226.6+/-44.8 MUm, P<0.05). The baseline CRAE did not differ significantly in these patients (156.1+/-22.7 vs 142+/-17.5 MUm, P=0.17). CONCLUSIONS: A wider baseline retinal venular calibre may be a predictor of better visual outcome in DMO eyes treated with ranibizumab. Further prospective studies with a larger sample size and a broader range of disease severity and visual acuity are needed to confirm this finding. PMID- 25145459 TI - Reply to commentary on "a nationwide survey of knowledge of and compliance with cancer pain management guidelines by korean physicians". PMID- 25145460 TI - Improving academic self-efficacy, school connectedness, and identity in struggling middle school girls: a preliminary study of the REAL girls program. AB - Girls struggling to be successful in middle school are often dealing with negative life experiences that affect their ability to achieve academically. Frequently, their academic failures and problem behaviors are associated with feeling overwhelmed by difficult and challenging life circumstances. In the absence of intervention, these patterns may contribute to girls chronically underperforming in school, dropping out of school, and becoming involved in delinquent and high-risk behaviors. This article describes a quasi-experimental, mixed-methods study of the REAL Girls program. REAL Girls was designed to help struggling middle school girls develop resilience--particularly academic self efficacy, school connectedness, and identity--and achieve successful outcomes in school and life. In this study, using a crossover design, 48 girls identified as experiencing academic failure, school behavior problems, or truancy participated in one of two implementations of this 3-day intervention. Findings based on both quantitative and qualitative data suggest that REAL Girls contributed to positive increases in academic self-efficacy, school connectedness, and identity. Repeated measures analysis of variance and paired t tests suggest significant increases in each outcome variable, both immediately after program delivery and 2 weeks later, and effect size estimates suggest moderate to large program impact. Focus groups conducted 90 days after implementation of the program confirmed the quantitative findings and support the efficacy of the REAL Girls program and approach. PMID- 25145461 TI - Word and world knowledge among deaf learners with and without cochlear implants. AB - Deaf learners frequently demonstrate significantly less vocabulary knowledge than hearing age-mates. Studies involving other domains of knowledge, and perhaps deaf learners' academic performance, indicate similar lags with regard to world knowledge. Such gaps often are attributed to limitations on deaf children's incidental learning by virtue of not having access to the conversations of others. Cochlear implants (CIs) have been described as providing such access, and rapid growth in vocabularies following pediatric cochlear implantation has suggested that, over time, children with implants might close the gap relative to hearing peers. Two experiments evaluated this possibility through the assessment of word and world knowledge among deaf college students with and without CIs and a hearing comparison group. Results across essentially all tasks indicated hearing students to outperform deaf students both with and without CIs with no significant differences between the latter two groups. Separate analyses of a subset of implant users who received their implants at a young age did not reveal any long-term advantages, nor was age of implantation related to enhanced performance on any of the tasks. Results are discussed in terms of incidental learning and the accessibility of word and world knowledge to deaf learners with and without CIs. PMID- 25145462 TI - Exploitation of the hepatic stellate cell Raman signature for their detection in native tissue samples. AB - Hepatic stellate cells (HSCs) surround liver sinusoids and store retinol while they are quiescent. During fibrotic liver diseases and acute-on-chronic liver failure they change to the activated state in which they proliferate, lose their retinol content and deposit extracellular matrix molecules. The process of HSC activation is of utmost interest, but so far only insufficiently understood, because there is a lack of techniques to address the function of single HSCs in the tissue context. In this contribution, the potential of Raman micro spectroscopy for the label-free detection of HSCs in mouse liver samples is demonstrated. First, culture-induced activation of primary mouse HSCs is followed in vitro and characterized by means of Raman spectroscopy. The HSC activation state is confirmed by immunofluorescence labeling of glial fibrillary acidic protein (GFAP) and alpha-smooth muscle actin (ASMA). As expected, the unique Raman spectrum of retinol in quiescent HSCs is lost during activation. Nevertheless, successful discrimination of HSCs from primary hepatocytes is possible during all states of activation. A classification model based on principal component analysis followed by linear discriminant analysis (PCA-LDA) of the lipid droplet Raman data yields a prediction accuracy of 99%. The in vitro results are transferred to fresh liver slices and freshly sampled livers. Quiescent HSCs and a HSC transforming from quiescent to activated state are identified based on their Raman signature. This provides valuable information on HSC activation state in the liver. PMID- 25145463 TI - Unwanted hair growth induced by topical epidermal growth factor during wound healing: true or myth? PMID- 25145464 TI - Cell-based therapies for cardiac disease: a cellular therapist's perspective. AB - Cell-based therapy is an exciting, promising, and a developing new treatment for cardiac diseases. Stem cell-based therapies have the potential to fundamentally transform the treatment of ischemic cardiac injury and heart failure by achieving what would have been unthinkable only a few years ago-the Holy Grail of myocardial regeneration. Recent therapeutic approaches involve bone marrow (BM) derived mononuclear cells and their subsets such as mesenchymal stem/stromal cells (MSCs), endothelial progenitor cells as well as adipose tissue-derived MSCs, cardiac tissue-derived stem cells, and cell combinations. Clinical trials employing these cells have demonstrated that cellular therapy is feasible and safe. Regarding delivery methods, the safety of catheter-based, transendocardial and -epicardial stem cell injection has been established. However, the results, while variable, suggest rather modest clinical efficacy overall in both heart failure and ischemic heart disease, such as in acute myocardial infarction. Future studies will focus on determining the most efficacious cell type(s) and/or cell combinations and the most reasonable indications and optimal timing of transplantation, as well as the mechanisms underlying their therapeutic effects. We will review and summarize the clinical trial results to date. In addition, we discuss challenges and operational issues in cell processing for cardiac applications. PMID- 25145467 TI - One-year outcomes of spinal cord stimulation of the dorsal root ganglion in the treatment of chronic neuropathic pain. AB - OBJECTIVES: Spinal cord stimulation of the dorsal root ganglion (DRG-SCS) is a new therapy for treating chronic neuropathic pain. Previous work has demonstrated the effectiveness of DRG-SCS for pain associated with failed back surgery syndrome, complex regional pain syndrome, chronic postsurgical pain, and other etiologies through 6 months of treatment; this report describes the maintenance of pain relief, improvement in mood, and quality of life through 12 months. MATERIALS AND METHODS: Subjects with intractable pain in the back and/or lower limbs were implanted with an active neurostimulator device. Up to four percutaneous leads were placed epidurally near DRGs. Subjects were tracked prospectively for 12 months. RESULTS: Overall, pain was reduced by 56% at 12 months post-implantation, and 60% of subjects reported greater than 50% improvement in their pain. Pain localized to the back, legs, and feet was reduced by 42%, 62%, and 80%, respectively. Measures of quality of life and mood were also improved over the course of the study, and subjects reported high levels of satisfaction. Importantly, excellent pain-paresthesia overlap was reported, remaining stable through 12 months. DISCUSSION: Despite methodological differences in the literature, DRG-SCS appears to be comparable to traditional SCS in terms of pain relief and associated benefits in mood and quality of life. Its benefits may include the ability to achieve precise pain-paresthesia concordance, including in regions that are typically difficult to target with SCS, and to consistently maintain that coverage over time. PMID- 25145466 TI - Physical and biological characterization of ferromagnetic fiber networks: effect of fibrin deposition on short-term in vitro responses of human osteoblasts. AB - Ferromagnetic fiber networks have the potential to deform in vivo imparting therapeutic levels of strain on in-growing periprosthetic bone tissue. 444 Ferritic stainless steel provides a suitable material for this application due to its ability to support cultures of human osteoblasts (HObs) without eliciting undue inflammatory responses from monocytes in vitro. In the present article, a 444 fiber network, containing 17 vol% fibers, has been investigated. The network architecture was obtained by applying a skeletonization algorithm to three dimensional tomographic reconstructions of the fiber networks. Elastic properties were measured using low-frequency vibration testing, providing globally averaged properties as opposed to mechanical methods that yield only local properties. The optimal region for transduction of strain to cells lies between the ferromagnetic fibers. However, cell attachment, at early time points, occurs primarily on fiber surfaces. Deposition of fibrin, a fibrous protein involved in acute inflammatory responses, can facilitate cell attachment within this optimal region at early time points. The current work compared physiological (3 and 5 g.L(-1)) and supraphysiological fibrinogen concentrations (10 g.L(-1)), using static in vitro seeding of HObs, to determine the effect of fibrin deposition on cell responses during the first week of cell culture. Early cell attachment within the interfiber spaces was observed in all fibrin-containing samples, supported by fibrin nanofibers. Fibrin deposition influenced the seeding, metabolic activity, and early stage differentiation of HObs cultured in the fibrin-containing fiber networks in a concentration-dependant manner. While initial cell attachment for networks with fibrin deposited from low physiological concentrations was similar to control samples without fibrin deposition, significantly higher HObs attached onto high physiological and supraphysiological concentrations. Despite higher cell numbers with supraphysiological concentrations, cell metabolic activities were similar for all fibrinogen concentrations. Further, cells cultured on supraphysiological concentrations exhibited lower cell differentiation as measured by alkaline phosphatase activity at early time points. Overall, the current study suggests that physiological fibrinogen concentrations would be more suitable than supraphysiological concentrations for supporting early cell activity in porous implant coatings. PMID- 25145465 TI - Transcriptome-wide analysis of trypanosome mRNA decay reveals complex degradation kinetics and suggests a role for co-transcriptional degradation in determining mRNA levels. AB - African trypanosomes are an excellent system for quantitative modelling of post transcriptional mRNA control. Transcription is constitutive and polycistronic; individual mRNAs are excised by trans splicing and polyadenylation. We here measure mRNA decay kinetics in two life cycle stages, bloodstream and procyclic forms, by transcription inhibition and RNASeq. Messenger RNAs with short half lives tend to show initial fast degradation, followed by a slower phase; they are often stabilized by depletion of the 5'-3' exoribonuclease XRNA. Many longer lived mRNAs show initial slow degradation followed by rapid destruction: we suggest that the slow phase reflects gradual deadenylation. Developmentally regulated mRNAs often show regulated decay, and switch their decay pattern. Rates of mRNA decay are good predictors of steady state levels for short mRNAs, but mRNAs longer than 3 kb show unexpectedly low abundances. Modelling shows that variations in splicing and polyadenylation rates can contribute to steady-state mRNA levels, but this is completely dependent on competition between processing and co-transcriptional mRNA precursor destruction. PMID- 25145468 TI - Cervical spine. PMID- 25145469 TI - Engaging GPs in insulin therapy initiation: a qualitative study evaluating a support program in the Belgian context. AB - BACKGROUND: A program supporting the initiation of insulin therapy in primary care was introduced in Belgium, as part of a larger quality improvement project on diabetes care. This paper reports on a study exploring factors influencing the engagement of general practitioners (GPs) in insulin therapy initiation (research question 1) and exploring factors relevant for future program development (research question 2). METHODS: We have used semi-structured interviews to answer the first research question: two focus group interviews with GPs who had at least one patient in the insulin initiation program and 20 one-to-one interviews with GPs who were not regular users of the overall support program in the region. To explore factors relevant for future program development, the data from the GPs were triangulated with data obtained from individual interviews with patients (n = 10), the diabetes nurse educator (DNE) and the specialist involved in the program, and data extracted from meeting reports evaluating the insulin initiation support program. RESULTS: We found differences between GPs engaged and those not engaged in insulin initiation in attitude, subjective norm and perceived behavioural control regarding insulin initiation. In general the support program was evaluated in a positive way by users of the program. Some aspects need further consideration: job boundaries between the DNE and GPs, job boundaries between GPs and specialists, protocol adherence and limited case load. CONCLUSION: The study shows that the transition of insulin initiation from secondary care to the primary care setting is a challenge. Although a support program addressing known barriers to insulin initiation was provided, a substantial number of GPs were reluctant to engage in this aspect of care. Important issues for future program development are: an interdisciplinary approach to job clarification, a dynamic approach to the integration of expertise in primary care and feedback on protocol adherence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00824499. PMID- 25145471 TI - Neutrophils and oral squamous cell carcinoma: lessons learned and future directions. AB - The role of cells of the innate immune system in the pathogenesis of squamous cell carcinoma has been the subject of intense research in recent years. In particular, neutrophils have been shown recently to have either a pro-tumor or anti-tumor phenotype in different cancers. Here, we review the role of neutrophils as tumor microenvironment and signaling modulators of OSCC and their possible role as biomarkers of OSCC prognosis. Current evidence supports a pro tumor role for neutrophils in OSCC, but more research is needed to clarify the precise mechanisms involved. PMID- 25145470 TI - Vascular gene transfer from metallic stent surfaces using adenoviral vectors tethered through hydrolysable cross-linkers. AB - In-stent restenosis presents a major complication of stent-based revascularization procedures widely used to re-establish blood flow through critically narrowed segments of coronary and peripheral arteries. Endovascular stents capable of tunable release of genes with anti-restenotic activity may present an alternative strategy to presently used drug-eluting stents. In order to attain clinical translation, gene-eluting stents must exhibit predictable kinetics of stent-immobilized gene vector release and site-specific transduction of vasculature, while avoiding an excessive inflammatory response typically associated with the polymer coatings used for physical entrapment of the vector. This paper describes a detailed methodology for coatless tethering of adenoviral gene vectors to stents based on a reversible binding of the adenoviral particles to polyallylamine bisphosphonate (PABT)-modified stainless steel surface via hydrolysable cross-linkers (HC). A family of bifunctional (amine- and thiol reactive) HC with an average t1/2 of the in-chain ester hydrolysis ranging between 5 and 50 days were used to link the vector with the stent. The vector immobilization procedure is typically carried out within 9 hr and consists of several steps: 1) incubation of the metal samples in an aqueous solution of PABT (4 hr); 2) deprotection of thiol groups installed in PABT with tris(2 carboxyethyl) phosphine (20 min); 3) expansion of thiol reactive capacity of the metal surface by reacting the samples with polyethyleneimine derivatized with pyridyldithio (PDT) groups (2 hr); 4) conversion of PDT groups to thiols with dithiothreitol (10 min); 5) modification of adenoviruses with HC (1 hr); 6) purification of modified adenoviral particles by size-exclusion column chromatography (15 min) and 7) immobilization of thiol-reactive adenoviral particles on the thiolated steel surface (1 hr). This technique has wide potential applicability beyond stents, by facilitating surface engineering of bioprosthetic devices to enhance their biocompatibility through the substrate mediated gene delivery to the cells interfacing the implanted foreign material. PMID- 25145472 TI - Significant increases of pituitary tumors and resections from 1993 to 2011. AB - BACKGROUND: Pituitary tumors comprise 10% to 15% of all diagnosed intracranial tumors; 90% are adenomas. Though benign, significant morbidity via compression of surrounding structures or aberrant hormone secretion can occur. This study investigated rates of pituitary tumor diagnoses and treatment trends from 1993 to 2011. METHODS: This study was a retrospective review of the 1993 to 2011 Nationwide Inpatient Sample for patients diagnosed with pituitary tumor as well as those patients who underwent pituitary tumor resection. Incidences of pituitary lesions, surgical approaches, and clinical and economic outcomes were evaluated. RESULTS: The rate of primary and secondary diagnoses of pituitary tumor per 100,000 persons significantly grew over the study period (correlation coefficient = 0.934 and 0.987, respectively, p < 0.001); a significant increase in the number of pituitary resections performed annually (correlation coefficient = 0.942, p < 0.001) were also seen. Admissions with a primary diagnosis of pituitary neoplasm experienced significant decreases in length of stay over time (correlation coefficient = -0.913, p < 0.001) and mortality (correlation coefficient = -0.697, p = 0.001). Interestingly, hospital charges more than triple over the same time span (correlation coefficient = 0.970, p < 0.001). Transfrontal resections decreased linearly with time. CONCLUSION: Pituitary tumor diagnoses and resections have grown significantly over the past 20 years. Transsphenoidal surgical resection among this patient population has increased significantly, whereas transfrontal resections have decreased. PMID- 25145473 TI - Visible-light-induced water oxidation mediated by a mononuclear-cobalt(II) substituted silicotungstate. AB - A mononuclear-cobalt(II)-substituted silicotungstate, K10[Co(H2O)2(gamma SiW10O35)2]?23 H2O (POM-1), has been evaluated as a light-driven water-oxidation catalyst. With in situ photogenerated [Ru(bpy)3](3+) (bpy=2,2'-bipyridine) as the oxidant, quite high catalytic turnover number (TON; 313), turnover frequency (TOF; 3.2 s(-1)), and quantum yield (Phi(QY); 27%) for oxygen evolution at pH 9.0 were acquired. Comparison experiments with its structural analogues, namely [Ni(H2O)2(gamma-SiW10O35)2](10-) (POM-2) and [Mn(H2O)2(gamma-SiW10O35)2](10-) (POM-3), gave the conclusion that the cobalt center in POM-1 is the active site. The hydrolytic stability of the title polyoxometalate (POM) was confirmed by extensive experiments, including UV/Vis spectroscopy, linear sweep voltammetry (LSV), and cathodic adsorption stripping analysis (CASA). As the [Ru(bpy)3](2+)/visible light/sodium persulfate system was introduced, a POM photosensitizer complex formed within minutes before visible-light irradiation. It was demonstrated that this complex functioned as the active species, which remained intact after the oxygen-evolution reaction. Multiple experimental parameters were investigated and the catalytic activity was also compared with the well-studied POM-based water-oxidation catalysts (i.e., [Co4(H2O)2(alpha PW9O34)2](10-) (Co4-POM) and [Co(III)Co(II)(H2O)W11O39](7-) (Co2-POM)) under optimum conditions. PMID- 25145474 TI - VEGF and angiopoietins promote inflammatory cell recruitment and mature blood vessel formation in murine sponge/Matrigel model. AB - A key feature in the induction of pathological angiogenesis is that inflammation precedes and accompanies the formation of neovessels as evidenced by increased vascular permeability and the recruitment of inflammatory cells. Previously, we and other groups have shown that selected growth factors, namely vascular endothelial growth factor (VEGF) and angiopoietins (Ang1 and Ang2) do not only promote angiogenesis, but can also induce inflammatory response. Herein, given a pro-inflammatory environment, we addressed the individual capacity of VEGF and angiopoietins to promote the formation of mature neovessels and to identify the different types of inflammatory cells accompanying the angiogenic process over time. Sterilized polyvinyl alcohol (PVA) sponges soaked in growth factor-depleted Matrigel mixed with PBS, VEGF, Ang1, or Ang2 (200 ng/200 ul) were subcutaneously inserted into anesthetized mice. Sponges were removed at day 4, 7, 14, or 21 post procedure for histological, immunohistological (IHC), and flow cytometry analyses. As compared to PBS-treated sponges, the three growth factors promoted the recruitment of inflammatory cells, mainly neutrophils and macrophages, and to a lesser extent, T- and B-cells. In addition, they were more potent and more rapid in the recruitment of endothelial cells (ECs) and in the formation and maturation (ensheating of smooth muscle cells around ECs) of neovessels. Thus, the autocrine/paracrine interaction among the different inflammatory cells in combination with VEGF, Ang1, or Ang2 provides a suitable microenvironment for the formation and maturation of blood vessels. PMID- 25145475 TI - The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. AB - Plasma aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) are usually increased in patients with nonalcoholic fatty liver disease (NAFLD). However, the factors behind their elevation remain unclear. The aim of this study was to assess the role of insulin resistance (IR) and liver triglyceride content in relation to histology in patients with NAFLD/nonalcoholic steatohepatitis (NASH) with normal or elevated ALT levels. To this end, we enrolled 440 patients, divided into three groups: no NAFLD (n = 60); NAFLD with normal ALT (n = 165); and NAFLD with elevated ALT (n = 215). We measured: (1) liver fat by proton magnetic resonance spectroscopy ((1)H-MRS); (2) severity of liver disease by biopsy (n = 293); and (3) insulin sensitivity in liver, muscle, and adipose tissue by a euglycemic hyperinsulinemic clamp with 3 (3)H-glucose. Patients with NAFLD and elevated ALT, even when well matched for body mass index to those with normal ALT, had worse adipose tissue insulin resistance (ATIR; P < 0.0001), higher liver triglyceride content (P < 0.0001), and lower plasma adiponectin (P < 0.05), but no differences in hepatic insulin resistance. Similar results were found when only patients with NASH were compared: both ATIR (P < 0.0001) and liver triglyceride content by (1)H-MRS (P < 0.0001) were worse in NASH with elevated ALT. Consistent with the (1)H-MRS data, steatosis on liver biopsy was also significantly increased in patients with NASH and elevated ALT levels (P < 0.0001). However, and most important, there were no differences in inflammation (P = 0.62), ballooning (P = 0.13), or fibrosis (P = 0.12). CONCLUSION: In patients with NAFLD or NASH, ATIR (but not HIR) and liver triglyceride content are major factors in the elevation of plasma aminotransferase levels. Patients with normal versus elevated ALT had similar severity of NASH, suggesting that plasma aminotransferase levels are misleading parameters for guiding clinical management. PMID- 25145476 TI - Tumorigenesis: FBP1 is suppressed in kidney tumours. PMID- 25145481 TI - RNA dynamics: destabilizing mRNAs promotes metastasis. PMID- 25145483 TI - DMAP-BODIPY alkynes: a convenient tool for labeling biomolecules for bimodal PET optical imaging. AB - Several new boron dipyrromethene/N,N-dimethylaminopyridine (BODIPY-DMAP) assemblies were synthesized as precursors for bimodal imaging probes (optical imaging, OI/positron emission tomography, PET). The photophysical properties of the new compounds were also studied. The first proof-of-concept was obtained with the preparation of several new BODIPY-labeled bombesins and evaluation of the affinity for bombesin receptors by using a competition binding assay. Fluorination reactions were investigated on DMAP-BODIPY precursors as well as on DMAP-BODIPY-labeled bombesins. Chemical modifications on the BODIPY core were also performed to obtain luminescent dyes emitting in the therapeutic window (650 900 nm), suitable for in vivo imaging, making these compounds promising precursors for PET/optical dual-modality imaging agents. PMID- 25145484 TI - Work ability in vibration-exposed workers. AB - BACKGROUND: Hand-arm vibration exposure may cause hand-arm vibration syndrome (HAVS) including sensorineural disturbances. AIMS: To investigate which factors had the strongest impact on work ability in vibration-exposed workers. METHODS: A cross-sectional study in which vibration-exposed workers referred to a department of occupational and environmental medicine were compared with a randomized sample of unexposed subjects from the general population of the city of Gothenburg. All participants underwent a structured interview, answered several questionnaires and had a physical examination including measurements of hand and finger muscle strength and vibrotactile and thermal perception thresholds. RESULTS: The vibration-exposed group (47 subjects) showed significantly reduced sensitivity to cold and warmth in digit 2 bilaterally (P < 0.01) and in digit 5 in the left hand (P < 0.05) and to warmth in digit 5 in the right hand (P < 0.01), compared with the 18 referents. Similarly, tactilometry showed significantly raised vibration perception thresholds among the workers (P < 0.05). A strong relationship was found for the following multiple regression model: estimated work ability = 11.4 0.1 * age - 2.3 * current stress level - 2.5 * current pain in hands/arms (multiple r = 0.68; P < 0.001). CONCLUSIONS: Vibration-exposed workers showed raised vibrotactile and thermal perception thresholds, compared with unexposed referents. Multiple regression analysis indicated that stress disorders and muscle pain in hands/arms must also be considered when evaluating work ability among subjects with HAVS. PMID- 25145485 TI - Working conditions and mental health in teachers: a preliminary study. AB - BACKGROUND: Unfavourable working conditions are associated with poor mental health and many studies show that teachers are at risk of this. AIMS: To investigate if and to what extent specific dimensions of working conditions are associated with symptoms of depression and anxiety in teachers in state schools in Italy. METHODS: A cross-sectional questionnaire survey of Italian state schoolteachers using the Karasek Job Content Questionnaire, the Self-Rating Anxiety Scale (SAS) and the Center for Epidemiologic Studies Depression Scale (CES-D). We tested the hypotheses that high job demand, low decision latitude and low support are associated with anxiety and depression in teachers using a correlation matrix and hierarchical multiple regression models. RESULTS: 113/180 (63%) of schoolteachers invited to participate completed the survey. 49% scored above the cut-off on CES-D and 11% on SAS. CES-D was positively correlated with job demand (r = 0.517, P < 0.01) and negatively with social support (r = -0.226, P < 0.05). SAS was positively correlated with job demand (r = 0.408, P < 0.01). Hierarchical multiple regression analysis showed that job demand was significantly associated with CES-D and SAS scores, explaining 28 and 25% of variance respectively. CONCLUSIONS: About half of the teachers in this study scored above the threshold for depression and ~1 in 10 for anxiety on self-rating questionnaires. Poor mental health in teachers is significantly associated with high job demand and low social support. These results should be confirmed in larger, more representative samples. PMID- 25145482 TI - The impact of the endoplasmic reticulum protein-folding environment on cancer development. AB - The endoplasmic reticulum (ER) is an essential organelle in eukaryotic cells for the storage and regulated release of calcium and as the entrance to the secretory pathway. Protein misfolding in the ER causes accumulation of misfolded proteins (ER stress) and activation of the unfolded protein response (UPR), which has evolved to maintain a productive ER protein-folding environment. Both ER stress and UPR activation are documented in many different human cancers. In this Review, we summarize the impact of ER stress and UPR activation on every aspect of cancer and discuss outstanding questions for which answers will pave the way for therapeutics. PMID- 25145486 TI - Folate and vitamin B12 may play a critical role in lowering the HPV 16 methylation-associated risk of developing higher grades of CIN. AB - We previously reported that a higher degree of methylation of CpG sites in the promoter (positions 31, 37, 43, 52, and 58) and enhancer site 7862 of human papillomavirus (HPV) 16 was associated with a lower likelihood of being diagnosed with HPV 16-associated CIN 2+. The purpose of this study was to replicate our previous findings and, in addition, to evaluate the influence of plasma concentrations of folate and vitamin B12 on the degree of HPV 16 methylation (HPV 16m). The study included 315 HPV 16-positive women diagnosed with either CIN 2+ or <=CIN 1. Pyrosequencing technology was used to quantify the degree of HPV 16m. We reproduced the previously reported inverse association between HPV 16m and risk of being diagnosed with CIN 2+. In addition, we observed that women with higher plasma folate and HPV 16m or those with higher plasma vitamin B12 and HPV 16m were 75% (P < 0.01) and 60% (P = 0.02) less likely to be diagnosed with CIN 2+, respectively. With a tertile increase in the plasma folate or vitamin B12, there was a 50% (P = 0.03) and 40% (P = 0.07) increase in the odds of having a higher degree of HPV 16m, respectively. This study provides initial evidence that methyl donor micronutrients, folate and vitamin B12, may play an important role in maintaining a desirably high degree of methylation at specific CpG sites in the HPV E6 promoter and enhancer that are associated with the likelihood of being diagnosed with CIN 2+. PMID- 25145487 TI - C-reactive protein and risk of colorectal adenomas or serrated polyps: a prospective study. AB - Serum C-reactive protein (CRP) is a sensitive marker of systemic inflammation. Because there is a well-recognized relationship between local inflammation and colorectal cancer, we aimed to evaluate whether serum CRP levels were associated with the occurrence of colorectal adenomas and serrated polyps using data from a large adenoma prevention trial. A total of 930 participants with a history of colorectal adenomas were enrolled in a randomized trial of calcium supplementation (1,200 mg/day) for the prevention of colorectal adenomas. Outcomes in this analysis are metachronous adenomas (and advanced neoplasms specifically), and serrated polyps at follow-up colonoscopy. High-sensitivity CRP levels were measured 1 year following baseline colonoscopy. Multivariate analysis was performed to estimate risk ratios (RR) using Poisson regression, controlling for potential confounders. We measured serum CRP levels in 689 participants (mean CRP, 3.62 +/- 5.72 mg/L). There was no difference in CRP levels with respect to calcium versus placebo treatment assignment (P = 0.99). After adjustment for potential confounders, we found no association between CRP level and risk of recurrent adenoma or advanced lesion [quartile 4 vs. quartile 1: RR, 95% confidence interval (CI) = 0.99 (0.73-1.34) and 0.92 (0.49-1.75), respectively]. Similarly, no association was seen between CRP levels and risk of serrated polyps or proximal serrated polyps [quartile 4 vs. quartile 1: RR (95% CI) = 1.32 (0.85 2.03) and 1.19 (0.54-2.58), respectively]. In conclusion, this large prospective colorectal adenoma chemoprevention study found no significant relationship between CRP levels and occurrence of adenomas, advanced neoplasms, or serrated polyps. PMID- 25145488 TI - Development of a mild and versatile directed cycloaddition approach to pyridines. AB - The aza-Diels-Alder cycloaddition of 1,2,4-triazines with alkynes offers a rapid and convenient method for the synthesis of highly substituted pyridines, but often requires harsh conditions and long reaction times. The present study offers a solution to these limitations by use of a temporary tether established by a Lewis acid-base complexation of in situ generated alkynylboranes and triazines bearing a Lewis basic donor. The cycloaddition reactions take place within 20 min at 40 degrees C and provide direct access to a broad range of pyridines with complete and predictable regiocontrol. The carbon?boron bond can be further functionalised by cross-coupling allowing further functionality to be introduced after cycloaddition. PMID- 25145489 TI - End-of-life treatment preferences: a key to reducing ethnic/racial disparities in advance care planning? AB - BACKGROUND: The objective of this study was to identify targets for interventions to reduce end-of-life care disparities among patients with advanced cancer. To do this, the authors evaluated the degree to which end-of-life care values and preferences are associated with advance care planning within racial/ethnic minority groups. METHODS: The Coping with Cancer study recruited patients with advanced cancer from outpatient clinics in 5 states from 2002 to 2008. Then, the rates of 1 type of advance care planning-do-not-resuscitate (DNR) orders-reported at baseline interviews by 606 patients were investigated. Bivariate tests determined associations among DNR order completion, religious values, and treatment preferences within racial/ethnic groups. RESULTS: Non-Latino white patients were significantly more likely to have a DNR order (45%) than black (25%) and Latino (20%) patients (P<.001). A preference against specific life prolonging treatment (eg, chemotherapy, ventilation) was the only factor significantly associated with higher DNR order likelihood in each group, with non Latino white patients more likely than Latino or black patients to express preferences against life-prolonging care (eg, 26% of non-Latino white patients, 46% of black patients, and 41% of Latino patients wanted a feeding tube if it would extend life for 1 more day; P<.001). CONCLUSIONS: Preferences against life prolonging care differ dramatically by race/ethnicity, but they have a uniform significant association with DNR order completion rates across racial/ethnic groups of patients with advanced cancer. Advance care planning interventions that target preferences associated with DNR orders across racial/ethnic groups may reach a broad patient population and reduce end-of-life care disparities. PMID- 25145490 TI - Elective neck dissection during salvage total laryngectomy--a beneficial prognostic effect in locally advanced recurrent tumours. AB - OBJECTIVES: Elective neck dissection during salvage laryngectomy is controversial. The goal of our study was to evaluate the effect of elective neck dissection during salvage laryngectomy in patients with locally advanced disease at recurrence. DESIGN: Multicentre, retrospective study. SETTINGS: Two tertiary medical centres. PARTICIPANTS: Eighty-seven patients treated by salvage laryngectomy. MAIN OUTCOME MEASURES: Disease-Free and Overall Survival. RESULTS: Fifty-seven patients underwent salvage total laryngectomy for locally advanced recurrent squamous cell carcinoma of the larynx, and 30 patients underwent salvage laryngectomy for limited recurrent disease. Elective lateral neck dissection was performed in 48 patients. The groups were similar in age, sex, initial TNM stage and pre-operative treatment. Survival analysis showed that both disease-free survival and overall survival were improved in patients with locally advanced disease who underwent elective neck dissection. This beneficial effect was not demonstrated in patients with limited disease at recurrence. Multivariate analysis showed that the extent of the recurrent disease as well as elective neck dissection was associated with improved disease-free survival and overall survival. CONCLUSIONS: Elective neck dissection during salvage total laryngectomy seems to improve survival in patients with advanced local disease at recurrence. The role of neck dissection in the treatment of smaller tumours awaits further studies. PMID- 25145493 TI - A pH-responsive prodrug for real-time drug release monitoring and targeted cancer therapy. AB - A novel cancer targeting and pH-responsive prodrug was successfully designed and synthesized. This M-prodrug was demonstrated to have real-time drug release monitoring capability based on the concept of contact-mediated quenching between doxorubicin and a coumarin derivative. PMID- 25145492 TI - Hydrogel nanoparticle harvesting of plasma or urine for detecting low abundance proteins. AB - Novel biomarker discovery plays a crucial role in providing more sensitive and specific disease detection. Unfortunately many low-abundance biomarkers that exist in biological fluids cannot be easily detected with mass spectrometry or immunoassays because they are present in very low concentration, are labile, and are often masked by high-abundance proteins such as albumin or immunoglobulin. Bait containing poly(N-isopropylacrylamide) (NIPAm) based nanoparticles are able to overcome these physiological barriers. In one step they are able to capture, concentrate and preserve biomarkers from body fluids. Low-molecular weight analytes enter the core of the nanoparticle and are captured by different organic chemical dyes, which act as high affinity protein baits. The nanoparticles are able to concentrate the proteins of interest by several orders of magnitude. This concentration factor is sufficient to increase the protein level such that the proteins are within the detection limit of current mass spectrometers, western blotting, and immunoassays. Nanoparticles can be incubated with a plethora of biological fluids and they are able to greatly enrich the concentration of low molecular weight proteins and peptides while excluding albumin and other high molecular weight proteins. Our data show that a 10,000 fold amplification in the concentration of a particular analyte can be achieved, enabling mass spectrometry and immunoassays to detect previously undetectable biomarkers. PMID- 25145491 TI - Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis. AB - BACKGROUND: In twin pregnancies, the rates of adverse perinatal outcome and subsequent long-term morbidity are substantial, and mainly result from preterm birth (PTB). OBJECTIVES: To assess the effectiveness of progestogen treatment in the prevention of neonatal morbidity or PTB in twin pregnancies using individual participant data meta-analysis (IPDMA). SEARCH STRATEGY: We searched international scientific databases, trial registration websites, and references of identified articles. SELECTION CRITERIA: Randomised clinical trials (RCTs) of 17-hydroxyprogesterone caproate (17Pc) or vaginally administered natural progesterone, compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: Investigators of identified RCTs were asked to share their IPD. The primary outcome was a composite of perinatal mortality and severe neonatal morbidity. Prespecified subgroup analyses were performed for chorionicity, cervical length, and prior spontaneous PTB. MAIN RESULTS: Thirteen trials included 3768 women and their 7536 babies. Neither 17Pc nor vaginal progesterone reduced the incidence of adverse perinatal outcome (17Pc relative risk, RR 1.1; 95% confidence interval, 95% CI 0.97-1.4, vaginal progesterone RR 0.97; 95% CI 0.77-1.2). In a subgroup of women with a cervical length of <=25 mm, vaginal progesterone reduced adverse perinatal outcome when cervical length was measured at randomisation (15/56 versus 22/60; RR 0.57; 95% CI 0.47-0.70) or before 24 weeks of gestation (14/52 versus 21/56; RR 0.56; 95% CI 0.42-0.75). AUTHOR'S CONCLUSIONS: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of <=25 mm; however, further research is warranted to confirm this finding. PMID- 25145494 TI - Comparative analysis of the intestinal bacterial communities in different species of carp by pyrosequencing. AB - Gut microbiota is increasingly regarded as an integral component of the host, due to important roles in the modulation of the immune system, the proliferation of the intestinal epithelium and the regulation of the dietary energy intake. Understanding the factors that influence the composition of these microbial communities is essential to health management, and the application to aquatic animals still requires basic investigation. In this study, we compared the bacterial communities harboured in the intestines and in the rearing water of grass carp (Ctenopharyngodon idellus), crucian carp (Carassius cuvieri), and bighead carp (Hypophthalmichthys nobilis), by using 454-pyrosequencing with barcoded primers targeting the V4 to V5 regions of the bacterial 16S rRNA gene. The specimens of the three species were cohabiting in the same pond. Between 6,218 and 10,220 effective sequences were read from each sample, resulting in a total of 110,398 sequences for 13 samples from gut microbiota and pond water. In general, the microbial communities of the three carps were dominated by Fusobacteria, Firmicutes, Proteobacteria and Bacteroidetes, but the abundance of each phylum was significantly different between species. At the genus level, the overwhelming group was Cetobacterium (97.29 +/- 0.46 %) in crucian carp, while its abundance averaged c. 40 and 60 % of the sequences read in the other two species. There was higher microbial diversity in the gut of filter-feeding bighead carp than the gut of the two other species, with grazing feeding habits. The composition of intestine microbiota of grass carp and crucian carp shared higher similarity when compared with bighead carp. The principal coordinates analysis (PCoA) with the weighted UniFrac distance and the heatmap analysis suggested that gut microbiota was not a simple reflection of the microbial community in the local habitat but resulted from species-specific selective pressures, possibly dependent on behavioural, immune and metabolic characteristics. PMID- 25145495 TI - Dual stimulation with bacterial and viral components increases the expression of hepcidin in human monocytes. AB - Hepcidin belongs to the antimicrobial peptide (AMP) family and is the key regulator of iron metabolism. It modulates iron homeostasis by binding to, and degrading the iron exporter molecule, ferroportin, thus inhibiting cellular iron efflux. Many antimicrobial peptides have a dual function; some are able to act directly as an antimicrobial agent as well as having an immunoregulatory role in the host. Toll-like receptors (TLRs) bind to components of microorganisms, activate cellular signal transduction pathways and stimulate innate immune responses. The effect of TLR3 (poly I:C) and TLR9 (CpG) co-stimulation of THP-1 derived monocytes using purified TLR ligands showed that 24 h after exposure poly I:C and CpG ligands in combination, hepcidin expression was significantly increased (10-fold) when compared to the untreated control. This combination of TLR ligands mimics simultaneous bacterial and viral infections, thus suggesting a potential key role for hepcidin in combined infections. Additionally, using a chequerboard assay, we have shown that hepcidin has an antagonistic effect in combination with the antibiotics rifampicin and tetracycline against Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyogenes, evidenced by a fractional inhibitory concentration index (FICI) > 4. This finding has important implications for future treatment regimens especially in an era of increasing antimicrobial resistance. PMID- 25145496 TI - Drosophila adult olfactory shock learning. AB - Drosophila have been used in classical conditioning experiments for over 40 years, thus greatly facilitating our understanding of memory, including the elucidation of the molecular mechanisms involved in cognitive diseases. Learning and memory can be assayed in larvae to study the effect of neurodevelopmental genes and in flies to measure the contribution of adult plasticity genes. Furthermore, the short lifespan of Drosophila facilitates the analysis of genes mediating age-related memory impairment. The availability of many inducible promoters that subdivide the Drosophila nervous system makes it possible to determine when and where a gene of interest is required for normal memory as well as relay of different aspects of the reinforcement signal. Studying memory in adult Drosophila allows for a detailed analysis of the behavior and circuitry involved and a measurement of long-term memory. The length of the adult stage accommodates longer-term genetic, behavioral, dietary and pharmacological manipulations of memory, in addition to determining the effect of aging and neurodegenerative disease on memory. Classical conditioning is induced by the simultaneous presentation of a neutral odor cue (conditioned stimulus, CS(+)) and a reinforcement stimulus, e.g., an electric shock or sucrose, (unconditioned stimulus, US), that become associated with one another by the animal. A second conditioned stimulus (CS(-)) is subsequently presented without the US. During the testing phase, Drosophila are simultaneously presented with CS+ and CS- odors. After the Drosophila are provided time to choose between the odors, the distribution of the animals is recorded. This procedure allows associative aversive or appetitive conditioning to be reliably measured without a bias introduced by the innate preference for either of the conditioned stimuli. Various control experiments are also performed to test whether all genotypes respond normally to odor and reinforcement alone. PMID- 25145497 TI - Early changes of muscle membrane properties in porcine faecal peritonitis. AB - INTRODUCTION: Sepsis-induced myopathy and critical illness myopathy (CIM) are possible causes of muscle weakness in intensive care patients. They have been attributed to muscle membrane dysfunction. The aim of this study was to investigate membrane properties in the early stage of experimental sepsis by evaluating muscle excitability. METHODS: In total, 20 anesthetized and mechanically ventilated pigs were randomized to either faecal peritonitis (n = 10) or to non-septic controls (n = 10). Resuscitation with fluids and vasoactive drugs was started 3 hours after peritonitis induction. Muscle membrane properties were investigated by measuring muscle velocity recovery cycles before induction of peritonitis as well as 6, 18 and 27 hours thereafter. Muscle relative refractory period (MRRP) and early supernormality (ESN) were assessed. RESULTS: Peritonitis lasting 27 hours was associated with an increase of MRRP by 28% from 2.38 +/- 0.18 ms (mean +/- SD) to 3.47 +/- 1.79 ms (P <0.01) and a decrease of ESN by 31% from 9.64 +/- 2.82% to 6.50 +/- 2.64% (P <0.01). ESN reduction was already apparent 6 hours after induction of peritonitis. Values in controls did not show any significant alterations. CONCLUSIONS: Muscle membrane abnormalities consistent with membrane depolarization and/or sodium channel inactivation occurred within 6 hours of peritonitis induction. This indicates that changes that have been described in established sepsis-induced myopathy and/or CIM start early in the course of sepsis. Muscle excitability testing facilitates evaluation of the time course of these changes. PMID- 25145498 TI - Trends in malaria admissions at the Mbakong Health Centre of the North West Region of Cameroon: a retrospective study. AB - BACKGROUND: Malaria is the leading cause of death worldwide. It is urgent to assess the impact of interventions and scaled-up control efforts. Despite reported reduction in malaria prevalence in Africa, the trends in Cameroon are not yet fully understood. The aim of this study was to investigate the trends in malaria admissions among febrile patients seeking treatment over a seven-year period (2006-2012) in an endemic area in Cameroon, hypothesizing a declining trend. This period followed changes in malaria treatment policy. The objectives were to identify possible trends in malaria admissions and to evaluate the impact of changes to treatment guidelines on the prevalence. METHODS: Data was collected through consultation and perusal of laboratory and prescription registers of the Mbakong Health Centre. Data analysis was conducted using SPSS and SAS Statistics. RESULTS: Analysis revealed that 4,230 febrile patients were received from 2006 2012. Of these febrile cases, 29.30% were confirmed positive. Between 2006 and 2012 confirmed malaria positive cases of those tested fluctuated, dropping from 53.21% in 2006 to 17.20% in 2008; then rising to 35.00% in 2011 and, finally, dropping to 18.2% of those tested in 2012. The prevalence in females and males across all age groups were similar: a slightly higher risk of males to have malaria (OR = 1.08, 95% CI 0.94-1.25) were not practically significant. Of those tested, the 5 to < 15 years and the 1 to < 5 years age groups were the hardest hit by malaria in the area. A practically visible and significant association was observed between the age and gender with regards to the number of malaria positive results (Pearson *2 = 153.675, p < 0.00001, Cramer's V = 0.352). Malaria prevalence exhibited a fluctuating yet declining trend, as observed over the 28 quarters between January, 2006 and December, 2012. CONCLUSIONS: The changes to the treatment guidelines appear to result in a declining trend as was observed between 2006 and 2008. However, malaria admissions fluctuated between 2008 and 2012. There is, therefore, a need to step up control efforts of especially the vulnerable groups, such as the very young. PMID- 25145499 TI - Polymerization of tellurophene derivatives by microwave-assisted palladium catalyzed ipso-arylative polymerization. AB - We report the synthesis of a tellurophene-containing low-bandgap polymer, PDPPTe2T, by microwave-assisted palladium-catalyzed ipso-arylative polymerization of 2,5-bis[(alpha-hydroxy-alpha,alpha-diphenyl)methyl]tellurophene with a diketopyrrolopyrrole (DPP) monomer. Compared with the corresponding thiophene analog, PDPPTe2T absorbs light of longer wavelengths and has a smaller bandgap. Bulk heterojunction solar cells prepared from PDPPTe2T and PC71 BM show PCE values of up to 4.4%. External quantum efficiency measurements show that PDPPTe2T produces photocurrent at wavelengths up to 1 um. DFT calculations suggest that the atomic substitution from sulfur to tellurium increases electronic coupling to decrease the length of the carbon-carbon bonds between the tellurophene and thiophene rings, which results in the red-shift in absorption upon substitution of tellurium for sulfur. PMID- 25145501 TI - Survival paradox between stage IIB/C (T4N0) and stage IIIA (T1-2N1) colon cancer. AB - BACKGROUND: The survival paradox between stage IIB/C (T4N0) and stage IIIA (T1 2N1) colon cancer remains in the 7th edition of the American Joint Committee on Cancer staging system. This multicenter study aimed to compare the oncologic outcomes of T4N0 and T1-2N1 colon cancers and to investigate the presumptive prognostic factors that might influence the survival paradox. METHODS: Patients who underwent curative surgery for pT4N0 (n = 224) and pT1-2N1 (n = 135) primary colon cancer between January 1999 and December 2010 at five tertiary referral cancer centers were included for analysis. The clinicopathologic, treatment related factors, and oncologic outcomes in terms of the 5-year overall survival (5-OS) and 5-year disease-free survival (5-DFS) were compared. RESULTS: The T4N0 group had significantly worse 5-OS and 5-DFS rates than the T1-2N1 group (5-OS: 84.0 vs. 92.3 %, p = 0.012; 5-DFS: 73.6 vs. 88.0 %, p = 0.001). T4N0 cancers more frequently showed elevated preoperative carcinoembryonic antigen, lower grade of differentiation, larger tumor size, and higher proportions of perineural invasion, microsatellite instability, obstruction, and perforation than T1-2N1 cancers. Peritoneal seeding and liver metastasis were the predominant recurrence pattern in the T4N0 and T1-2N1 groups, respectively (p = 0.042). The T4N0 group showed inferior survival to the T1-2N1 group in postoperative adjuvant chemotherapy (5-OS: 87.1 vs. 93.2 %, p = 0.045; 5-DFS: 76.1 vs. 89.0 %, p = 0.001). CONCLUSIONS: T4N0 colon cancer had significantly worse oncologic outcomes than T1-2N1 cancer regardless of adjuvant chemotherapy. The survival paradox may result from the biologic aggressiveness of T4N0 colon carcinomas. PMID- 25145500 TI - A multicenter phase I dose escalation trial to evaluate safety and tolerability of intra-arterial temozolomide for patients with advanced extremity melanoma using normothermic isolated limb infusion. AB - BACKGROUND: L-phenylalanine mustard (LPAM) has been the standard for use in regional chemotherapy (RC) for unresectable in-transit melanoma. Preclinical data demonstrated that regional temozolomide (TMZ) may be more effective. METHODS: Patients with AJCC Stage IIIB or IIIC extremity melanoma who failed previous LPAM based RC were treated with TMZ via isolated limb infusion (ILI) according to a modified accelerated titration design. Drug pharmacokinetic (PK) analysis, tumor gene expression, methylation status of the O6-methylguanine methyltransferase (MGMT) promoter, and MGMT expression were evaluated. Primary objectives were to (1) determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of TMZ via ILI and (2) explore biomarker correlates of response. RESULTS: 28 patients completed treatment over 2.5 years at 3 institutions. 19 patients were treated at the MTD defined as 3,200 mg/m(2) [multiplied by 0.09 (arm), 0.18 (leg)]. Two of five patients had DLTs at the 3,600 mg/m(2) level while only grade 1 (n = 15) and grade 2 (n = 4) clinical toxicities occurred at the MTD. At 3 month post-ILI, 10.5 % (2/19) had CR, 5.3 % (1/19) had PR, 15.8 % (3/19) had SD, and 68.4 % (13/19) had PD. Neither PK parameters of TMZ nor MGMT levels were associated with response or toxicity. CONCLUSION: In this first ever use of intra arterial TMZ in ILI for melanoma, the MTD was determined. While we could not define a marker for TMZ response, the minimal toxicity of TMZ ILI may allow for repeated treatments to increase the response rate as well as clarify the role of MGMT expression. PMID- 25145502 TI - Genome-wide association study of survival in early-stage non-small cell lung cancer. AB - BACKGROUND: Lung cancer, especially non-small cell lung cancer (NSCLC), is the leading cause of cancer-related deaths all over the world. Studies have indicated that molecular biomarkers, including genetic variants, may provide additional values for the targeted treatments and clinical outcomes of NSCLC patients. To better understand the effects of molecular biomarkers on the treatment of NSCLC, we conducted a genome-wide analysis to investigate the prognostic implications of genetic variants in early-stage NSCLC patients with surgery. METHODS: A genome wide scan of 906,703 single-nucleotide polymorphisms (SNPs) was conducted in a cohort with 365 early-stage NSCLC patients with surgery, followed by a fast-track replication in another independent cohort of 327 NSCLC patients from Nanjing, China. Cox models were used to screen and validate significant SNPs associated with the overall survival of early-stage NSCLC patients. RESULTS: We found that rs10023113 in calcium/calmodulin-dependent protein kinase II delta (CAMK2D) was consistently associated with survival of early-stage NSCLC in the GWAS scan and the replication cohort [GWAS scan: hazard ratio (HR) 2.84; 95 % confidence interval (CI) 1.90-4.23, P = 1.29 * 10(-6); replication cohort: HR 2.19, 95 % CI 1.15-4.21, P = 1.80 * 10(-2)]. When combining all the patients, the results showed that the variant allele of rs10023113 was significantly associated with poor prognosis of early-stage NSCLC with P value of 3.40 * 10(-7) (HR 2.30, 95 % CI 1.67-3.17). CONCLUSIONS: These findings suggest that CAMK2D rs10023113 may be a potentially prognostic marker for overall survival of early-stage NSCLC patients in Chinese population. PMID- 25145503 TI - Androgen receptor expression predicts decreased survival in early stage triple negative breast cancer. AB - BACKGROUND: A subset of triple-negative breast cancer (TNBC) has been reported to express androgen receptor (AR); however, the clinical significance of AR expression in TNBC is unclear. METHODS: We examined immunohistochemical expression of AR in a large cohort of TNBC cases and correlated its expression with clinicopathologic features and clinical outcome. RESULTS: AR expression was found in 17.7% (87/492) of TNBCs. Positive expression of AR showed significant correlation with older age (p < 0.001), apocrine histology (p = 0.001), and lower histologic grade (p < 0.001). AR was a poor prognostic marker for overall survival (OS) in univariate (p = 0.026) and multivariate (p = 0.008) analyses. In the lymph node-negative (n = 316) subgroup, AR expression was a significant predictor of worse OS and disease-free survival (DFS) in both univariate (p = 0.028 and 0.011) and multivariate (p = 0.024 and 0.01, respectively) analyses. AR expression also was a prognostic factor in pT1 subgroup (OS, p = 0.007; DFS, p = 0.01); however, its prognostic value was not observed in TNBC patients with lymph node metastasis or tumor size larger than pT1. CONCLUSIONS: AR-expressing TNBCs represent a distinct breast cancer subgroup with adverse clinical outcome and AR blockade could be a potential endocrine therapy for these TNBC patients. Evaluation of AR status may provide additional information on prognosis and treatment in patients with TNBC. PMID- 25145505 TI - Clinical significance of thrombocytosis before preoperative chemoradiotherapy in rectal cancer: predicting pathologic tumor response and oncologic outcome. AB - BACKGROUND: Thrombocytosis is considered an adverse prognostic factor in various malignancies. However, the clinical significance of thrombocytosis in rectal cancer patients is unknown. We investigated the predictive value of thrombocytosis for pathologic tumor response to preoperative chemoradiotherapy (CRT) and oncologic outcomes in patients with rectal cancer. METHODS: A total of 314 patients who underwent preoperative CRT and subsequent rectal resection for rectal cancer were retrospectively evaluated at two tertiary institutions. Univariate and multivariate analyses of the clinical parameters were performed to identify markers predictive of a pathologic complete response (pCR). The Kaplan Meier method was used to estimate 3-year disease-free and overall survival rates. RESULTS: Sixty-nine patients (22 %) had thrombocytosis before CRT, which significantly correlated with a large tumor size and advanced tumor depth. Thirty nine patients (12.4 %) achieved a pCR. In the multivariate analyses, a platelet count of <370,000/MUl (odds ratio 5.483; 95 % confidence interval, 1.271-23.653; P = 0.023) and a carcinoembryonic antigen (CEA) level of <5 ng/dl (odds ratio, 3.084; 95 % confidence interval, 1.291-7.368; P = 0.011) were identified as independent predictive factors for a pCR. Patients with pretreatment thrombocytosis had lower 3-year disease-free (P = 0.037) and overall survival (P = 0.001) rates than patients with normal pretreatment platelet counts. CONCLUSIONS: Thrombocytosis is a negative predictive factor for a pCR and has an adverse impact on survival in rectal cancer. The predictive value of this easily available clinical factor should not be underestimated, and better therapeutic strategies for these tumors are required. PMID- 25145504 TI - Predictors of progression in high-grade appendiceal or colorectal peritoneal carcinomatosis after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: Long-term survival of patients with appendiceal or colorectal peritoneal carcinomatosis (PC) may be achieved by combining cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Unfortunately, such favorable outcomes are realized in a minority of patients. Given the morbidity of the CRS/HIPEC and the uncertain role of postresection systemic therapy, it is important that prognostic factors in high-grade PC be clearly defined. METHODS: This single center, retrospective, cohort study examined the outcomes of CRS/HIPEC performed on patients with high-grade PC secondary to appendiceal or colorectal adenocarcinoma between 2007 and 2013. Cox regression analysis was utilized to evaluate the association between potential prognostic factors [age, sex, primary site, lymph node (LN) status, peritoneal cancer index (PCI) score, completeness of cytoreduction score (CC score), number of visceral resections, and systemic chemotherapy] and progression-free survival (PFS). RESULTS: A total of 70 patients with high-grade appendiceal or colorectal PC underwent CRS/HIPEC during the study period; 82.9 % underwent complete (CC-0) cytoreduction with a median PFS of 9.7 months. Positive LNs at the time of CRS/HIPEC were predictors of worse PFS on univariate and multivariate analysis. No association was demonstrated between pre- or post-HIPEC systemic chemotherapy and PFS. CONCLUSIONS: High-grade PC secondary to appendiceal or colorectal adenocarcinoma can be managed with CRS/HIPEC. The number of LN metastases at the time of CRS/HIPEC is the strongest predictor of progression and must be considered when determining patient eligibility for this aggressive treatment. PMID- 25145506 TI - Seizures and epilepsy in hypoglycaemia caused by inborn errors of metabolism. AB - AIM: The aim of the study was to characterize seizures and epilepsy related to hypoglycaemia. METHOD: We analyzed the files of 170 consecutive patients referred for hypoglycaemia (onset 1h to 4y) caused by inborn errors of metabolism (glycogen storage disease type I, fatty acid beta-oxidation disorders, and hyperinsulinism). RESULTS: Ninety patients (42 males and 48 females; 38 neonates and 52 infants/children) had brief hypoglycaemic seizures (68%) or status epilepticus (32%). Status epilepticus occurred earlier (mean 1.4d) than brief neonatal seizures (4.3d, p=0.02). Recurrent status epilepticus followed initial status epilepticus and was often triggered by fever. Epilepsy developed in 21 patients. In 18 patients, epilepsy followed hypoglycaemic status epilepticus and began with shorter delay when associated with grey matter lesions (1.9mo, standard error of the mean [SEM] 1mo) than with white matter damage (3.3y [SEM 1y], p=0.003). Three patients with hyperinsulinism developed idiopathic epilepsy following brief neonatal seizures. INTERPRETATION: Brief neonatal hyperinsulinaemic hypoglycaemic seizures have characteristics of idiopathic neonatal seizures. Neonatal status epilepticus should be prevented by the systematic measurement of glucose blood level. Recurrent seizures never consist of status epilepticus when following brief initial seizures. Epilepsy is symptomatic of brain damage with shorter delay in the case of grey rather than white matter lesions, except in a few idiopathic cases in which epilepsy and hyperinsulinism may share a common genetic background. PMID- 25145508 TI - Investigating Leggett-Garg inequality for a two level system under decoherence in a non-Markovian dephasing environment. AB - Leggett-Garg inequalities (LGI) test the correlations of a single system measured at different times. Violation of LGI implies either the absence of a realistic description of the system or the impossibility of measuring the system without disturbing it. We investigate the violation of the Leggett-Garg inequality for a two level system under decoherence in a non-Markovian dephasing environment. We discuss the non-Markovian dynamics of the violation of LGI at zero temperature and also at finite temperature for different structured environments. An enhanced quantum coherence is shown through the violation of Leggett-Garg inequality in the strong non-Markovian regime of the environment. PMID- 25145507 TI - Meta-analysis of adjunctive non-NK1 receptor antagonist medications for the control of acute and delayed chemotherapy-induced nausea and vomiting. AB - PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a distressing chemotherapy-induced symptom that may adversely impact the quality of life of cancer patients. METHODS: We conducted a systematic search of the Pubmed, Bireme, and Cochrane databases for randomized clinical trials that were published in English and that evaluated the combination of adjunctive non-neurokinin 1 (NK1) antagonist drugs (i.e., neuroleptics, anticonvulsants, benzodiazepines, and cannabinoids) with 5-hydroxytryptamine 3 (5-HT3) antagonists for adult cancer patients who were scheduled to receive moderate or highly emetogenic chemotherapy. We employed the Review Manager (RevMan) Computer program Version 5.2 for statistical calculations. RESULTS: We included 13 studies with a total of 1,669 patients. We observed a higher complete protection for acute CINV with adjunctive medications (risk ratio (RR) = 0.55; 95% confidence interval (CI) 0.30 1.01; p = 0.05; I2 = 47%), which was not the case for the delayed period (RR = 0.89; 95% CI 0.73-1.10, p = 0.29, I2 = 15%). We also observed that these adjunctive medications significantly increased the complete control of nausea (RR = 0.72; 95% CI 0.55-0.95; p = 0.02, I2 = 83%) and vomiting (RR = 0.61; 95% CI 0.50-0.75; p < 0.00001; I2 = 60%). There was no subgroup analysis evidence of the superiority of any single group of adjunctive medications. CONCLUSIONS: We conclude that adjunctive non-NK1 antagonist medications may be useful for CINV control. Prospective randomized studies incorporating these low-cost medications into new regimens combining 5-HT3 and NK1 antagonists may be warranted. PMID- 25145509 TI - Familial hypercholesterolemia--screening to facilitate early prevention. PMID- 25145510 TI - Familial hypercholesterolemia: developments in diagnosis and treatment. AB - BACKGROUND: Familial hypercholesterolemia (FH) is a congenital disorder of lipid metabolism characterized by a marked elevation of the plasma concentration of LDL (low-density lipoprotein) cholesterol beginning in childhood and by the early onset of coronary heart disease. It is among the commonest genetic disorders, with an estimated prevalence in Germany of at least 1 per 500 persons. METHOD: Review of pertinent literature retrieved by a selective search. RESULTS: FH is underdiagnosed and undertreated in Germany. It is clinically diagnosed on the basis of an elevated LDL cholesterol concentration (>190 mg/dL [4.9 mmol/L]), a family history of hypercholesterolemia, and early coronary heart disease, or the demonstration of xanthomas. The gold standard of diagnosis is the identification of the underlying genetic defect, which is possible in 80% of cases and enables the identification of affected relatives of the index patient. The recommended goals of treatment, based on the results of observational studies, are to lower the LDL cholesterol concentration by at least 50% or to less than 100 mg/dL (2.6 mmol/L) (for children: <135 mg/dL [3.5 mmol/L]). The target value is lower for patients with clinically overt atherosclerosis (<70 mg/dL [1.8 mmol/L]). Statins, combined with a health-promoting lifestyle, are the treatment of choice. Lipoprotein apheresis is used in very severe cases; its therapeutic effects on clinical endpoints and its side effect profile have not yet been documented in randomized controlled trials. CONCLUSION: Familial hypercholesterolemia is a common disease that can be diagnosed simply and reliably on clinical grounds and by molecular genetic testing. Timely diagnosis and appropriate treatment can lower the risk of atherosclerosis in heterozygous patients to that of the general population. PMID- 25145511 TI - An inter-state comparison of cardiovascular risk factors in Germany: towards an explanation of high ischemic heart disease mortality in Saxony-Anhalt. AB - BACKGROUND: For years, the state of Saxony-Anhalt has had one of the highest mortality rates from ischemic heart disease among all federal states in Germany. In this article, we provide an overview of the prevalence of known risk factors for ischemic heart disease across the German states and discuss possible artefacts in mortality statistics. METHODS: On the basis of data from a selective literature review and from official statistics, we compare, if available, age standardized prevalences of diabetes, obesity, increased waist circumference, metabolic syndrome, and cigarette smoking across the German states. We also present statistics on completion of schooling, dropping out of school, and unemployment. RESULTS: Saxony-Anhalt was in first or second place among German states for all of the risk factors considered. It was also among the leaders in the percentage of school dropouts (14.1%), and, in 2011, it had the lowest percentage of persons educated to matriculation level (19.2%). The unemployment rate in Saxony-Anhalt was 11.5% in 2012, one of the highest rates in Germany. Even after unclear and unknown causes of death are taken into account, the high mortality from ischemic heart disease in Saxony-Anhalt (153.3 per 100 000 person years cannot be attributed completely to an artefact. CONCLUSION: The high prevalence of risk factors and the unfavorable profile of social factors are consistent with the observed high mortality from ischemic heart disease in Saxony Anhalt. There is an urgent need for lasting prevention strategies on all levels societal, behavioral, and clinical. PMID- 25145512 TI - Breast cancer morbidity: questionnaire survey of patients on the long term effects of disease and adjuvant therapy. AB - BACKGROUND: Many women have symptoms of various kinds after being treated for breast cancer. It is unclear how frequently these different side effects of treatment arise. METHOD: All women who underwent surgery for breast cancer and subsequently received adjuvant systemic treatment in a single certified breast cancer center from 2006 to 2010 were asked to fill out a standardized questionnaire. Medical data were retrieved from their charts and statistically analyzed together with the questionnaire responses. The questionnaire was also given to an age-adjusted control group. RESULTS: 734 questionnaires were filled out and returned (response rate, 70%). The mean interval from the diagnosis of breast cancer to the time of response to the questionnaire was 38 months. The median age at time of response to the questionnaire was 65 years (range, 30 to 91 years). The distribution of UICC stages at the time of initial diagnosis was as follows: I 46%, II 42%, III 12%. 78% of the patients underwent breat conserving surgery, 85% had radio - therapy, 85% had antihormonal treatment, and 49% had chemotherapy. 91% were satisfied or very satisfied with the outcome of surgery. 34% reported operation site pain; 35% reported limitations of shoulder or arm function. Younger patients suffered from emotional sequelae more than older ones did. 25% reported a change in their relationship with their spouse. Before being diagnosed with breast cancer, 9% had consulted a psychiatrist or psychotherapist; after the diagnosis, 19% did. 14% had taken psychoactive medication before the diagnosis, and 26% did afterward. CONCLUSION: Treatment for breast cancer has negative physical, emotional, and social effects on many patients. They suffer these effects to varying degrees depending on age, type of surgery, and systemic treatment. PMID- 25145513 TI - Additions warranted. PMID- 25145514 TI - In reply. PMID- 25145515 TI - Vision defect owing to metastasis. PMID- 25145516 TI - In reply. PMID- 25145517 TI - HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy. AB - BACKGROUND: Familial forms of primary sinus bradycardia have sometimes been attributed to mutations in HCN4, SCN5A, and ANK2. In these studies, no structural cardiac alterations were reported in mutation carriers. However, a cluster of reports in the literature describe patients presenting with sinus bradycardia in association with left ventricular noncompaction cardiomyopathy (LVNC), pointing to a shared genetic cause. OBJECTIVES: This study sought to identify the genetic defect underlying the combined clinical presentation of bradycardia and LVNC, hypothesizing that these 2 clinical abnormalities have a common genetic cause. METHODS: Exome sequencing was carried out in 2 cousins from the index family that were affected by the combined bradycardia-LVNC phenotype; shared variants thus identified were subsequently overlaid with the chromosomal regions shared among 5 affected family members that were identified using single nucleotide polymorphism array analysis. RESULTS: The combined linkage analysis and exome sequencing in the index family identified 11 novel variants shared among the 2 affected cousins. One of these, p.Gly482Arg in HCN4, segregated with the combined bradycardia and LVNC phenotype in the entire family. Subsequent screening of HCN4 in 3 additional families with the same clinical combination of bradycardia and LVNC identified HCN4 mutations in each. In electrophysiological studies, all found HCN4 mutations showed a more negative voltage dependence of activation, consistent with the observed bradycardia. CONCLUSIONS: Although mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence to our knowledge that mutations in this ion channel gene also may be associated with structural abnormalities of the myocardium. PMID- 25145518 TI - The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel. AB - BACKGROUND: Inherited arrhythmias were originally considered isolated electrical defects. There is growing evidence that ion channel dysfunction also contributes to myocardial disorders, but genetic overlap has not been reported for sinus node dysfunction (SND) and noncompaction cardiomyopathy (NCCM). OBJECTIVES: The study sought to investigate a familial electromechanical disorder characterized by SND and NCCM, and to identify the underlying genetic basis. METHODS: The index family and a cohort of unrelated probands with sinus bradycardia were examined by electrocardiography, Holter recording, exercise stress test, echocardiography, and/or cardiac magnetic resonance imaging. Targeted next-generation and direct sequencing were used for candidate gene analysis and mutation scanning. Ion channels were expressed in HEK293 cells and studied using patch-clamp recordings. RESULTS: SND and biventricular NCCM were diagnosed in multiple members of a German family. Segregation analysis suggested autosomal-dominant inheritance of the combined phenotype. When looking for potentially disease-causing gene variants with cosegregation, a novel hyperpolarization-activated cyclic nucleotide channel 4 (HCN4)-G482R mutation and a common cysteine and glycine-rich protein 3 (CSRP3)-W4R variant were identified. HCN4-G482R is located in the highly conserved channel pore domain. Mutant subunits were nonfunctional and exerted dominant-negative effects on wild-type current. CSRP3-W4R has previously been linked to dilated and hypertrophic cardiomyopathy, but was also found in healthy subjects. Moreover, different truncation (695X) and missense (P883R) HCN4 mutations segregated with a similar combined phenotype in an additional, unrelated family and a single unrelated proband respectively, which both lacked CSRP3-W4R. CONCLUSIONS: The symptom complex of SND and NCCM is associated with heritable HCN4 defects. The NCCM phenotype may be aggravated by a common CSRP3 variant in one of the families. PMID- 25145519 TI - Ion channel dysfunction associated with arrhythmia, ventricular noncompaction, and mitral valve prolapse: a new overlapping phenotype. PMID- 25145520 TI - Accuracy of coronary CT angiography using a submillisievert fraction of radiation exposure: comparison with invasive coronary angiography. AB - BACKGROUND: Coronary computed tomography angiography (CTA) is increasingly being used for evaluation of coronary artery disease (CAD). As a result of the widely reported potential of carcinogenic risk from x-ray based examinations, many strategies have been developed for dose reduction with CTA. OBJECTIVES: The purpose of this study was to assess the diagnostic accuracy of CTA acquired with a submillisievert fraction of effective radiation dose reconstructed with a model based iterative reconstruction (MBIR) using invasive coronary angiography (ICA) as a standard of reference. METHODS: In 36 patients (body mass index range 17 to 39 kg/m(2)) undergoing ICA for CAD evaluation, a CTA was acquired using very low tube voltage (80 to 100 kV) and current (150 to 210 mA) and was reconstructed with MBIR. CAD (defined as >=50% luminal narrowing) was assessed on CTA and on ICA. RESULTS: CTA resulted in an estimated radiation dose exposure of 0.29 +/- 0.12 mSv (range 0.16 to 0.53 mSv), yielding 96.9% (436 of 450) interpretable segments. On an intention-to-diagnose basis, no segment was excluded, and vessels with at least 1 nonevaluable segment and no further finding were classified as false positive. This resulted in a sensitivity, specificity, positive, and negative predictive value and accuracy of 100%, 74%, 77%, 100%, and 86% per patient and 85%, 86%, 56%, 96%, and 85% per vessel, respectively. CONCLUSIONS: The use of MBIR reconstruction allows accurate noninvasive diagnosis of CAD with CTA at a submillisievert fraction of effective radiation dose comparable with a chest x-ray in 2 views. PMID- 25145521 TI - Minimizing CT angiography radiation burden while maintaining accuracy through noise reduction: is lower always better? PMID- 25145523 TI - Optimal blood pressure targets in older adults: how low is low enough? PMID- 25145522 TI - 2014 Eighth Joint National Committee panel recommendation for blood pressure targets revisited: results from the INVEST study. AB - BACKGROUND: The 2014 Eighth Joint National Committee panel recommendations for management of high blood pressure (BP) recommend a systolic BP threshold for initiation of drug therapy and a therapeutic target of <150 mm Hg in those >=60 years of age, a departure from prior recommendations of <140 mm Hg. However, it is not known whether this is an optimal choice, especially for the large population with coronary artery disease (CAD). OBJECTIVES: This study sought to evaluate optimal BP in patients >=60 years of age. METHODS: Patients 60 years of age or older with CAD and baseline systolic BP >150 mm Hg randomized to a treatment strategy on the basis of either atenolol/hydrochlorothiazide or verapamil-SR (sustained release)/trandolapril in INVEST (INternational VErapamil SR Trandolapril STudy) were categorized into 3 groups on the basis of achieved on treatment systolic BP: group 1, <140 mm Hg; group 2, 140 to <150 mm Hg; and group 3, >=150 mm Hg. Primary outcome was first occurrence of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke. Secondary outcomes were all-cause mortality, cardiovascular mortality, total MI, nonfatal MI, total stroke, nonfatal stroke, heart failure, or revascularization, tabulated separately. Outcomes for each group were compared in unadjusted and multiple propensity score adjusted models. RESULTS: Among 8,354 patients included in this analysis with an accumulated 22,308 patient-years of follow-up, 4,787 (57%) achieved systolic BP of <140 mm Hg (group 1), 1,747 (21%) achieved systolic BP of 140 to <150 mm Hg (group 2), and 1,820 (22%) achieved systolic BP of >=150 mm Hg (group 3). In unadjusted models, group 1 had the lowest rates of the primary outcome (9.36% vs. 12.71% vs. 21.32%; p < 0.0001), all-cause mortality (7.92% vs. 10.07% vs. 16.81%; p < 0.0001), cardiovascular mortality (3.26% vs. 4.58% vs. 7.80%; p < 0.0001), MI (1.07% vs. 1.03% vs. 2.91%; p < 0.0001), total stroke (1.19% vs. 2.63% vs. 3.85%; p <0.0001), and nonfatal stroke (0.86% vs 1.89% vs 2.86%; p<0.0001) compared with groups 2 and 3, respectively. In multiple propensity score-adjusted models, compared with the reference group of <140 mm Hg (group 1), the risk of cardiovascular mortality (adjusted hazard ratio [HR]: 1.34; 95% confidence interval [CI]: 1.01 to 1.77; p = 0.04), total stroke (adjusted HR: 1.89; 95% CI: 1.26 to 2.82; p = 0.002) and nonfatal stroke (adjusted HR: 1.70; 95% CI: 1.06 to 2.72; p = 0.03) was increased in the group with BP of 140 to <150 mm Hg, whereas the risk of primary outcome, all-cause mortality, cardiovascular mortality, total MI, nonfatal MI, total stroke, and nonfatal stroke was increased in the group with BP >=150 mm Hg. CONCLUSIONS: In hypertensive patients with CAD who are >=60 years of age, achieving a BP target of 140 to <150 mm Hg as recommended by the JNC-8 panel was associated with less benefit than the previously recommended target of <140 mm Hg. PMID- 25145525 TI - Disparities in heart failure care: now is the time to focus on health care delivery. PMID- 25145524 TI - Clinical effectiveness of CRT and ICD therapy in heart failure patients by racial/ethnic classification: insights from the IMPROVE HF registry. AB - BACKGROUND: Clinical trials have demonstrated benefit for cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator (ICD) therapies in patients with heart failure with reduced ejection fraction (HFrEF); yet, questions have been raised with regard to the benefit of device therapy for minorities. OBJECTIVES: The purpose of this study was to determine the clinical effectiveness of CRT and ICD therapies as a function of race/ethnicity in outpatients with HFrEF (ejection fraction <=35%). METHODS: Data from IMPROVE HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) were analyzed by device status and race/ethnicity among guideline-eligible patients for mortality at 24 months. Multivariate Generalized Estimating Equations analyses were conducted, adjusting for patient and practice characteristics. RESULTS: The ICD/cardiac resynchronization defibrillator (CRT-D) eligible cohort (n = 7,748) included 3,391 (44%) non-Hispanic white, 719 (9%) non Hispanic black, and 3,638 (47%) other racial/ethnic minorities or race-not documented patients. The cardiac resynchronization pacemaker (CRT-P)/CRT-D eligible cohort (n = 1,188) included 596 (50%) non-Hispanic white, 99 (8%) non Hispanic black, and 493 (41%) other/not-documented patients. There was clinical benefit associated with ICD/CRT-D therapy (adjusted odds ratio: 0.64, 95% confidence interval: 0.52 to 0.79, p = 0.0002 for 24-month mortality), which was of similar proportion in white, black, and other minority/not-documented patients (device-race/ethnicity interaction p = 0.7861). For CRT-P/CRT-D therapy, there were also associated mortality benefits (adjusted odds ratio: 0.55, 95% confidence interval: 0.33 to 0.91, p = 0.0222), and the device-race/ethnicity interaction was not significant (p = 0.5413). CONCLUSIONS: The use of guideline directed CRT and ICD therapy was associated with reduced 24-month mortality without significant interaction by racial/ethnic group. Device therapies should be offered to eligible heart failure patients, without modification based on race/ethnicity. PMID- 25145526 TI - Blood transfusion during acute myocardial infarction: association with mortality and variability across hospitals. AB - BACKGROUND: Blood transfusion is controversial for anemic patients with acute myocardial infarction (AMI), with some previous studies reporting increased risk of transfusion-associated mortality. OBJECTIVES: The goal of this study was to examine variability in blood transfusions across hospitals and the relationship between blood transfusion and in-hospital mortality in a large, contemporary cohort of consecutive AMI patients. METHODS: Among 34,937 AMI hospitalizations from 57 centers, patients receiving at least 1 packed red blood cell transfusion were compared with those who were not transfused. Using 45 disease severity, comorbidity, laboratory, and in-hospital treatment variables, we propensity matched patients who did and did not receive a packed red blood cell transfusion. A conditional logistic regression model was used to identify the association between transfusion and in-hospital mortality. RESULTS: A total of 1,778 patients (5.1%) had at least 1 transfusion. In unadjusted analyses, transfusion was associated with higher in-hospital mortality (odds ratio: 2.05 [95% confidence interval: 1.76 to 2.40]). The vast majority of patients (91.1%) with and without transfusion had nonoverlapping propensity scores, reflecting incomparable clinical profiles. Thus, they were excluded from the propensity-matched analyses. After propensity matching those with overlapping scores, blood transfusion was associated with a reduced risk of in-hospital death (odds ratio: 0.73 [95% confidence interval: 0.58 to 0.92]). CONCLUSIONS: The majority of patients undergoing blood transfusion in clinical practice cannot be matched with nontransfused patients due to their markedly different clinical profiles. Among comparable patients, blood transfusion was associated with a lower risk of in hospital mortality. These findings suggest that previous observational reports of increased mortality with transfusion may have been influenced by selection bias, and they highlight the need for randomized trials to establish the role of transfusion during AMI. PMID- 25145527 TI - Blood transfusion in myocardial infarction: opening old wounds for comparative effectiveness research. PMID- 25145528 TI - Atrial fibrillation ablation: translating basic mechanistic insights to the patient. AB - Atrial fibrillation (AF) ablation is widely performed and is progressively supplanting drug therapy. Catheter-based AF ablation modalities have evolved progressively in parallel to our understanding of underlying mechanisms. Initial attempts to mimic the surgical maze procedure, which were based on the multiple wavelet model, failed because of adverse outcomes and insufficient effectiveness. A major advance was the targeting of pulmonary veins, which is highly effective for paroxysmal AF. Active research on the underlying mechanisms continues. The main challenge is reconnection, but procedures to minimize this are being developed. Ablation procedures for persistent AF are presently limited by suboptimal success rates and long-term disease progression that causes recurrences. Basic research into the underlying mechanisms has led to promising driver mechanism-directed clinical approaches along with pathways toward the prevention of atrial remodeling. Here, we review the role of basic research in the development of presently used AF-ablation procedures and look toward future contributions in improving outcomes. PMID- 25145530 TI - The power of resilience. PMID- 25145531 TI - Inspiring possibility. PMID- 25145529 TI - A roadmap to investigate the genetic basis of bicuspid aortic valve and its complications: insights from the International BAVCon (Bicuspid Aortic Valve Consortium). AB - Bicuspid aortic valve (BAV) is the most common adult congenital heart defect and is found in 0.5% to 2.0% of the general population. The term "BAV" refers to a heterogeneous group of disorders characterized by diverse aortic valve malformations with associated aortopathy, congenital heart defects, and genetic syndromes. Even after decades of investigation, the genetic determinants of BAV and its complications remain largely undefined. Just as BAV phenotypes are highly variable, the genetic etiologies of BAV are equally diverse and vary from complex inheritance in families to sporadic cases without any evidence of inheritance. In this paper, the authors discuss current concepts in BAV genetics and propose a roadmap for unraveling unanswered questions about BAV through the integrated analysis of genetic and clinical data. PMID- 25145532 TI - Lack of negative interaction between use of beta-blockers and statins on cardiovascular outcomes among patients with or at risk for atherothrombosis. PMID- 25145533 TI - Knowing plasma concentrations improves management of the effects of dabigatran. PMID- 25145534 TI - Pro-inflammatory interleukin genotypes potentiate early and advanced atherosclerosis differently. PMID- 25145535 TI - MicroRNA-29a is a friend or foe for cardiac hypertrophy? PMID- 25145536 TI - Perinatal antibiotic-induced shifts in gut microbiota have differential effects on inflammatory lung diseases. AB - BACKGROUND: Resident gut microbiota are now recognized as potent modifiers of host immune responses in various scenarios. Recently, we demonstrated that perinatal exposure to vancomycin, but not streptomycin, profoundly alters gut microbiota and enhances susceptibility to a TH2 model of allergic asthma. OBJECTIVE: Here we sought to further clarify the etiology of these changes by determining whether perinatal antibiotic treatment has a similar effect on the TH1/TH17-mediated lung disease, hypersensitivity pneumonitis. METHODS: Hypersensitivity pneumonitis was induced in C57BL/6 wild-type or recombination activating gene 1-deficient mice treated perinatally with vancomycin or streptomycin by repeated intranasal administration of Saccharopolyspora rectivirgula antigen. Disease severity was assessed by measuring lung inflammation, pathology, cytokine responses, and serum antibodies. Microbial community analyses were performed on stool samples via 16S ribosomal RNA pyrosequencing and correlations between disease severity and specific bacterial taxa were identified. RESULTS: Surprisingly, in contrast to our findings in an allergic asthma model, we found that the severity of hypersensitivity pneumonitis was unaffected by vancomycin, but increased dramatically after streptomycin treatment. This likely reflects an effect on the adaptive, rather than innate, immune response because the effects of streptomycin were not observed during the early phases of disease and were abrogated in recombination-activating gene 1 deficient mice. Interestingly, Bacteroidetes dominated the intestinal microbiota of streptomycin-treated animals, while vancomycin promoted the expansion of the Firmicutes. CONCLUSIONS: Perinatal antibiotics exert highly selective effects on resident gut flora, which, in turn, lead to very specific alterations in susceptibility to TH2- or TH1/TH17-driven lung inflammatory disease. PMID- 25145537 TI - Naphtho[2,1-b:3,4-b']dithiophene-based bulk heterojunction solar cells: how molecular structure influences nanoscale morphology and photovoltaic properties. AB - Organic bulk heterojunction photovoltaic devices based on a series of three naphtho[2,1-b:3,4-b']dithiophene (NDT) derivatives blended with phenyl-C71 butyric acid methyl ester were studied. These three derivatives, which have NDT units with various thiophene-chain lengths, were employed as the donor polymers. The influence of their molecular structures on the correlation between their solar-cell performances and their degree of crystallization was assessed. The grazing-incidence angle X-ray diffraction and atomic force microscopy results showed that the three derivatives exhibit three distinct nanoscale morphologies. We correlated these morphologies with the device physics by determining the J-V characteristics and the hole and electron mobilities of the devices. On the basis of our results, we propose new rules for the design of future generations of NDT based polymers for use in bulk heterojunction solar cells. PMID- 25145538 TI - Vortioxetine: a review of its use in major depressive disorder. AB - Vortioxetine (Brintellix((r))) is a serotonin (5-HT) transporter inhibitor that also acts on several 5-HT receptors, such as the 5-HT3 and 5-HT1A receptors. It is approved in the US and the EU for the treatment of adult patients with major depressive disorder (MDD); this article reviews the pharmacological properties of oral vortioxetine and its clinical efficacy and tolerability in these patients. Vortioxetine is generally efficacious in patients with MDD in acute treatment trials (including elderly patients), in a relapse-prevention trial, and in open label extension trials. It is associated with improved cognitive function in patients with MDD; this does not occur solely via improvement in depressive symptom severity. It is well tolerated, but is associated with significantly increased sexual dysfunction at the highest dosage; however, vortioxetine was shown to improve previous-treatment-emergent sexual dysfunction in patients with well-treated MDD to a greater degree than escitalopram. Vortioxetine extends the available treatment options for patients with MDD, and further investigation into its comparative efficacy versus other antidepressants will allow for more accurate placement among these treatment options. PMID- 25145539 TI - Expediting SRM assay development for large-scale targeted proteomics experiments. AB - Because of its high sensitivity and specificity, selected reaction monitoring (SRM)-based targeted proteomics has become increasingly popular for biological and translational applications. Selection of optimal transitions and optimization of collision energy (CE) are important assay development steps for achieving sensitive detection and accurate quantification; however, these steps can be labor-intensive, especially for large-scale applications. Herein, we explored several options for accelerating SRM assay development evaluated in the context of a relatively large set of 215 synthetic peptide targets. We first showed that HCD fragmentation is very similar to that of CID in triple quadrupole (QQQ) instrumentation and that by selection of the top 6 y fragment ions from HCD spectra, >86% of the top transitions optimized from direct infusion with QQQ instrumentation are covered. We also demonstrated that the CE calculated by existing prediction tools was less accurate for 3+ precursors and that a significant increase in intensity for transitions could be obtained using a new CE prediction equation constructed from the present experimental data. Overall, our study illustrated the feasibility of expediting the development of larger numbers of high-sensitivity SRM assays through automation of transition selection and accurate prediction of optimal CE to improve both SRM throughput and measurement quality. PMID- 25145541 TI - Early and late response of Nematostella vectensis transcriptome to heavy metals. AB - Environmental contamination from heavy metals poses a global concern for the marine environment, as heavy metals are passed up the food chain and persist in the environment long after the pollution source is contained. Cnidarians play an important role in shaping marine ecosystems, but environmental pollution profoundly affects their vitality. Among the cnidarians, the sea anemone Nematostella vectensis is an advantageous model for addressing questions in molecular ecology and toxicology as it tolerates extreme environments and its genome has been published. Here, we employed a transcriptome-wide RNA-Seq approach to analyse N. vectensis molecular defence mechanisms against four heavy metals: Hg, Cu, Cd and Zn. Altogether, more than 4800 transcripts showed significant changes in gene expression. Hg had the greatest impact on up regulating transcripts, followed by Cu, Zn and Cd. We identified, for the first time in Cnidaria, co-up-regulation of immediate-early transcription factors such as Egr1, AP1 and NF-kappaB. Time-course analysis of these genes revealed their early expression as rapidly as one hour after exposure to heavy metals, suggesting that they may complement or substitute for the roles of the metal mediating Mtf1 transcription factor. We further characterized the regulation of a large array of stress-response gene families, including Hsp, ABC, CYP members and phytochelatin synthase, that may regulate synthesis of the metal-binding phytochelatins instead of the metallothioneins that are absent from Cnidaria genome. This study provides mechanistic insight into heavy metal toxicity in N. vectensis and sheds light on ancestral stress adaptations. PMID- 25145540 TI - Mesenchymal stem cells, not conditioned medium, contribute to kidney repair after ischemia-reperfusion injury. AB - INTRODUCTION: Studies have shown that stem cells exert their therapeutic effects on acute kidney injury (AKI) through paracrine/endocrine actions. If the protective effect is mediated in an endocrine manner, the injection of the factors that these cells secrete could be effective, but the effect of conditioned medium (CM) remains controversial. METHODS: In this study, we cultured mesenchymal stem cells (MSCs) and then transplanted them into an ischemia-reperfusion (I/R) injury model. CM was also injected into mice, and the histological changes, level of cell proliferation, loss of peritubular capillaries and anti-inflammatory and anti-apoptotic effects were examined at different time points. RESULTS: The results showed that MSC infusion improved renal function and histological alterations, leading to significantly reduced mortality. MSC administration also promoted kidney microvasculature repair, attenuated kidney peritubular capillary loss, increased the proliferation of parenchymal cells and decreased CD68-positive macrophage infiltration and apoptotic cells. Although we determined that CM contained proangiogenic factors, including hepatocyte growth factor (HGF), vascular endothelial growth factor-A (VEGF-A) and insulin-like growth factor-1 (IGF-1), no favorable effects were observed during the course of repair. CONCLUSIONS: Our data show that MSC infusion promotes kidney repair in a variety of ways, including enhancement of the repair of peritubular capillaries and tubular epithelial cells and anti inflammatory and anti-apoptotic effects. MSCs can secrete high levels of proangiogenic growth factors, but CM results in a nonsignificant improvement, indicating that MSCs play a role in kidney repair through paracrine rather than endocrine mechanisms. These results indicate that MSC infusion is a promising therapeutic strategy for promoting kidney repair after injury. PMID- 25145542 TI - Antithrombin-binding oligosaccharides: structural diversities in a unique function? AB - Heparin-antithrombin interaction is one of the most documented examples of heparin/protein complexes. The specific heparin sequence responsible for the binding corresponds to a pentasaccharide sequence with an internal 3-O-sulfated glucosamine residue. Moreover, the position of the pentasaccharide along the chain as well as the structure of the neighbor units affects the affinity to antithrombin. The development of separation and purification techniques, in conjunction with physico-chemical approaches (mostly NMR), allowed to characterize several structural variants of antithrombin-binding oligosaccharides, both in the free state and in complex with antithrombin. The article provides an overview of the studies that lead to the elucidation of the mechanism of interaction as well as acquiring new knowledge in heparin biosynthesis. PMID- 25145543 TI - The effect of electromagnetic fields on the proliferation and the osteogenic or adipogenic differentiation of mesenchymal stem cells modulated by dexamethasone. AB - Although glucocorticoids provide benefits for inflammation or autoimmune disorders, high-dose and long-term use could cause osteonecrosis or osteoporosis as adverse effect for patients. Electromagnetic field (EMF) treatments have been clinically used for many years to promote fracture healing, but whether EMF can attenuate the deleterious effects of glucocorticoids is not clear. In this study, the effects of different concentrations of dexamethasone (DEX) on proliferation and adipogenic or osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) were detected and compared, and the effects of EMF treatment (15 Hz, 1 mT, 4 h/day) on 0.1 uM DEX-modulated BMSCs' proliferation and adipogenic or osteogenic differentiation were investigated. Higher concentrations of DEX (0.1 and 1 uM) inhibited proliferation of BMSCs but promoted expression of adipogenic related genes, increasing the number of lipid droplets. In the early stage of differentiation, DEX restrained expression of RUNX2 and alkaline phosphatase (ALP), but amplified expression of ALP and osteopontin (OPN) in the late stage. EMF treatment of BMSCs influenced by 0.1 uM DEX inhibited the high expression of adipogenic-related genes, stimulated the expression of RUNX2, ALP, OPN, and osteocalcin, and increased the activity of ALP. EMF exposure augmented the expression of p-ERK, which DEX reduced. After using mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway inhibitor, U0126, the effect of EMF was reduced. In conclusion, EMF exposure accelerates BMSCs proliferation, inhibits adipogenic differentiation, and promotes osteogenic differentiation of BMSCs modulated by DEX, and these effects are mediated at least in part by MEK/ERK signaling pathway. PMID- 25145544 TI - In patients with type 1 diabetes simultaneous pancreas and kidney transplantation preserves long-term kidney graft ultrastructure and function better than transplantation of kidney alone. AB - AIMS/HYPOTHESIS: In patients with type 1 diabetes and end-stage renal disease (ESRD) we aimed to determine whether long-term normoglycaemia, as achieved by successful simultaneous pancreas and kidney (SPK) transplantation, would preserve kidney graft structure and function better than live donor kidney (LDK) transplantation alone. METHODS: Estimated GFR (eGFR) was calculated in SPK (n = 25) and LDK (n = 17) recipients in a stable phase 3 months after transplantation and annually during follow-up. Kidney graft biopsies were obtained at follow-up for measurement of glomerular volume (light microscopy), glomerular basement membrane (GBM) and podocyte foot process widths and mesangial volume fraction (electron microscopy). RESULTS: SPK and LDK recipients were similar in age and diabetes duration at engraftment. Donor age was higher in the LDK group. Median follow-up time was 10.1 years. Mean HbA1c levels during follow-up were 5.5 +/- 0.4% (37 +/- 5 mmol/mol) and 8.3 +/- 1.5% (68 +/- 16 mmol/mol) in the SPK and LDK group, respectively (p < 0.001). Compared with SPK recipients, LDK recipients had wider GBM (369 +/- 109 nm vs 281 +/- 57 nm; p = 0.008) and increased mesangial volume fraction (median 0.23 [range 0.13-0.59] vs 0.16 [0.10-0.41]; p = 0.007) at follow-up. Absolute eGFR change from baseline was -11 +/- 21 and -23 +/- 15 ml min(-1) 1.73 m(-2) (p = 0.060), whereas eGFR slope was -1.1 (95% CI -1.7, -0.5) and -2.6 (95% CI -3.1, -2.1) ml min(-1) 1.73 m(-2) per year in the SPK and LDK group, respectively (p = 0.001). CONCLUSIONS/INTERPRETATION: In patients with type 1 diabetes and long-term normoglycaemia after successful SPK transplantation, kidney graft ultrastructure and function were better preserved compared with LDK transplantation alone. PMID- 25145545 TI - Does genetic heterogeneity account for the divergent risk of type 2 diabetes in South Asian and white European populations? AB - AIMS/HYPOTHESIS: South Asians are up to four times more likely to develop type 2 diabetes than white Europeans. It is postulated that the higher prevalence results from greater genetic risk. To evaluate this hypothesis, we: (1) systematically reviewed the literature for single nucleotide polymorphisms (SNPs) predisposing to type 2 diabetes in South Asians; (2) compared risk estimates, risk alleles and risk allele frequencies of predisposing SNPs between South Asians and white Europeans; and (3) tested the association of novel SNPs discovered from South Asians in white Europeans. METHODS: MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the Cochrane registry were searched for studies of genetic variants associated with type 2 diabetes in South Asians. Meta-analysis estimates for common and novel bi allelic SNPs in South Asians were compared with white Europeans from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. The population burden from predisposing SNPs was assessed using a genotype score. RESULTS: Twenty-four SNPs from 21 loci were associated with type 2 diabetes in South Asians after meta-analysis. The majority of SNPs increase odds of the disorder by 15-35% per risk allele. No substantial differences appear to exist in risk estimates between South Asians and white Europeans from SNPs common to both groups, and the population burden also does not differ. Eight of the 24 are novel SNPs discovered from South Asian genome-wide association studies, some of which show nominal associations with type 2 diabetes in white Europeans. CONCLUSIONS/INTERPRETATION: Based on current literature there is no strong evidence to indicate that South Asians possess a greater genetic risk of type 2 diabetes than white Europeans. PMID- 25145548 TI - Additional information regarding the SEVITENSION study. PMID- 25145546 TI - Global DNA methylation levels in human adipose tissue are related to fat distribution and glucose homeostasis. AB - AIMS/HYPOTHESIS: Epigenetic alterations may influence the metabolic pathways involved in human obesity. We hypothesised that global DNA methylation levels in adipose tissue might be associated with obesity and related phenotypes. METHODS: We measured global DNA methylation levels in paired samples of subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) from 51 individuals, and in leucocytes from 559 Sorbs, a population from Germany, using LUminometric Methylation Assay (LUMA). To further investigate the underlying mechanisms of the observed associations, we measured global methylation levels in 3T3-L1 adipocytes exposed to glucose, insulin and lipids. RESULTS: Global methylation levels (+/-SD) were significantly higher in OVAT (74.27% +/- 2.2%) compared with SAT (71.97% +/- 2.4%; paired t test, p < 1 * 10(-9)). Furthermore, global methylation levels in SAT were positive correlates of measures of fat distribution (waist measurement, WHR) and glucose homeostasis (HbA1c) (all p < 0.015 after accounting for multiple testing and covariates). Global methylation levels in the German Sorb cohort were associated with glucose homeostasis, but this association did not withstand adjustment for covariates. Exposure of 3T3-L1 adipocytes to insulin, palmitate and glucose decreased global methylation levels 1 h after treatment relative to controls. CONCLUSIONS/INTERPRETATION: Our data suggest that the variability in global methylation in adipose tissue might be related to alterations in glucose metabolism. PMID- 25145549 TI - Melanoma: diagnosis, staging, and treatment. Consensus group recommendations. AB - The incidence of malignant melanoma is increasing worldwide. In Spain, its incidence is increasing faster than any other cancer type, with a 5-year survival rate of about 85%. The impact and characteristics of malignant melanoma in the Spanish population can be ascertained from the national melanoma registry of the Academia Espanola de Dermatologia y Venereologia. This review presents consensus group recommendations for the diagnosis, staging and treatment of malignant melanoma in Spain. Incidence and mortality are discussed, as well as evaluation of various prevention and treatment strategies. Prognostic factors, such as BRAF and C-KIT mutations, which are expected to become routine staging procedures over the next few years, are outlined, especially in relation to treatment options. The use of recently approved targeted agents such as ipilimumab, a cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitor, and vemurafenib, a BRAF inhibitor, in metastatic disease are also discussed. PMID- 25145550 TI - Predicting other-cause mortality: the minimalistic approach. PMID- 25145551 TI - Conditional survival after radical nephroureterectomy for upper tract carcinoma. AB - BACKGROUND: Conditional survival (CS) provides better estimates of the survival probability at each follow-up time, and its usefulness has been proven in several solid malignancies. OBJECTIVE: To assess the changes in 5-yr CS rates after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) and to determine how well-established prognostic factors evolve over time. DESIGN, SETTING, AND PARTICIPANTS: We analysed data from 3544 patients treated with RNU at 15 international academic centres between 1989 and 2012. INTERVENTION: RNU. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Conditional intravesical recurrence-free (IVRFS), cancer-specific survival (CSS), and overall survival (OS) estimates were calculated using the Kaplan-Meier method. A multivariable Cox regression model was used to calculate proportional hazard ratios for the prediction of mortality. RESULTS AND LIMITATIONS: The 5-yr bladder cancer recurrence-free survival, CSS, and OS rates were 54.9%, 72.2%, and 62.6%, respectively. Given a 1-, 2-, 3-, and 4-yr survivorship, the 5-yr conditional OS rates improved to 65.2%, 69.3%, 71.5%, and 73.0%, respectively. The 5-yr CS improvement was primarily noted among surviving patients with advanced-stage disease. The impact of pathologic parameters on CS estimates decreased over time for both CSS and OS, whereas the impact of age and gender increased with survivorship. No survival benefit was noted regarding the adjuvant chemotherapy status. Findings were confirmed upon multivariable analyses. Tumour location, the presence of carcinoma in situ, and the type of bladder cuff excision were continuously predictive for IVRFS whatever the survivorship. A limitation is the retrospective design. CONCLUSIONS: CS analysis demonstrates that the patient risk profile evolves during the post-RNU follow-up. The probability of survival markedly increases over time in patients having high-stage disease. The impact of prognostic pathologic features decreases over time and can disappear for long term CS. PATIENT SUMMARY: In this study, we found that the risk of intravesical recurrence, cancer-specific survival, and overall mortality evolves over the follow-up after surgery. Taking into account the survivorship provides better estimates of the survival probability at each follow-up time. PMID- 25145552 TI - Ruxolitinib: long-term management of patients with myelofibrosis and future directions in the treatment of myeloproliferative neoplasms. AB - Considerable clinical experience regarding the long-term efficacy and safety of ruxolitinib has been gathered since the drug was approved in the USA for patients with intermediate or high-risk myelofibrosis (MF) in November 2011. Findings from the pivotal phase 3 COMFORT studies showed that ruxolitinib-associated reductions in MF-related splenomegaly and symptom burden occur rapidly and in the majority of patients. Two- and 3-year follow-up data further suggest that the benefits of ruxolitinib are durable and associated with a survival advantage compared with conventional therapies. However, careful management of treatment-related thrombocytopenia and anemia with dose modifications and supportive care is critical to allow chronic therapy. Based on preliminary evidence, ruxolitinib also allows spleen size and symptom reduction before allogeneic stem cell transplantation without negative effect on engraftment or outcomes. In recent studies, ruxolitinib provided effective management of hematologic parameters and symptoms in patients with polycythemia vera refractory to or intolerant of hydroxyurea. PMID- 25145553 TI - Controversies in multiple myeloma: to transplant or not? AB - The treatment of multiple myeloma (MM) has dramatically changed in the last decade due to the introduction of the immunomodulatory drugs (IMIDs) and proteasome inhibitors, otherwise known as the novel agents. Prior to the advent of the novel agents, the gold standard of treatment had been high-dose chemotherapy with autologous stem cell transplantation (HDT/ASCT) for eligible candidates. Given the remarkable activity of the novel agents, and the significant morbidity of HDT/ASCT, the role of stem cell transplantation has now come into question. In this review, we explore the benefits and drawbacks to HDT/ASCT in the era of the novel therapies. PMID- 25145554 TI - High correlation between thermotolerance and photosystem II activity in tall fescue. AB - Heat stress affects a broad spectrum of cellular components and metabolism. The objectives of this study were to investigate the behavior of Photosystem II (PSII) in tall fescue (Festuca arundinacea Schreb) with various thermotolerance capacities and to broaden our comprehension about the relationship between thermotolerance and PSII function. Heat-tolerant and heat-sensitive accessions were incubated at 24 degrees C (control) and 46 degrees C (heat stress) for 5 h. The fluorescence transient curves (OJIP curves), slow Chl fluorescence kinetic, and light response curve were employed to study the behavior of PSII subjected to heat stress. After heat stress, performance index for energy conservation from photons absorbed by PSII antenna until the reduction of PSI acceptors (PITotal), the value of electrons produced per photon (a), and the maximal rate of electron transport (ETRmax) of heat-tolerant accessions were lower than those of heat-sensitive accessions. Relatively lower reactive oxygen species (ROS) contents were detected in heat-tolerant accessions. Simultaneously, there was a significant decline in the quantum yield of photochemical energy conversion in PS II (Y(II)), probability that a PSII Chl molecule functions as reaction center (gammaRC), and the increase of quantum yield for non-regulated non-photochemical energy loss (Y(NO)) in heat-tolerant accessions. Moreover, a significant inverse correlation between heat tolerance indexes (HTI) and Y(II) was observed. Therefore, maintaining a lower photochemical activity in heat tolerant accessions could be a crucial strategy to improve their thermotolerance. This finding could be attributed to the structural difference in the reaction center, and for heat-tolerant accessions, it could simultaneously limit energy input into linear electron transport, and dissipate more energy through non regulated non-photochemical energy loss processes. PMID- 25145555 TI - Is cervix removal associated with patient-centered outcomes of pain, dyspareunia, well-being and satisfaction after laparoscopic hysterectomy? AB - PURPOSE: To determine the effect of cervix removal at hysterectomy on patient centered outcomes including post-operative pain, dyspareunia, well-being, and overall satisfaction during the 3-month post-operative period. METHODS: This is a prospective cohort study of 228 women who underwent elective abdominal, laparoscopic and robotic hysterectomy without concomitant urogynecological or cancer-related procedures, at the Henry Ford Hospital (Detroit, MI). Participants completed a baseline survey evaluating quality of life measures including pain, well-being, sexual and daily function and repeated this survey at serial intervals through 12 weeks post-operatively. Medical record review was performed to confirm demographic and obtain surgical data. RESULTS: Hierarchical generalized linear models were used to model the trajectory of pain, well-being and satisfaction over the course of the post-surgical period. Subanalysis including only laparoscopic cases was performed. There was no difference in satisfaction (p = 0.48, OR 0.80 [CI 95% 0.43, 1.48]), well-being (p = 0.55, OR 1.12 [CI 95% 0.84, 1.79]), or dyspareunia (p = 0.57, OR 0.75 [CI 95% 0.27, 2.04]) scores between laparoscopic/robotic supracervical and total hysterectomy groups. This was unchanged when all hysterectomy approaches were included in analysis. Cervix removal was associated with higher pain scores with all surgical approaches although this did not reach statistical significance. CONCLUSIONS: Patient-centered outcomes suggest overall equivalent tolerance of supracervical and total hysterectomy procedures with a trend towards short-term pain improvement with cervical retention. PMID- 25145557 TI - Decline in overall, smear-negative and HIV-positive TB incidence while smear positive incidence stays stable in Guinea-Bissau 2004-2011. AB - OBJECTIVE: To calculate Tuberculosis (TB) incidence rates in Guinea-Bissau over an 8-year period. METHODS: Since 2003, a surveillance system has registered all TB cases in six suburban districts of Bissau. In this population-based prospective follow-up study, 1205 cases of pulmonary TB were identified between January 2004 and December 2011. Incidence rates were calculated using census data from the Bandim Health and Demographic Surveillance System (HDSS). RESULTS: The overall incidence of pulmonary TB was 279 per 100,000 person-years of observation; the male incidence being 385, and the female 191. TB incidence rates increased significantly with age in both sexes, regardless of smear or HIV status. Despite a peak with unknown cause of 352 per 100,000 in 2007, the overall incidence of pulmonary TB declined over the period. The incidence of HIV infected TB cases declined significantly from 108 to 39 per 100,000, while the incidence of smear-positive TB cases remained stable; the overall figure was 188 per 100,000. CONCLUSIONS: Overall incidence of pulmonary TB in Guinea-Bissau has declined from 2004 to 2011. The decline was also seen in the subgroups of smear negative and HIV-positive TB cases, probably due to antiretroviral treatment. Smear-positive TB incidence remains stable over the period. PMID- 25145558 TI - Latent classes of posttraumatic stress and growth. AB - BACKGROUND AND OBJECTIVES: Potentially traumatic events may lead to different patterns of posttraumatic stress symptoms and posttraumatic growth. The objective of the present study was to identify subgroups with different patterns of posttraumatic reactions, and to determine whether these subgroups differed in terms of personal and social resources and indicators of adjustment. DESIGN: This study used survey data collected 10 months after the 2011 Oslo bombing attack to investigate patterns of reactions among ministerial employees (N=1970). METHODS: We applied latent class analyses with covariates to extract subgroups of individuals. RESULTS: Three classes of individual reactions were extracted, and these were similar among those who were and those who were not physically proximate to the bombing attack: "High stress/high growth" (27% and 11%, respectively), "Low stress/high growth" (74% and 42%, respectively), and "Low stress/low growth" (only among the not physically proximate: 47%). The classes differed in terms of gender, neuroticism, and social support as well as life satisfaction and daily functioning. CONCLUSIONS: Heterogeneous patterns of posttraumatic reactions were found. Physical proximity is not necessary to experience posttraumatic stress or growth after political violence. Among individuals with low stress, posttraumatic growth may not encompass higher life satisfaction or functioning. PMID- 25145559 TI - MiR-618 inhibits anaplastic thyroid cancer by repressing XIAP in one ATC cell line. AB - X-linked inhibitor of apoptosis protein (XIAP) is a major factor in cancer growth and progression. Reduction of XIAP induces apoptosis of anaplastic thyroid cancer (ATC), which accounts for more than 50% of thyroid cancer mortality. MicroRNAs (miRNAs) are short non-coding RNA molecules, which modulate gene expression via interaction with mRNA by binding to the 3'-untranslated region (3'-UTR), playing a critical role in cell proliferation, migration, and invasion. In this study, we recruited the ATC cell line 8305C and normal human thyroid cell Nthy-ori 3-1, aiming to find the miRNA which could regulate XIAP and therefore inhibit the growth and invasion of ATC. We first used quantitative real-time PCR (qPCR) to reveal that XIAP mRNA expression was 4.6+/-0.56 folds (P=0.029) up-regulated in 8305C cells, compared with Nthy-ori 3-1 cells. Then miR-618, predicted to target XIAP directly, was detected 0.24+/-0.06 folds (P=0.019) down-regulated in 8305C cells. Next we used Luciferase assay showing that XIAP was a target gene of miR 618, which could repress the XIAP expression at both mRNA and protein levels. After that, CCK-8 assay was performed to show that over-expression of miR-618 could inhibit the growth of 8305C cells. Finally, we employed transwell method to prove that miR-618 could prevent the invasion and migration of 8305C cells. In conclusion, our collective data showed that over-expression of miR-618 could inhibit ATC cells by targeting XIAP gene. PMID- 25145560 TI - Effects of levothyroxine treatment on insulin sensitivity, endothelial function and risk factors of atherosclerosis in hypothyroid women. AB - OBJECTIVES: Contradictory results are encountered in literature regarding the effects of hypothyroidism on the risk factors of atherosclerosis. We aimed to explore the changes in atherosclerotic risk factors and insulin sensitivity before and after levothyroxine replacement therapy in women with primary hypothyroidism and compare with that of healthy controls. PATIENTS AND METHODS: Twelve patients (mean age of 34+/-11.7years) without an evident disease except for primary hypothyroidism (TSH>=20mIU/L) and eleven euthyroid, age-matched (33.8+/-8.4years) female volunteers as controls were included. Baseline thyroid hormones, lipid parameters, homocysteine, fibrinogen levels were measured in both groups. Flow-mediated endothelial-dependent vasodilatation (FMD) method was used to evaluate endothelial dysfunction. Insulin sensitivity was assessed by M values based on euglycemic hyperinsulinemic clamp technique. The same measurements were performed after 6months of levothyroxine treatment and recovery of euthyroid state in hypothyroid patients. RESULTS: Treatment reduced total cholesterol (P<0.005), LDL-cholesterol (P<0.005), lipoprotein(a) (P<0.01), fibrinogen (P<0.0001) and homocysteine (P<0.0005) levels. Treatment significantly improved M values of hypothyroid patients (3.68+/-1.53mg/kg.min vs 6.02+/-1.21mg/kg.min, P<0.0001) and FMD (9.1+/-3.7% vs 16.4+/-4.4%, hypothyroid vs euthyroid, P<0.0001). Significant correlations were found between M values and TSH (r=-0.6, P<0.005), fibrinogen (r=-0.53, P<0.01) measurements, free T3 (r=0.51, P<0.02) and free T4 (r=0.49, P<0.02) levels. FMD was significantly correlated with fibrinogen levels (r=-0.49, P<0.05). CONCLUSION: Insulin resistance, endothelial dysfunction, atherosclerotic risk markers improves with treatment of hypothyroidism. PMID- 25145561 TI - Quantification of periodontal pathogens cell counts by capillary electrophoresis. AB - Gingivitis is a highly prevalent periodontal disease around the worldwide. Porphyromonas gingivalis (P.g), Treponema denticola (T.d) and Tannerela forsythia (T.f) were considered to be three important periodontal pathogens related to gingivitis, and research shows that the counts of periodontal pathogen cells in the patients before, during, and after fixed orthodontic appliance therapy were quite different. We proposed a simple method to extract the periodontal pathogens from the periodontal pocket in this work and demonstrated a new approach to determine periodontal pathogen level based on capillary electrophoresis (CE). After polymerase chain reaction amplification of P.g (197 bp), T.d (311 bp), and T.f (641 bp), it shows that they can rapidly identified by CE within 5 min. The peak area in the eletropherogram is linearly related to the concentration of P.g, T.d, and T.f, and the correlation coefficients R(2) corresponding to them are 0.993, 0.993, and 0.956, respectively. According to this linearly relationship, the estimated concentration of P.g, T.d, and T.f in gingival crevicular fluid from one volunteer was inferred to be about 9.90*10(2), 1.48*10(3), and 9.01*10(2)cells/MUl, respectively. PMID- 25145556 TI - Predictors and correlates of adherence to combination antiretroviral therapy (ART) for chronic HIV infection: a meta-analysis. AB - BACKGROUND: Adherence to combination antiretroviral therapy (ART) is a key predictor of the success of human immunodeficiency virus (HIV) treatment, and is potentially amenable to intervention. Insight into predictors or correlates of non-adherence to ART may help guide targets for the development of adherence enhancing interventions. Our objective was to review evidence on predictors/correlates of adherence to ART, and to aggregate findings into quantitative estimates of their impact on adherence. METHODS: We searched PubMed for original English-language papers, published between 1996 and June 2014, and the reference lists of all relevant articles found. Studies reporting on predictors/correlates of adherence of adults prescribed ART for chronic HIV infection were included without restriction to adherence assessment method, study design or geographical location. Two researchers independently extracted the data from the same papers. Random effects models with inverse variance weights were used to aggregate findings into pooled effects estimates with 95% confidence intervals. The standardized mean difference (SMD) was used as the common effect size. The impact of study design features (adherence assessment method, study design, and the United Nations Human Development Index (HDI) of the country in which the study was set) was investigated using categorical mixed effects meta regression. RESULTS: In total, 207 studies were included. The following predictors/correlates were most strongly associated with adherence: adherence self-efficacy (SMD = 0.603, P = 0.001), current substance use (SMD = -0.395, P = 0.001), concerns about ART (SMD = -0.388, P = 0.001), beliefs about the necessity/utility of ART (SMD = 0.357, P = 0.001), trust/satisfaction with the HIV care provider (SMD = 0.377, P = 0.001), depressive symptoms (SMD = -0.305, P = 0.001), stigma about HIV (SMD = -0.282, P = 0.001), and social support (SMD = 0.237, P = 0.001). Smaller but significant associations were observed for the following being prescribed a protease inhibitor-containing regimen (SMD = -0.196, P = 0.001), daily dosing frequency (SMD = -0.193, P = 0.001), financial constraints (SMD -0.187, P = 0.001) and pill burden (SMD = -0.124, P = 0.001). Higher trust/satisfaction with the HIV care provider, a lower daily dosing frequency, and fewer depressive symptoms were more strongly related with higher adherence in low and medium HDI countries than in high HDI countries. CONCLUSIONS: These findings suggest that adherence-enhancing interventions should particularly target psychological factors such as self-efficacy and concerns/beliefs about the efficacy and safety of ART. Moreover, these findings suggest that simplification of regimens might have smaller but significant effects. PMID- 25145562 TI - Improved sensitivity of the nano ultra-high performance liquid chromatography tandem mass spectrometric analysis of low-concentrated neuropeptides by reducing aspecific adsorption and optimizing the injection solvent. AB - Obtaining maximal sensitivity of nano UHPLC-MS/MS methods is primordial to quantify picomolar concentrations of neuropeptides in microdialysis samples. Since aspecific adsorption of peptides to Eppendorf tubes, pipette tips and UHPLC vials is detrimental for method sensitivity, a strategy is presented to reduce adsorption of these peptides during standard preparation. Within this respect, all procedural steps from dissolution of the lyophilized powder until the injection of the sample onto the system are investigated. Two peptides of the neuromedin family, i.e. neuromedin B and neuromedin N, and a neuromedin N-related neuropeptide, neurotensin, are evaluated. The first part of this study outlines a number of parameters which are known to affect peptide solubility. The main focus of the second part involves the optimization of the sample composition in the UHPLC vial by using design of experiments. Contradictory findings are observed concerning the influence of acetonitrile, salts and matrix components. They are found important for injection of the peptides into the system, but crucially need to be excluded from the dilution solvent. Furthermore, the type of surface material, temperature and the pipetting protocol considerably affect the adsorption phenomenon. Statistical analysis on the results of the central composite design reveals that the highest peptide responses are obtained with the injection solvent consisting of 13.1% V/V ACN and 4.4% V/V FA. This aspect of the optimization strategy can be identified as the main contributor to the gain in method sensitivity. Since the reduction of peptide adsorption and the optimization of the injection solvent resulted in a clear and quantifiable signal of the three peptides, optimization of both issues should be considered in the early stage of method development, in particular when the analysis of low concentration peptide solutions is envisaged. PMID- 25145563 TI - Fractionation of complex lipid mixtures by hydroxyapatite chromatography for lipidomic purposes. AB - The comprehensive analysis of natural lipid mixtures is often challenging due to the simultaneous occurrence of functionally and structurally heterogeneous compounds. Modern analytical approaches in system-wide lipidomics essentially rely on mass spectrometry (MS). The overabundant amount of triacylglycerols (TAGs) in most samples hinders the direct detection of phospholipids (PLs) or other low-abundance lipids; therefore, a fractionation step is most often required to reduce sample complexity prior to MS analysis. In this work, we explore the use of hydroxyapatite (HAP) as a chromatographic stationary phase (gel HAP) or chemo-affinity sorbent material (ceramic HAP) to selectively enrich PLs and polar lipids from chicken egg yolk and buttermilk. Due to the affinity of phosphate-containing compounds for HAP, both in-column and in-batch HAP-based chromatography were effective to deplete TAGs before releasing PLs with an eluting ternary system containing sodium phosphate as the displacing agent. Buttermilk gangliosides and PLs co-eluted, indicating that HAP also exhibits a high affinity for sialylated glycolipids and that polar lipids are retained through a combined mechanism of chemo-affinity and hydrogen bonding. To the best of our knowledge, this is the first report in which HAP is proposed as an alternative stationary phase for separating both the PLs and sialylated glycolipids from TAGs in complex lipidomes. The HAP-based chromatography has potential to be improved for the separation of the polar lipid classes. PMID- 25145564 TI - Occurrence of turbulent flow conditions in supercritical fluid chromatography. AB - Having similar densities as liquids but with viscosities up to 20 times lower (higher diffusion coefficients), supercritical CO2 is the ideal (co-)solvent for fast and/or highly efficient separations without mass-transfer limitations or excessive column pressure drops. Whereas in liquid chromatography the flow remains laminar in both the packed bed and tubing, except in extreme cases (e.g. in a 75 MUm tubing, pure acetonitrile at 5 ml/min), a supercritical fluid can experience a transition from laminar to turbulent flow in more typical operation modes. Due to the significant lower viscosity, this transition for example already occurs at 1.3 ml/min for neat CO2 when using connection tubing with an ID of 127 MUm. By calculating the Darcy friction factor, which can be plotted versus the Reynolds number in a so-called Moody chart, typically used in fluid dynamics, higher values are found for stainless steel than PEEK tubing, in agreement with their expected higher surface roughness. As a result turbulent effects are more pronounced when using stainless steel tubing. The higher than expected extra column pressure drop limits the kinetic performance of supercritical fluid chromatography and complicates the optimization of tubing ID, which is based on a trade-off between extra-column band broadening and pressure drop. One of the most important practical consequences is the non-linear increase in extra-column pressure drop over the tubing downstream of the column which leads to an unexpected increase in average column pressure and mobile phase density, and thus decrease in retention. For close eluting components with a significantly different dependence of retention on density, the selectivity can significantly be affected by this increase in average pressure. In addition, the occurrence of turbulent flow is also observed in the detector cell and connection tubing. This results in a noise-increase by a factor of four when going from laminar to turbulent flow (e.g. going from 0.5 to 2.5 ml/min for neat CO2). PMID- 25145565 TI - Magnetic porous carbon as an adsorbent for the enrichment of chlorophenols from water and peach juice samples. AB - In this paper, porous carbon with a highly ordered structure was synthesized using zeolite ZSM-5 as a template and sucrose as a carbon source. Through the in situ reduction of Fe(3+), magnetic property was successfully introduced into the ordered porous carbon, resulting in a magnetic porous carbon (MPC). MPC was used as an adsorbent for the extraction of some chlorophenols (2-chlorophenol, 3 chlorophenol, 2,3-dichlorophenol and 3,4-dichlorophenol) from water and peach juice samples followed by high performance liquid chromatography-ultraviolet detection. Good linearity was observed in the range 1.0-100.0 ng mL(-1) and 2.0 100.0 ng mL(-1) for water and peach juice sample, respectively. The limits of detection (S/N=3) were between 0.10 and 0.30 ng mL(-1). The relative standard deviations were less than 5.3% and the recoveries of the method for the compounds were in the range from 87.8% to 102.3%. The results demonstrated that the MPC had a high adsorptive capability toward the four chlorophenols from water and peach juice samples. PMID- 25145566 TI - Sharp-bounded zones link to the effect in planar chromatography-bioassay-mass spectrometry. AB - The traditional direct bioautography workflow was substantially altered to yield narrow, sharp-bounded effective zones. For the first time, microorganisms quantitatively detected the single effective compounds in complex samples, separated in parallel on a planar chromatogram. This novel effect-directed workflow was demonstrated and optimized for the discovery of endocrine disrupting compounds (EDCs) reacting with the human estrogen receptor down to the femtogram per-zone range, like 250fg/zone for 17beta-estradiol (E2). For application volumes of up to 0.5mL, estrogen-effective compounds could directly be detected in complex samples at the ultratrace level (ng/kg-range). Sharp-bounded, estrogen effective zones discovered were further characterized by direct elution into the mass spectrometer. HPTLC-ESI-MS mass spectra of (xeno)estrogens were shown for the first time. Owed to the substantially improved zone resolution, compound assignment was reliable and a comparison of the receptor affinities was conducted for six (xeno)estrogens. Also, long-term cell cultivation of the genetically modified yeast was demonstrated on the HPTLC plate. The optimized HPTLC-pYES workflow was proven for real food samples, exemplarily shown for beer. The general applicability of generating sharp-bounded zones was successfully proven by transfer of the fundamentally improved workflow to the Bacillus subtilis bioassay used for discovery of antibiotics in plant extracts. This new era of quantitative direct bioautography in combination with mass spectrometry will accelerate the scientific understanding in a wide application field via the streamlined access to fast and reliable information on effective components in complex samples. PMID- 25145567 TI - Incorporation of metal-organic framework HKUST-1 into porous polymer monolithic capillary columns to enhance the chromatographic separation of small molecules. AB - Metal-organic framework (MOF) HKUST-1 nanoparticles have been incorporated into poly(glycidyl methacrylate-co-ethylene dimethacrylate) (HKUST-1-poly(GMA-co EDMA)) monoliths to afford stationary phases with enhanced chromatographic performance of small molecules in the reversed phase capillary liquid chromatography. The effect of HKUST-1 nanoparticles in the polymerization mixture on the performance of the monolithic column was explored in detail. While the bare poly(GMA-co-EDMA) monolith exhibited poor resolution (Rs<1.0) and low efficiency (800-16,300plates/m), addition of a small amount of HKUST-1 nanoparticles to the polymerization mixture provide high increased resolution (Rs>=1.3) and high efficiency ranged from 16,300 to 44,300plates/m. Chromatographic performance of HKUST-1-poly(GMA-co-EDMA) monolith was demonstrated by separation of various analytes including polycyclic aromatic hydrocarbons, ethylbenzene and styrene, phenols and aromatic acids using a binary polar mobile phase (CH3CN/H2O). The HKUST-1-poly(GMA-co-EDMA) monolith displayed enhanced hydrophobic and pi-pi interaction characteristics in the reversed phase separation of test analytes compared to the bare poly(GMA-co-EDMA) monolith. The experiment results showed that HKUST-1-poly(GMA-co-EDMA) monoliths are an alternative to enhance the chromatographic separation of small molecules. PMID- 25145568 TI - Graphene oxide assisted spontaneous growth of V2O5 nanowires at room temperature. AB - Graphene-decorated single crystalline V2O5 nanowires (G-VONs) have been synthesized by mixing graphene oxide (GO) and V2O5 suspensions at room temperature. In this process, V2O5 nanowires (VONs) are formed spontaneously from commercial V2O5 particles with the aid of GO. The as-formed one dimensional G VONs were characterized by using a X-ray diffractometer, a X-ray photoelectron spectrometer, a scanning electron microscope, and a transmission electron microscope. GO plays a vital role in the VON formation with the simultaneous reduction of GO. A single G-VON showed superior electrical conductivity compared with that of the pure VONs obtained from the sol-gel method. This could be ascribed to the insertion of rGO sheets into the V2O5 layered structure, which was further confirmed by electron energy loss spectroscopy. PMID- 25145569 TI - Effect of trophic status in lakes on fungal species diversity and abundance. AB - The objective of this study was to determine the species diversity and abundance of fungi in relation to the hydrochemical conditions, with special emphasis on the trophic status and degree of pollution of lakes. The study was conducted in 14 lakes of the Augustow Lakeland (central Europe, NE Poland) with different hydrological conditions, type of stratification and trophic status. The analyses were performed in the hydrological year 2013. In the waters of the studied lakes, the mean abundance of fungi was 5600+/-3600 CFU/mL. The minimum value (800 CFU/mL) was recorded for the mesotrophic Plaskie Lake, and the maximum value (14,000 CFU/mL) was recorded for the eutrophic Pobojno Lake. A total of 38 species of fungi were identified, including 11 belonging to the aquatic hyphomycetes; up to 14 species were potentially pathogenic fungi. The potentially pathogenic fungi, particularly Candida albicans and Scopulariopsis fusca, were found in lakes with increased concentrations of chloride and sulphate(VI) ions and may thus serve as indicators of the degree of water pollution. This paper illustrates that the species diversity and abundance of fungi in limnic waters depend on the concentration of organic matter, chlorophyll a concentration, and the degree of water pollution. The results suggest that aquatic fungi can be a valuable indicator of the degree of pollution and the sanitary quality of the water. PMID- 25145570 TI - Perceived cancer risk and risk attributions among African-American residents of a low-income, predominantly African-American neighborhood. AB - OBJECTIVE: In some national surveys, African-Americans have had lower scores on perceived cancer risk items than whites. Our goals were to confirm low perceptions of cancer risk in an African-American community sample and explore participants' attributions for their perceived cancer risk. DESIGN: Data were from three cross-sectional surveys. We report levels of perceived absolute and comparative cancer risk in a community sample of African-Americans (N = 88), and African-Americans (Ns = 655, 428) and whites (Ns = 5262, 1679) from two nationally representative Health Information National Trends Surveys (HINTS). We analyzed the content of spontaneously-provided explanations for perceived risk from the community sample. RESULTS: Perceived absolute and comparative cancer risk were lower in the community and national samples of African-Americans than in the national sample of whites. Participants' spontaneous attributions for low or lower than average risk included not having family history or behavioral risk factors, classes of attributions noted elsewhere in the literature. However, participants also explained that they wanted to avoid wishing cancer on themselves (positive affirmations) and hoped their risk was low (wishful thinking), responses rarely reported for majority-white samples. CONCLUSIONS: Results provide further evidence that cancer risk perceptions are lower among African-Americans than whites. Some participant explanations for low perceived risk (wishful thinking, affirmations) are inconsistent with behavioral scientists' assumptions about perceived risk questions. Results reveal a need to expand cancer risk attribution typologies to increase applicability to diverse populations, and may indicate that perceived cancer risk questions have lower validity in African-American populations. PMID- 25145571 TI - Disseminating treatment for anxiety disorders step 2: peer recommendations to seek help. AB - Despite the high prevalence of and significant psychological burden caused by anxiety disorders, as few as 25% of individuals with these disorders seek treatment, and treatment seeking by African-Americans is particularly uncommon. This purpose of the current study was to gather information regarding the public's recommendations regarding help-seeking for several anxiety disorders and to compare Caucasian and African-American participants on these variables. A community sample of 577 US adults completed a telephone survey that included vignettes portraying individuals with generalized anxiety disorder (GAD), social phobia/social anxiety disorder (SP/SAD), panic disorder (PD), and for comparison, depression. The sample was 1/2 Caucasian and 1/2 African American. Respondents were significantly less likely to recommend help-seeking for SP/SAD and GAD (78.8% and 84.3%, respectively) than for depression (90.9%). In contrast, recommendations to seek help for panic disorder were common (93.6%) and similar to rates found for depression. The most common recommendations were to seek help from a primary care physician (PCP). African Americans were more likely to recommend help-seeking for GAD than Caucasians. Findings suggested that respondents believed individuals with anxiety disorders should seek treatment. Given that respondents often recommended consulting a PCP, we recommend educating PCPs about anxiety disorders and empirically-supported interventions. PMID- 25145572 TI - Multiplexed electrochemical detection of trypsin and chymotrypsin based on distinguishable signal nanoprobes. AB - In this work, we developed a novel multisignal output for simultaneous detection of multiple proteases by using nanoprobes labeled with distinguishable electrochemical probes. First, biotinylated peptide1 (S1) and biotinylated peptide2 (S2) were associated with biotinylated DNA1 and DNA2 via biotin streptavidin interaction, forming DNA1-S1 and DNA2-S2, respectively. Two distinguishable signal nanoprobes (DNA1'-Au NPs-Thi and DNA2'-Au NPs-Fc) were prepared by initial assembling DNA1' and DNA2' on the Au NPs surface, respectively, and then carrying corresponding thionine (Thi) and 6 (Ferrocenyl)hexanethiol (Fc). Then, the peptide substrates (DNA1-S1 and DNA2-S2) were immobilized on gold electrode surface through Au-S bonds, and the DNA1'-Au NPs-Thi and DNA2'-Au NPs-Fc were assembled to the peptide-DNA-modified electrode surface via DNA hybridization. The targets of trypsin and chymotrypsin can specifically recognize and cleave peptides with different sequences, releasing DNA1'-Au NPs-Thi and DNA2'-Au NPs-Fc from the electrode surface into solution, thus decreasing the current of Thi and Fc. The decrease in the electrochemical currents of the two signal nanoprobes enables us to simultaneously and quantitatively determine the targets trypsin and chymotrypsin. More importantly, this strategy can be extended easily by designing various proteases-specific peptide substrates and utilizing corresponding electrochemical detectable elements for simultaneous multiplex protease assay in various biosystems. PMID- 25145573 TI - A retrospective study of anesthesia during rigid bronchoscopy for airway foreign body removal in children: propofol and sevoflurane with spontaneous ventilation. AB - BACKGROUND: Tracheobronchial foreign body aspiration is a significant cause of childhood morbidity and mortality. We analyzed our experience in management of aspirated foreign bodies, including methods of anesthesia used, over a 4-year period. METHODS: We retrospectively reviewed the records of tracheobronchial foreign body removal by rigid bronchoscopy with spontaneous ventilation in 435 children. All patients had received initial anesthesia with inhaled sevoflurane. One hundred and ninety-seven patients (Group PropRemi) then received intravenous propofol and remifentanyl for maintenance of anesthesia; the remaining 238 patients (Group PropSevo) received propofol and sevoflurane. RESULTS: Tracheobronchial foreign body was found in 405 children (93.1%) and successfully removed from 402 (99.3%) children. Among three patients who failed bronchoscopy, one child suffered cardiac arrest and died during the bronchoscopy, and two required subsequent tracheotomy for foreign body removal. Adverse effects (intraoperative coughing, breath holding, body movement, bronchospasm, and laryngospasm) were significantly more frequent in Group PropRemi than in Group PropSevo. No complications such as bleeding, pneumothorax, pneumomediastinum, or the need for thoracotomy were encountered. CONCLUSION: Sevoflurane induction followed by a combination of sevoflurane and continuous infusion of propofol resulted in fewer adverse events than sevoflurane induction followed by TIVA with propofol and remifentanyl during rigid bronchoscopy for airway foreign body removal in children with spontaneous ventilation. PMID- 25145574 TI - Development of a microsimulation of melanoma mortality for evaluating the effectiveness of population-based skin cancer screening. AB - BACKGROUND: A nationwide skin cancer screening (SCS) was implemented in Germany in 2008. It aims at improving early detection of melanoma in order to reduce melanoma mortality. While the idea of early detection is compelling, demonstrating the effectiveness of melanoma screening is crucial. Since it is not feasible to conduct epidemiological studies to investigate the impact of factors such as screening interval or targeted age groups, we developed a microsimulation model that is able to predict melanoma mortality in Germany under several SCS conditions. METHODS: Using German cancer registry data, population data, and other published data on melanoma progression and screening participation, we developed a stochastic microsimulation model. With this model, 10,000 populations of 100,000 persons and their melanoma-related life histories were simulated separately for women and for men and calibrated to observed melanoma incidence. In a second step, life histories of melanoma were changed by an SCS. RESULTS: Compared with a nonscreening scenario (age-standardized mortality rate: 1.6 and 2.9 per 100,000 for women and men), a biennial SCS of the 35- to 85-year-old population with a participation probability of 20% for each screening-eligible individual and a test sensitivity of 80% reduced mortality by up to 0.7 and 1.4 deaths per 100,000 person-years for women and men, respectively, corresponding to a relative reduction of melanoma mortality by 45% in women and men. CONCLUSIONS: We developed a microsimulation model of melanoma mortality that can be used to evaluate the effectiveness of population-based skin cancer screening. The simulation provided plausible melanoma mortality predictions and is a tool for comparing different SCS scenarios. However, it does not provide estimates on total costs of SCS. PMID- 25145575 TI - Societal preferences for distributive justice in the allocation of health care resources: a latent class discrete choice experiment. AB - Economic theory suggests that resources should be allocated in a way that produces the greatest outputs, on the grounds that maximizing output allows for a redistribution that could benefit everyone. In health care, this is known as QALY (quality-adjusted life-year) maximization. This justification for QALY maximization may not hold, though, as it is difficult to reallocate health. Therefore, the allocation of health care should be seen as a matter of distributive justice as well as efficiency. A discrete choice experiment was undertaken to test consistency with the principles of QALY maximization and to quantify the willingness to trade life-year gains for distributive justice. An empirical ethics process was used to identify attributes that appeared relevant and ethically justified: patient age, severity (decomposed into initial quality and life expectancy), final health state, duration of benefit, and distributional concerns. Only 3% of respondents maximized QALYs with every choice, but scenarios with larger aggregate QALY gains were chosen more often and a majority of respondents maximized QALYs in a majority of their choices. However, respondents also appeared willing to prioritize smaller gains to preferred groups over larger gains to less preferred groups. Marginal analyses found a statistically significant preference for younger patients and a wider distribution of gains, as well as an aversion to patients with the shortest life expectancy or a poor final health state. These results support the existence of an equity-efficiency tradeoff and suggest that well-being could be enhanced by giving priority to programs that best satisfy societal preferences. Societal preferences could be incorporated through the use of explicit equity weights, although more research is required before such weights can be used in priority setting. PMID- 25145577 TI - Cognitive biases and heuristics in medical decision making: a critical review using a systematic search strategy. AB - BACKGROUND: The role of cognitive biases and heuristics in medical decision making is of growing interest. The purpose of this study was to determine whether studies on cognitive biases and heuristics in medical decision making are based on actual or hypothetical decisions and are conducted with populations that are representative of those who typically make the medical decision; to categorize the types of cognitive biases and heuristics found and whether they are found in patients or in medical personnel; and to critically review the studies based on standard methodological quality criteria. METHOD: Data sources were original, peer-reviewed, empirical studies on cognitive biases and heuristics in medical decision making found in Ovid Medline, PsycINFO, and the CINAHL databases published in 1980-2013. Predefined exclusion criteria were used to identify 213 studies. During data extraction, information was collected on type of bias or heuristic studied, respondent population, decision type, study type (actual or hypothetical), study method, and study conclusion. RESULTS: Of the 213 studies analyzed, 164 (77%) were based on hypothetical vignettes, and 175 (82%) were conducted with representative populations. Nineteen types of cognitive biases and heuristics were found. Only 34% of studies (n = 73) investigated medical personnel, and 68% (n = 145) confirmed the presence of a bias or heuristic. Each methodological quality criterion was satisfied by more than 50% of the studies, except for sample size and validated instruments/questions. Limitations are that existing terms were used to inform search terms, and study inclusion criteria focused strictly on decision making. CONCLUSIONS: Most of the studies on biases and heuristics in medical decision making are based on hypothetical vignettes, raising concerns about applicability of these findings to actual decision making. Biases and heuristics have been underinvestigated in medical personnel compared with patients. PMID- 25145576 TI - An emerging field of research: challenges in pediatric decision making. AB - There is growing interest in pediatric decision science, spurred by policies advocating for children's involvement in medical decision making. Challenges specific to pediatric decision research include the dynamic nature of child participation in decisions due to the growth and development of children, the family context of all pediatric decisions, and the measurement of preferences and outcomes that may inform decision making in the pediatric setting. The objectives of this article are to describe each of these challenges, to provide decision researchers with insight into pediatric decision making, and to establish a blueprint for future research that will contribute to high-quality pediatric medical decision making. Much work has been done to address gaps in pediatric decision science, but substantial work remains. Understanding and addressing the challenges that exist in pediatric decision making may foster medical decision making science across the age spectrum. PMID- 25145578 TI - Fournier's gangrene current approaches. AB - Fournier's gangrene is a rare but highly mortal infectious disease characterised by fulminant necrotising fasciitis involving the genital and perineal regions. The objective of this study is to analyse the demographics, clinical feature and treatment approaches as well as outcomes of Fournier's gangrene. Data were collected retrospectively from medical records and operative notes. Patient data were analysed by demographics, aetiological factors, clinical features, treatment approaches and outcomes. Twelve patients (five female and seven male) were enrolled in this study. The most common aetiology was perianal abscess (41.6%). Wound cultures showed a mixture of microorganisms in six (50%) patients. For faecal diversion, while colostomy was performed in six cases (50%), Flexi-Seal was used in two cases (16.6%). In four patients (33.4%), no faecal diversion was performed. Negative pressure wound therapy (NPWT) system was effective in the last four patients (33.4%). The mean hospitalisation period in patients who used NPWT was 18 days, while it was 20 days in the others. NPWT in Fournier's gangrene is a safe dressing method. It promotes granulation formation. Flexi-Seal faecal management is an alternative method to colostomy and provides protection from its associated complications. The combination of two devices (Flexi-Seal and NPWT) is an effective and comfortable method in the management of Fournier's gangrene in appropriate patients. PMID- 25145579 TI - In vivo clonal tracking of hematopoietic stem and progenitor cells marked by five fluorescent proteins using confocal and multiphoton microscopy. AB - We developed and validated a fluorescent marking methodology for clonal tracking of hematopoietic stem and progenitor cells (HSPCs) with high spatial and temporal resolution to study in vivo hematopoiesis using the murine bone marrow transplant experimental model. Genetic combinatorial marking using lentiviral vectors encoding fluorescent proteins (FPs) enabled cell fate mapping through advanced microscopy imaging. Vectors encoding five different FPs: Cerulean, EGFP, Venus, tdTomato, and mCherry were used to concurrently transduce HSPCs, creating a diverse palette of color marked cells. Imaging using confocal/two-photon hybrid microscopy enables simultaneous high resolution assessment of uniquely marked cells and their progeny in conjunction with structural components of the tissues. Volumetric analyses over large areas reveal that spectrally coded HSPC-derived cells can be detected non-invasively in various intact tissues, including the bone marrow (BM), for extensive periods of time following transplantation. Live studies combining video-rate multiphoton and confocal time-lapse imaging in 4D demonstrate the possibility of dynamic cellular and clonal tracking in a quantitative manner. PMID- 25145580 TI - Transfusion reactions in pediatric compared with adult patients: a look at rate, reaction type, and associated products. AB - BACKGROUND: The majority of reports on transfusion reactions address adult patients. Less is known about the types, incidence, and other clinical details of transfusion reactions in pediatric populations. Furthermore, to our knowledge, there have been no previous reports directly comparing these aspects between adults and pediatric patient populations to assess if there are differences. STUDY DESIGN AND METHODS: Between the period of January 1, 2011, and February 1, 2013, all reported adult and pediatric transfusion reactions at Vanderbilt University Medical Center (VUMC) were evaluated by transfusion medicine clinical service. The information was subsequently shared with the hemovigilance database. Data provided to hemovigilance included age, sex, blood product associated with the reaction, severity of the reaction, and the type of transfusion reactions. These were collated with hospital and blood bank information system-acquired data on overall admission and product transfusion. RESULTS: A total of 133,671 transfusions were performed at VUMC during the study period including 20,179 platelet (PLT) transfusions, 31,605 plasma transfusions, 79,933 red blood cell (RBC) transfusions, and 2154 cryoprecipitate transfusions. Over the same period, 108 pediatric and 277 adult transfusion reactions were recorded. This corresponds to an incidence of 6.2 reactions per 1000 transfusions within the pediatric (age < 21) population and an incidence of 2.4 reactions per 1000 transfusions within the adult population. In both adult and pediatric populations, transfusion reactions were most commonly associated with PLT, followed by RBC, and then plasma transfusions. Within the pediatric population, subset analysis identified multiple differences when compared to the adult population, including an increased incidence of allergic transfusion reactions (2.7/1000 vs. 1.1/1000, p < 0.001), febrile nonhemolytic transfusion reactions (1.9/1000 vs. 0.47/1000, p < 0.001), and hypotensive transfusion reactions (0.29/1000 vs. 0.078/1000, p < 0.05). Interestingly, while the reaction incidence was the same between sexes in adults, in pediatric patients, reactions were more common in male patients (7.9/1000 pediatric males vs. 4.3/1000 pediatric females, p < 0.01). CONCLUSION: To our knowledge this is the first study to provide detailed comparisons of acute transfusion reactions to all blood products between pediatric and adult populations at a single institution and supported by a single transfusion service and culture. Collectively these data provide insight into pediatric transfusion reactions and demonstrate a general increase in the incidence of transfusion reactions within the pediatric compared to adult population. PMID- 25145581 TI - A comparison of the long-term results of crushing and crushing with intrinsic stripping techniques in concha bullosa surgery. AB - BACKGROUND: A prospective endoscopic and radiologic evaluation of long-term outcomes of crushing and crushing with intrinsic stripping, 2 minimally destructive techniques used for the surgical treatment of concha bullosa. METHODS: Forty-two patients who underwent concha bullosa surgery (a total of 55 conchae surgeries) were included in the study. The patients were allocated consecutively to either of the 2 groups: Group 1 (crushing, n = 28) and Group 2 (crushing with intrinsic stripping, n = 27). All procedures were performed endoscopically. The presurgical and 1-year postsurgical endoscopic nasal cavity images and computed tomography (CT) scans of all patients were recorded. Preoperative and postoperative measurements were compared using paired t test and Student t test. RESULTS: Gender and mean age of the 42 patients (55 conchae bullosa) were as follows: 23 males, mean age 25.6 (range, 18 to 41) years; 18 females, mean age 24.2 (range, 18 to 33) years. The patients were followed for 12.5 +/- 1.3 months. Comparisons of both the grading of endoscopic images and the concha bullosa volumes measured in CT images before and after treatment showed significant postsurgical reductions in both groups; comparison between groups showed significant postsurgical decreases for Group 2 in both concha bullosa volumes and in endoscopic scoring (p < 0.05). CONCLUSION: Crushing with intrinsic stripping is an effective and easy technique; when compared to crushing alone; this technique provides a significantly more decrease in middle concha volumes as demonstrated both by the CT and by endoscopic evaluations. PMID- 25145582 TI - Diverse chemotypes disrupt ion homeostasis in the Malaria parasite. AB - The antimalarial spiroindolones disrupt Plasmodium falciparum Na(+) regulation and induce an alkalinization of the parasite cytosol. It has been proposed that they do so by inhibiting PfATP4, a parasite plasma membrane P-type ATPase postulated to export Na(+) and import H(+) equivalents. Here, we screened the 400 antiplasmodial compounds of the open access 'Malaria Box' for their effects on parasite ion regulation. Twenty eight compounds affected parasite Na(+) and pH regulation in a manner consistent with PfATP4 inhibition. Six of these, with chemically diverse structures, were selected for further analysis. All six showed reduced antiplasmodial activity against spiroindolone-resistant parasites carrying mutations in pfatp4. We exposed parasites to incrementally increasing concentrations of two of the six compounds and in both cases obtained resistant parasites with mutations in pfatp4. The finding that diverse chemotypes have an apparently similar mechanism of action indicates that PfATP4 may be a significant Achilles' heel for the parasite. PMID- 25145584 TI - Ultrasonographic features of vascular closure devices: initial and 6-month follow up results. AB - PURPOSE: This study aimed to evaluate the ultrasonographic findings for various types of vascular closure devices (VCDs) immediately after the angiographic procedure and at 6-month follow-up. METHODS: We included 18 VCDs including Angio Seal (n=4), FemoSeal (n=8), ExoSeal (n=3), Perclose (n=2), and StarClose (n=1) in this study. Four patients were implanted with 2 VCDs at the each side of bilateral femoral arteries, while the remaining 8 patients were inserted 1 VCD at the right femoral artery. Ultrasonography was performed within 10 days and at approximately 6 months after the angiographic procedure. Ultrasonographic morphology of the attached VCD and its relationship with the arterial wall were analyzed. RESULTS: Initial ultrasonography revealed the attached VCD as the relevant unique structure with successful deployment and hemostasis. Follow-up ultrasonography demonstrated partial absorption of hemostatic materials in cases of Angio-Seal (n=3), FemoSeal (n=5), and ExoSeal (n=3), changes in the soft tissue surrounding the femoral artery in case of Angio-Seal (n=1), arterial intimal hyperplasia in cases of FemoSeal (n=3), and no gross changes as compared with the initial ultrasonographic findings in cases of Perclose (n=2) and StarClose (n=1). CONCLUSION: Initial ultrasonographic evaluation reflected the unique structure of each VCD, with most of them being easily distinguishable. Follow-up ultrasonography revealed various changes in the affected vessels. PMID- 25145585 TI - Motivation towards dual career of European student-athletes. AB - The present study aimed to investigate motivations for the dual career of European student-athletes living in countries providing different educational services for elite athletes: State-centric regulation-State as sponsor/facilitator (State), National Sporting Federations/Institutes as intermediary (Federation) and Laisser Faire, no formal structures (No Structure). Therefore, the European Student-athletes' Motivation towards Sports and Academics Questionnaire (SAMSAQ-EU) was administered to 524 European student-athletes. Exploratory Factor Analysis, and Confirmatory Factor Analysis were applied to test the factor structure, and the reliability and validity of the SAMSAQ-EU, respectively. A multivariate approach was applied to verify subgroup effects (P <= 0.05) according to gender (i.e., female and male), age (i.e., <= 24 years, > 24 years), type of sport (i.e., individual sport and team sport) and competition level (i.e., national and international). Insufficient confirmatory indexes were reported for the whole European student-athlete group, whereas distinct three factor models [i.e., Student Athletic Motivation (SAM); Academic Motivation (AM); Career Athletic Motivation (CAM)] emerged, with acceptable reliability estimates, for State (SAM = 0.82; AM = 0.75; and CAM = 0.75), Federation (SAM = 0.82; AM = 0.66; and CAM = 0.87) and No Structure (SAM = 0.78; AM = 0.74; and CAM = 0.79) subgroups. Differences between subgroups were found only for competition level (P < 0.001) in relation to SAM (P = 0.001) and CAM (P < 0.001). For SAM, the highest and lowest values emerged for Federation (national, 5.1 +/- 0.5; international, 5.4 +/- 0.5) and State (national, 4.5 +/- 0.9; international, 4.8 +/- 0.7). The opposite picture emerged for CAM (Federation: national, 3.3 +/- 0.7; international, 3.5 +/- 0.9; State: national, 5.0 +/- 0.8; international, 5.0 +/- 0.9). Therefore, despite SAMSAQ-EU demonstrated to be a useful tool, results showed that European student-athletes' motivation for dual career has to be specifically investigated according to social contexts. PMID- 25145583 TI - 4EBP1/eIF4E and p70S6K/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N-Ras proto-oncogenes in mice. AB - Concomitant expression of activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and Ras in mouse liver (AKT/Ras) leads to rapid tumor development through strong activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. mTORC1 functions by regulating p70S6K/ribosomal protein S6 (RPS6) and eukaryotic translation initiation factor 4E-binding protein 1/ eukaryotic translation initiation factor 4E (4EBP1/eIF4E) cascades. How these cascades contribute to hepatocarcinogenesis remains unknown. Here, we show that inhibition of the RPS6 pathway by rapamycin effectively suppressed, whereas blockade of the 4EBP1/eIF4E cascade by 4EBP1A4, an unphosphorylatable form of 4EBP1, significantly delayed, AKT/Ras-induced hepatocarcinogenesis. Combined treatment with rapamycin and 4EBP1A4 completely inhibited AKT/Ras hepatocarcinogenesis. This strong antineoplastic effect was successfully recapitulated by ablating regulatory associated protein of mTORC1, the major subunit of mTORC1, in AKT/Ras overexpressing livers. Furthermore, we demonstrate that overexpression of eIF4E, the proto-oncogene whose activity is specifically inhibited by 4EBP1, resulted in hepatocellular carcinoma (HCC) development in cooperation with activated Ras. Mechanistically, we identified the ectonucleoside triphosphate diphosphohydrolase 5/ adenylate kinase 1/cytidine monophosphate kinase 1 axis and the mitochondrial biogenesis pathway as targets of the 4EBP1/eIF4E cascade in AKT/Ras and Ras/eIF4E livers as well as in human HCC cell lines and tissues. CONCLUSIONS: Complete inhibition of mTORC1 is required to suppress liver cancer development induced by AKT and Ras proto-oncogenes in mice. The mTORC1 effectors, RPS6 and eIF4E, play distinct roles and are both necessary for AKT/Ras hepatocarcinogenesis. These new findings might open the way for innovative therapies against human HCC. PMID- 25145586 TI - Intraoperative ultrasound to facilitate removal of a submucosal foreign body. AB - A 61-year-old man with a history of fish bone ingestion and poorly localized symptoms was seen. His clinical examination was unremarkable, but CT demonstrated a foreign body deeply embedded within his tongue. Intraoperative ultrasound (US) guidance facilitated identification of a bone, allowing a needle to be placed as a guide to dissection. Repeat US scanning through the incision permitted precisely targeted surgery. CT and US are the most effective imaging techniques for localizing fish bones. Intraoperative US can be used to accurately locate a submucosal fish bone in mobile tissue such as the tongue, and focused, image guided dissection can reduce surgical tissue trauma. PMID- 25145587 TI - Exercise self-efficacy intervention in overweight and obese women. AB - This study investigated the effects of a brief tailored intervention on self efficacy beliefs and exercise energy expenditure in active and inactive overweight and obese women. Participants were randomly assigned to either control (N = 50) or intervention (N = 47) conditions, and their exercise self-efficacy was assessed three times over a 12-week period. Results showed that the intervention increased schedule, physical, exercise-worries efficacy, and energy expenditure in the previously inactive group. The results suggest that self efficacy interventions are effective at increasing exercise energy expenditure in inactive overweight and obese women. PMID- 25145588 TI - Salivary cortisol and alpha-amylase responses to repeated bouts of downhill running. AB - OBJECTIVES: To determine the hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenal (SA) system response to repeated bouts of downhill running. METHODS: Eleven active but untrained males (age: 19.7 +/- 0.4 y; VO2peak 47.8 +/- 3.6 ml/kg/min) performed two 60 min bouts of downhill running (-13.5% gradient), separated by 14 days, at a speed eliciting 75% of their VO2peak on a level grade. Saliva samples were collected before (baseline), after, and every hour for 12 h and every 24 h for 6 days after each run. Salivary cortisol and alpha-amylase levels were measured as markers of the HPA axis and SA response, respectively. Results were analyzed using repeated measures ANOVA (12 h period: 2 * 14; 24 h intervals 2 * 7, P <= 0.05) with Tukey post-hoc tests where appropriate. Paired samples t-tests were used to compare collapsed data vs. baseline measurements. RESULTS: There were no significant group * time interactions for cortisol or alpha-amylase for the hourly samples up to 12 h after each run, nor for the 24 h samples up to 6 days later. The 24 h samples for alpha-amylase showed a significant group effect between runs (Run 1: 69.77 +/- 7.68 vs. Run 2: 92.19 +/- 7.67 U/ml; P = 0.04). Significant time effects were measured for both cortisol (decreased 2 h to 12 h post-run) and alpha-amylase (elevated immediately after, 1 h and 2 h post-run) (P < 0.001). CONCLUSION: The 24 h period group effect for salivary alpha-amylase suggested an adaptation in the sympathoadrenal system that may alter the systemic inflammatory response to exercise-induced muscle damage but may also reflect enhanced mucosal immunity. PMID- 25145590 TI - Neurodegenerative diseases: Pillars of remyelination. PMID- 25145589 TI - Quality of life and health care consultation in 13 to 18 year olds with abdominal pain predominant functional gastrointestinal diseases. AB - BACKGROUND: Abdominal pain predominant functional gastrointestinal diseases (AP FGD) are commonly seen in the paediatric age group. It has significant impact on daily activities of affected children. Main objective of this study was to assess the health related quality of life (HRQoL) in children with AP-FGD. METHOD: This was a cross sectional survey conducted in children aged 13-18 years, in four randomly selected schools in Western province of Sri Lanka. Data was collected using a previously validated, self-administered questionnaire. It had questions on symptoms, HRQoL and health care consultation. AP-FGD were diagnosed using Rome III criteria. RESULTS: A total of 1850 questionnaires were included in the analysis [males 1000 (54.1%), mean age 14.4 years and SD 1.3 years]. Of them, 305 (16.5%) had AP-FGD [irritable bowel syndrome = 91(4.9%), functional dyspepsia = 11 (0.6%), abdominal migraine = 37 (1.9%) and functional abdominal pain = 180 (9.7%)]. Lower HRQoL scores for physical (83.6 vs. 91.4 in controls), social (85.0 vs. 92.7), emotional (73.6 vs. 82.7) and school (75.0 vs. 82.5) functioning domains, and lower overall scores (79.6 vs. 88.0) were seen in children with AP FGD (p < 0.001). A weak but significant negative correlation was observed between HRQoL score and severity of abdominal pain (r = -0.24, p < 0.0001). Eighty five children (27.9%) had sought healthcare for AP-FGD. Factors determining healthcare seeking were presence of abdominal bloating and vomiting (p < 0.05). CONCLUSIONS: Children with AP-FGD have lower quality of life in all 4 domains. Those with severe symptoms have lower HRQoL. Approximately 28% of children with AP-FGD seek healthcare for their symptoms. PMID- 25145591 TI - An audience with... Bob More. PMID- 25145592 TI - Epilepsy: endocannabinoid metabolism offers handle to dampen down excitability. PMID- 25145593 TI - The HIV pipeline. PMID- 25145594 TI - Neurodevelopmental disorders: righting Rett syndrome with IGF1. PMID- 25145595 TI - Ability of circulating human hematopoietic lineage negative cells to support hematopoiesis. AB - Hematopoietic stem cell (HSC) self-renewal is regulated by osteoblast and/or endothelial cells within the hematopoietic niche. However, the true identity of the supporting cells and the nature of the secreted factors remain uncertain. We developed a novel mouse model and analyzed whether circulating human peripheral hematopoietic lineage negative/AP+ (lin-/AP+) cells support hematopoiesis in vivo. Thus, immunocompromised (Rag) mice expressing thymidine kinase (Tk) under the control of the 3.6Col1alpha1 promoter (Tk-Rag) were treated with ganciclovir, resulting in osteoblast progenitor cell ablation and subsequent loss of hematopoiesis (evaluated by measuring mouse Ter119+ erythroid cells). Following hematopoietic cell depletion, human bone marrow-derived marrow stromal cells (MSCs) or lin-/AP+ cells were infused into Tk-Rag mice and compared with saline infusions. Ganciclovir significantly reduced (7.4-fold) Ter119+ cells in the bone marrow of Tk-Rag mice compared to saline injections. Infusion of either MSCs or lin-/AP+ cells into ganciclovir-treated mice resulted in a 3.3-fold and 2.7-fold increase (P < 0.01), respectively, in Ter119+ cells compared to mice receiving saline. Relative to lin-/AP- cells, lin-/AP+ cells expressed high levels of mesenchymal, endothelial, and hematopoiesis supporting genes. Thus, human peripheral blood lin-/AP+ cells represent a novel cell type capable of supporting hematopoiesis in a manner comparable to MSCs. PMID- 25145597 TI - Yoshiki Sasai: stem cell Sensei. AB - Stefano Piccolo looks back at the life and research of his friend and colleague Yoshiki Sasai. PMID- 25145596 TI - Usefulness of dynamic contrast-enhanced MRI in the evaluation of the viability of acute scaphoid fracture. AB - OBJECTIVE: To evaluate the usefulness of dynamic gadolinium-enhanced magnetic resonance imaging (MRI) for assessing the viability of the proximal pole of the scaphoid in patients with acute scaphoid fractures. METHODS: Eighteen consecutive patients with acute scaphoid fracture who underwent dynamic gadolinium-enhanced MRI 7 days or less before surgery were prospectively included between August 2011 and December 2012. All patients underwent MR imaging with unenhanced images, enhanced images, and dynamic enhanced images. A radiologist first classified the MRI results as necrotic or viable based on T1- and T2-weighted images only, followed by a second blinded interpretation, this time including analysis of pre- and post-gadolinium administration images and a third blinded interpretation based on the time-intensity curve of the dynamic enhanced study. The standard of reference was the histologic assessment of a cylindrical specimen of the proximal pole obtained during surgery in all patients. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for unenhanced, enhanced, and dynamic gadolinium-enhanced MRI studies. RESULTS: The sensitivity, specificity, PPV, and NPV were 67, 67, 50, and 80 % for unenhanced images, 83, 100, 100, and 92 for enhanced images, and 83, 92, 83, and 92 for dynamic contrast-enhanced images. CONCLUSIONS: Our data are consistent with previously reported data supporting contrast-enhanced MRI for assessment of viability, and showing that dynamic imaging with time-intensity curve analysis does not provide additional predictive value over standard delayed enhanced imaging for acute scaphoid fracture. PMID- 25145598 TI - Weight loss in pregnancy and cardiometabolic profile in childhood: findings from a longitudinal birth cohort. AB - OBJECTIVE: To investigate the consequences of weight loss in pregnancy on pregnancy outcomes and cardiometabolic profile in childhood. DESIGN: Prospective birth cohort (ABCD study). SETTING: Between 2003 and 2004, all pregnant women in Amsterdam were approached for study participation. POPULATION: 7818 pregnant women were included, of which 3165 consented to having their children examined at 5-6 years of age. In 1956 children fasting capillary blood samples were also taken. METHODS: At antenatal booking, women answered questions about their pregnancy and whether they suffered from severe weight loss (SWL; >5 kg). Pregnancy details and outcomes were available through the obstetric caregiver. MAIN OUTCOME MEASURES: At birth main outcome measures were prematurity (<37 weeks) and birthweight. At follow-up, body mass index (BMI), blood pressure, glucose and lipids were assessed. RESULTS: SWL occurred in 6.8% of cases. Women with SWL had similar preterm birth rates compared with women without these complaints (adjusted OR 1.1, 95%CI 0.7, 1.7). Birthweight (adjusted difference - 31 g, 95%CI -76, 15) and BMI at 5-6 years of age (adjusted difference 0.2 kg/m(2) , 95%CI 0.0, 0.5) were similar in children born to mothers with SWL and without SWL, but blood pressure was increased. For diastolic blood pressure this association was independent of confounders (adjusted difference 1.4 mmHg, 95%CI 0.4, 2.4). Lipid and glucose levels were not significantly different between these groups. CONCLUSION: Early pregnancy weight loss, usually occurring as a manifestation of hyperemesis gravidarum, could have long-term consequences for offspring health. PMID- 25145599 TI - Ivacaftor improves appearance of sinus disease on computerised tomography in cystic fibrosis patients with G551D mutation. AB - BACKGROUND: Most patients with Cystic fibrosis (CF) have chronic sinus disease which may require multiple sinus surgeries and antibiotic courses. Ivacaftor can improve lung function, lower sweat chloride levels and improve weight by targeting the primary defect, a faulty gene and its protein product, cystic fibrosis transmembrane conductance regulator (CFTR) in patients with the G551D mutation. Its role in improving sinus disease has not been evaluated. OBJECTIVE: The objective of this study was to evaluate efficacy of ivacaftor in improving CF related sinus disease. DESIGN: Observational study. PARTICIPANTS: Twelve patients with cystic fibrosis and a G551D-CFTR mutation. METHODS: Twelve patients with a G551D-CFTR mutation were monitored for at least one year before and after starting ivacaftor. OUTCOME MEASURES: Sinus disease progression was monitored by comparing computed tomography (CT) of sinuses before and at one year on therapy. Hospital admissions, pulmonary exacerbations, weight, BMI and lung function were also compared. RESULTS: Median age was 17 years (range 10-44). Weight, BMI, FEV1 significantly increased and sweat chloride significantly decreased by six months on ivacaftor therapy. CT of the sinuses in all patients improved. Seven patients had severe sinus disease, improved to moderate in three and mild in remaining four. Four patients had moderate disease which improved to mild in all. One patient had normal sinus CT before and after the therapy. CONCLUSIONS: Patients with CF and G551D mutation, within 6 months of starting ivacaftor had significant improvements in weight, BMI and mean % FEV1. Significant lessening of underlying sinus disease measured by CT scan was noted, suggesting a disease modifying effect. PMID- 25145600 TI - Preparation of a reduced graphene oxide wrapped lithium-rich cathode material by self-assembly. AB - A lithium-rich cathode material wrapped in sheets of reduced graphene oxide (RGO) and functionalized with polydiallyldimethylammonium chloride (PDDA) was prepared by self-assembly induced from the electrostatic interaction between PDDA-RGO and the Li-rich cathode material. At current densities of 1000 and 2000 mA g(-1), the PDDA-RGO sheet wrapped samples demonstrated increased discharge capacities, increasing from 125 to 155 mA h g(-1) and from 82 to 124 mA h g(-1), respectively. The decreased resistance implied by this result was confirmed from electrochemical impedance spectroscopy results, wherein the charge-transfer resistance of the pristine sample decreased after wrapping with the PDDA-RGO sheets. The PDDA-RGO sheets served as a protective layer sand as a conductive material, which resulted in an improvement in the retention capacity from 56 to 81% after 90 cycles. PMID- 25145601 TI - Culturing Caenorhabditis elegans in axenic liquid media and creation of transgenic worms by microparticle bombardment. AB - In this protocol, we present the required materials, and the procedure for making modified C. elegans Habituation and Reproduction media (mCeHR). Additionally, the steps for exposing and acclimatizing C. elegans grown on E. coli to axenic liquid media are described. Finally, downstream experiments that utilize axenic C. elegans illustrate the benefits of this procedure. The ability to analyze and determine C. elegans nutrient requirement was illustrated by growing N2 wild type worms in axenic liquid media with varying heme concentrations. This procedure can be replicated with other nutrients to determine the optimal concentration for worm growth and development or, to determine the toxicological effects of drug treatments. The effects of varied heme concentrations on the growth of wild type worms were determined through qualitative microscopic observation and by quantitating the number of worms that grew in each heme concentration. In addition, the effect of varied nutrient concentrations can be assayed by utilizing worms that express fluorescent sensors that respond to changes in the nutrient of interest. Furthermore, a large number of worms were easily produced for the generation of transgenic C. elegans using microparticle bombardment. PMID- 25145604 TI - C-H functionalization/asymmetric Michael addition cascade enabled by relay catalysis: metal carbenoid used for C-C bond formation. AB - A combination of either ruthenium(II) or rhodium(II) complexes and quinine derived squaramide enables 3-diazooxindoles, indoles, and nitroalkenes to undergo highly efficient asymmetric three-component reactions, thus affording optically active 3,3'-bis(indole)s through a consecutive C-C bond-forming sequence, which turned out to be applicable to the facile total synthesis of (-)-folicanthine. PMID- 25145605 TI - The benzylperoxyl radical as a source of hydroxyl and phenyl radicals. AB - The benzyl radical (1) is a key intermediate in the combustion and tropospheric oxidation of toluene. Because of its relevance, the reaction of 1 with molecular oxygen was investigated by matrix-isolation IR and EPR spectroscopy as well as computational methods. The primary reaction product of 1 and O2 is the benzylperoxyl radical (2), which exists in several conformers that can easily interconvert even at cryogenic temperatures. Photolysis of radical 2 at 365 nm results in a formal [1,3]-H migration and subsequent cleavage of the O-O bond to produce a hydrogen-bonded complex between the hydroxyl radical and benzaldehyde (4). Prolonged photolysis produces the benzoyl radical (5) and water, which finally yield the phenyl radical (7), CO, and H2O. Thus, via a sequence of exothermic reactions 1 is transformed into radicals of even higher reactivity, such as OH and 7. Our results have implications for the development of models for the highly complicated process of combustion of aromatic compounds. PMID- 25145603 TI - Risk factors for self-reported arm lymphedema among female breast cancer survivors: a prospective cohort study. AB - INTRODUCTION: Lymphedema is a potentially debilitating condition that occurs among breast cancer survivors. This study examines the incidence of self-reported lymphedema, timing of lymphedema onset, and associations between sociodemographic, clinical and lifestyle factors and lymphedema risk across racial-ethnic groups using data from a multicenter, multiethnic prospective cohort study of breast cancer survivors, the Health, Eating, Activity and Lifestyle Study. METHODS: A total of 666 women diagnosed with breast cancer staged as in situ, localized or regional disease at ages 35 to 64 years were recruited through the Surveillance, Epidemiology, and End Results registries in New Mexico (non-Hispanic white and Hispanic white), Los Angeles County (black), and Western Washington (non-Hispanic white) and followed for a median of 10.2 years. We evaluated sociodemographic factors, breast cancer- and treatment related factors, comorbidities, body mass index (BMI), hormonal factors, and lifestyle factors in relation to self-reported lymphedema by fitting Cox proportional hazards models, estimating hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Over the follow-up period, 190 women (29%) reported lymphedema. The median time from breast cancer diagnosis to onset of lymphedema was 10.5 months (range: 0.5 to 134.9 months). Factors independently associated with lymphedema were total/modified radical mastectomy (versus partial/less than total mastectomy; HR = 1.37, 95% CI: 1.01 to 1.85), chemotherapy (versus no chemotherapy; HR = 1.48, 95% CI: 1.09 to 2.02), no lymph nodes removed (versus >=10 lymph nodes removed; HR = 0.17, 95% CI: 0.08 to 0.33), pre-diagnostic BMI >=30 kg/m2 (versus BMI <25 kg/m2; HR = 1.59, 95% CI: 1.09 to 2.31), and hypertension (versus no hypertension; HR = 1.49, 95% CI: 1.06 to 2.10). After adjusting for demographics and breast cancer- and treatment-related factors, no significant difference in lymphedema risk was observed across racial/ethnic groups. Analyses stratified by race/ethnicity showed that hypertension and chemotherapy were lymphedema risk factors only for black women. CONCLUSIONS: Breast cancer patients who have undergone extensive surgery or extensive lymph node dissection, or who have a higher BMI should be closely monitored for detection and treatment of lymphedema. Further studies are needed to understand the roles of chemotherapy and hypertension in the development of lymphedema. PMID- 25145602 TI - Designing silk-silk protein alloy materials for biomedical applications. AB - Fibrous proteins display different sequences and structures that have been used for various applications in biomedical fields such as biosensors, nanomedicine, tissue regeneration, and drug delivery. Designing materials based on the molecular-scale interactions between these proteins will help generate new multifunctional protein alloy biomaterials with tunable properties. Such alloy material systems also provide advantages in comparison to traditional synthetic polymers due to the materials biodegradability, biocompatibility, and tenability in the body. This article used the protein blends of wild tussah silk (Antheraea pernyi) and domestic mulberry silk (Bombyx mori) as an example to provide useful protocols regarding these topics, including how to predict protein-protein interactions by computational methods, how to produce protein alloy solutions, how to verify alloy systems by thermal analysis, and how to fabricate variable alloy materials including optical materials with diffraction gratings, electric materials with circuits coatings, and pharmaceutical materials for drug release and delivery. These methods can provide important information for designing the next generation multifunctional biomaterials based on different protein alloys. PMID- 25145606 TI - Metabolism of D-galactose is dispensable for the induction of the beta galactosidase (bgaD) and lactose permease (lacpA) genes in Aspergillus nidulans. AB - In this study, we analyze the expression of the Aspergillus nidulans bgaD-lacpA gene couple (encoding an intracellular beta-galactosidase and a lactose permease) in the presence of D-galactose. This monosaccharide can be catabolized via alternative, independent pathways in this model organism. The inductive capabilities of intermediates of the two alternative routes of D-galactose utilization were addressed in loss-of-function mutants defective in a defined step in one of the two pathways. In a galactokinase (galE9) mutant, the cluster is strongly induced by D-galactose, suggesting that formation of Leloir pathway intermediates is not required. The expression profiles of bgaD and lacpA were similar in wild type, L-arabinitol dehydrogenase (araA1), and hexokinase (hxkA1) negative backgrounds, indicating that intermediates of the oxido-reductive pathway downstream of galactitol are not necessary either. Furthermore, bgaD lacpA transcription was not induced in any of the tested strains when galactitol was provided as the growth substrate. An hxkA1/galE9 double mutant cannot grow on d-galactose at all, but still produced bgaD and lacpA transcripts upon transfer to d-galactose. We therefore concluded that the physiological inducer of the bgaD lacpA gene cluster upon growth on D-galactose is the nonmetabolized sugar itself. PMID- 25145607 TI - Re-analysis of the association between perinatal androgens and postnatal head circumference growth. PMID- 25145608 TI - Usage and acceptability of HIV self-testing in men who have sex with men in Hong Kong. AB - Whilst studies on over-the-counter HIV tests continue to accumulate after FDA's approval of OraQuick Advance in 2012, few have focused on men who have sex with men (MSM) in Asian cities. An internet survey was conducted on 1,122 MSM in Hong Kong, revealing a low usage (6.1 %) and acceptability rate (43.8 %) on self testing despite its availability in the market. Hierarchical logistic regression models showed that having received relevant information and users' attitudes on self-testing were the determinants of usage and acceptability. These factors had greater effects than sexual behaviors and social-networking on MSM's decision on self-testing. Majority of ever self-testers only repeated the self-test after a non-negative result, and overall only 26.6 % went for a formal test subsequent to the self-test. Concerns regarding the tests' accuracy were expressed by respondents. In conclusion, appropriate and accessible information and evidence based guidance are needed to incorporate self-testing into HIV prevention strategies targeting MSM. PMID- 25145610 TI - An aggregation-induced emission (AIE) active probe renders Al(III) sensing and tracking of subsequent interaction with DNA. AB - An aggregation-induced emission (AIE) active probe (L) displayed TURN-ON fluorescence response toward Al(3+) under physiological conditions and in HeLa cells. The L-Al(3+) ensemble could subsequently facilitate tracking of interaction with DNA in solution. PMID- 25145609 TI - Non-polio enteroviruses from acute flaccid paralysis surveillance in Shandong Province, China, 1988-2013. AB - Enteroviruses (EVs) are important human pathogens associated with various clinical syndromes. This study represents an overview of non-polio enteroviruses (NPEVs) isolated from acute flaccid paralysis (AFP) surveillance in Shandong Province, China from 1988 to 2013. Altogether 792 and 170 NPEV isolates were isolated from stool specimens of 9263 AFP cases and 1059 contacts, respectively. Complete VP1 sequencing and typing on all 962 isolates revealed 53 NPEV types in which echovirus (E) 6 (7.6%), E14 (7.6%), E11 (7.4%), coxsackievirus (CV) B3 (7.4%), E25 (5.6%), CVB5 (4.9%), E7 (4.5%) and EV-A71 (4.4%) were the eight most commonly reported serotypes. Distinct summer-fall seasonality was observed, with June-October accounting for 79.3% of isolation from AFP cases with known month of specimen collection. Increase of isolation of EV-A71 and CVA--the predominant pathogens for the hand, foot, and mouth disease--was observed in recent years. Sequence analysis on VP1 coding region of EV-A71 and E6 suggested Shandong strains had great genetic divergence with isolates from other countries. The results described in this study provide valuable information on the circulation and emergence of different EV types in the context of limited EV surveillance in China. PMID- 25145611 TI - Theoretical optimization of the removal of cryoprotective agents using a dilution filtration system. AB - BACKGROUND: In the cryopreservation of blood, removing cryoprotectants from the cryopreserved blood safely and effectively is always being focused on. In our previous work, a dilution-filtration system was proposed to achieve the efficient clearance of cryoprotectants from the cryopreserved blood. METHOD: In this study, a theoretical method is presented to optimize the diluent flow rate in the system to further reduce the osmotic damage to red blood cells (RBCs) and shorten the washing time necessary to remove cryoprotective agents (CPAs), based on a discrete mass transfer concept. In the method, the diluent flow rate is automatically adjusted by a program code in each cycle to maximize the clearance of CPAs, whereas the volume of RBCs is always maintained below the upper volume tolerance limit. RESULTS: The results show that the optimized diluent flow rate can significantly decrease the washing time of CPAs. The washing time under the optimized diluent flow rate can be reduced by over 50%, compared to the one under the fixed diluent flow rate. In addition, the advantage of our method becomes more significant when the blood flow rate is lower, the dilution region volume is larger, the initial CPA concentration is higher, or the cell-swelling limit set by the system is smaller. CONCLUSION: The proposed method for the dilution filtration system is an ideal solution for not only guaranteeing the volume safety of RBCs but also shortening the washing time of CPAs. In practice, the optimization strategies provided here will be useful in the rapid preparation of cryopreserved blood for clinical use. PMID- 25145612 TI - Rhodium(III)-catalyzed intramolecular redox-neutral annulation of tethered alkynes: formal total synthesis of (+/-)-goniomitine. AB - A Rh(III)-catalyzed intramolecular redox-neutral atom-economic annulation of a tethered alkyne has been developed to efficiently construct 2-amidealkyl indoles with completely reversed regioselectivity by a C-H activation pathway. Furthermore, using the Rh(III)-catalyzed C-H activation/annulation as a key step, a one-pot synthesis of pyrido[1,2-a]indoles has also been developed and applied to a highly efficient formal total synthesis of (+/-)-goniomitine. PMID- 25145613 TI - Private sector benefits the most from efforts to market NHS skills abroad. PMID- 25145614 TI - Is propofol more neurotoxic in the developing brain? PMID- 25145617 TI - A longitudinal examination of the interrelationship of multiple health behaviors. AB - BACKGROUND: Evaluating the interrelationship of health behaviors could assist in the development of effective public health interventions. Furthermore, the ability to identify cognitive mediators that may influence multiple behavioral changes requires evaluation. PURPOSE: To evaluate covariation among health behaviors, specifically alcohol consumption, leisure-time physical activity, and smoking, and examine whether mastery acts as a mediating social-cognitive mechanism that facilitates multiple health behavior change in a longitudinal analysis. METHODS: In 2010, secondary data analysis was conducted on the first seven cycles of the Canadian National Population Health Survey. Data collection began in 1994-1995 and has continued biennially. At the time of this analysis, only seven cycles of data (2006-2007) were available. Parallel process growth curve models were used to analyze covariation between health behaviors and the potential mediating effects of perceived mastery. RESULTS: Increases in leisure time physical activity were associated with reductions in tobacco use, whereas declines in alcohol consumption were associated with decreases in tobacco use. Covariation between alcohol consumption and leisure-time physical activity did not reach statistical significance. For the most part, mastery was unsuccessful in mediating the interrelationship of multiple behavioral changes. CONCLUSIONS: Health behaviors are not independent but rather interrelated. In order to optimize limited prevention resources, these results suggest that population level intervention efforts targeting multiple modifiable behavioral risk factors may not need to occur simultaneously. PMID- 25145616 TI - Comparison of hepatitis C virus testing strategies: birth cohort versus elevated alanine aminotransferase levels. AB - BACKGROUND: Hepatitis C virus (HCV) infection is unidentified in an estimated 40% 85% of infected adults. Surveillance and modeling data have found significant increases in HCV-associated morbidity and mortality. PURPOSE: To compare two HCV antibody (anti-HCV) testing strategies based on (1) elevated alanine aminotransferase levels (ALT) and (2) a birth cohort approach for people born during 1945-1965. METHODS: Data from 19,055 adults aged 20-70 years who completed the National Health and Nutrition Examination Survey in 1999-2008 were analyzed in 2013. Two independent models were evaluated, based on membership in the 1945 1965 birth cohort or elevated ALT, to compare the number of identified anti-HCV positive (anti-HCV+) individuals; proportion of total identified cases; and the number of people that would be tested using either strategy. RESULTS: The prevalence of anti-HCV among adults aged 20-70 years was estimated at 2.0% (95% CI=1.8%, 2.3%), representing about 3.6 million people. The birth cohort strategy would result in testing about 85.4 million people and identifying nearly 2.8 million anti-HCV+ people with a sensitivity of 76.6%. The ALT strategy would test about 21.5 million adults and identify approximately 1.8 million anti-HCV+ people with a sensitivity of 50.0%. Implementing both strategies concurrently would identify 87.3% of anti-HCV+ adults. CONCLUSIONS: The birth cohort strategy, which is recommended by both the CDC and the U.S. Preventive Services Task Force, would identify 1 million more anti-HCV+ people than the elevated ALT approach. Concurrent implementation would identify an even larger number of individuals ever infected. PMID- 25145618 TI - A systematic review of mandatory influenza vaccination in healthcare personnel. AB - CONTEXT: Influenza is a major cause of patient morbidity. Mandatory influenza vaccination of healthcare personnel (HCP) is increasingly common yet has uncertain clinical impact. This study systematically examines published evidence of the benefits and harm of influenza vaccine mandates. EVIDENCE ACQUISITION: MEDLINE, Embase, the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Science Citation Index Expanded, and Conference Proceedings Citations Index were searched and analyzed in 2013. Studies must have assessed the effect of a requirement of influenza vaccination among HCP for continued employment or clinical practice. Studies were not limited by comparison group, outcome, language, or study design. Two reviewers independently abstracted data and assessed bias risk. EVIDENCE SYNTHESIS: Twelve observational studies were included in the study from 778 citations. Following implementation of a vaccine mandate, vaccination rates increased in all eight studies reporting this outcome, exceeding 94%. Three studies documented increased vaccination rates in hospitals with mandates compared to those without (p<0.001 for all comparisons). Two single institution studies reported limited, inconclusive results on absenteeism among HCP. No studies reported on clinical outcomes among patients. Medical and religious exemptions and terminations or voluntary resignations were rare. CONCLUSIONS: Evidence from observational studies suggests that a vaccine mandate increases vaccination rates, but evidence on clinical outcomes is lacking. Although challenging, large healthcare employers planning to implement a mandate should develop a strategy to evaluate HCP and patient outcomes. Further studies documenting the impact of HCP influenza vaccination on clinical outcomes would inform decisions on the use of mandatory vaccine policies in HCP. PMID- 25145619 TI - Economics of mass media health campaigns with health-related product distribution: a community guide systematic review. AB - CONTEXT: The objective of this systematic review was to determine the costs, benefits, and overall economic value of communication campaigns that included mass media and distribution of specified health-related products at reduced price or free of charge. EVIDENCE ACQUISITION: Economic evaluation studies from a literature search from January 1980 to December 2009 were screened and abstracted following systematic economic review methods developed by The Community Guide. Data were analyzed in 2011. EVIDENCE SYNTHESIS: The economic evidence was grouped and assessed by type of product distributed and health risk addressed. A total of 15 evaluation studies were included in the economic review, involving campaigns promoting the use of child car seats or booster seats, pedometers, condoms, recreational safety helmets, and nicotine replacement therapy. CONCLUSIONS: Economic merits of the intervention could not be determined for health communication campaigns associated with use of recreational helmets, child car seats, and pedometers, primarily because available economic information and analyses were incomplete. There is some evidence that campaigns with free condom distribution to promote safer sex practices were cost-effective among high-risk populations and the cost per quit achieved in campaigns promoting tobacco cessation with nicotine replacement therapy products may translate to a cost per quality-adjusted life-year less than $50,000. Many interventions were publicly funded trials or programs, and the failure to properly evaluate their economic cost and benefit is a serious gap in the science and practice of public health. PMID- 25145621 TI - Combination of mass media health campaigns and health-related product distribution is recommended to improve healthy behaviors. PMID- 25145620 TI - Mass media health communication campaigns combined with health-related product distribution: a community guide systematic review. AB - CONTEXT: Health communication campaigns including mass media and health-related product distribution have been used to reduce mortality and morbidity through behavior change. The intervention is defined as having two core components reflecting two social marketing principles: (1) promoting behavior change through multiple communication channels, one being mass media, and (2) distributing a free or reduced-price product that facilitates adoption and maintenance of healthy behavior change, sustains cessation of harmful behaviors, or protects against behavior-related disease or injury. EVIDENCE ACQUISITION: Using methods previously developed for the Community Guide, a systematic review (search period, January 1980-December 2009) was conducted to evaluate the effectiveness of health communication campaigns that use multiple channels, including mass media, and distribute health-related products. The primary outcome of interest was use of distributed health-related products. EVIDENCE SYNTHESIS: Twenty-two studies that met Community Guide quality criteria were analyzed in 2010. Most studies showed favorable behavior change effects on health-related product use (a median increase of 8.4 percentage points). By product category, median increases in desired behaviors ranged from 4.0 percentage points for condom promotion and distribution campaigns to 10.0 percentage points for smoking-cessation campaigns. CONCLUSIONS: Health communication campaigns that combine mass media and other communication channels with distribution of free or reduced-price health-related products are effective in improving healthy behaviors. This intervention is expected to be applicable across U.S. demographic groups, with appropriate population targeting. The ability to draw more specific conclusions about other important social marketing practices is constrained by limited reporting of intervention components and characteristics. PMID- 25145622 TI - Comparison of endocrine changes, timing of ovulations, ovarian follicular growth, and efficacy associated with Estradoublesynch and Heatsynch protocols in Murrah buffalo cows (Bubalus bubalis). AB - Poor estrus expression and the difficulty encountered in predicting the time of ovulation compromise the reproductive efficiency of Murrah buffalo cows. Synchronization of ovulation and timed artificial insemination are able to precisely control the time of ovulation and thus avoid the need for estrus detection. Recently, the Estradoublesynch protocol (administration of a PGF2alpha injection 2 days before Heatsynch protocol; GnRH 0, PGF2alpha 7, estradiol benzoate [EB] 8) was developed that precisely synchronized ovulation twice, i.e., after GnRH and EB injections and resulted in satisfactory pregnancy rates in Murrah buffaloes. The present study was conducted on 104 cycling and 31 anestrus buffaloes to compare (1) the endocrine changes, timing of ovulations, ovarian follicular growth, and efficacy of Estradoublesynch and Heatsynch protocols in cycling and (2) the efficacy of Estradoublesynch and Heatsynch protocols for the improvement of fertility in cycling and anestrus Murrah buffalo cows. Ovulation was confirmed after all GnRH and EB treatments by ultrasonographic examination at 2-hour intervals. Plasma progesterone and total estrogen concentrations were determined in blood samples collected at daily intervals, beginning 2 days before the onset of protocols until the day of second ovulation detection. Ovulatory follicle size was measured by ultrasonography at six time points (first PGF2alpha administration of Estradoublesynch protocol every 2 days before the onset of Heatsynch protocol, GnRH administration of both protocols, 2 hours before ovulation detection after GnRH administration of both protocols, second PGF2alpha injection of Estradoublesynch protocol, PGF2alpha injection of Heatsynch protocol, EB injection of both protocols and, 2 hours before ovulation detection after EB administration of both protocols). Plasma LH, total estrogen, and progesterone concentrations were determined in blood samples collected at 30 minute intervals for 8 hours, beginning GnRH and EB injections, and thereafter at 2-hour intervals until 2 hours after the detection of ovulation. The first ovulatory rate was significantly higher (P<0.05) in the Estradoublesynch protocol (84.6%) than that in the Heatsynch protocol (36.4%). The first LH peak concentration (74.6+/-10.4 ng/mL) in the Estradoublesynch protocol was significantly higher (P<0.05) than that of the Heatsynch protocol (55.3+/-7.4 ng/mL). In Estradoublesynch protocol, the total estrogen concentration gradually increased from the day of GnRH administration coinciding with LH peak, and then gradually declined to the basal level until the time of ovulation detection. However, in Heatsynch protocol, the gradual increase in total estrogen concentration after GnRH administration was observed only in those buffalo cows, which responded to treatment with ovulation. In both Estradoublesynch and Heatsynch protocols, ovulatory follicle size increased by treatment with GnRH and EB until the detection of ovulation. The pregnancy rate after the Estradoublesynch protocol (60.0%) was significantly higher (P<0.05) than that achieved after the Heatsynch protocol (32.5%). Satisfactory success rate using the Estradoublesynch protocol was attributed to the higher release of LH after treatment with GnRH, leading to ovulation in most of the animals and hence creating the optimum follicular size at EB injection for ovulation and pregnancy to occur. PMID- 25145625 TI - Type-dependent identification of DNA nucleobases by using diamondoids. AB - The possibility of distinguishing between DNA nucleobases of different sizes is manifested here through quantum-mechanical simulations. By using derivatives of small, modified diamond clusters, known as diamondoids, it is possible to separate the pyrimidines (cytosine and thymine) from the larger purines (adenine and guanine), according to the collective electronic and binding properties of these DNA nucleobases and the diamondoid. The latter acts as a probe with which these properties can be examined in detail. Short single-stranded DNA is built up from single nucleobases to reveal the effect of each DNA unit on the sensing abilities of the diamondoid probe. Several ways of orienting the nucleobases, nucleosides, nucleotides, and short single-stranded DNA are investigated; these lead to quite different electronic properties and may or may not enhance the possibility of separating the DNA nucleobases. For the optimum orientation, that is, one that promotes stronger hydrogen bonding of the diamondoid to the short DNA strand, it is found that the electronic band gaps of a purine strand lie in a completely different range to the band gaps of a pyrimidine strand. This difference can be over 1 eV, which is measurable and shows the potential of using diamondoids and their derivatives in biosensing devices. PMID- 25145624 TI - The safety of olanzapine in young children: a systematic review and meta analysis. AB - BACKGROUND: Olanzapine is frequently prescribed in young children for psychiatric conditions. It may be an option for chemotherapy-induced nausea and vomiting (CINV) control in children. The objective of this review was to describe the safety of olanzapine in children less than 13 years of age to determine if safety concerns would be a barrier to its use for CINV prevention. METHODS: Electronic searches were performed in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science and Scopus. All studies in English reporting adverse effects associated with olanzapine use in children younger than 13 years or with a mean/median age less than 13 years were included. Adverse outcomes were synthesized for prospective studies. RESULTS: A total of 47 studies (17 prospective) involving 387 children aged 0.6-18 years were included; nine described olanzapine poisonings. Weight gain or sedation were reported in 78 % [95 % confidence interval (CI) 63-95] and 48 % (95 % CI 35-67), respectively. Extrapyramidal symptoms or electrocardiogram abnormalities were reported in 9 % (95 % CI 4-21) and 14 % (95 % CI 7-26), respectively. Elevation in liver function tests or blood glucose abnormalities were reported in 7 % (95 % CI 2-20) and 4 % (95 % CI 1-17), respectively. No deaths were attributed to olanzapine. LIMITATIONS: No studies were identified with a primary focus on evaluating safety, and the adverse effects reported in the included studies were heterogeneous. CONCLUSIONS: Most adverse events associated with olanzapine use in children less than 13 years of age are of minor clinical significance. These findings support the exploration of olanzapine for the prevention of CINV in children in future trials. PMID- 25145626 TI - Impact on offspring methylation patterns of maternal gestational diabetes mellitus and intrauterine growth restraint suggest common genes and pathways linked to subsequent type 2 diabetes risk. AB - Size at birth, postnatal weight gain, and adult risk for type 2 diabetes may reflect environmental exposures during developmental plasticity and may be mediated by epigenetics. Both low birth weight (BW), as a marker of fetal growth restraint, and high birth weight (BW), especially after gestational diabetes mellitus (GDM), have been linked to increased risk of adult type 2 diabetes. We assessed DNA methylation patterns using a bead chip in cord blood samples from infants of mothers with GDM (group 1) and infants with prenatal growth restraint indicated by rapid postnatal catch-up growth (group 2), compared with infants with normal postnatal growth (group 3). Seventy-five CpG loci were differentially methylated in groups 1 and 2 compared with the controls (group 3), representing 72 genes, many relevant to growth and diabetes. In replication studies using similar methodology, many of these differentially methylated regions were associated with levels of maternal glucose exposure below that defined by GDM [the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study] or were identified as changes observed after randomized periconceptional nutritional supplementation in a Gambian cohort characterized by maternal deprivation. These studies provide support for the concept that similar epigenetic modifications may underpin different prenatal exposures and potentially increase long-term risk for diseases such as type 2 diabetes. PMID- 25145627 TI - UCP4A protects against mitochondrial dysfunction and degeneration in pink1/parkin models of Parkinson's disease. AB - Genetic mutations in parkin or pink1 are the most common causes of familial Parkinson's disease. PINK1 and Parkin are components of a mitochondrial quality control pathway that degrades dysfunctional mitochondria via autophagy. Using a candidate gene approach, we discovered that overexpression of uncoupling protein 4A (ucp4A) suppresses a range of pink1 mutant phenotypes, including male sterility, locomotor defects, and muscle degeneration that result from abnormal mitochondrial morphology and function. Furthermore, UCP4A overexpression in pink1 mutants rescued mitochondria-specific phenotypes associated with mitochondrial membrane potential, production of reactive oxygen species, resistance to oxidative stress, efficiency of the electron transport chain, and mitochondrial morphology. Consistent with its role in protecting mitochondria, UCP4A rescued mitochondrial phenotypes of parkin mutant flies, as well. Finally, the genetic deletion of ucp4A resulted in increased sensitivity to oxidative stress, a phenotype that was enhanced by the loss of PINK1. Taken together, these results indicate that UCP4A prevents mitochondrial dysfunction and that modulation of UCP activity protects cells in a situation relevant for human Parkinson's disease. PMID- 25145628 TI - Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy. AB - Expression of microRNA-652 (miR-652) increases in the diseased heart, decreases in a setting of cardioprotection, and is inversely correlated with heart function. The aim of this study was to assess the therapeutic potential of inhibiting miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Mice were subjected to a sham operation or transverse aortic constriction (TAC) for 4 wk to induce hypertrophy and cardiac dysfunction, followed by administration of a locked nucleic acid (LNA)-antimiR-652 (miR-652 inhibitor) or LNA control. Cardiac function was assessed before and 8 wk post-treatment. Expression of miR-652 increased in hearts subjected to TAC compared to sham surgery (2.9-fold), and this was suppressed by ~95% in LNA-antimiR-652-treated TAC mice. Inhibition of miR-652 improved cardiac function in TAC mice (fractional shortening:29+/-1% at 4 wk post TAC compared to 35+/-1% post-treatment) and attenuated cardiac hypertrophy. Improvement in heart function was associated with reduced cardiac fibrosis, less apoptosis and B-type natriuretic peptide gene expression, and preserved angiogenesis. Mechanistically, we identified Jagged1 (a Notch1 ligand) as a novel direct target of miR-652. In summary, these studies provide the first evidence that silencing of miR-652 protects the heart against pathological remodeling and improves heart function. PMID- 25145630 TI - Do personality traits predict outcome of psychodynamically oriented psychosomatic inpatient treatment beyond initial symptoms? AB - OBJECTIVES: Whether personality characteristics have an impact on treatment outcome is an important question in psychotherapy research. One of the most common approaches for the description of personality is the five-factor model of personality. Only few studies investigated whether patient personality as measured with the NEO-Five-Factor Inventory (NEO-FFI, Costa & McCrae [1992b]. Revised NEO-PI-R and NEO-FFI. Professional manual. Odessa, FL: Psychological Assessment Recources) predicts outcome. Results were inconsistent. Studies reporting personality to be predictive of outcome did not control for baseline symptoms, while studies controlling initial symptoms could not support these findings. We hypothesized that after taking into account baseline symptoms, the NEO-FFI would not predict outcome and tested this in a large sample of inpatients at a psychosomatic clinic. DESIGN: Naturalistic, non-controlled study using patients' data for multiple regression analysis to identify predictors of outcome. METHODS: Data of 254 inpatients suffering primarily from depressive, anxiety, stress, and somatoform disorders were analysed. Personality was assessed at the beginning of therapy. For psychotherapy outcome, changes in anxiety and depression (Hospital Anxiety and Depression Scale; HADS), overall psychopathology (Symptom Checklist-90-R Global Severity Index [GSI]), and interpersonal problems (Inventory of Interpersonal Problems; IIP) were measured. RESULTS: The treatment resulted in significant decreases on all outcome measures corresponding to moderate to large effect sizes (HADS: d = 1.03; GSI: d = 0.90; IIP: d = 0.38). Consistent with our hypothesis, none of the personality domains predicted outcome when baseline symptoms were controlled for. CONCLUSIONS: Personality assessment at baseline does not seem to have an added value in the prediction of inpatient psychotherapy outcome beyond initial symptoms. PRACTITIONER POINTS: Clinical implications Personality dimensions overlap with symptomatic distress. Rather than serve as predictors of outcome, the domains tapped by the NEO-FFI reflect current psychological symptomatology in inpatients with depressive, anxiety, stress or somatoform disorders. From a clinician's point of view monitoring individual progress by using actuarial measures is more valuable than trying to predict who will benefit from treatment using personality assessments. Limitations of the study Diagnostic assessment was solely based on clinical evaluation rather than structured interviews. Twenty-five per cent of the original sample had to be excluded due to missing data. There was a focus on only one set of client characteristics (i.e., five-factor model personality traits). Assessment of personality domains in the acute phase of a mental disorder may be problematic and could have influenced findings. PMID- 25145629 TI - Local receptors as novel regulators for peripheral clock expression. AB - Mammalian circadian control is determined by a central clock in the brain suprachiasmatic nucleus (SCN) and synchronized peripheral clocks in other tissues. Increasing evidence suggests that SCN-independent regulation of peripheral clocks also occurs. We examined how activation of excitatory receptors influences the clock protein PERIOD 2 (PER2) in a contractile organ, the urinary bladder. PERIOD2::LUCIFERASE-knock-in mice were used to report real-time PER2 circadian dynamics in the bladder tissue. Rhythmic PER2 activities occurred in the bladder wall with a cycle of ~ 24 h and peak at ~ 12 h. Activation of the muscarinic and purinergic receptors by agonists shifted the peak to an earlier time (7.2 +/- 2.0 and 7.2 +/- 0.9 h, respectively). PER2 expression was also sensitive to mechanical stimulation. Aging significantly dampened PER2 expression and its response to the agonists. Finally, muscarinic agonist-induced smooth muscle contraction also exhibited circadian rhythm. These data identified novel regulators, endogenous receptors, in determining local clock activity, in addition to mediating the central control. Furthermore, the local clock appears to reciprocally align receptor activity to circadian rhythm for muscle contraction. The interaction between receptors and peripheral clock represents an important mechanism for maintaining physiological functions and its dysregulation may contribute to age-related organ disorders. PMID- 25145633 TI - Why quality counts. PMID- 25145632 TI - Cardiovascular risk stratification in diabetic patients: is all in METS? PMID- 25145634 TI - Early post-stress LV dyssynchrony: a new marker for significant CAD. PMID- 25145635 TI - Does perfusion pattern influence stress-induced changes in left ventricular mechanical dyssynchrony on thallium-201-gated SPECT myocardial perfusion imaging? AB - BACKGROUND: The relationship between perfusion pattern and stress-induced changes in left ventricular mechanical dyssynchrony (LVMD) on stress-rest thallium-201 gated SPECT myocardial perfusion imaging (Tl-201 SPECT MPI) is not clear. The aim of the study is to assess the relation of perfusion pattern with stress-induced changes in LVMD on Tl-201 MPI. METHODS: Data of 194 patients who underwent exercise-rest Tl-201 MPI between January to December 2012 at our institute was retrospectively evaluated. Institute Ethical committee approval was obtained. Fifty patients who underwent Tl-201 MPI for suspected CAD and had normal LV perfusion and function on MPI were taken as normal group. Patients with perfusion abnormalities (n = 144) were divided into three groups: ischemia (n = 66), infarct (n = 32), and mixed group (n = 46; ischemia and infarct both). Summed stress score, summed rest score, summed difference score (SDS), and LV ejection fraction (EF) were evaluated. Two LVMD parameters, phase standard deviation (PSD) and phase histogram bandwidth (PHB), were assessed in post-stress and rest MPI images. DeltaPSD (post-stress PSD - rest PSD) and DeltaPHB (post-stress PHB - rest PHB) were calculated to measure stress-induced changes in LVMD. RESULTS: In all the groups, mean post-stress LVMD parameters were lower as compared to LVMD parameters at rest. Post-stress PSD was significantly lower than rest PSD in all groups. Similar trend was noted with PHB values also, but it was statistically significant in the normal and ischemia group only. Post-stress worsening of at least one of the LVMD parameters was noted in 28 patients and all these patients had perfusion abnormalities. But on subgroup analysis, no difference was found in proportion of patients showing post-stress worsening of LVMD between ischemia (13.6%), infarct (25%), and mixed (23.6%) groups. No significant correlation was found between DeltaPSD/DeltaPHB and DeltaLVEF/SDS in any group. CONCLUSION: LV mechanical dyssynchrony parameters are smaller in post-exercise stress as compared to rest on Tl-201 MPI, regardless of perfusion pattern. Stress-induced worsening of LV dyssynchrony was observed only in patients with perfusion abnormalities, but this is not related to the type of perfusion abnormality. PMID- 25145631 TI - Improvement of cardiac function by placenta-derived mesenchymal stem cells does not require permanent engraftment and is independent of the insulin signaling pathway. AB - INTRODUCTION: The objective of this work was to evaluate the efficacy of placenta derived mesenchymal stem cell (MSC) therapy in a mouse model of myocardial infarction (MI). Since MSCs can be obtained from two different regions of the human term placenta (chorionic plate or villi), cells obtained from both these regions were compared so that the best candidate for cell therapy could be selected. METHODS: For the in vitro studies, chorionic plate MSCs (cp-MSCs) and chorionic villi MSCs (cv-MSCs) were extensively characterized for their genetic stability, clonogenic and differentiation potential, gene expression, and immunophenotype. For the in vivo studies, C57Bl/6 mice were submitted to MI and, after 21 days, received weekly intramyocardial injections of cp-MSCs for 3 weeks. Cells were also stably transduced with a viral construct expressing luciferase, under the control of the murine stem cell virus (MSCV) promoter, and were used in a bioluminescence assay. The expression of genes associated with the insulin signaling pathway was analyzed in the cardiac tissue from cp-MSCs and placebo groups. RESULTS: Morphology, differentiation, immunophenotype, and proliferation were quite similar between these cells. However, cp-MSCs had a greater clonogenic potential and higher expression of genes related to cell cycle progression and genome stability. Therefore, we considered that the chorionic plate was preferable to the chorionic villi for the isolation of MSCs. Sixty days after MI, cell-treated mice had a significant increase in ejection fraction and a reduction in end-systolic volume. This improvement was not caused by a reduction in infarct size. In addition, tracking of cp-MSCs transduced with luciferase revealed that cells remained in the heart for 4 days after the first injection but that the survival period was reduced after the second and third injections. Quantitative reverse transcription-polymerase chain reaction revealed similar expression of genes involved in the insulin signaling pathway when comparing cell-treated and placebo groups. CONCLUSIONS: Improvement of cardiac function by cp-MSCs did not require permanent engraftment and was not mediated by the insulin signaling pathway. PMID- 25145636 TI - Exploring potential virulence regulators in Paracoccidioides brasiliensis isolates of varying virulence through quantitative proteomics. AB - Few virulence factors have been identified for Paracoccidioides brasiliensis, the agent of paracoccidioidomycosis. In this study, we quantitatively evaluated the protein composition of P. brasiliensis in the yeast phase using minimal and rich media to obtain a better understanding of its virulence and to gain new insights into pathogen adaptation strategies. This analysis was performed on two isolates of the Pb18 strain showing distinct infection profiles in B10.A mice. Using liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis, we identified and quantified 316 proteins in minimal medium, 29 of which were overexpressed in virulent Pb18. In rich medium, 29 out of 295 proteins were overexpressed in the virulent fungus. Three proteins were found to be up-regulated in both media, suggesting the potential roles of these proteins in virulence regulation in P. brasiliensis. Moreover, genes up-regulated in virulent Pb18 showed an increase in its expression after the recovery of virulence of attenuated Pb18. Proteins up regulated in both isolates were grouped according to their functional categories. Virulent Pb18 undergoes metabolic reorganization and increased expression of proteins involved in fermentative respiration. This approach allowed us to identify potential virulence regulators and provided a foundation for achieving a molecular understanding of how Paracoccidioides modulates the host-pathogen interaction to its advantage. PMID- 25145637 TI - Estimating the minimum important change in the 15D scores. AB - PURPOSE: To facilitate the interpretation of empirical results produced by the 15D, a generic, preference-based instrument for measuring health-related quality of life (HRQoL), a subjective five-category global assessment scale (GAS) was used as an external anchor to determine the minimum important change (MIC) in the 15D scores. METHODS: Altogether 4,903 hospital patients representing sixteen disease entities and having the 15D score at baseline repeated the HRQoL assessment at 6 months after treatment and answered the question: compared to the situation before treatment, my overall health status is now (1) much better, (2) slightly better, (3) much the same, (4) slightly worse, (5) much worse. Regression analysis was used to estimate the MIC for improvement/deterioration, defined as the lower/upper limit of 99.9 % confidence interval of the regression coefficient, standardized for baseline HRQoL, for categories (2) and (4), respectively, and confirmed by ROC curve analysis. RESULTS: The limits or intervals for classifying the changes of 15D scores into GAS categories were >.035 for (1), .015-.035 for (2),>-.015 and<.015 for (3), -.035--.015 for (4) and <-.035 for (5). The lower/upper limits of +/-.015 for categories (2) and (4) can be regarded as the generic MIC thresholds for improvement/deterioration, respectively. CONCLUSIONS: The generic MICs for the change of 15D scores are +/ .015. Follow-up studies using the 15D should report the mean change in the 15D score, its statistical significance, relationship to the MIC, and the distribution of the changes of the 15D scores into the five categories. PMID- 25145638 TI - Diazinon and permethrin mitigation across a grass-wetland buffer. AB - Vegetated buffers of different designs are often used as edge-of-field treatment practices to remove pesticides that may be entrained in agricultural runoff. However, buffer system efficacy in pesticide runoff mitigation varies widely due to a multitude of factors including, but not limited to, pesticide chemistry, vegetation composition, and hydrology. Two experimental systems, a control (no vegetation) and a grass-wetland buffer system, were evaluated for their ability to retain diazinon and permethrin associated with a simulated storm runoff. The two systems were equally inefficient at retaining diazinon (mean 9.6 % retention for control and buffer). Grass-wetland buffers retained 83 % and 85 % of cis- and trans-permethrin masses, respectively, while the control only retained 39 % and 44 % of cis- and trans-permethrin masses, respectively. Half-distances (the distance required to decrease pesticide concentration by one-half) for both permethrin isomers were 26 %-30 % shorter in grass buffers (22-23 m) than in the control (32 m). The current study demonstrates treatment efficacy was a function of pesticide properties with the more strongly sorbing permethrin retained to a greater degree. The study also demonstrates challenges in remediating multiple pesticides with a single management practice. By using suites of management practices, especially those employing vegetation, better mitigation of pesticide impacts may be accomplished. PMID- 25145639 TI - For the Sake of Justice: Should We Prioritize Rare Diseases? AB - This article is about the justifiability of accepting worse cost effectiveness for orphan drugs, that is, treatments for rare diseases, in a publicly financed health care system. Recently, three arguments have been presented that may be used in favour of exceptionally advantageous economic terms for orphan drugs. These arguments share the common feature of all referring to considerations of justice or fairness: the argument of the irrelevance of group size, the argument from the principle of need, and the argument of identifiability. It is argued that all of these arguments fail to support the conclusion that orphan drugs should be subsidized to a larger extent than treatments for common diseases. The argument of the irrelevance fails to distinguish between directly and indirectly relevant considerations of fairness or justice. The recent attempt to revive the moral relevance of identifiability has provided no novel reasons to think that identifiability is morally relevant in itself or due to considerations of fairness and justice. The argument from the principle of need does not fail due to any inherent flaw in the principle as such. Rather, this principle can be interpreted in different ways, and none of these interpretations support exceptionally advantageous terms economically for treating rare diseases specifically. It is concluded that we are awaiting justice based reasons for the preferential treatment of orphan drugs. PMID- 25145641 TI - Variation in soil aluminium tolerance genes is associated with local adaptation to soils at the Park Grass Experiment. AB - Studies of the wild grass Anthoxanthum odoratum at the long-term Park Grass Experiment (PGE, Harpenden, UK) document a well-known example of rapid plant evolution in response to environmental change. Repeated fertilizer applications have acidified the soil in some experimental plots over the past 150+ years, and Anthoxanthum subpopulations have quickly become locally adapted. Early reciprocal transplants showed subpopulation differentiation specifically in response to soil aluminium (Al) toxicity across the experiment, even at small (30 m) spatial scales. Almost 40 years after its original measurement, we reassessed the degree of local adaptation to soil Al at the PGE using updated phenotyping methods and identified genes with variation linked to the tolerance trait. Root growth assays show that plants are locally adapted to soil Al at both the seedling and adult growth stages, but to a smaller extent than previously inferred. Among a large suite of candidate loci that were previously shown to have Al-sensitive expression differences between sensitive and tolerant plants, three loci contained SNPs that are associated with both Al tolerance and soil acidity: an Al sensitive malate transporter (ALMT), a tonoplast intrinsic protein (TIP) and the putative homolog of the rice cell-wall modification gene STAR1. Natural genetic variation at these loci is likely to have contributed to the recent rapid evolution at PGE. Continued study of Al tolerance variants in Anthoxanthum will allow us to test hypotheses about the nature and source of genetic variation that enables some species to adapt to soil acidification and other types of rapid environmental change. PMID- 25145640 TI - Ornithine aminotransferase versus GABA aminotransferase: implications for the design of new anticancer drugs. AB - Ornithine aminotransferase (OAT) and gamma-aminobutyric acid aminotransferase (GABA-AT) are classified under the same evolutionary subgroup and share a large portion of structural, functional, and mechanistic features. Therefore, it is not surprising that many molecules that bind to GABA-AT also bind well to OAT. Unlike GABA-AT, OAT had not been viewed as a potential therapeutic target until recently; consequently, the number of therapeutically viable molecules that target OAT is very limited. In this review the two enzymes are compared with respect to their active-site structures, catalytic and inactivation mechanisms, and selective inhibitors. Insight is offered that could aid in the design and development of new selective inhibitors of OAT for the treatment of cancer. PMID- 25145642 TI - Effect of depth of general anesthesia on the threshold of electrically evoked compound action potential in cochlear implantation. AB - The purpose of the present study was to evaluate effect of depth of general anesthesia on the threshold of electrically evoked compound action potential in cochlear implantation. A prospective clinical study in a single-subject design was conducted in the cochlear implant center of a tertiary care University-based hospital. Sixty-one cochlear-implanted children with bilateral, severe to profound sensory neural hearing loss were enrolled in the study. During the operation electrically evoked compound action potentials (e-ECAP) were measured in two phase of general anesthesia; in deep and in light anesthesia. Thresholds of e-ECAP in these two phases of anesthesia were compared. Thirty-one children received HiRes90k1j prosthesis and 30 children received CI24RE prosthesis. Thresholds difference of electrically evoked compound action potential between light and deep anesthesia in all tested electrodes in either group were statistically significant (P < 0.001). Non-measurable e-ECAP in some electrodes at deep anesthesia was measurable in light phase of anesthesia. Depth of anesthesia can have significant influence on e-ECAP threshold and it is important to reduce the depth of anesthesia to achieve better results. PMID- 25145643 TI - A combination of modified transnasal endoscopic maxillectomy via transnasal prelacrimal recess approach with or without radiotherapy for selected sinonasal malignancies. AB - An external approach for resection of sinonasal tumors is associated with increased morbidity. Therefore, we employed a modified transnasal endoscopic maxillectomy combined with pre and/or postoperative radiotherapy for early stage maxillary carcinomas. It aims to evaluate our early experience with endoscopic resection of selected malignant sinonasal tumors. The medical and radiology records of patients who underwent endonasal endoscopic resection of malignant sinonasal tumors between 2008 and 2012 were retrospectively reviewed. Ten cases of selected malignant tumor were performed to resect by modified transnasal endoscopic maxillectomy. All the patients were without evidence of disease at a mean follow-up of 26.8 months. No major complications were recorded. The mean hospitalization stay was 6.6 days. In very carefully selected cases of malignant tumors, modified transnasal endoscopic maxillectomy is acceptable. The postoperative complication rate is low, cosmetic outcome is excellent and patients do not require a long hospitalization. PMID- 25145644 TI - Metabolic engineering and classical selection of the methylotrophic thermotolerant yeast Hansenula polymorpha for improvement of high-temperature xylose alcoholic fermentation. AB - BACKGROUND: The methylotrophic yeast, Hansenula polymorpha is an industrially important microorganism, and belongs to the best studied yeast species with well developed tools for molecular research. The complete genome sequence of the strain NCYC495 of H. polymorpha is publicly available. Some of the well-studied strains of H. polymorpha are known to ferment glucose, cellobiose and xylose to ethanol at elevated temperature (45 - 50 degrees C) with ethanol yield from xylose significantly lower than that from glucose and cellobiose. Increased yield of ethanol from xylose was demonstrated following directed metabolic changes but, still the final ethanol concentration achieved is well below what is considered feasible for economic recovery by distillation. RESULTS: In this work, we describe the construction of strains of H. polymorpha with increased ethanol production from xylose using an ethanol-non-utilizing strain (2EthOH-) as the host. The transformants derived from 2EthOH- overexpressing modified xylose reductase (XYL1m) and native xylitol dehydrogenase (XYL2) were isolated. These transformants produced 1.5-fold more ethanol from xylose than the original host strain. The additional overexpression of XYL3 gene coding for xylulokinase, resulted in further 2.3-fold improvement in ethanol production with no measurable xylitol formed during xylose fermentation. The best ethanol producing strain obtained by metabolic engineering approaches was subjected to selection for resistance to the known inhibitor of glycolysis, the anticancer drug 3 bromopyruvate. The best mutant selected had an ethanol yield of 0.3 g/g xylose and produced up to 9.8 g of ethanol/l during xylose alcoholic fermentation at 45 degrees C without correction for ethanol evaporation. CONCLUSIONS: Our results indicate that xylose conversion to ethanol at elevated temperature can be significantly improved in H. polymorpha by combining methods of metabolic engineering and classical selection. PMID- 25145646 TI - Response of thymus lymphocytes to streptozotocin-induced diabetes and exogenous vitamin C administration in rats. AB - Diabetes causes oxidative stress, which in turn generates excessive free radicals resulting in cellular damage. Vitamin C is an antioxidant that protects tissues and organs from oxidative stress. The thymus is one of the most important lymphoid organs, which regulates T-lymphocyte proliferation and maturation. The aim of this study is to investigate the protective effects of vitamin C on the thymus of streptozotocin (STZ)-induced diabetic rats. The mitotic activity and cell integrity of thymic lymphocytes were explored. Wistar Albino rats were divided into three groups: control (Group 1), STZ-diabetes (Group 2) and vitamin C-treated STZ-diabetics (Group 3). Rats received a single intraperitoneal injection of 45 mg/kg STZ to induce diabetes. Vitamin C (20 mg/kg) was administered intragastrically. Semithin and ultrathin sections were examined under a light or an electron microscope, respectively. Considerable numbers of mitotic lymphocytes were observed in the thymus of control rats. In the diabetic rats, however, numbers of mitotic lymphocytes decreased to ~57% of controls, and cell division abnormalities were observed. Additionally, diabetic rats showed degeneration in the structure of the thymus including trabecular thickening, accumulation of lipid vacuoles, heterochromatic nuclei and loss of mitochondrial cristae. Degradation of medullar and cortical integrity was also detected. In the vitamin C-treated STZ-diabetic group, the structure of the thymus and mitotic activity of the lymphocytes were similar to the control group. These results suggest that vitamin C protects the thymus against injury caused by diabetes and restores thymocyte mitotic activity. PMID- 25145647 TI - Dual-axis 360 degrees rotation specimen holder for analysis of three-dimensional magnetic structures. AB - A dual-axis 360 degrees rotation specimen holder was developed for use in reconstructing the three-dimensional (3D) distribution of a magnetic field using a combination of electron holography and tomography. Pillar-shaped specimens are used to obtain accurate reconstruction without a missing angle. The holder's rotation rod can be turned >360 degrees ; the pillar is set +/-45 degrees to the azimuth for both x- and y-axis rotation. Two rotation series of holograms in individual axes are recorded for vector field tomography. The two vector components of the magnetic field are reconstructed directly from the two series of holograms, and the remaining component is calculated using Maxwell's equation, div B = 0. As a result, all 3D magnetic fields are reconstructed. PMID- 25145648 TI - Atomic force microscope-assisted scanning tunneling spectroscopy under ambient conditions. AB - We have developed a method of atomic force microscopy (AFM)-assisted scanning tunneling spectroscopy (STS) under ambient conditions. An AFM function is used for rapid access to a selected position prior to performing STS. The AFM feedback is further used to suppress vertical thermal drift of the tip-sample distance during spectroscopy, enabling flexible and stable spectroscopy measurements at room temperature. PMID- 25145645 TI - Advances in HIV prevention for serodiscordant couples. AB - Serodiscordant couples play an important role in maintaining the global HIV epidemic. This review summarizes biobehavioral and biomedical HIV prevention options for serodiscordant couples focusing on advances in 2013 and 2014, including World Health Organization guidelines and best evidence for couples counseling, couple-based interventions, and the use of antiviral agents for prevention. In the past few years, marked advances have been made in HIV prevention for serodiscordant couples and numerous ongoing studies are continuously expanding HIV prevention tools, especially in the area of pre exposure prophylaxis. Uptake and adherence to antiviral therapy remains a key challenge. Additional research is needed to develop evidence-based interventions for couples, and especially for male-male couples. Randomized trials have demonstrated the prevention benefits of antiretroviral-based approaches among serodiscordant couples; however, residual transmission observed in recognized serodiscordant couples represents an important and resolvable challenge in HIV prevention. PMID- 25145649 TI - Longitudinal study of perception of structured optic flow and random visual motion in infants using high-density EEG. AB - Electroencephalogram (EEG) was used in infants at 3-4 months and 11-12 months to longitudinally study brain electrical activity as the infants were exposed to structured forwards and reversed optic flow, and non-structured random visual motion. Analyses of visual evoked potential (VEP) and temporal spectral evolution (TSE, time-dependent amplitude changes) were performed on EEG data recorded with a 128-channel sensor array. VEP results showed infants to significantly differentiate between the radial motion conditions, but only at 11-12 months where they showed shortest latency for forwards optic flow and longest latency for random visual motion. When the TSE results of the motion conditions were compared with those of a static non-flow dot pattern, infants at 3-4 and 11-12 months both showed significant differences in induced activity. A decrease in amplitudes at 5-7 Hz was observed as desynchronized theta-band activity at both 3 4 and 11-12 months, while an increase in amplitudes at 9-13 Hz was observed as synchronized alpha-band activity only at 11-12 months. It was concluded that brain electrical activities related to visual motion perception change during the first year of life, and these changes can be observed both in the VEP and induced activities of EEG. With adequate neurobiological development and locomotor experience infants around 1 year of age rely, more so than when they were younger, on structured optic flow and show a more adult-like specialization for motion where faster oscillating cell assemblies have fewer but more specialized neurons, resulting in improved visual motion perception. PMID- 25145650 TI - Rapid or normal gastric emptying as new supportive criteria for diagnosing cyclic vomiting syndrome in adults. AB - BACKGROUND: Cyclic vomiting syndrome (CVS) in adults is a disorder characterized by recurrent and stereotypic episodes of severe nausea, vomiting and abdominal pain separated by symptom-free intervals. Our goal was to investigate gastric emptying (GE) in CVS patients. MATERIAL AND METHODS: This was a retrospective study of 30 adult patients who met Rome III diagnostic criteria for CVS. Rapid GE was defined using two different predefined criteria as either <50% isotope retention or <65% isotope retention at 1st hour and/or <20% at 2nd hour. RESULTS: Of the 30 patients (25 had 4-hr GE) diagnosed with CVS, 22 were females and 8 males with a mean age of 39 years. Overall, 20 (80%) of the 25 CVS patients met the predefined criteria of <50% retention for rapid GE in the first hour. Fifteen (60%) met the 2-hour criteria for rapid emptying of <20% retention. Five (16.6%) patients of the 25 had a normal GE with a mean retention at the first hour of 65% (52-78%). Nine (36%) also met another predefined criteria of <35% retention for rapid GE in the first hour. Sixteen (64%) met criteria for normal GE. CONCLUSIONS: (1) In adult CVS patients, GE is either rapid or normal, clearly distinguishing this entity from gastroparesis. (2) Cyclic vomiting syndrome is an important new etiology to explain the finding of rapid GE on a radionuclide test. (3) We suggest that rapid gastric emptying should be added as supportive criteria for diagnosing CVS in adults. PMID- 25145651 TI - Verification and comparison of four numerical schemes for a 1D viscoelastic blood flow model. AB - A reliable and fast numerical scheme is crucial for the 1D simulation of blood flow in compliant vessels. In this paper, a 1D blood flow model is incorporated with a Kelvin-Voigt viscoelastic arterial wall. This leads to a nonlinear hyperbolic-parabolic system, which is then solved with four numerical schemes, namely: MacCormack, Taylor-Galerkin, monotonic upwind scheme for conservation law and local discontinuous Galerkin. The numerical schemes are tested on a single vessel, a simple bifurcation and a network with 55 arteries. The numerical solutions are checked favorably against analytical, semi-analytical solutions or clinical observations. Among the numerical schemes, comparisons are made in four important aspects: accuracy, ability to capture shock-like phenomena, computational speed and implementation complexity. The suitable conditions for the application of each scheme are discussed. PMID- 25145652 TI - Vagus nerve stimulation magnet activation for seizures: a critical review. AB - Some patients receiving VNS Therapy report benefit from manually activating the generator with a handheld magnet at the time of a seizure. A review of 20 studies comprising 859 subjects identified patients who reported on-demand magnet mode stimulation to be beneficial. Benefit was reported in a weighted average of 45% of patients (range 0-89%) using the magnet, with seizure cessation claimed in a weighted average of 28% (range 15-67%). In addition to seizure termination, patients sometimes reported decreased intensity or duration of seizures or the post-ictal period. One study reported an isolated instance of worsening with magnet stimulation (Arch Pediatr Adolesc Med, 157, 2003 and 560). All of the reviewed studies assessed adjunctive magnet use. No studies were designed to provide Level I evidence of efficacy of magnet-induced stimulation. Retrospective analysis of one pivotal randomized trial of VNS therapy showed significantly more seizures terminated or improved in the active stimulation group vs the control group. Prospective, controlled studies would be required to isolate the effect and benefit of magnet mode stimulation and to document that the magnet-induced stimulation is the proximate cause of seizure reduction. Manual application of the magnet to initiate stimulation is not always practical because many patients are immobilized or unaware of their seizures, asleep or not in reach of the magnet. Algorithms based on changes in heart rate at or near the onset of the seizure provide a methodology for automated responsive stimulation. Because literature indicates additional benefits from on-demand magnet mode stimulation, a potential role exists for automatic activation of stimulation. PMID- 25145653 TI - Nitrogen-doped one-dimensional (1D) macroporous carbonaceous nanotube arrays and their application in electrocatalytic oxygen reduction reactions. AB - A nitrogen(N)-doped one-dimensional (1D) macroporous carbonaceous nanotube array was fabricated by using an anodic alumina oxide (AAO) template. The large diameter of the nanotubes (~200 nm) could overcome the sluggish mass transfer phenomena in the common micro/mesoporous carbon-based electrodes. Combining the activation of the pi electrons of the sp(2) carbon array by N-doping, the novel 1D macroporous carbonaceous nanotube array exhibited high performance for the oxygen reduction reaction (ORR). PMID- 25145654 TI - Novel Hg2+-induced nephropathy in rats and mice lacking Mrp2: evidence of axial heterogeneity in the handling of Hg2+ along the proximal tubule. AB - The role of the multi-resistance protein 2 (Mrp2) in the nephropathy induced by inorganic mercuric mercury (Hg(2+)) was studied in rats (TR(-)) and mice (Mrp2(-/ )), which lack functional Mrp2, and control animals. Animals were exposed to nephrotoxic doses of HgCl2. Forty-eight or 24 hours after exposure, tissues were harvested and analyzed for Hg content and markers of injury. Histological analyses revealed that the proximal tubular segments affected pathologically by Hg(2+) were significantly different between Mrp2-deficient animals and controls. In the absence of Mrp2, cellular injury localized almost exclusively in proximal tubular segments in the subcapsular (S1) to midcortical regions (early S2) of the kidney. In control animals, cellular death occurred mainly in the proximal tubular segments in the inner cortex (late S2) and outer stripe of the outer medulla (S3). These differences in renal pathology indicate that axial heterogeneity exists along the proximal tubule with respect to how mercuric ions are handled. Total renal and hepatic accumulation of mercury was also greater in animals lacking Mrp2 than in controls, indicating that Mrp2 normally plays a significant role in eliminating mercuric ions from within proximal tubular cells and hepatocytes. Analyses of plasma creatinine, BUN, and renal expression of Kim 1 and Ngal tend to support the severity of the nephropathies detected histologically. Collectively, our findings indicate that a fraction of mercuric ions is normally secreted by Mrp2 in early portions of proximal tubules into the lumen and then is absorbed downstream in straight portions, where mercuric species typically induce toxic effects. PMID- 25145656 TI - Tissue sensitivity of the rat upper and lower extrapulmonary airways to the inhaled electrophilic air pollutants diacetyl and acrolein. AB - The target site for inhaled vapor-induced injury often differs in mouth-breathing humans compared with nose-breathing rats, thus complicating the use of rat inhalation toxicity data for assessment of human risk. We sought to examine sensitivity of respiratory/transitional nasal (RTM) and tracheobronchial (TBM) mucosa to two electrophilic irritant vapors: diacetyl and acrolein. Computational fluid dynamic physiologically based pharmacokinetic modeling was coupled with biomarker assessment to establish delivered dose-response relationships in RTM and TBM in male F344 rats following 6 h exposure to diacetyl or acrolein. Biomarkers included glutathione status, proinflammatory and antioxidant gene mRNA levels, and nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Modeling revealed that 0.0094-0.1653 MUg acrolein/min-cm(2) and 3.9-21.6 MUg diacetyl/min-cm(2) were deposited into RTM/TBM. Results indicate RTM and TBM were generally of similar sensitivity to diacetyl and acrolein. For instance, both tissues displayed induction of antioxidant and proinflammatory genes, and nuclear accumulation of Nrf2 after electrophile exposure. Hierarchical cellular response patterns were similar in RTM and TBM but differed between vapors. Specifically, diacetyl exposure induced proinflammatory and antioxidant genes concomitantly at low exposure levels, whereas acrolein induced antioxidant genes at much lower exposure levels than that required to induce proinflammatory genes. Generally, diacetyl was less potent than acrolein, as measured by maximal induction of transcripts. In conclusion, the upper and lower extrapulmonary airways are of similar sensitivity to inhaled electrophilic vapors. Dosimetrically based extrapolation of nasal responses in nose-breathing rodents may provide an approach to predict risk to the lower airways of humans during mouth-breathing. PMID- 25145655 TI - Systems level metabolic phenotype of methotrexate administration in the context of non-alcoholic steatohepatitis in the rat. AB - Adverse drug reactions (ADRs) represent a significant clinical challenge with respect to patient morbidity and mortality. We investigated the hepatotoxicity and systems level metabolic phenotype of methotrexate (MTX) in the context of a prevalent liver disease; non-alcoholic steatohepatitis (NASH). A nuclear magnetic resonance spectroscopic-based metabonomic approach was employed to analyze the metabolic consequences of MTX (0, 10, 40, and 100 mg/kg) in the urine and liver of healthy rats (control diet) and in a model of NASH (methionine-choline deficient diet). Histopathological analysis confirmed baseline (0 mg/kg) liver necrosis, liver inflammation, and lipid accumulation in the NASH model. Administration of MTX (40 and 100 mg/kg) led to liver necrosis in the control cohort, whereas the NASH cohort also displayed biliary hyperplasia and liver fibrosis (100 mg/kg), providing evidence of the synergistic effect of MTX and NASH. The complementary hepatic and urinary metabolic phenotypes of the NASH model, at baseline, revealed perturbation of multiple metabolites associated with oxidative and energetic stress, and folate homeostasis. Administration of MTX in both diet cohorts showed dose-dependent metabolic consequences affecting gut microbial, energy, nucleobase, nucleoside, and folate metabolism. Furthermore, a unique panel of metabolic changes reflective of the synergistic effect of MTX and NASH was identified, including the elevation of hepatic phenylalanine, urocanate, acetate, and both urinary and hepatic formiminoglutamic acid. This systems level metabonomic analysis of the hepatotoxicity of MTX in the context of NASH provided novel mechanistic insight of potential wider clinical relevance for further understanding the role of liver pathology as a risk factor for ADRs. PMID- 25145657 TI - Human hepatocytes support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogen sodium phenobarbital in an in vivo study using a chimeric mouse with humanized liver. AB - High doses of sodium phenobarbital (NaPB), a constitutive androstane receptor (CAR) activator, have been shown to produce hepatocellular tumors in rodents by a mitogenic mode of action (MOA) involving CAR activation. The effect of 1-week dietary treatment with NaPB on liver weight and histopathology, hepatic CYP2B enzyme activity and CYP2B/3A mRNA expression, replicative DNA synthesis and selected genes related to cell proliferation, and functional transcriptomic and metabolomic analyses was studied in male CD-1 mice, Wistar Hannover (WH) rats, and chimeric mice with human hepatocytes. The treatment of chimeric mice with 1000-1500-ppm NaPB resulted in plasma levels around 3-5-fold higher than those observed in human subjects given therapeutic doses of NaPB. NaPB produced dose dependent increases in hepatic CYP2B activity and CYP2B/3A mRNA levels in all animal models. Integrated functional metabolomic and transcriptomic analyses demonstrated that the responses to NaPB in the human liver were clearly different from those in rodents. Although NaPB produced a dose-dependent increase in hepatocyte replicative DNA synthesis in CD-1 mice and WH rats, no increase in replicative DNA synthesis was observed in human hepatocyte-originated areas of chimeric mice. In addition, treatment with NaPB had no effect on Ki-67, PCNA, GADD45beta, and MDM2 mRNA expression in chimeric mice, whereas significant increases were observed in CD-1 mice and/or WH rats. However, increases in hepatocyte replicative DNA synthesis were observed in chimeric mice both in vivo and in vitro after treatment epidermal growth factor. Thus, although NaPB could activate CAR in both rodent and human hepatocytes, NaPB did not increase replicative DNA synthesis in human hepatocytes of chimeric mice, whereas it was mitogenic to rat and mouse hepatocytes. As human hepatocytes are refractory to the mitogenic effects of NaPB, the MOA for NaPB-induced rodent liver tumor formation is thus not relevant for humans. PMID- 25145658 TI - Stable isotope labeling method for the investigation of protein haptenation by electrophilic skin sensitizers. AB - The risk of contact sensitization is a major consideration in the development of new formulations for personal care products. However, developing a mechanistic approach for non-animal risk assessment requires further understanding of haptenation of skin proteins by sensitizing chemicals, which is the molecular initiating event causative of skin sensitization. The non-stoichiometric nature of protein haptenation results in relatively low levels of modification, often of low abundant proteins, presenting a major challenge for their assignment in complex biological matrices such as skin. Instrumental advances over the last few years have led to a considerable increase in sensitivity of mass spectrometry (MS) techniques. We have combined these advancements with a novel dual labeling/LC-MS(E) approach to provide an in-depth direct comparison of human serum albumin (HSA), 2,4-dinitro-1-chlorobenzene (DNCB), 5-chloro-2-methyl-4 isothiazolin-3-one (MCI), trans-cinnamaldehyde, and 6-methyl coumarin. These data have revealed novel insights into the differences in protein haptenation between sensitizers with different reaction mechanisms and sensitizing potency; the extreme sensitizers DNCB and MCI were shown to modify a greater number of nucleophilic sites than the moderate sensitizer cinnamaldehyde; and the weak/non sensitizer 6-methyl coumarin was restricted to only a single nucleophilic residue within HSA. The evaluation of this dual labeling/LC-MS(E) approach using HSA as a model protein has also demonstrated that this strategy could be applied to studying global haptenation in complex mixtures of skin-related proteins by different chemicals. PMID- 25145659 TI - Incorporating population variability and susceptible subpopulations into dosimetry for high-throughput toxicity testing. AB - Momentum is growing worldwide to use in vitro high-throughput screening (HTS) to evaluate human health effects of chemicals. However, the integration of dosimetry into HTS assays and incorporation of population variability will be essential before its application in a risk assessment context. Previously, we employed in vitro hepatic metabolic clearance and plasma protein binding data with in vitro in vivo extrapolation (IVIVE) modeling to estimate oral equivalent doses, or daily oral chemical doses required to achieve steady-state blood concentrations (Css) equivalent to media concentrations having a defined effect in an in vitro HTS assay. In this study, hepatic clearance rates of selected ToxCast chemicals were measured in vitro for 13 cytochrome P450 and five uridine 5'-diphospho glucuronysyltransferase isozymes using recombinantly expressed enzymes. The isozyme-specific clearance rates were then incorporated into an IVIVE model that captures known differences in isozyme expression across several life stages and ethnic populations. Comparison of the median Css for a healthy population against the median or the upper 95th percentile for more sensitive populations revealed differences of 1.3- to 4.3-fold or 3.1- to 13.1-fold, respectively. Such values may be used to derive chemical-specific human toxicokinetic adjustment factors. The IVIVE model was also used to estimate subpopulation-specific oral equivalent doses that were directly compared with subpopulation-specific exposure estimates. This study successfully combines isozyme and physiologic differences to quantitate subpopulation pharmacokinetic variability. Incorporation of these values with dosimetry and in vitro bioactivities provides a viable approach that could be employed within a high-throughput risk assessment framework. PMID- 25145661 TI - Electroencephalography for children with autistic spectrum disorder: a sedation protocol. AB - OBJECTIVES: To report the effectiveness and efficiency of a predetermined sedation protocol for providing sedation for electroencephalograph (EEG) studies in children with autism. METHODS: Sleep EEG has been advocated for the majority of children with autism spectrum disorder. In most cases, sedation is required to allow adequate studies. Most sedation drugs have negative effects on the EEG pattern. The sedation protocol we adopted included chloral hydrate, dexmedetomidine, and ketamine and was evaluated prospectively for 2 years. RESULTS: One hundred and eighty-three children with autistic spectrum disorder were sedated with the described drug protocol that was efficient, provided adequate EEG readings, and was not associated with serious adverse events. CONCLUSIONS: Our protocol kept costs to a minimum but provided appropriate escalation in care when required. PMID- 25145662 TI - Prior schemata transfer as an account for assessing the intuitive use of new technology. AB - New devices are considered intuitive when they allow users to transfer prior knowledge. Drawing upon fundamental psychology experiments that distinguish prior knowledge transfer from new schema induction, a procedure was specified for assessing intuitive use. This procedure was tested with 31 participants who, prior to using an on-board computer prototype, studied its screenshots in reading vs. schema induction conditions. Distinct patterns of transfer or induction resulted for features of the prototype whose functions were familiar or unfamiliar, respectively. Though moderated by participants' cognitive style, these findings demonstrated a means for quantitatively assessing transfer of prior knowledge as the operation that underlies intuitive use. Implications for interface evaluation and design, as well as potential improvements to the procedure, are discussed. PMID- 25145660 TI - Cardiac epithelial-mesenchymal transition is blocked by monomethylarsonous acid (III). AB - Arsenic exposure during embryonic development can cause ischemic heart pathologies later in adulthood which may originate from impairment in proper blood vessel formation. The arsenic-associated detrimental effects are mediated by arsenite (iAs(III)) and its most toxic metabolite, monomethylarsonous acid [MMA (III)]. The impact of MMA (III) on coronary artery development has not yet been studied. The key cellular process that regulates coronary vessel development is the epithelial-mesenchymal transition (EMT). During cardiac EMT, activated epicardial progenitor cells transform to mesenchymal cells to form the cellular components of coronary vessels. Smad2/3 mediated TGFbeta2 signaling, the key regulator of cardiac EMT, is disrupted by arsenite exposure. In this study, we compared the cardiac toxicity of MMA (III) with arsenite. Epicardial progenitor cells are 15 times more sensitive to MMA (III) cytotoxicity when compared with arsenite. MMA (III) caused a significant blockage in epicardial cellular transformation and invasion at doses 10 times lower than arsenite. Key EMT genes including TGFbeta ligands, TbetaRIII, Has2, CD44, Snail1, TBX18, and MMP2 were down regulated by MMA (III) exposure. MMA (III) disrupted Smad2/3 activation at a dose 20 times lower than arsenite. Both arsenite and MMA (III) significantly inhibited Erk1/2 and Erk5 phosphorylation. Nuclear translocation of Smad2/3 and Erk5 was also blocked by arsenical exposure. However, p38 activation, as well as smooth muscle differentiation, was refractory to the inhibition by the arsenicals. Collectively, these findings revealed that MMA (III) is a selective disruptor of cardiac EMT and as such may predispose to arsenic-associated cardiovascular disorders. PMID- 25145664 TI - When are food deserts? Integrating time into research on food accessibility. AB - The food desert concept is used as a means for defining regions as having inadequate spatial and socioeconomic access to vendors selling nutritious foods. This primarily aggregate-level and static method for understanding the food environment is commonly used by researchers and policy makers seeking to improve health outcomes of those affected by reduced access. However, recent research findings have brought the association between living in a food desert and adverse health outcomes into question. In this viewpoint, we put forward the idea that the food desert concept, and food accessibility research more generally, should be expanded to include a temporal component, and note potential avenues for future research. PMID- 25145665 TI - In search of versatile organisms for quorum-sensing inhibitors: acyl homoserine lactones (AHL)-acylase and AHL-lactonase. PMID- 25145663 TI - Normalization of elevated cardiac, kidney, and hemolysis plasma markers within 48 h in Mexican Tarahumara runners following a 78 km race at moderate altitude. AB - OBJECTIVES: The aim of this study was to examine to what extent extreme endurance exercise results in changes of plasma markers associated with cardiac and renal damage, as well as hemolysis in male, Mexican Tarahumara runners. METHODS: Ten Tarahumara runners (mean (sd) age of 38 (12) years) participated in a 78 km race in Chihuahua, Mexico at 2,400 m above sea level. Cardiac, kidney, and hematology plasma markers were measured pre-race and <5 min, 1 h, 3 h, 6 h, 24 h, and 48 h post-race. Anthropometry, blood pressure, pulse rate, electrocardiography, HbA1c, hemoglobin and VO2max (estimated from heart rate following step test) were assessed pre-race, while physical activity energy expenditure and intensity were estimated during the race, and oxygen partial pressure saturation (SpO2 ) <30 min post-race. RESULTS: Estimated mean VO2max was 48 (9) mLO2 min(-1) kg(-1) and relative intensity during the race was 68 (11)%VO2 max. Mean SpO2 was 92 (3)% <30 min post-race. Plasma concentrations of especially total creatine kinase, creatine kinase-MB isoform, and haptoglobin changed significantly from pre-race values (P < 0.001) up to 24 h post-race, but had returned to pre-race values after 48 h. The plasma concentrations of mid-regional proatrial natiuretic peptide and copeptin returned to pre-race concentrations after 1 and 6 h, respectively. CONCLUSIONS: Altered cardiac, renal, and hemolysis plasma markers were normalized after 48 h following 78 km of running, suggesting that the impact of exercise-induced cardiac and kidney damage as well as hemolysis in the Mexican Tarahumara is low. PMID- 25145667 TI - FXR, intestinal FiXeR of hepatocellular carcinoma? PMID- 25145666 TI - Factors influencing apical node metastasis in colorectal cancer patients treated with laparoscopic radical resection with D3 lymphadenectomy: results from two centers in China. AB - PURPOSE: To identify the risk factors for apical node metastasis in colorectal cancer (CRC) patients who underwent laparoscopic radical resection with D3 lymphadenectomy. METHODS: The subjects were 578 consecutive patients who underwent laparoscopic radical resection with D3 lymphadenectomy for CRC between February, 2003 and December, 2009. The Cox proportional regression model was used to evaluate the association between apical node metastasis and survival and the logistic regression model was used to identify the risk factors for apical node metastasis. RESULTS: Thirty patients (5.2 %) had apical node metastasis, which was an independent risk factor for poor disease-free survival [hazard ratio (HR) = 3.02, P = 0.019]. Multivariate logistic regression analysis revealed that poor differentiation [odds ratio (OR) = 4.58, P < 0.001] and ulcerative/infiltrative morphology (OR = 5.57, P = 0.023) were independent risk factors for apical node metastasis. In the subgroup analysis based on pT3-4 tumors, multivariate logistic regression analysis also suggested that these factors were significantly associated with apical node metastasis. CONCLUSIONS: Apical node metastasis is an independent risk factor for poor oncologic outcome. T3-4 stage, poor differentiation, and ulcerative/infiltrative morphology are significantly associated with apical node metastasis. Notably, in this study, T1-2 stage tumors had no apical node metastasis, suggesting that D3 lymphadenectomy may be over performed without considering the T stage of tumors. PMID- 25145669 TI - Synergy between the NAMPT inhibitor GMX1777(8) and pemetrexed in non-small cell lung cancer cells is mediated by PARP activation and enhanced NAD consumption. AB - GMX1778 and its prodrug GMX1777 represent a new class of cancer drugs that targets nicotinamide phosphoribosyltransferase (NAMPT) as a new strategy to interfere with biosynthesis of the key enzymatic cofactor NAD, which is critical for a number of cell functions, including DNA repair. Using a genome-wide synthetic lethal siRNA screen, we identified the folate pathway-related genes, deoxyuridine triphosphatase and dihydrofolate reductase, the silencing of which sensitized non-small cell lung carcinoma (NSCLC) cells to the cytotoxic effects of GMX. Pemetrexed is an inhibitor of dihydrofolate reductase currently used to treat patients with nonsquamous NSCLC. We found that combining pemetrexed with GMX1777 produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model of lung cancer. Pemetrexed is known to activate PARPs, thereby accelerating NAD consumption. Genetic or pharmacologic blockade of PARP activity inhibited this effect, impairing cell death by pemetrexed either alone or in combination with GMX1777. Conversely, inhibiting the base excision repair pathway accentuated NAD decline in response to GMX and the cytotoxicity of both agents either alone or in combination. These findings provide a mechanistic rationale for combining GMX1777 with pemetrexed as an effective new therapeutic strategy to treat nonsquamous NSCLC. PMID- 25145668 TI - AEG-1 promoter-mediated imaging of prostate cancer. AB - We describe a new imaging method for detecting prostate cancer, whether localized or disseminated and metastatic to soft tissues and bone. The method relies on the use of imaging reporter genes under the control of the promoter of AEG-1 (MTDH), which is selectively active only in malignant cells. Through a systemic, nanoparticle-based delivery of the imaging construct, lesions can be identified through bioluminescence imaging and single-photon emission computed tomography in the PC3-ML murine model of prostate cancer at high sensitivity. This approach is applicable for the detection of prostate cancer metastases, including bone lesions for which there is no current reliable agent for noninvasive clinical imaging. Furthermore, the approach compares favorably with accepted and emerging clinical standards, including PET with [(18)F]fluorodeoxyglucose and [(18)F]sodium fluoride. Our results offer a preclinical proof of concept that rationalizes clinical evaluation in patients with advanced prostate cancer. PMID- 25145670 TI - Development of novel ADCs: conjugation of tubulysin analogues to trastuzumab monitored by dual radiolabeling. AB - Tubulysins are highly toxic tubulin-targeting agents with a narrow therapeutic window that are interesting for application in antibody-drug conjugates (ADC). For full control over drug-antibody ratio (DAR) and the effect thereof on pharmacokinetics and tumor targeting, a dual-labeling approach was developed, wherein the drug, tubulysin variants, and the antibody, the anti-HER2 monoclonal antibody (mAb) trastuzumab, are radiolabeled. (131)I-radioiodination of two synthetic tubulysin A analogues, the less potent TUB-OH (IC50 > 100 nmol/L) and the potent TUB-OMOM (IC50, ~1 nmol/L), and their direct covalent conjugation to (89)Zr-trastuzumab were established. Radioiodination of tubulysins was 92% to 98% efficient and conversion to N-hydroxysuccinimide (NHS) esters more than 99%; esters were isolated in an overall yield of 68% +/- 5% with radiochemical purity of more than 99.5%. Conjugation of (131)I-tubulysin-NHS esters to (89)Zr trastuzumab was 45% to 55% efficient, resulting in ADCs with 96% to 98% radiochemical purity after size-exclusion chromatography. ADCs were evaluated for their tumor-targeting potential and antitumor effects in nude mice with tumors that were sensitive or resistant to trastuzumab, using ado-trastuzumab emtansine as a reference. ADCs appeared stable in vivo. An average DAR of 2 and 4 conferred pharmacokinetics and tumor-targeting behavior similar to parental trastuzumab. Efficacy studies using single-dose TUB-OMOM-trastuzumab (DAR 4) showed dose dependent antitumor effects, including complete tumor eradications in trastuzumab sensitive tumors in vivo. TUB-OMOM-trastuzumab (60 mg/kg) displayed efficacy similar to ado-trastuzumab emtansine (15 mg/kg) yet more effective than trastuzumab. Our findings illustrate the potential of synthetic tubulysins in ADCs for cancer treatment. PMID- 25145671 TI - Complex formation and function of estrogen receptor alpha in transcription requires RIP140. AB - RIP140 is a transcriptional coregulator involved in energy homeostasis, ovulation, and mammary gland development. Although conclusive evidence is lacking, reports have implicated a role for RIP140 in breast cancer. Here, we explored the mechanistic role of RIP140 in breast cancer and its involvement in estrogen receptor alpha (ERalpha) transcriptional regulation of gene expression. Using ChIP-seq analysis, we demonstrate that RIP140 shares more than 80% of its binding sites with ERalpha, colocalizing with its interaction partners FOXA1, GATA3, p300, CBP, and p160 family members at H3K4me1-demarcated enhancer regions. RIP140 is required for ERalpha-complex formation, ERalpha-mediated gene expression, and ERalpha-dependent breast cancer cell proliferation. Genes affected following RIP140 silencing could be used to stratify tamoxifen-treated breast cancer cohorts, based on clinical outcome. Importantly, this gene signature was only effective in endocrine-treated conditions. Cumulatively, our data suggest that RIP140 plays an important role in ERalpha-mediated transcriptional regulation in breast cancer and response to tamoxifen treatment. PMID- 25145673 TI - Stage-dependent C-reflex, pain-like behavior and opioid analgesia during the induction of chronic arthritis in rats. AB - Chronic arthritis (CA) is a common clinical entity associated with persistent pain and limited response to opioid analgesic therapy. However, it is unknown whether these features of CA change depending on its stage of evolution. To address this, in a well-established animal model of CA we studied the time course of electromyographic responses to electrical stimulation of C fibers (C-reflex), pain-like behavior as a response to mechanical nociceptive stimulation, and the inhibition of both responses by a prototypic opioid analgesic, morphine. To induce CA, rats received a single injection of complete Freund's adjuvant into the ankle joint and the C-reflex responses to electrical stimuli or the nociceptive response to paw pressure test were studied 2, 4 or 6 weeks later. The C-reflexes evoked by threshold and supra-threshold electrical stimulation exhibited progressive increases together with enhancement of the nociceptive behavior to mechanical stimulation during induction of monoarthritis. Notably, while systemic morphine produced antinociceptive effects upon both experimental approaches, the effects were markedly reduced during the early stages of CA but enhanced at later stages. These data indicate that C-reflex and pain-like responses evolve in parallel, and are inhibited by morphine in a stage-dependent manner through the induction of CA. The present results may contribute to explain the enhanced pain response and variable analgesic efficacy of opioids that characterize arthritic pain in humans. PMID- 25145672 TI - SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. AB - Blocking the oncoprotein murine double minute 2 (MDM2)-p53 protein-protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite the potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report a novel small-molecule inhibitor of the MDM2-p53 interaction, SAR405838 (MI-77301), that has been advanced into phase I clinical trials. SAR405838 binds to MDM2 with K(i) = 0.88 nmol/L and has high specificity over other proteins. A cocrystal structure of the SAR405838:MDM2 complex shows that, in addition to mimicking three key p53 amino acid residues, the inhibitor captures additional interactions not observed in the p53-MDM2 complex and induces refolding of the short, unstructured MDM2 N-terminal region to achieve its high affinity. SAR405838 effectively activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell-cycle arrest and/or apoptosis. At well-tolerated dose schedules, SAR405838 achieves either durable tumor regression or complete tumor growth inhibition in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer, and HCT-116 colon cancer. Remarkably, a single oral dose of SAR405838 is sufficient to achieve complete tumor regression in the SJSA-1 model. Mechanistically, robust transcriptional upregulation of PUMA induced by SAR405838 results in strong apoptosis in tumor tissue, leading to complete tumor regression. Our findings provide a preclinical basis upon which to evaluate SAR405838 as a therapeutic agent in patients whose tumors retain wild type p53. PMID- 25145675 TI - Higher nurse to patient ratios on stroke units could cut one death in 25, research shows. PMID- 25145674 TI - Widespread non-adherence to evidence-based maternity care guidelines: a population-based cluster randomised household survey. AB - OBJECTIVE: To assess the quality of maternity care in an Indian metropolitan city. STUDY DESIGN: Three-stage cluster randomised cross-sectional survey. SETTING: Sixty selected colonies of Delhi. POPULATION: One thousand eight hundred and one subjects (of 2286 eligible) were enrolled from 118 446 houses. Women who had delivered a live viable birth in the past 6 months were selected for the study. METHODS: In stage 1, 20 wards (of 150) were selected using a probability proportionate-to-size systematic method. In stage 2, one colony from each income stratum (high, middle and low) was selected from each ward by simple random sampling. In stage 3, a house-to-house survey was conducted to recruit 30 women for administering a peer-reviewed and pilot-trialled questionnaire. MAIN OUTCOME MEASURES: Caesarean section rate, induction rate and episiotomy rate. RESULTS: National health targets such as iron supplementation advice (>96%), tetanus vaccination (>81%), and >=3 antenatal visits (>90%) were largely achieved across health care facilities but not in home deliveries. Interventions were lower in public than private hospitals: caesarean section [23.7% (20.2-27.7) versus 53.8% (49.3-58.3)], induction [20.6% (17.5-24.25) versus 30.8% (26.8-33.2)] and episiotomy [57.8% (52.3-63.1) versus 79.4% (71.0-85.9)]. Private hospitals achieved better labour support rates [1.1% (0.5-2.2) versus 14.6% (8.5-24.1)] and pain relief [0.9% (0.4-2.0) versus 9.9 (6.5-14.8)]. Pubic hair shaving [16.2% (11.5-22.5) versus 36.4% (29.9-43.4)], enema [20.2% (15.5-26.0) versus 57.3% (49.5-64.8)], and IV fluids during labour [44.0% (36.2-52.2) versus 38.7% (29.3 49.1)] were widely prevalent in public and private hospitals. CONCLUSION: Present practices fall short of evidence-based guidelines, with relative overuse of interventions in private hospitals and deficiency of patient-centred practices such as labour support in public hospitals. PMID- 25145676 TI - The long arm of mentoring: a counterfactual analysis of natural youth mentoring and employment outcomes in early careers. AB - Young people often develop natural mentoring relationships with nonparental adults during adolescence and young adulthood. While much has been learned about the benefits of natural mentoring for more proximate outcomes such as mental health and education, relatively little is known about the causal impact of youth mentoring relationships on career opportunities. This study uses data from the National Longitudinal Study of Adolescent Health (Add Health) survey to explore the effects of different kinds of natural mentoring relationships on employment outcomes during the early career years (when workers are in their late twenties and early thirties). Whereas traditional methods of causal conditioning show a broad range of employment benefits from being mentored, results from counterfactual analysis using propensity score matching reveal that the benefits of mentoring are confined to intrinsic job rewards. The findings imply that mentors help steer youth toward intrinsically rewarding careers. PMID- 25145679 TI - Comparative evaluation of in vitro mechanical properties of different designs of epoxy-pin external skeletal fixation systems. PMID- 25145678 TI - From voxels to knowledge: a practical guide to the segmentation of complex electron microscopy 3D-data. AB - Modern 3D electron microscopy approaches have recently allowed unprecedented insight into the 3D ultrastructural organization of cells and tissues, enabling the visualization of large macromolecular machines, such as adhesion complexes, as well as higher-order structures, such as the cytoskeleton and cellular organelles in their respective cell and tissue context. Given the inherent complexity of cellular volumes, it is essential to first extract the features of interest in order to allow visualization, quantification, and therefore comprehension of their 3D organization. Each data set is defined by distinct characteristics, e.g., signal-to-noise ratio, crispness (sharpness) of the data, heterogeneity of its features, crowdedness of features, presence or absence of characteristic shapes that allow for easy identification, and the percentage of the entire volume that a specific region of interest occupies. All these characteristics need to be considered when deciding on which approach to take for segmentation. The six different 3D ultrastructural data sets presented were obtained by three different imaging approaches: resin embedded stained electron tomography, focused ion beam- and serial block face- scanning electron microscopy (FIB-SEM, SBF-SEM) of mildly stained and heavily stained samples, respectively. For these data sets, four different segmentation approaches have been applied: (1) fully manual model building followed solely by visualization of the model, (2) manual tracing segmentation of the data followed by surface rendering, (3) semi-automated approaches followed by surface rendering, or (4) automated custom designed segmentation algorithms followed by surface rendering and quantitative analysis. Depending on the combination of data set characteristics, it was found that typically one of these four categorical approaches outperforms the others, but depending on the exact sequence of criteria, more than one approach may be successful. Based on these data, we propose a triage scheme that categorizes both objective data set characteristics and subjective personal criteria for the analysis of the different data sets. PMID- 25145680 TI - Solvent-free synthesis, coating and morphogenesis of conductive polymer materials through spontaneous generation of activated monomers. AB - Synthesis, coating, and morphogenesis of conductive polymers were achieved on a variety of substrates through spontaneous generation of activated monomer vapors under ambient pressure and low temperature conditions. The present approach facilitates the generation of complex hierarchical morphologies and the conductive coating for improvement of electrochemical properties. PMID- 25145677 TI - Glucose availability and glycolytic metabolism dictate glycosphingolipid levels. AB - Cancer therapeutics has seen an emergence and re-emergence of two metabolic fields in recent years, those of bioactive sphingolipids and glycolytic metabolism. Anaerobic glycolysis and its implications in cancer have been at the forefront of cancer research for over 90 years. More recently, the role of sphingolipids in cancer cell metabolism has gained recognition, notably ceramide's essential role in programmed cell death and the role of the glucosylceramide synthase (GCS) in chemotherapeutic resistance. Despite this knowledge, a direct link between these two fields has yet to be definitively drawn. Herein, we show that in a model of highly glycolytic cells, generation of the glycosphingolipid (GSL) glucosylceramide (GlcCer) by GCS was elevated in response to increased glucose availability, while glucose deprivation diminished GSL levels. This effect was likely substrate dependent, independent of both GCS levels and activity. Conversely, leukemia cells with elevated GSLs showed a significant change in GCS activity, but no change in glucose uptake or GCS expression. In a leukemia cell line with elevated GlcCer, treatment with inhibitors of glycolysis or the pentose phosphate pathway (PPP) significantly decreased GlcCer levels. When combined with pre-clinical inhibitor ABT-263, this effect was augmented and production of pro-apoptotic sphingolipid ceramide increased. Taken together, we have shown that there exists a definitive link between glucose metabolism and GSL production, laying the groundwork for connecting two distinct yet essential metabolic fields in cancer research. Furthermore, we have proposed a novel combination therapeutic option targeting two metabolic vulnerabilities for the treatment of leukemia. PMID- 25145681 TI - Magnetic force microscopy reveals meta-stable magnetic domain states that prevent reliable absolute palaeointensity experiments. AB - Obtaining reliable estimates of the absolute palaeointensity of the Earth's magnetic field is notoriously difficult. The heating of samples in most methods induces magnetic alteration--a process that is still poorly understood, but prevents obtaining correct field values. Here we show induced changes in magnetic domain state directly by imaging the domain configurations of titanomagnetite particles in samples that systematically fail to produce truthful estimates. Magnetic force microscope images were taken before and after a heating step typically used in absolute palaeointensity experiments. For a critical temperature (250 degrees C), we observe major changes: distinct, blocky domains before heating change into curvier, wavy domains thereafter. These structures appeared unstable over time: after 1-year of storage in a magnetic-field-free environment, the domain states evolved into a viscous remanent magnetization state. Our observations qualitatively explain reported underestimates from otherwise (technically) successful experiments and therefore have major implications for all palaeointensity methods involving heating. PMID- 25145682 TI - Increasing mitochondrial membrane phospholipid content lowers the enzymatic activity of electron transport complexes. AB - Activities of the enzymes involved in cellular respiration are markedly influenced by the composition of the phospholipid environment of the inner mitochondrial membrane. Contrary to previous suppositions, we show that fusion of mitochondria isolated from healthy cardiac muscle with cardiolipin or dioleoylphosphatidylcholine results in a 2-6-fold reduction in the activity of complexes I, II, and IV. The activity of complex III was unaffected by increased phospholipid levels. Phospholipid content had an indiscriminate yet detrimental effect on the combined activities of complexes I+III and II+III. These results have strong implications for therapeutic lipid replacement strategies, in which phospholipid modification of the mitochondria is proposed to enhance mitochondrial function. PMID- 25145684 TI - Electrochemical intramolecular aminooxygenation of unactivated alkenes. AB - An electrochemical approach to the intramolecular aminooxygenation of unactivated alkenes has been developed. This process is based on the addition of nitrogen centered radicals, generated through electrochemical oxidation, to alkenes followed by trapping of the cyclized radical intermediate with 2,2,6,6 tetramethylpiperidine-N-oxyl radical (TEMPO). Difunctionalization of a variety of alkenes with easily available carbamates/amides and TEMPO affords aminooxygenation products in high yields and with excellent trans selectivity for cyclic systems (d.r. up to>20:1). The approach provides a much-needed complementary route to existing cis-selective methods. PMID- 25145683 TI - Hyperammonia induces specific liver injury through an intrinsic Ca2+-independent apoptosis pathway. AB - BACKGROUND: Numerous pathological processes that affect liver function in patients with liver failure have been identified. Among them, hyperammonia is one of the most common phenomena.The purpose of this study was to determine whether hyperammonia could induced specific liver injury. METHODS: Hyperammonemic cells were established using NH4Cl. The cells were assessed by MTT, ELISA, and flow cytometric analyses. The expression levels of selected genes and proteins were confirmed by quantitative RT-PCR and western blot analyses. RESULTS: The effects of 20 mM NH4Cl pretreatment on the cell proliferation and apoptosis of primary hepatocytes and other cells were performed by MTT assays and flow cytometric analyses. Significant increasing in cytotoxicity and apoptosis were only observed in hepatocytes. The cell damage was reduced after adding BAPTA-AM but unchanged after adding EGTA. The expression levels of caspase-3, cytochrome C, calmodulin, and inducible nitric oxide synthase were increased and that of bcl-2 was reduced. The Na+-K+-ATPase activities in hyperammonia liver cells was no signiaficant difference compaired with the control group, but was decreased in astrocytes. NH4Cl pretreatment of primary hepatocytes promoted the activation of mitochondrial permeability transition pores and the mitochondria swelled irregularly. CONCLUSIONS: Hyperammonia induces specific liver injury through an intrinsic Ca2+-independent apoptosis pathway. PMID- 25145686 TI - Maltreatment and Delinquency in China: Examining and Extending the Intervening Process of General Strain Theory. AB - Using a sample of 1,163 adolescents from four middle schools in China, this study explores the intervening process of how adolescent maltreatment is related to delinquency within the framework of general strain theory (GST) by comparing two models. The first model is Agnew's integrated model of GST, which examines the mediating effects of social control, delinquent peer affiliation, state anger, and depression on the relationship between maltreatment and delinquency. Based on this model, with the intent to further explore the mediating effects of state anger and depression and to investigate whether their effects on delinquency can be demonstrated more through delinquent peer affiliation and social control, an extended model (Model 2) is proposed by the authors. The second model relates state anger to delinquent peer affiliation and state depression to social control. By comparing the fit indices and the significance of the hypothesized paths of the two models, the study found that the extended model can better reflect the mechanism of how maltreatment contributes to delinquency, whereas the original integrated GST model only receives partial support because of its failure to find the mediating effects of state negative emotions. PMID- 25145685 TI - P-glycoprotein inhibition promotes prednisone retention in human sinonasal polyp explants. AB - BACKGROUND: P-glycoprotein (P-gp) is an efflux pump, which is part of the innate chemo-immunity defense system and is overexpressed in chronic rhinosinusitis with nasal polyps (CRSwNP). P-gp is capable of regulating corticosteroid retention and thus P-gp upregulation has been implicated in steroid resistance in several inflammatory disorders. The goal of this study is to determine whether P-gp regulates intracellular steroid retention in CRSwNP. METHODS: This was a Massachusetts Eye and Ear Infirmary Institutional Review Board (IRB)-approved study in nasal polyp explants. Polyps were exposed to 50 MUg/mL of prednisone for 30 minutes with or without the presence of a P-gp inhibitor (Verapamil 12.5 MUM or Zosuquidar 0.31 MUM) followed by a 40-minute washout period (n = 16 per group). Intracellular steroid retention was determined by quantifying the concentration of both intracytoplasmic and secreted steroid using an enzyme linked immunosorbent assay (ELISA). Concentrations relative to control were compared using a Student t test. RESULTS: The intracytoplasmic prednisone concentration was significantly greater relative to control following P-gp inhibition with Verapamil (155.28% +/- 22.48%, p < 0.05) and Zosuquidar (125.81% +/- 12.41%, p < 0.05). Similarly, the amount of prednisone secreted by the explant was significantly reduced at 30 minutes following P-gp inhibition with Zosuquidar (78.64% +/- 2.98%, p < 0.05) and 40 minutes following P-gp inhibition with Verapamil (80.56% +/- 5.02%, p < 0.05). CONCLUSION: Inhibition of P-gp enhances the intracellular accumulation of prednisone in nasal polyps. This suggests that P-gp participates in regulation of glucocorticoid retention in sinonasal mucosa. These findings, coupled with the known overexpression of P-gp in CRSwNP, may point to a possible mechanism for steroid resistance in this patient population. PMID- 25145687 TI - Evidence of a Gene * Environment Interaction Between Birth Weight and Genetic Risk in the Prediction of Criminogenic Outcomes Among Adolescent Males. AB - A number of studies have revealed that low birth weight children have a heightened risk of various maladaptive outcomes, including academic challenges and delinquent involvement. However, very little research to date has examined whether the relationship between low birth weight, poor academic performance, and delinquent peer affiliation is moderated by genetic risk. Using data from the National Longitudinal study of Adolescent Health, the present study examines whether male adolescents born at very low birth weights are significantly predisposed to poor academic performance and delinquent peer affiliation. Moreover, we test whether the effect of birth weight on these outcomes is conditioned by level of genetic risk. We find no evidence that very low birth weight males are more likely to affiliate with delinquent peers or perform poorly in school during adolescence. However, upon examining gene-environment interactions, we find that being born at a very low birth weight does significantly increase the odds of poor academic performance and delinquent peer affiliation among males who possess a higher level of genetic risk. Limitations are noted and the implications of the findings are discussed. PMID- 25145688 TI - Including mental health among the new sustainable development goals. PMID- 25145690 TI - Revised McDonald criteria for multiple sclerosis diagnostics in central Russia: sensitivity and specificity. AB - BACKGROUND: The 2010 revised McDonald criteria were developed with data gathered from Caucasian European and North American populations, and their applicability has been questioned for the Russian population. OBJECTIVE: The objective of this report is to compare the specificity, accuracy, sensitivity and predictive value of MRI criteria incorporated to the new (2010) and old (2005) McDonald criteria for early multiple sclerosis (MS) diagnostics in the Nyzhnyi Novgorod (Russia) population. METHODS: A total of 103 patients with symptoms suggestive of MS were recruited from 2008 to 2011 retrospectively. Patients were followed up until MS was confirmed or other proved diagnoses were determined. Their baseline and follow-up brain and spinal cord MRIs were retrospectively evaluated. Sixty-two patients (60%) converted to MS during the follow-up period (mean in 11+/-4.2 months). RESULTS: In 41 cases (38%) diagnoses another than MS were established. The sensitivity, specificity, accuracy, PPV and NPV of the revised MRI criteria were 74%, 93%, 82%, 94%, 70%, respectively. CONCLUSIONS: Despite the limitations of our study, we conclude that the ability of the revised MRI criteria for early MS diagnostics in the Russian population is approximately similar to that determined by the international panel in Europe. PMID- 25145689 TI - Regional patterns of grey matter atrophy and magnetisation transfer ratio abnormalities in multiple sclerosis clinical subgroups: a voxel-based analysis study. AB - BACKGROUND: In multiple sclerosis (MS), demyelination and neuro-axonal loss occur in the brain grey matter (GM). We used magnetic resonance imaging (MRI) measures of GM magnetisation transfer ratio (MTR) and volume to assess the regional localisation of reduced MTR (reflecting demyelination) and atrophy (reflecting neuro-axonal loss) in relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). METHODS: A total of 98 people with MS (51 RRMS, 28 SPMS, 19 PPMS) and 29 controls had T1-weighted volumetric and magnetisation transfer scans. SPM8 was used to undertake voxel-based analysis (VBA) of GM tissue volumes and MTR. MS subgroups were compared with controls, adjusting for age and gender. A voxel-by-voxel basis correlation analysis between MTR and volume within each subject group was performed, using biological parametric mapping. RESULTS: MTR reduction was more extensive than atrophy. RRMS and SPMS patients showed proportionately more atrophy in the deep GM. SPMS and PPMS patients showed proportionately greater cortical MTR reduction. RRMS patients demonstrated the most correlation of MTR reduction and atrophy in deep GM. In SPMS and PPMS patients, there was less extensive correlation. CONCLUSIONS: These results suggest that in the deep GM of RRMS patients, demyelination and neuro-axonal loss may be linked, while in SPMS and PPMS patients, neuro-axonal loss and demyelination may occur mostly independently. PMID- 25145691 TI - Serum anti-Mullerian hormone levels in reproductive-age women with relapsing remitting multiple sclerosis. AB - BACKGROUND: Fertility might be reduced in women with multiple sclerosis (MS), although only few studies exist and the underlying reasons are not well understood. Similar to other autoimmune diseases, a decreased ovarian reserve may contribute to impaired fertility in women with MS. Anti-Mullerian hormone (AMH) is an established marker of the ovarian reserve and an objective indicator of ovarian function, which is independent of the hypothalamus-pituitary-gonadal axis function. OBJECTIVE: The purpose of this study was to determine AMH levels in females with relapsing-remitting MS (RRMS) in combination with other reproduction and lifestyle factors. METHODS: A total of 76 reproductive-age females with RRMS and 58 healthy controls were included in this case control study. An enzymatically amplified two-site immunoassay was used to measure serum AMH level. RESULTS: Mean AMH level was significantly decreased in females with RRMS (p<0.04), and a higher proportion of females with RRMS showed very low AMH values (<0.4 ng/ml) compared to healthy controls (p<0.05). The majority of these women were currently without any disease modifying treatment. CONCLUSIONS: Our data contribute to our understanding of impaired fertility in women with MS. The unexpected finding that the majority of MS subjects with very low AMH levels were currently without medication requires further evaluation. PMID- 25145692 TI - Cingulum bundle alterations underlie subjective fatigue in multiple sclerosis. AB - OBJECTIVE: To evaluate the neural basis of subjective fatigue in subjects with multiple sclerosis (MS) using a connectionist framework. METHODS: Seventy seven subjects with relapsing-remitting MS were recruited in the study and underwent subjective fatigue evaluations and a diffusion MRI scan. Firstly, local white matter Fractional Anisotropy values were correlated with subjective fatigue scores using a voxel-wise approach. The long-range loss of connectivity due to structural damage in the white matter voxels thus associated with subjective fatigue was then assessed using the Network Modification (NeMo) package. RESULTS: A voxel-wise regression analysis with fatigue scores revealed a significant association between structural damage and fatigue levels in two discrete white matter clusters, both included in the left cingulate bundle. The connectivity analysis revealed that damage in these clusters was associated with loss of structural connectivity in the anterior and medial cingulate cortices, dorsolateral prefrontal areas and in the left caudate. DISCUSSION: Our data point to the cingulum bundle and its projections as the key network involved in subjective fatigue perception in MS. More generally, these results suggest the potential of the connectionist framework to generate coherent models of the neural basis of complex symptomatology in MS. PMID- 25145694 TI - Extreme temperatures, foundation species, and abrupt ecosystem change: an example from an iconic seagrass ecosystem. AB - Extreme climatic events can trigger abrupt and often lasting change in ecosystems via the reduction or elimination of foundation (i.e., habitat-forming) species. However, while the frequency/intensity of extreme events is predicted to increase under climate change, the impact of these events on many foundation species and the ecosystems they support remains poorly understood. Here, we use the iconic seagrass meadows of Shark Bay, Western Australia--a relatively pristine subtropical embayment whose dominant, canopy-forming seagrass, Amphibolis antarctica, is a temperate species growing near its low-latitude range limit--as a model system to investigate the impacts of extreme temperatures on ecosystems supported by thermally sensitive foundation species in a changing climate. Following an unprecedented marine heat wave in late summer 2010/11, A. antarctica experienced catastrophic (>90%) dieback in several regions of Shark Bay. Animal borne video footage taken from the perspective of resident, seagrass-associated megafauna (sea turtles) revealed severe habitat degradation after the event compared with a decade earlier. This reduction in habitat quality corresponded with a decline in the health status of largely herbivorous green turtles (Chelonia mydas) in the 2 years following the heat wave, providing evidence of long-term, community-level impacts of the event. Based on these findings, and similar examples from diverse ecosystems, we argue that a generalized framework for assessing the vulnerability of ecosystems to abrupt change associated with the loss of foundation species is needed to accurately predict ecosystem trajectories in a changing climate. This includes seagrass meadows, which have received relatively little attention in this context. Novel research and monitoring methods, such as the analysis of habitat and environmental data from animal-borne video and data-logging systems, can make an important contribution to this framework. PMID- 25145695 TI - Bringing systems biology to cancer, immunology and infectious disease. AB - A report on the seventh annual 'International Conference on Systems Biology of Human Disease' held in Boston, Massachusetts, USA, 17-19 June, 2014. PMID- 25145693 TI - Similar biological effect of high-dose oral versus intravenous methylprednisolone in multiple sclerosis relapses. AB - Our aim was to investigate differences in immune mechanisms in multiple sclerosis (MS) relapse, after high-dose oral methylprednisolone (oMP) or intravenous methylprednisolone (ivMP). We measured serum cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-alpha and IFN-gamma) in 39 of 49 MS patients with moderate-severe relapse, whom were treated with ivMP or oMP in a placebo-controlled, non inferiority clinical trial. We assessed these cytokine levels at baseline and at 1 and 4 weeks post-treatment. The cytokine levels between oMP and ivMP were similar at any time. Proinflammatory cytokines (IL-6 and IFN-gamma) were significantly decreased in both groups at week 1 (p = 0.05 / p = 0.03) and at week 4 (p = 0.04 / p = 0.05). This study provides further confirmatory evidence that oMP is not inferior to ivMP. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00753792. PMID- 25145696 TI - Research fraud: how to do it and how to stop it. PMID- 25145697 TI - Tree growth and intrinsic water-use efficiency of inland riparian forests in northwestern China: evaluation via delta13C and delta18O analysis of tree rings. AB - The rising atmospheric CO2 concentration (Ca) has increased tree growth and intrinsic water-use efficiency (iWUE). However, the magnitude of this effect on long-term iWUE and whether this increase could stimulate the growth of riparian forests in extremely arid regions remain poorly understood. We investigated the relationship between growth [ring width; basal area increment (BAI)] and iWUE in a riparian Populus euphratica Oliv. forest to test whether growth was enhanced by increasing CO2 and whether this compensated for environmental stresses in the lower reaches of the inland Heihe River, northwestern China. We accomplished this using dendrochronological methods and carbon (delta(13)C) and oxygen (delta(18)O) isotopic analysis. We found an increase in BAI before 1958, followed by a decrease from 1958 to 1977 and an increase to a peak around 2000. Tree-ring carbon discrimination (Delta) and delta(18)O indicated significant negative overall trends from 1920 to 2012. However, the relationship shifted in strength and direction around 1977 from significantly negative to a weak connection. The seasonal minimum temperature in April to July showed strong influence on Delta, and delta(18)O was controlled by relative humidity (negatively correlated) and temperature (positively correlated) in June and July. The patterns of internal to atmospheric CO2 (Ci/Ca) suggest a specific adaptation of tree physiology to increasing CO2. Intrinsic water-use efficiency increased significantly (by 36.4%) during the study period. The increased iWUE explained 19.8 and 39.1% of the observed yearly and high-frequency (first-order difference) variations in BAI, respectively, after 1977. Our results suggest significant CO2 stimulation of riparian tree growth, which compensated for the negative influences of reductions in river streamflow and a drying climate during the study period. PMID- 25145698 TI - Influence of stem temperature changes on heat pulse sap flux density measurements. AB - While natural spatial temperature gradients between measurement needles have been thoroughly investigated for continuous heat-based sap flow methods, little attention has been given to how natural changes in stem temperature impact heat pulse-based methods through temporal rather than spatial effects. By modelling the theoretical equation for both an ideal instantaneous pulse and a step pulse and applying a finite element model which included actual needle dimensions and wound effects, the influence of a varying stem temperature on heat pulse-based methods was investigated. It was shown that the heat ratio (HR) method was influenced, while for the compensation heat pulse and Tmax methods changes in stem temperatures of up to 0.002 degrees C s(-1) did not lead to significantly different results. For the HR method, rising stem temperatures during measurements led to lower heat pulse velocity values, while decreasing stem temperatures led to both higher and lower heat pulse velocities, and to imaginary results for high flows. These errors of up to 40% can easily be prevented by including a temperature correction in the data analysis procedure, calculating the slope of the natural temperature change based on the measured temperatures before application of the heat pulse. Results of a greenhouse and outdoor experiment on Pinus pinea L. show the influence of this correction on low and average sap flux densities. PMID- 25145699 TI - Ex vivo preparations of the intact vomeronasal organ and accessory olfactory bulb. AB - The mouse accessory olfactory system (AOS) is a specialized sensory pathway for detecting nonvolatile social odors, pheromones, and kairomones. The first neural circuit in the AOS pathway, called the accessory olfactory bulb (AOB), plays an important role in establishing sex-typical behaviors such as territorial aggression and mating. This small (<1 mm(3)) circuit possesses the capacity to distinguish unique behavioral states, such as sex, strain, and stress from chemosensory cues in the secretions and excretions of conspecifics. While the compact organization of this system presents unique opportunities for recording from large portions of the circuit simultaneously, investigation of sensory processing in the AOB remains challenging, largely due to its experimentally disadvantageous location in the brain. Here, we demonstrate a multi-stage dissection that removes the intact AOB inside a single hemisphere of the anterior mouse skull, leaving connections to both the peripheral vomeronasal sensory neurons (VSNs) and local neuronal circuitry intact. The procedure exposes the AOB surface to direct visual inspection, facilitating electrophysiological and optical recordings from AOB circuit elements in the absence of anesthetics. Upon inserting a thin cannula into the vomeronasal organ (VNO), which houses the VSNs, one can directly expose the periphery to social odors and pheromones while recording downstream activity in the AOB. This procedure enables controlled inquiries into AOS information processing, which can shed light on mechanisms linking pheromone exposure to changes in behavior. PMID- 25145700 TI - N-type calcium channel blockade: a new approach to preventing sudden cardiac death? PMID- 25145701 TI - Monitoring of chimerism following allogeneic haematopoietic stem cell transplantation (HSCT): technical recommendations for the use of short tandem repeat (STR) based techniques, on behalf of the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping Chimerism Working Group. AB - Analysis of short tandem repeats (STR) is the predominant method for post transplant monitoring of donor engraftment. It can enable early detection of disease relapse, level of engraftment and provide useful information on the graft versus-host disease (GVHD)/graft-versus-tumour (GVT) effect, facilitating therapeutic intervention. Harmonization and standardization of techniques and result interpretation is essential to reduce the impact of laboratory variability on both clinical management and the results of multi-centre clinical trials. However, the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping (UK NEQAS LI) has highlighted significant issues inherent in STR testing that impact upon inter- and intra- laboratory variation. We present here consensus best practice guidelines and recommendations for STR chimerism testing, data interpretation and reporting that have been drawn up and agreed by a consortium of 11 UK and Eire clinical laboratories. This document uses data obtained from the UK NEQAS LI Post-Stem Cell Transplant (SCT) Chimerism Monitoring Programme. PMID- 25145702 TI - Cancer screening in elderly people with limited life expectancy is common in US, study finds. PMID- 25145703 TI - Optimized negative staining: a high-throughput protocol for examining small and asymmetric protein structure by electron microscopy. AB - Structural determination of proteins is rather challenging for proteins with molecular masses between 40 - 200 kDa. Considering that more than half of natural proteins have a molecular mass between 40 - 200 kDa, a robust and high-throughput method with a nanometer resolution capability is needed. Negative staining (NS) electron microscopy (EM) is an easy, rapid, and qualitative approach which has frequently been used in research laboratories to examine protein structure and protein-protein interactions. Unfortunately, conventional NS protocols often generate structural artifacts on proteins, especially with lipoproteins that usually form presenting rouleaux artifacts. By using images of lipoproteins from cryo-electron microscopy (cryo-EM) as a standard, the key parameters in NS specimen preparation conditions were recently screened and reported as the optimized NS protocol (OpNS), a modified conventional NS protocol. Artifacts like rouleaux can be greatly limited by OpNS, additionally providing high contrast along with reasonably high-resolution (near 1 nm) images of small and asymmetric proteins. These high-resolution and high contrast images are even favorable for an individual protein (a single object, no average) 3D reconstruction, such as a 160 kDa antibody, through the method of electron tomography. Moreover, OpNS can be a high-throughput tool to examine hundreds of samples of small proteins. For example, the previously published mechanism of 53 kDa cholesteryl ester transfer protein (CETP) involved the screening and imaging of hundreds of samples. Considering cryo-EM rarely successfully images proteins less than 200 kDa has yet to publish any study involving screening over one hundred sample conditions, it is fair to call OpNS a high-throughput method for studying small proteins. Hopefully the OpNS protocol presented here can be a useful tool to push the boundaries of EM and accelerate EM studies into small protein structure, dynamics and mechanisms. PMID- 25145704 TI - Increased morbidity in early childhood among HIV-exposed uninfected children in Uganda is associated with breastfeeding duration. AB - Human immunodeficiency virus (HIV)-exposed uninfected children (HEU) have an increased risk of morbidity and mortality compared with HIV-unexposed uninfected children (HUU); however, prior studies have not fully accounted for the role of both breastfeeding and age on this association. In this cohort of HEU and HUU in Uganda, non-breastfeeding HEU, from 6-11 months compared with non-breastfeeding HUU had a higher risk of hospitalizations [relative risk (RR): 10.1, 95% confidence interval (CI): 3.70-27.6], severe febrile illness (RR: 3.84, 95% CI: 2.06-7.17), severe diarrhea (RR: 6.37, 95% CI: 2.32-17.4) and severe malnutrition (RR: 18.4, 95% CI: 4.68-72.0). There were no differences between morbidity outcomes between breastfeeding HEU and HUU children, aged 6-11 months. In the 12 24 month age group, the only difference in morbidity outcomes among non-breast feeding children was an increased risk of severe malnutrition for HEU. These data suggest that the increased risk of morbidity among HEU aged 6-11 years is partially explained by early cessation of breastfeeding. PMID- 25145706 TI - Axons from the medial habenular nucleus are topographically sorted in the fasciculus retroflexus. AB - We generated transgenic mice lines with a construct consisting of the zif268/egr1 promoter and the gene for the normal long-life yellow fluorescent protein (Venus) with a membrane localization sequence. One of the lines exhibited topographic labeling in the medial habenular nucleus (MHb) during postnatal development, which confirmed the previous findings that the medial, lateral, and dorsal areas of MHb project to the ventral, dorsal, and lateral parts of the interpeduncular nucleus, respectively. In addition, the membranous localization of the labeling allowed us to observe spacial arrangement of the labeled axons in the fasciculus retroflexus (FR) in the transgenic mice. Here, we report topographic sorting of the MHb axons in the FR. At postnatal day (P) 5 and P10, the labeled axons from the medial MHb were fasciculated and ran through the narrow path in the core of the FR. At P24, the labeled axons from the medial and dorsal MHb were fasciculated and ran through the broad path in the FR core. No labeling occurred in the lateral MHb throughout development; correspondingly, parts of the FR core remained unlabeled. The results indicated that the axons from the medial and dorsal areas of the MHb are grouped together in the FR of this transgenic line and are sorted out from the axons from the lateral MHb. PMID- 25145705 TI - Transducin beta-like 1 X-linked receptor 1 suppresses cisplatin sensitivity in nasopharyngeal carcinoma via activation of NF-kappaB pathway. AB - BACKGROUND: Transducin beta-like 1 X-linked receptor 1 (TBL1XR1) is an important transcriptional cofactor involved in the regulation of many signaling pathways, and is associated with carcinogenesis and tumor progression. However, the precise role of TBL1XR1 in these processes is not well understood. METHODS: We detected the expression of TBL1XR1 protein and mRNA in nasopharyngeal carcinoma (NPC) cell lines and biopsies by western blotting, real-time PCR and immunohistochemical staining (IHC). Overexpression of TBL1XR1 in NPC enhanced chemoresistance to cisplatin using two NPC cell lines in vitro and in vivo. RESULTS: TBL1XR1 was upregulated in NPC cell lines and clinical samples. The expression of TBL1XR1 was correlated with several clinicopathological factors including clinical stage, T classification, N classification and patient survival. Univariate and multivariate analysis revealed that TBL1XR1 was an independent prognostic factor for patient survival. In vitro and in vivo studies demonstrated that TBL1XR1 high expression induced resistance to cisplatin-induced apoptosis in NPC cells. Furthermore, we found that TBL1XR1 activated the NF-kappaB pathway and promoted transcription of genes downstream of NF-kappaB, especially anti-apoptotic genes. CONCLUSIONS: Upregulation of TBL1XR1 induces NPC cells resistance to cisplatin by activating the NF-kappaB pathway, and correlates with poor overall survival of NPC patients. TBL1XR1 has a pivotal role in NPC and could be a valuable prognostic factor as well as a novel biomarker for tailoring appropriate therapeutic regimes. PMID- 25145707 TI - Clear cell sarcoma-like tumor of the gastrointestinal tract: a case report and review of the literature. AB - Clear cell sarcoma is a rare tumor classically associated with tendons and aponeuroses of lower extremities of young adults and has a distinctive histopathologic and molecular profile. It has been rarely described in other locations other than soft tissues, including the gastrointestinal tract. Herein we report a case of clear cell sarcoma of gastrointestinal tract arising in the ileum, which is rich in osteoclast-like giant cells with a review of the literature. PMID- 25145708 TI - Pure glandular endometrioid-like yolk sac tumor of the testis. PMID- 25145709 TI - White emitters by tuning the excited-state intramolecular proton-transfer fluorescence emission in 2-(2'-hydroxybenzofuran)benzoxazole dyes. AB - The synthesis, structural, and photophysical properties of a new series of original dyes based on 2-(2'-hydroxybenzofuran)benzoxazole (HBBO) is reported. Upon photoexcitation, these dyes exhibit intense dual fluorescence with contribution from the enol (E*) and the keto (K*) emission, with K* being formed through excited-state intramolecular proton transfer (ESIPT). We show that the ratio of emission intensity E*/K* can be fine-tuned by judiciously decorating the molecular core with electron-donating or -attracting substituents. Push-pull dyes 9 and 10 functionalized by a strong donor (nNBu2 ) and a strong acceptor group (CF3 and CN, respectively) exhibit intense dual emission, particularly in apolar solvents such as cyclohexane in which the maximum wavelength of the two bands is the more strongly separated. Moreover, all dyes exhibit strong solid-state dual emission in a KBr matrix and polymer films with enhanced quantum yields reaching up to 54 %. A wise selection of substituents led to white emission both in solution and in the solid state. Finally, these experimental results were analyzed by time-dependent density functional theory (TD-DFT) calculations, which confirm that, on the one hand, only E* and K* emission are present (no rotamer) and, on the other hand, the relative free energies of the two tautomers in the excited state guide the ratio of the E*/K* emission intensities. PMID- 25145711 TI - Recruitment of healthcare specialists. PMID- 25145710 TI - Community pharmacy interventions for public health priorities: protocol for a systematic review of community pharmacy-delivered smoking, alcohol and weight management interventions. AB - BACKGROUND: Community pharmacists can deliver health care advice at an opportunistic level, related to prescription or non-prescription medicines and as part of focused services designed to reduce specific risks to health. Obesity, smoking and excessive alcohol intake are three of the most significant modifiable risk factors for morbidity and mortality in the UK, and interventions led by community pharmacists, aimed at these three risk factors, have been identified by the government as public health priorities. In 2008, the Department of Health for England stated that 'a sound evidence base that demonstrates how pharmacy delivers effective, high quality and value for money services is needed'; this systematic review aims to respond to this requirement. METHODS/DESIGN: We will search the databases MEDLINE, Embase, CINAHL, PsycINFO, Social Sciences Citation Index, ASSIA, IBSS, Sociological Abstracts, Scopus and NHS Economic Evaluation Database for studies that have evaluated interventions based on community pharmacies that aim to target weight management, smoking cessation and alcohol misuse. We will include all randomised controlled trials (RCTs), non-randomised controlled trials (NRCTs), controlled before-after studies (CBAs) and interrupted time series (ITS) and repeated measures studies. Data from included studies will be extracted by two independent reviewers and will include study details methods, results, intervention implementation/costs and methodological quality. Meta analysis will be conducted if appropriate; if not, the synthesis will be restricted to a narrative overview of individual studies looking at the same question. DISCUSSION: The review aims to summarise the evidence base on the effectiveness of community pharmacy interventions on health and health behaviours in relation to weight management, smoking cessation and alcohol misuse. It will also explore if, and how, socio-economic status, gender, ethnicity and age moderate the effect of the interventions and will describe how the interventions included in the review have been organised, implemented and delivered, since context is an important factor governing the success of public health interventions. The findings from this review will have an impact on the commissioning of public health services aiming to promote healthy weight, smoking cessation and prevent excessive alcohol consumption. SYSTEMATIC REVIEW REGISTRATION: The review has been registered with PROSPERO (registration no. CRD42013005943). Available at: http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42013005943. PMID- 25145712 TI - Synthesis and self-assembly of thermoresponsive amphiphilic biodegradable polypeptide/poly(ethyl ethylene phosphate) block copolymers. AB - We report the design and synthesis of new fully biodegradable thermoresponsive amphiphilic poly(gamma-benzyl L-glutamate)/poly(ethyl ethylene phosphate) (PBLG-b PEEP) block copolymers by ring-opening polymerization of N-carboxy-gamma-benzyl L glutamate anhydride (BLG-NCA) with amine-terminated poly(ethyl ethylene phosphate) (H2N-PEEP) as a macroinitiator. The fluorescence technique demonstrated that the block copolymers could form micelles composed of a hydrophobic core and a hydrophilic shell in aqueous solution. The morphology of the micelles as determined by transmission electron microscopy (TEM) was spherical. The size and critical micelle concentration (CMC) values of the micelles showed a decreasing trend as the PBLG segment increased. However, UV/Vis measurements showed that these block copolymers exhibited a reproducible temperature-responsive behavior with a lower critical solution temperature (LCST) that could be tuned by the block composition and the concentration. PMID- 25145713 TI - Playing well with others. PMID- 25145714 TI - Leaning in. PMID- 25145716 TI - Addressing adolescent pregnancy with legislation. AB - Adolescent pregnancy is a concern among many women's health practitioners. While it is practical and appropriate to work to prevent adolescent pregnancy by educating adolescents in health care clinics, schools and adolescent-friendly community-based organizations, suggesting and supporting legislative efforts to reduce adolescent pregnancy can help address the issue on an even larger scale. This article aims to help nurses better understand current legislation that addresses adolescent pregnancy, and to encourage support of future adolescent pregnancy prevention legislation. PMID- 25145717 TI - The role of nurses in comprehensive care management of pregnant women with drug addiction. AB - Drug addiction during pregnancy is a complex health and social issue that requires an interdisciplinary health care team providing nonjudgmental, comprehensive care. Critical challenges include onset of and attendance at prenatal care, potential obstetric complications, transition to extrauterine life and potential neonatal abstinence syndrome for the neonate, newborn feeding issues, postpartum depression and risk of relapse for women. PMID- 25145718 TI - A quality improvement project focused on women's perceptions of skin-to-skin contact after cesarean birth. AB - A quality improvement (QI) project was designed to identify women's perceptions of the benefits of skin-to-skin contact with newborns immediately following cesarean birth. Women reported positive experiences associated with skin-to-skin contact with their newborns. A major theme that emerged was that women who had cesarean birth felt that this QI project resulted in a birthing experience comparable to that of mothers who had vaginal deliveries. Participants also experienced decreased anxiety regarding the health and welfare of their newborns, as compared to a previous cesarean birth experience in which they did not have skin-to-skin contact. PMID- 25145719 TI - Dispelling myths to support breastfeeding in women with postpartum depression. AB - Increasing attention is being paid to the possible connection between infant feeding practices and postpartum depression. Nurses caring for women and their families in the postpartum period might wonder how to best support the breastfeeding relationship if a woman has a history of depression. Using evidence from the scientific literature, this article dispels some myths regarding breastfeeding and depression, and provides suggested dialogue nurses can use when counseling women about depression and breastfeeding. PMID- 25145720 TI - Overview of latest evidence on uterine fibroids. AB - Uterine fibroids are the most common type of benign gynecologic mass, and are present in up to 80 percent of women. Research exploring risk factors for fibroids presents conflicting or inconclusive findings. Symptoms for up to 50 percent of women experiencing fibroids include heavy menstrual bleeding, pelvic pressure or pain and gastrointestinal and genitourinary changes. Diagnosis is made by history and symptoms, physical examination and imaging. Several treatment options are available, and are based on symptoms, preferences and reproductive plans. Given the high prevalence of fibroids and the potential for women's health implications, it is essential that clinicians are aware of the latest evidence regarding fibroids to provide the highest quality of care for women whose health is affected by this condition. PMID- 25145721 TI - Improving efficiency, consistency and satisfaction on a mother-baby unit with the discharge nurse position. AB - We created a discharge nurse position on a mother-baby unit in the hopes of improving outcomes related to the discharge process. Using the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS), we documented improved outcomes with regard to efficiency, consistency, standardization of patient education and patient satisfaction. PMID- 25145722 TI - How to succeed as an adjunct clinical nurse instructor. AB - Adjunct clinical nurse instructors who are proactive about staying clinically current and who form collaborative relationships with nurses, physicians and other health care professionals are able to teach safe care and engender staff nurses' trust. It's important for nurse educators to continually work to remain effective in the clinical setting to provide an optimal learning environment for students and optimal working environment for staff. PMID- 25145724 TI - Hospitals partner with AWHONN to prevent maternal deaths. PMID- 25145725 TI - On becoming a nurse. PMID- 25145726 TI - Introduction to the Suicide Prevention Research Prioritization Task Force special supplement: the topic experts. PMID- 25145727 TI - Experiences and wisdom behind the numbers: qualitative analysis of the National Action Alliance for Suicide Prevention's Research Prioritization Task Force stakeholder survey. AB - BACKGROUND: The Research Prioritization Task Force of the National Action Alliance for Suicide Prevention conducted a stakeholder survey including 716 respondents from 49 U.S. states and 18 foreign countries. PURPOSE: To conduct a qualitative analysis on responses from individuals representing four main stakeholder groups: attempt and loss survivors, researchers, providers, and policy/administrators. This article focuses on a qualitative analysis of the early-round, open-ended responses collected in a modified online Delphi process, and, as an illustration of the research method, focuses on analysis of respondents' views of the role of life and emotional skills in suicide prevention. METHODS: Content analysis was performed using both inductive and deductive code and category development and systematic qualitative methods. After the inductive coding was completed, the same data set was re-coded using the 12 Aspirational Goals (AGs) identified by the Delphi process. RESULTS: Codes and thematic categories produced from the inductive coding process were, in some cases, very similar or identical to the 12 AGs (i.e., those dealing with risk and protective factors, provider training, preventing reattempts, and stigma). Other codes highlighted areas that were not identified as important in the Delphi process (e.g., cultural/social factors of suicide, substance use). CONCLUSIONS: Qualitative and mixed-methods research are essential to the future of suicide prevention work. By design, qualitative research is explorative and appropriate for complex, culturally embedded social issues such as suicide. Such research can be used to generate hypotheses for testing and, as in this analysis, illuminate areas that would be missed in an approach that imposed predetermined categories on data. PMID- 25145728 TI - The baby or the bath water? Lessons learned from the National Action Alliance for Suicide Prevention Research Prioritization Task Force literature review. AB - CONTEXT: The Research Prioritization Task Force of the National Action Alliance for Suicide Prevention conducted a comprehensive literature review of suicide prevention/intervention trials to assess the quality of the scientific evidence. EVIDENCE ACQUISITION: A literature "review of reviews" was conducted by searching the most widely used databases for mental health and public health research. The quality of the reviews was evaluated using the Revised Assessment of Multiple Systematic Reviews system; the quality of the scientific evidence for the suicide preventions/interventions was assessed using U.S. Preventive Services Task Force criteria. The reviews were limited to peer-reviewed publications with human subjects published in English. EVIDENCE SYNTHESIS: Ninety-eight systematic reviews and 45 primary sources on suicide prevention/interventions published between January 2000 and September 2012 were evaluated. The results suggest that the quality of both the systematic reviews and the scientific evidence for suicide preventions/interventions were mixed. The majority of the systematic reviews and prevention/interventions were evaluated as fair to poor in quality. CONCLUSIONS: There are many promising suicide prevention/intervention trials, but research findings are often inconclusive because of methodologic problems. Methodologic problems across systematic reviews include not conducting hand searches, not surveying gray literature, and being unable to aggregate data across studies. Methodologic problems with the scientific quality of the prevention/intervention trials include paucity of information on sample demographic characteristics, poorly defined outcomes, and excluding actively suicidal participants. Suggestions for ways to improve the quality of the systematic reviews and suicide preventions/interventions are provided. PMID- 25145729 TI - Improving national data systems for surveillance of suicide-related events. AB - BACKGROUND: Describing the characteristics and patterns of suicidal behavior is an essential component in developing successful prevention efforts. The Data and Surveillance Task Force (DSTF) of the National Action Alliance for Suicide Prevention was charged with making recommendations for improving national data systems for public health surveillance of suicide-related problems, including suicidal thoughts, suicide attempts, and deaths due to suicide. PURPOSE: Data from the national systems can be used to draw attention to the magnitude of the problem and are useful for establishing national health priorities. National data can also be used to examine differences in rates across groups (e.g., sex, racial/ethnic, and age groups) and geographic regions, and are useful in identifying patterns in the mechanism of suicide, including those that rarely occur. METHODS: Using evaluation criteria from the CDC, WHO, and the U.S.A.-based Safe States Alliance, the DSTF reviewed 28 national data systems for feasibility of use in the surveillance of suicidal behavior, including deaths, nonfatal attempts, and suicidal thoughts. The review criteria included attributes such as the aspects of the suicide-related spectrum (e.g., thoughts, attempts, deaths) covered by the system; how the data are collected (e.g., census, sample, survey, administrative data files, self-report, reporting by care providers); and the strengths and limitations of the survey or data system. RESULTS: The DSTF identified common strengths and challenges among the data systems based on the underlying data source (e.g., death records, healthcare provider records, population-based surveys, health insurance claims). From these findings, the DSTF proposed several recommendations for improving existing data systems, such as using standard language and definitions, adding new variables to existing surveys, expanding the geographic scope of surveys to include areas where data are not currently collected, oversampling of underrepresented groups, and improving the completeness and quality of information on death certificates. CONCLUSIONS: Some of the DSTF recommendations are potentially achievable in the short term (<1-3 years) within existing data systems, whereas others involve more extensive changes and will require longer-term efforts (4-10 years). Implementing these recommendations would assist in the development of a national coordinated program of fatal and nonfatal suicide surveillance to facilitate evidence-based action to reduce the incidence of suicide and suicidal behavior in all populations. PMID- 25145730 TI - Data for building a national suicide prevention strategy: what we have and what we need. AB - Suicide is a leading cause of death in the U.S. As both the rate and number of suicides continue to climb, the country struggles with how to reverse this alarming trend. Using population-based data from publically available sources including the Web-based Injury Statistics Query and Reporting System, National Survey on Drug Use and Health, the authors identified patterns of suicide that can be used to steer a public health-based suicide prevention strategy. That most suicide deaths occur upon the first attempt, for example, suggests that a greater investment in primary prevention is needed. The fact that definable subgroups receiving care through identifiable service systems, such as individuals in specialty substance use treatment, exhibit greater concentrations of suicide risk than the general public suggests that integrating suicide prevention strategies into those service system platforms is an efficient way to deliver care to those with heightened need. The data sets that reveal these patterns have both strengths (e.g., population-level) and weaknesses (e.g., lack of longitudinal data linking changing health status, intervention encounters, suicidal behavior, and death records). Some of the data needed for crafting a comprehensive, public health-based approach for dramatically reducing suicide are currently available or may be available in the near term. Other resources will have to be built, perhaps by enhancing existing federal surveillance systems or constructing new ones. The article concludes with suggestions for immediate and longer-term actions that can strengthen public data resources in the service of reducing suicide in the U.S. PMID- 25145731 TI - Population health outcome models in suicide prevention policy. AB - BACKGROUND: Suicide is a leading cause of death in the U.S. and results in immense suffering and significant cost. Effective suicide prevention interventions could reduce this burden, but policy makers need estimates of health outcomes achieved by alternative interventions to focus implementation efforts. PURPOSE: To illustrate the utility of health outcome models to help in achieving goals defined by the National Action Alliance for Suicide Prevention's Research Prioritization Task Force. The approach is illustrated specifically with psychotherapeutic interventions to prevent suicide reattempt in emergency department settings. METHODS: A health outcome model using decision analysis with secondary data was applied to estimate suicide attempts and deaths averted from evidence-based interventions. RESULTS: Under optimal conditions, the model estimated that over 1 year, implementing evidence-based psychotherapeutic interventions in emergency departments could decrease the number of suicide attempts by 18,737, and if offered over 5 years, it could avert 109,306 attempts. Over 1 year, the model estimated 2,498 fewer deaths from suicide, and over 5 years, about 13,928 fewer suicide deaths. CONCLUSIONS: Health outcome models could aid in suicide prevention policy by helping focus implementation efforts. Further research developing more sophisticated models of the impact of suicide prevention interventions that include a more complex understanding of suicidal behavior, longer time frames, and inclusion of additional outcomes that capture the full benefits and costs of interventions would be helpful next steps. PMID- 25145734 TI - Suicide risk screening and assessment: designing instruments with dissemination in mind. AB - This paper summarizes recommendations made regarding the National Action Alliance for Suicide Prevention Research Prioritization Task Force's Aspirational Goal 2, to "determine the degree of suicide risk (e.g., imminent, near-term, long-term) among individuals in diverse populations and in diverse settings through feasible and effective screening and assessment approaches." We recommend that researchers shift to using "design for dissemination" principles to maximize both the goodness of fit and validity of screening and assessment measures for a given setting. Three specific recommendations to guide research efforts are made to achieve this shift: (1) the parameters related to each setting, including the logistics, scope of practice, infrastructure, and decision making required, should be identified and used to choose or design screening and assessment instruments that have a good fit; (2) to the greatest feasible extent, technology should be used to support screening and assessment; and (3) researchers should study the best methods for translating validated instruments into routine clinical practice. We discuss the potential barriers to implementing these recommendations and illustrate the paradigm shift within the emergency department setting. PMID- 25145732 TI - Epigenetics and suicidal behavior research pathways. AB - Suicide and suicidal behaviors are complex, heterogeneous phenomena that are thought to result from the interactions among distal factors increasing predisposition and proximal factors acting as precipitants. Epigenetic factors are likely to act both distally and proximally. Aspirational Goal 1 aims to find clear targets for suicide and suicidal behavior intervention through greater understanding of the interplay among the biological, psychological, and social risk and protective factors associated with suicide. This paper discusses Aspirational Goal 1, focusing on the research pathway related to epigenetics, suicide, and suicidal behaviors. Current knowledge on epigenetic factors associated with suicide and suicidal behaviors is reviewed and avenues for future research are discussed. Epigenetic factors are a promising area of further investigation in the understanding of suicide and suicidal behaviors and may hold clues to identifying targets or avenues for intervention. PMID- 25145733 TI - Neurobiological risk factors for suicide: insights from brain imaging. AB - CONTEXT: This article reviews neuroimaging studies on neural circuitry associated with suicide-related thoughts and behaviors to identify areas of convergence in findings. Gaps in the literature for which additional research is needed are identified. EVIDENCE ACQUISITION: A PubMed search was conducted and articles published before March 2014 were reviewed that compared individuals who made suicide attempts to those with similar diagnoses who had not made attempts or to healthy comparison subjects. Articles on adults with suicidal ideation and adolescents who had made attempts, or with suicidal ideation, were also included. Reviewed imaging modalities included structural magnetic resonance imaging, diffusion tensor imaging, single photon emission computed tomography, positron emission tomography, and functional magnetic resonance imaging. EVIDENCE SYNTHESIS: Although many studies include small samples, and subject characteristics and imaging methods vary across studies, there were convergent findings involving the structure and function of frontal neural systems and the serotonergic system. CONCLUSIONS: These initial neuroimaging studies of suicide behavior have provided promising results. Future neuroimaging efforts could be strengthened by more strategic use of common data elements and a focus on suicide risk trajectories. At-risk subgroups defined by biopsychosocial risk factors and multidimensional assessment of suicidal thoughts and behaviors may provide a clearer picture of the neural circuitry associated with risk status-both current and lifetime. Also needed are studies investigating neural changes associated with interventions that are effective in risk reduction. PMID- 25145735 TI - Screening youth for suicide risk in medical settings: time to ask questions. AB - This paper focuses on the National Action Alliance for Suicide Prevention's Research Prioritization Task Force's Aspirational Goal 2 (screening for suicide risk) as it pertains specifically to children, adolescents, and young adults. Two assumptions are forwarded: (1) strategies for screening youth for suicide risk need to be tailored developmentally; and (2) we must use instruments that were created and tested specifically for suicide risk detection and developed specifically for youth. Recommendations for shifting the current paradigm include universal suicide screening for youth in medical settings with validated instruments. PMID- 25145736 TI - Improving the short-term prediction of suicidal behavior. AB - Aspirational Goal 3 of the National Action Alliance for Suicide Prevention's Research Prioritization Task Force is to predict who is at risk for attempting suicide in the near future. Despite decades of research devoted to the study of risk and protective factors for suicide and suicidal behavior, surprisingly little is known about the short-term prediction of these behaviors. In this paper, we propose several questions that, if answered, could improve the identification of short-term, or imminent, risk for suicidal behavior. First, what factors predict the transition from suicidal thoughts to attempts? Second, what factors are particularly strong predictors of making this transition over the next hours, days, or weeks? Third, what are the most important objective markers of short-term risk for suicidal behavior? And fourth, what method of combining information about risk and protective factors yields the best prediction? We propose that the next generation of research on the assessment and prediction of suicidal behavior should shift, from cross-sectional studies of bivariate risk and protective factors, to prospective studies aimed at identifying multivariate, short-term prediction indices, examining methods of synthesizing this information, and testing the ability to predict and prevent suicidal events. PMID- 25145737 TI - Prognostic models to detect and monitor the near-term risk of suicide: state of the science. AB - Aspirational Goal 3 of the National Action Alliance for Suicide Prevention's Research Prioritization Task Force research agenda is to "find ways to assess who is at risk for attempting suicide in the immediate future." Suicide risk assessment is the practice of detecting patient-level conditions that may rapidly progress toward suicidal acts. With hundreds of thousands of risk assessments occurring every year, this single activity arguably represents the most broadly implemented, sustained suicide prevention activity practiced in the U.S. Given this scope of practice, accurate and reliable risk assessment capabilities hold a central and irreplaceable position among interventions mounted as part of any public health approach to suicide prevention. Development of more reliable methods to detect and measure the likelihood of impending suicidal behaviors, therefore, represents one of the more substantial advancements possible in suicide prevention science today. Although past "second-generation" risk models using largely static risk factors failed to show predictive capabilities, the current "third-generation" dynamic risk prognostic models have shown initial promise. Methodologic improvements to these models include the advent of real time, in vivo data collection processes, common data elements across studies and data sharing to build knowledge around key factors, and analytic methods designed to address rare event outcomes. Given the critical need for improved risk detection, these promising recent developments may well foreshadow advancement toward eventual achievement of this Aspirational Goal. PMID- 25145738 TI - Evidence-based psychotherapies for suicide prevention: future directions. AB - Psychotherapeutic interventions targeting suicidal thoughts and behaviors are essential for reducing suicide attempts and deaths by suicide. To determine whether specific psychotherapies are efficacious in preventing suicide and suicide-related behaviors, it is necessary to rigorously evaluate therapies using RCTs. To date, a number of RCTs have demonstrated efficacy for several interventions focused on preventing suicide attempts and reducing suicidal ideation. Although these studies have contributed greatly to the understanding of treatment for suicidal thoughts and behaviors, the extant literature is hampered by a number of gaps and methodologic limitations. Thus, further research employing increased methodologic rigor is needed to improve psychotherapeutic suicide prevention efforts. The aims of this paper are to briefly review the state of the science for psychotherapeutic interventions for suicide prevention, discuss gaps and methodologic limitations of the extant literature, and suggest next steps for improving future studies. PMID- 25145740 TI - Alcohol and suicidal behavior: what is known and what can be done. AB - Research on associations between substances of abuse and suicidal behaviors is a large, complex area. Herein, alcohol, the most commonly abused intoxicant worldwide, is examined with a focus on two topics: (1) acute use of alcohol (AUA) shortly prior to suicidal behavior; and (2) more chronic alcohol use disorder (AUD) and suicidal behavior. First, a brief summary of what is known about AUA, AUD, and suicidal behavior is provided. Next, we draw on preliminary evidence, practical considerations, and our own experience to offer recommendations for intervention research that may lower risk associated with AUA and AUD. The literature on AUD and suicidal behavior is more developed, thus we discuss separately research designed to: (1) prevent individuals with AUD with suicidal ideation from engaging in suicidal behavior; and (2) prevent individuals with AUD who have made a suicide attempt from reattempting. Our focus is on clinical intervention strategies for individuals at risk for suicidal behavior that use alcohol or have developed AUD. We also focus on applied research that may directly lead to practical prevention efforts. Although clinical interventions are important components of a comprehensive suicide prevention strategy, they should be complemented with primary prevention efforts. PMID- 25145739 TI - Existing and novel biological therapeutics in suicide prevention. AB - We summarize outcomes for several pharmacologic and neurostimulatory approaches that have been considered potential treatments to reduce suicide risk, namely, by reducing suicide deaths, attempts, and ideation in various clinical populations. Available treatments include clozapine, lithium, antidepressants, antipsychotics, electroconvulsive therapy, and transcranial magnetic stimulation. The novel repurposing of ketamine as a potential suicide risk-mitigating agent in the acute setting is also discussed. Research pathways to better understand and treat suicidal ideation and behavior from a neurobiological perspective are proposed in light of this foundation of information and the limitations and challenges inherent in suicide research. Such pathways include trials of fast-acting medications, registry approaches to identify appropriate patients for trials, identification of biomarkers, neuropsychological vulnerabilities, and endophenotypes through the study of known suicide risk-mitigating agents in hope of determining mechanisms of pathophysiology and the action of protective biological interventions. PMID- 25145741 TI - A review of evidence-based follow-up care for suicide prevention: where do we go from here? AB - CONTEXT: Follow-up services are an important component of a comprehensive, national strategy for suicide prevention. Increasing our knowledge of effective follow-up care has been identified as an Aspirational Goal by The National Action Alliance for Suicide Prevention's Research Prioritization Task Force. EVIDENCE ACQUISITION: Several recent comprehensive reviews informed the selection of studies included in this brief review. Studies of follow-up services that reported significant effects for the outcomes of death by suicide, suicide attempts, or suicidal ideation were included. EVIDENCE SYNTHESIS: Although there is a paucity of research in this area, promising paradigms that have demonstrated effectiveness in preventing suicide and suicide attempts and reducing suicidal ideation will be discussed. The major limitations of the literature in this area include numerous methodological flaws in the design and analyses of such studies and the lack of replication of studies with positive findings. CONCLUSIONS: This paper identifies several breakthroughs that would be helpful for advancing this area of research and describes a comprehensive research pathway for achieving both short- and long-term research objectives. PMID- 25145742 TI - Advancing training to identify, intervene, and follow up with individuals at risk for suicide through research. AB - Research and training on suicide is critical given the fact that the majority of suicide deaths are preventable with accurate identification of risk and intervention by trained individuals. However, implementing and evaluating training is difficult because of the multiple factors involved, including, but not limited to, the heterogeneity of trainees, their diverse roles in suicide prevention, absence of clear guidelines for training content across settings, and limited methods for assessing outcomes. Here, three groups of trainees are discussed: community and professional gatekeepers and behavioral health providers. The roles each group plays in managing suicide risk and the training content it needs to be effective are addressed. A staged training approach is proposed, building on the core components of currently used suicide training: knowledge, attitudes, and skills/behaviors. Limitations of current assessment methods are identified and recommendations for alternative methods are provided. The article concludes with a discussion of next steps in moving the field forward, including overcoming challenges and identifying and engaging opportunities. PMID- 25145743 TI - National pathways for suicide prevention and health services research. AB - CONTEXT: In 2012, the National Action Alliance for Suicide Prevention's Research Prioritization Task Force (RPTF) released a series of Aspirational Goals (AGs) to decrease suicide deaths and attempts. The RPTF asked experts to summarize what was known about particular AGs and to propose research pathways that would help reach them. This manuscript describes what is known about the benefits of access to health care (AG8) and continuity of care (AG9) for individuals at risk for suicide. Research pathways are proposed to address limitations in current knowledge, particularly in U.S. healthcare-based research. EVIDENCE ACQUISITION: Using a three-step process, the expert panel reviewed available literature from electronic databases. For two AGs, the experts summarized the current state of knowledge, determined breakthroughs needed to advance the field, and developed a series of research pathways to achieve prevention goals. EVIDENCE SYNTHESIS: Several components of healthcare provision have been found to be associated with reduced suicide ideation, and in some cases they mitigated suicide deaths. Randomized trials are needed to provide more definitive evidence. Breakthroughs that support more comprehensive patient data collection (e.g., real-time surveillance, death record linkage, and patient registries) would facilitate the steps needed to establish research infrastructure so that various interventions could be tested efficiently within various systems of care. Short-term research should examine strategies within the current healthcare systems, and long-term research should investigate models that redesign the health system to prioritize suicide prevention. CONCLUSIONS: Evidence exists to support optimism regarding future suicide prevention, but knowledge is limited. Future research is needed on U.S. healthcare services and system enhancements to determine which of these approaches can provide empirical evidence for reducing suicide. PMID- 25145744 TI - Prioritizing research to reduce youth suicide and suicidal behavior. AB - The goal of the National Action Alliance for Suicide Prevention is to reduce suicide and suicide attempts in the U.S. by 40% in the next decade. In this paper, a public health approach is applied to suicide prevention to illustrate how reductions in youth suicide and suicidal behavior might be achieved by prioritizing research in two areas: (1) increasing access to primary care-based behavioral health interventions for depressed youth and (2) improving continuity of care for youth who present to emergency departments after a suicide attempt. Finally, some scientific, clinical, and methodologic breakthroughs needed to achieve rapid, substantial, and sustained reductions in youth suicide and suicidal behavior are discussed. PMID- 25145745 TI - Increasing help-seeking and referrals for individuals at risk for suicide by decreasing stigma: the role of mass media. AB - Increasing help-seeking and referrals for at-risk individuals by decreasing stigma has been defined as Aspirational Goal 10 in the National Action Alliance for Suicide Prevention's Research Prioritization Task Force's 2014 prioritized research agenda. This article reviews the research evidence on the impact of mass media awareness campaigns on reducing stigma and increasing help-seeking. The review will focus on both beneficial and iatrogenic effects of suicide preventive interventions using media campaigns to target the broad public. A further focus is on collaboration between public health professionals and news media in order to reduce the risk of copycat behavior and enhance help-seeking behavior. Examples of multilevel approaches that include both mass media interventions and individual-level approaches to reduce stigma and increase referrals are provided as well. Multilevel suicide prevention programs that combine various approaches seem to provide the most promising results, but much more needs to be learned about the best possible composition of these programs. Major research and practice challenges include the identification of optimal ways to reach vulnerable populations who likely do not benefit from current awareness strategies. Caution is needed in all efforts that aim to reduce the stigma of suicidal ideation, mental illness, and mental health treatment in order to avoid iatrogenic effects. The article concludes with specific suggestions for research questions to help move this line of suicide research and practice forward. PMID- 25145746 TI - Suicide later in life: challenges and priorities for prevention. AB - Suicide in later life is a major public health concern in the U.S., where more than 6,000 older adults take their own lives every year. Suicide prevention in this age group is made challenging by the high lethality of older adults' suicidal behavior; few survive their first attempt to harm themselves. Research has revealed that factors in each of five domains place older adults at increased risk for suicide-psychiatric illness, personality traits and coping styles, medical illness, life stressors and social disconnectedness, and functional impairment. Little research has examined the effectiveness of interventions to reduce the toll of suicide in older adulthood. The study of strategies to decrease suicide deaths in later life should emphasize four areas. First is approaches to early detection of older people at risk through improved understanding of multi-dimensional determinants and their interactions. Second is research on the impact of general health promotion that optimizes well-being and independent functioning for older adults on suicide outcomes. Third concerns the study of approaches to the provision of mental health care that is evidence based, accessible, affordable, acceptable, and integrated with other aspects of care. The fourth area of high priority for research is approaches to improvement of social connectedness and its impact on suicide in older adults. PMID- 25145747 TI - Developmental approach to prevent adolescent suicides: research pathways to effective upstream preventive interventions. AB - The 2012 National Strategy for Suicide Prevention expands the current suicide prevention paradigm by including a strategic direction aimed at promoting healthy populations. Childhood and adolescence are key suicide prevention window periods, yet knowledge of suicide prevention pathways through universal interventions is limited (Aspirational Goal 11). Epidemiologic evidence suggests that prevention programs in normative social systems such as schools are needed for broad suicide prevention impact. Prevention trial results show that current universal prevention programs for children and young adolescents are effective in reducing adolescent emotional and behavioral problems that are risk factors for suicidal behavior, and in the case of the Good Behavior Game, suicide attempts. A developmentally sequenced upstream suicide prevention approach is proposed: (1) childhood programs to strengthen a broad set of self-regulation skills through family and school-based programs, followed by (2) adolescent programs that leverage social influences to prevent emerging risk behaviors such as substance abuse and strengthen relationships and skills. Key knowledge breakthroughs needed are evidence linking specific intervention strategies to reduced suicidal behaviors and mortality and their mechanisms of action. Short- and long-term objectives to achieve these breakthroughs include combining evidence from completed prevention trials, increasing motivators for prevention researchers to assess suicide-related outcome, and conducting new trials of upstream interventions in populations using efficient designs acceptable to communities. In conclusion, effective upstream prevention programs have been identified that modify risk and protective factors for adolescent suicide, and key knowledge breakthroughs can jump-start progress in realizing the suicide prevention potential of specific strategies. PMID- 25145748 TI - Promising strategies for advancement in knowledge of suicide risk factors and prevention. AB - Suicide is an important public health problem. Although there have been advances in our knowledge of suicide, gaps remain in knowledge about suicide risk factors and prevention. Here, we discuss research pathways that have the potential to rapidly advance knowledge in suicide risk assessment and reduction of suicide deaths over the next decade. We provide a concise overview of the methodologic approaches that have the capacity to rapidly increase knowledge and change practice, which have been successful in past work in psychiatry and other areas of medicine. We suggest three specific pathways to advance knowledge of suicide risk factors and prevention. First, analysis of large-scale epidemiologic surveys and administrative data sets can advance the understanding of suicide. Second, given the low base rate of suicide, there is a need for networks/consortia of investigators in the field of suicide prevention. Such consortia have the capacity to analyze existing epidemiologic data sets, create multi-site cohort studies of high-risk groups to increase knowledge of biological and other risk factors, and create a platform for multi-site clinical trials. Third, partnerships with policymakers and researchers would facilitate careful scientific evaluation of policies and programs aimed at reducing suicide. Suicide intervention policies are often multifaceted, expensive, and rarely evaluated. Using quasi-experimental methods or sophisticated analytic strategies such as propensity score-matching techniques, the impact of large-scale interventions on suicide can be evaluated. Furthermore, such partnerships between policymakers and researchers can lead to the design and support of prospective RCTs (e.g., cluster randomized trials, stepped wedge designs, waiting list designs) in high-risk groups (e.g., people with a history of suicide attempts, multi-axial comorbidity, and offspring of people who have died by suicide). These research pathways could lead to rapid knowledge uptake between communities and have the strong potential to reduce suicide. PMID- 25145749 TI - Reducing a suicidal person's access to lethal means of suicide: a research agenda. AB - Reducing the availability of highly lethal and commonly used suicide methods has been associated with declines in suicide rates of as much as 30%-50% in other countries. The theory and evidence underlying means restriction is outlined. Most evidence of its efficacy comes from population-level interventions and natural experiments. In the U.S., where 51% of suicides are completed with firearms and household firearm ownership is common and likely to remain so, reducing a suicidal person's access to firearms will usually be accomplished not by fiat or other legislative initiative but rather by appealing to individual decision, for example, by counseling at-risk people and their families to temporarily store household firearms away from home or otherwise making household firearms inaccessible to the at-risk person until they have recovered. Providers, gatekeepers, and gun owner groups are important partners in this work. Research is needed in a number of areas: communications research to identify effective messages and messengers for "lethal means counseling," clinical trials to identify effective interventions, translational research to ensure broad uptake of these interventions across clinical and community settings, and foundational research to better understand method choice and substitution. Approaches to suicide methods other than firearms are discussed. Means restriction is one of the few empirically based strategies to substantially reduce the number of suicide deaths. PMID- 25145750 TI - Reflections on expert recommendations for U.S. research priorities in suicide prevention. PMID- 25145751 TI - One-year evolution of sleep quality in older users of benzodiazepines: a longitudinal cohort study in belgian nursing home residents. AB - OBJECTIVES: Chronic use of benzodiazepines and z-drugs (BZD/Zs), the most commonly used symptomatic treatment for sleep problems, is discouraged because of the unproven long-term effectiveness. In this study, we evaluated 1-year evolution of subjective sleep quality of chronic BZD/Z users compared with nonusers. METHODS: All cognitively competent residents from ten Belgian nursing homes were screened and compiled in a group of chronic BZD/Z users or nonusers, based on the medication chart. We collected demographic, functional and psychometric characteristics (depressive symptoms with the 8-item Geriatric Depression Scale), sleep parameters (with the Pittsburgh Sleep Quality Index PSQI) and medication use. We analysed evolution of sleep quality with nonparametric statistics. Associations with worsening of sleep quality were analysed with linear regression. RESULTS: We collected data of 131 BZD/Z users and 95 nonusers. The mean age in both groups was 85 years and 77 % was female. Over a period of 1 year, the PSQI score evolved from 5.2 to 5.8 (p = 0.035) in the BZD/Z users, and from 4.3 to 4.7 (p = 0.078) in the nonusers. Though the mean deterioration in 1 year did not differ significantly between both groups, the BZD/Z users had a significantly worse sleep quality compared with nonusers at both time points. Depressive symptoms were significantly associated with worsening sleep quality (beta = -0.243, p < 0.001). CONCLUSION: Sleep quality in chronic BZD/Z users significantly decreased over 1 year and was significantly worse than in nonusers at the end of this period. This study suggests that using BZD/Zs chronically does not maintain or improve sleep quality. Depressive symptoms are an important factor in the deterioration of sleep quality. PMID- 25145752 TI - Altered brain-gut axis in autism: comorbidity or causative mechanisms? AB - The concept that alterated communications between the gut microbiome and the brain may play an important role in human brain disorders has recently received considerable attention. This is the result of provocative preclinical and some clinical evidence supporting early hypotheses about such communication in health and disease. Gastrointestinal symptoms are a common comorbidity in patients with autism spectrum disorders (ASD), even though the underlying mechanisms are largely unknown. In addition, alteration in the composition and metabolic products of the gut microbiome has long been implicated as a possible causative mechanism contributing to ASD pathophysiology, and this hypothesis has been supported by several recently published evidence from rodent models of autism induced by prenatal insults to the mother. Recent evidence in one such model involving maternal infection, that is characterized by alterations in behavior, gut physiology, microbial composition, and related metabolite profile, suggests a possible benefit of probiotic treatment on several of the observed abnormal behaviors. PMID- 25145753 TI - Regulatory T cells: alarmin(g) control. PMID- 25145754 TI - Inflammasomes: new LPS receptors discovered. PMID- 25145759 TI - Determination of solubility parameters of ionic liquids and ionic liquid/solvent mixtures from intrinsic viscosity. AB - The total and partial solubility parameters (dispersion, polar and hydrogen bonding solubility parameters) of ten ionic liquids were determined. Intrinsic viscosity approaches were used that encompassed a one-dimensional method (1D Method), and two different three-dimensional methods (3D-Method1 and 3D-Method2). The effect of solvent type, the dimethylacetamide (DMA) fraction in the ionic liquid, and dissolution temperature on solubility parameters were also investigated. For all types of effect, both the 1D-Method and 3D-Method2 present the same trend in the total solubility parameter. The partial solubility parameters are influenced by the cation and anion of the ionic liquid. Considering the effect on partial solubility parameters of the solvent type in the ionic liquid, it was observed that in both 3D methods, the dispersion and polar parameters of a 1-ethyl-3-methylimidazolium acetate/solvent (60:40 vol %) mixture tend to increase as the total solubility parameter of the solvent increases. PMID- 25145755 TI - The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. AB - Following the discovery of T helper 17 (TH17) cells, the past decade has witnessed a major revision of the TH subset paradigm and substantial progress has been made in deciphering the molecular mechanisms of T cell lineage commitment and function. In this Review, we focus on the recent advances that have been made regarding the transcriptional control of TH17 cell plasticity and stability, as well as the effector functions of TH17 cells, and we highlight the mechanisms of IL-17 signalling in mesenchymal and barrier epithelial tissues. We also discuss the emerging clinical data showing that IL-17-specific and IL-23-specific antibody treatments are remarkably effective for treating many immune-mediated inflammatory diseases. PMID- 25145757 TI - Phenotypic models of T cell activation. AB - T cell activation is a crucial checkpoint in adaptive immunity, and this activation depends on the binding parameters that govern the interactions between T cell receptors (TCRs) and peptide-MHC complexes (pMHC complexes). Despite extensive experimental studies, the relationship between the TCR-pMHC binding parameters and T cell activation remains controversial. To make sense of conflicting experimental data, a variety of verbal and mathematical models have been proposed. However, it is currently unclear which model or models are consistent or inconsistent with experimental data. A key problem is that a direct comparison between the models has not been carried out, in part because they have been formulated in different frameworks. For this Analysis article, we reformulated published models of T cell activation into phenotypic models, which allowed us to directly compare them. We find that a kinetic proofreading model that is modified to include limited signalling is consistent with the majority of published data. This model makes the intriguing prediction that the stimulation hierarchy of two different pMHC complexes (or two different TCRs that are specific for the same pMHC complex) may reverse at different pMHC concentrations. PMID- 25145760 TI - Blood loss and blood transfusion at caesarean section: a prospective observational study covering 30 years. AB - OBJECTIVE: Attitudes to acute blood loss and transfusion have changed during the last 40 years. This study observed the trends in blood loss and transfusion rates at caesarean section during that period to identify any trends between 1976 and 2006. STUDY DESIGN: Prospective analysis of clinical notes of women delivered by caesarean sections in a major district hospital obstetric unit in the UK, delivering around 6000 annually during four 12-month periods every 10 years from 1976 to 2006. Details including demographic, pregnancy, delivery, blood loss, transfusion, and puerperal observations were recorded. RESULTS: 3222 of 22,998 women were delivered by caesarean section during the four study years, increasing from 7.2% in 1976 to 23.4% in 2006 (P<0.001). The median recorded blood loss was 500ml, which did not change significantly over the study years. The rate of excess blood loss however increased in low-risk cases in 2006 compared with 1996 (P<0.001); this increase followed the recommended restricted intra-operative oxytocin dose. Transfusion rates declined significantly from 22% in 1976 to 4-5% in 1996 and 2006 (P<0.001). CONCLUSIONS: Median blood loss remained steady for each of the study years but with an increase in excess blood loss cases in the last study year compared with the two previous study years. The explanation for this is presently uncertain, but was possibly influenced by the 2001 recommendation for a reduced dose of oxytocin at delivery. Transfusion rates declined, probably precipitated by anxieties over infections associated blood products. There was no indication of increased morbidity with the reduced transfusion rates accessed by the surrogate of post-delivery discharge times. PMID- 25145761 TI - The relationship between subclinical cardiovascular disease and lipocalin-2 levels in women with PCOS. AB - OBJECTIVE: In this study we aimed to investigate the relationship between lipocalin-2 (LCN2) levels and cardiovascular risk in patients with polycystic ovary syndrome (PCOS). STUDY DESIGN: Fifty patients with PCOS and 44 healthy women as controls were enrolled in the study. Laboratory and echocardiographic examinations were performed between the second and fifth days of the menstrual cycle. Serum LCN2 levels were measured with an enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Serum LCN2 levels were significantly lower in PCOS patients (75.8 [51.4-131.2] ng/ml vs. 85.3 [56.7-138.5] ng/ml, p=0.038). Carotid intima-media thickness (CIMT) was increased in patients with PCOS compared to controls (0.61+/-0.13mm vs. 0.50+/-0.07mm, p=0.001). Aortic strain was lower in patients with PCOS. Aortic stiffness (beta index) was significantly increased and distensibility was decreased in PCOS patients compared to control subjects. Serum LCN2 levels and the presence of PCOS were associated with CIMT in Spearman correlation analysis (p=0.05 and p<0.001) in all participants. There was no statistically significant relationship between LCN2 levels and CIMT in patients with PCOS (p=0.238). CONCLUSION: In the present study, we found that LCN2 levels were low in women with PCOS. Although our patients with PCOS had elevated cardiac risk, there was no correlation between LCN2 levels and early findings of atherosclerosis. PMID- 25145756 TI - A long-awaited merger of the pathways mediating host defence and programmed cell death. AB - Historically, cell death and inflammation have been closely linked, but the necessary divergence of the fields in the past few decades has enriched our molecular understanding of the signalling pathways that mediate various programmes of cell death and multiple types of inflammatory responses. The fields have now come together again demonstrating a surprising level of integration. Intimate interconnections at multiple levels are revealed between the cell death and inflammatory signal transduction pathways that are mobilized in response to the engagement of pattern recognition receptors during microbial infection. Molecules such as receptor-interacting protein kinase 1 (RIPK1), RIPK3, FAS associated death domain protein (FADD), FLICE-like inhibitory protein (FLIP) and caspase 8 - which are associated with different forms of cell death - are incorporated into compatible and exceedingly dynamic Toll-like receptor, NOD-like receptor and RIG-I-like receptor signalling modules. These signalling modules have a high capacity to switch from inflammation to cell death, or a programmed execution of both, all in an orchestrated battle for host defence and survival. PMID- 25145762 TI - A prospective randomized clinical trial comparing immediate versus delayed removal of urinary catheter following elective cesarean section. AB - OBJECTIVE: To compare immediate and 12h postoperative removal of urinary catheter after elective cesarean section. STUDY DESIGN: In a prospective clinical trial at a university teaching hospital, 300 eligible women admitted for primary or repeat elective cesarean section were randomized into two equal groups. In group A, the catheter was removed immediately after the procedure; whereas in group B, the catheter was removed 12h postoperatively. RESULTS: The incidence of postoperative significant bacteruria (p=0.020), dysuria (p=0.030), burning on micturition (p=0.016), urinary frequency (p=0.031), and urgency (p=0.011) were significantly lower in group A compared with group B. The mean postoperative ambulation time (p<0.001), time till the first voiding (p<0.001), and length of hospital stay (p<0.001) were also significantly shorter in group A. There were no significant differences between the two groups in the incidence of urinary retention necessitating recatheterization (p=0.371). CONCLUSION: Immediate removal of urinary catheter after elective cesarean section is associated with lower risk of urinary infection and earlier postoperative ambulation. PMID- 25145764 TI - Cameron rejects Salmond's claim that Scottish independence will protect NHS from privatisation. PMID- 25145765 TI - Vanadium-catalyzed solvent-free synthesis of quaternary alpha-trifluoromethyl nitriles by electrophilic trifluoromethylation. AB - The direct electrophilic trifluoromethylation of silyl ketene imines (SKIs) with hypervalent iodine reagents leads to the formation of quaternary alpha trifluoromethyl nitriles in good yields. This new reaction has been carried out with a variety of substituted SKIs under solvent-free conditions using a vanadium(IV) catalyst (5 mol %). The corresponding products may be transformed into useful organofluorine building blocks. PMID- 25145763 TI - Frozen section in borderline ovarian tumors: is it reliable? AB - OBJECTIVE: We reported the concordance of frozen/section (FS) diagnosis of borderline ovarian tumor (BOT) and identified the factors associated with the concordance. STUDY DESIGN: FS results of the patients with a final diagnosis of BOT operated between 1990 and 2012 were analyzed. The FS results were reported as benign, rule out borderline tumor, borderline tumor, at least borderline tumor and malign tumor intraoperatively. The concordance of FS diagnosis was determined by comparing the FS result with the final pathological diagnosis. We accepted the FS concordant with the final pathology when the FS result was borderline tumor or at least borderline tumor, since we managed these patients in a similar way intraoperatively. Data regarding histological subtype, tumor size, age of the patients, menopausal status, presence of bilateral disease, preoperative Ca-125 level and the final diagnosis were evaluated. RESULTS: FS results of 145 patients were analyzed. The concordance of FS analysis for the total group, for the ones with serous and mucinous BOT were 79%, 92% and 62%, respectively. Totally, 29 patients (20%) weren't staged intraoperatively due to inaccurate FS result. Mucinous histology and larger tumor size were associated with lower concordance of FS. Concordance wasn't associated with type of surgery (conservative vs radical), menopausal status, laterality of the tumor, age of the patients and Ca 125 level of the patients. CONCLUSION: The high discrepancy rate of FS, especially in mucinous and larger tumors should be kept in mind during intraoperative decision-making based on FS analysis for BOT. PMID- 25145767 TI - Adsorption-geometry induced transformation of self-assembled nanostructures of an aldehyde molecule on Cu(110). AB - From an interplay of high-resolution STM imaging/manipulation and DFT calculations, we have revealed that different self-assembled nanostructures of BA molecules on Cu(110) are attributable to specific molecular adsorption geometries, and thus the corresponding intermolecular hydrogen bonding patterns. The STM manipulations demonstrate the feasibility of switching such weak-hydrogen bonding patterns. PMID- 25145766 TI - Treatment with fibrinogen gamma-chain peptide-coated, adenosine 5'-diphosphate encapsulated liposomes as an infusible hemostatic agent against active liver bleeding in rabbits with acute thrombocytopenia. AB - BACKGROUND: We evaluated the hemostatic efficacy of H12-(adenosine 5'-diphosphate [ADP])-liposomes in the setting of active liver bleeding in rabbits with dilutional thrombocytopenia after massive transfusion. STUDY DESIGN AND METHODS: Acute thrombocytopenia (platelet [PLT] count < 50 * 10(9) /L) was induced in rabbits by repeated blood withdrawal and isovolemic transfusion of autologous washed red blood cells. Liver hemorrhage was initiated by a penetrating liver injury. Subsequently, the animals received tamponade treatment for the liver hemorrhage for 5 minutes and were intravenously administered H12-(ADP)-liposomes with PLT-poor plasma (PPP), PLT-rich plasma (PRP), PPP alone, H12-(phosphate buffered saline [PBS])-liposome/PPP, or H12-(ADP)-liposomes/PPP plus fibrinogen concentrate during the tamponade. RESULTS: Administration of H12-(ADP) liposomes/PPP rescued 60% of the rabbits from the liver hemorrhage; PRP administration rescued 50%. In contrast, rabbits receiving PPP or H12-(PBS) liposome/PPP achieved only 10 or 17% survival, respectively, for the first 24 hours. H12-(ADP)-liposomes/PPP as well as PRP consistently reduced bleeding volumes and shortened clotting times (CTs) in comparison to PPP administration. Specifically, bleeding volumes in the initial 5 minutes averaged 11 mL (H12-(ADP) liposomes/PPP) and 17 mL (PRP) versus 30 mL (PPP; p < 0.05); CTs averaged 270 and 306 seconds versus 401 seconds (p < 0.05). H12-(ADP)-liposomes were observed at the bleeding site with thrombus formation, suggesting an induction of thrombi. Neither macro- nor microthrombi were detected in the lung, kidney, spleen, or liver in rabbits treated with H12-(ADP)-liposomes. Supplementation of fibrinogen to H12-(ADP)-liposomes/PPP did not significantly improve rabbit survival. CONCLUSIONS: H12-(ADP)-liposomes might be a safe and effective therapeutic tool during damage control surgery for trauma patients with acute thrombocytopenia and massive bleeding. PMID- 25145768 TI - Visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis in a traveler returning from a pilgrimage to the Camino de Santiago. AB - We report the case of a 73-year-old American traveler who presented with 3 weeks of fatigue, fevers, chills, and pancytopenia. Clinical and laboratory findings were consistent with hemophagocytic lymphohystiocytosis (HLH) and bone marrow biopsy revealed amastigotes consistent with visceral leishmaniasis. The range of endemic visceral leishmaniasis transmission now extends into northern Spain and travelers to this region should use personal protective measures against sand fly exposure. PMID- 25145769 TI - Decreasing hepatitis B viral load is associated with a risk of significant liver fibrosis in hepatitis B e antigen positive chronic hepatitis B. AB - Alanine aminotransferase (ALT), hepatitis B virus (HBV) DNA levels and age are used commonly to assess liver histology in chronic hepatitis B. Increasing levels of HBV DNA are associated with the increasing prevalence of significant fibrosis in HBeAg-negative patients. It is unclear whether these data can be applied to HBeAg-positive patients. In present study, liver biopsies were performed and clinical parameters were measured in 234 treatment-naive chronic HBeAg-positive patients. The proportion of significant fibrosis in patients with ALT 1-2 * ULN was similar to in patients with ALT more than 2 * ULN (48.4% vs. 51.8%). Patients over 30 years of age (>30 years) had a higher prevalence of significant fibrosis than patients 30 years of age and younger (61.0% vs. 33.6%). Negative correlation between HBV DNA levels and significant fibrosis was observed in patients >30 years. The optimal level of serum HBV DNA to evaluate low risk of significant fibrosis was >=6.7 log10 IU/ml. Patients with serum HBV DNA levels >=8.5 log10 IU/ml all had no significant fibrosis, however, patients with HBV DNA levels <4.7 log10 IU/ml all had significant fibrosis. Logistic regressions showed that age, aspartate aminotransferase, platelet count, and HBV DNA levels were independent predictors of significant fibrosis. In summary, older age, elevated ALT, and lower HBV DNA levels are associated with significant fibrosis. Decreasing levels of HBV DNA are associated with increasing prevalence of significant fibrosis in patients >30 years. The threshold of HBV DNA levels for treatment of HBeAg positive patients needs to be combined with age. PMID- 25145770 TI - Public stroke awareness and intent to call 112 in Sweden. AB - BACKGROUND AND AIMS: Recognition of stroke symptoms and activation of emergency services are essential in minimizing delay for acute stroke treatments. In this study, we assessed public stroke awareness in Sweden. METHODS: One thousand and five hundred residents aged 18-79 years participated in a telephone survey. Open ended questions were used to assess knowledge of stroke symptoms, risk factors, and action if witnessing or experiencing a potential stroke. RESULTS: Seventy-two percentage could report at least one stroke symptom and 86% at least one risk factor. Only 13% could report three or more stroke symptoms. Female sex (OR, 1.79; 95% CI, 1.30-2.45) and high education (OR, 2.30; 95% CI, 1.38-3.80) were associated with knowledge of stroke symptoms. Sixty-five percentage indicated they would call the emergency number 112 if witnessing or experiencing a potential stroke. Female sex (OR, 1.48; 95% CI, 1.18-1.85) and high education (OR, 1.40; 95% CI, 1.01-1.93) were positively associated, while increasing age (OR, 0.99; 95% CI, 0.98-0.99) was negatively associated with intent to call 112. CONCLUSION: We confirm a rather low public awareness of stroke in Sweden, poorer among males and those with low education. With increasing age, a lower proportion indicated intent to call 112 for stroke symptoms. PMID- 25145771 TI - Adiponectin predicts MMP-2 activity independently of obesity. AB - BACKGROUND: Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, have been identified in atherosclerotic plaques and have been directly associated with plaque remodelling and vulnerability. Cardiovascular disease (CVD) is related to insulin resistance (IR) and obesity, characterized by changes in plasma levels of inflammatory markers, such as adiponectin and C-reactive protein (CRP). Our aim was to evaluate the impact of both proteins on MMP-2 and MMP-9 behaviour in individuals with IR. MATERIALS AND METHODS: Plasma MMP-2 and MMP-9 activity, adiponectin and hs-CRP concentration and lipoprotein profile were determined in 52 patients with metabolic syndrome (MS) and 27 controls. RESULTS: Patients with MS presented significantly higher MMP-2 activity than controls: 0.95 +/- 0.12 vs. 0.77 +/- 0.15 relative units (RU) (P < 0.001), while MMP-9 activity was not detectable. MMP-2 activity decreased across quartiles of adiponectin, being significantly reduced in individuals with the highest levels of adiponectin in compared with the lowest levels (0.75 +/- 0.17 vs. 0.93 +/- 0.09 RU, P < 0.005). This difference persisted significant after adjusting by obesity markers. MMP-2 activity was significantly increased in individuals with the highest levels (G3) compared with those with the lowest levels (G1) of hs-CRP (0.94 +/- 0.12 vs. 0.86 +/- 0.12, P = 0.041) CONCLUSION: In this study, we observed that adiponectin levels predicted MMP-2 plasma activity independently of obesity. This finding suggests that the inflammatory process, associated with the highest CVD risk, would be involved in MMPs vascular production. PMID- 25145772 TI - SeMet mediates anti-inflammation in LPS-induced U937 cells targeting NF-kappaB signaling pathway. AB - In previous studies, selenium (Se) was reported to play critical roles in anti inflammatory activities. Nevertheless, limited information could be obtained during inflammation about selenomethionine (SeMet) in U937 human macrophage cells. The purpose of this study was to investigate the effects of SeMet on the inflammatory responses to lipopolysaccharide (LPS)-induced U937 macrophage cells and the signaling pathways targeted. U937 cells were pretreated with SeMet (1 MUM) and subsequently induced with LPS (1 MUg/ml) for 24 h. In the cell counting kit-8 assay (CCK-8), SeMet significantly inhibits the proliferation of U937 cells. SeMet also inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2) stimulated by LPS. In the Western blot assay and real-time polymerase chain reaction (RT-PCR), SeMet significantly reduced protein expression and production of inducible NO synthase (iNOS), tumor necrosis factor-alpha (TNF alpha), and COX-2 in U937 cells. Furthermore, SeMet markedly suppressed the LPS mediated activation of nuclear factor-kappa B (NF-kappaB) by blocking the degradation of inhibitor-kappaB proteins (IkappaBalpha) and lessening the translocations of P50 subunit content of NF-kappaB in the nucleus. These findings suggested the anti-inflammatory activity of SeMet in U937 cells; indicating that SeMet might be a potential treatment for inflammation therapy. PMID- 25145773 TI - Exogenous IL-2 controls the balance in Th1, Th17, and Treg cell distribution in patients with progressive rheumatoid arthritis treated with TNF-alpha inhibitors. AB - Interleukin-2 (IL-2) has been suggested to control Treg/Th17 balance. Recently, we reported a relationship of rheumatoid arthritis (RA) activity/progression with irreversible systemic Treg and Th1 defects including serum IL-2 shortage. Herein, we explore the role of in vitro stimulation with rIL-2 in the observed immune alterations reversal. Patients with stable or progressive RA were assigned to methotrexate (MTX) group or to TNF-alpha inhibitors (iTNF) group, respectively. Flow cytometric analyses were performed before and after 6 months of treatment. Circulating Th1, Th17, and Treg cells were determined before and after 72-h culture with anti-CD3 + rIL-2. Before therapy, 72-h stimulation restored recently observed phenotypic Th cell alterations, except for the enriched Th17 subset normalized as late as after therapy in all patients. Under 6-month therapy, anti CD3 stimulation changed the Th cell distribution only in progressive RA; despite Th1 enrichment, it revealed Treg population defects, which were completely reversed by exogenous IL-2 added to the stimulating culture. Our paper shows that in aggressive RA patients exhibiting serum IL-2 shortage despite iTNF therapy, exogenous rIL-2 is capable of promoting Treg differentiation affected by chronic activation, thus supporting its use in the combined strategy of biologic treatment of the progressive form of RA. PMID- 25145774 TI - Two-dimensional high efficiency thin-film silicon solar cells with a lateral light trapping architecture. AB - Introducing light trapping structures into thin-film solar cells has the potential to enhance their solar energy harvesting as well as the performance of the cells; however, current strategies have been focused mainly on harvesting photons without considering the light re-escaping from cells in two-dimensional scales. The lateral out-coupled solar energy loss from the marginal areas of cells has reduced the electrical yield indeed. We therefore herein propose a lateral light trapping structure (LLTS) as a means of improving the light harvesting capacity and performance of cells, achieving a 13.07% initial efficiency and greatly improved current output of a-Si:H single-junction solar cell based on this architecture. Given the unique transparency characteristics of thin-film solar cells, this proposed architecture has great potential for integration into the windows of buildings, microelectronics and other applications requiring transparent components. PMID- 25145776 TI - Meningococcal carriage: the dilemma of 4CMenB vaccine. PMID- 25145775 TI - Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial. AB - BACKGROUND: Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year olds. METHODS: In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850. FINDINGS: Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1.2, 95% CI 0.8-1.7) or MenACWY-CRM (0.9, [0.6 1.3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18.2% [95% CI 3.4-30.8] carriage reduction), capsular groups BCWY (26.6% [10.5-39.9] carriage reduction), capsular groups CWY (29.6% [8.1-46.0] carriage reduction), and serogroups CWY (28.5% [2.8-47.5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39.0% (95% CI 17.3-55.0) carriage reduction for serogroup Y and 36.2% (15.6-51.7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. INTERPRETATION: Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. FUNDING: Novartis Vaccines. PMID- 25145777 TI - Israel-Gaza conflict. PMID- 25145778 TI - Activation of sulfur dioxide by bis[N,N'-diisopropylbenzamidinato(-)]silicon(II): synthesis of neutral six-coordinate silicon(IV) complexes with chelating O,O' Sulfito or O,O'-dithionito ligands. AB - The neutral six-coordinate silicon(IV) complexes 2 and 3 (mixture of cis-3 and trans-3) were synthesized by reaction of the donor-stabilized silylene bis[N,N' diisopropylbenzamidinato(-)]silicon(II) (1) with SO2 . Compounds 2 and 3 are the first silicon(IV) complexes with chelating sulfito or dithionito ligands, and 3 is even the first molecular compound with a chelating dithionito ligand. Compounds 2 and 3 were structurally characterized by crystal structure analyses and multinuclear NMR spectroscopic studies in the solid state and in solution. PMID- 25145779 TI - Dynamic connectivity among cortical layers in local and large-scale sensory processing. AB - Cortical processing of sensory stimuli typically recruits multiple areas, but how each area dynamically incorporates activity from other areas is not well understood. We investigated interactions between cortical columns of bilateral primary sensory regions (S1s) in rats by recording local field potentials and multi-unit activity simultaneously in both S1s with electrodes positioned at each cortical layer. Using dynamic connectivity analysis based on Granger-causal modeling, we found that, shortly after whisker stimulation (< 10 ms), contralateral S1 (cS1) already relays activity to granular and infragranular layers of S1 in the other hemisphere, after which cS1 shows a pattern of within column interactions that directs activity upwards toward superficial layers. This pattern of predominant upward driving was also observed in S1 ipsilateral to stimulation, but at longer latencies. In addition, we found that interactions between the two S1s most strongly target granular and infragranular layers. Taken together, the results suggest a possible mechanism for how cortical columns integrate local and large-scale neocortical computation by relaying information from deeper layers to local processing in superficial layers. PMID- 25145780 TI - Facile and scalable synthesis of silicon-based nanocomposites with slitlike nanopores: a solid-state exfoliation reaction using layered CaSi2. AB - Silicon-based nanocomposites with slitlike nanopores were prepared by heating a mixture of layered CaSi2 and NiCl2. The formation mechanism is based on a solid state exfoliation reaction wherein the formation of CaCl2 promotes the extraction of Ca from CaSi2, thereby exfoliating the layered structure. The nanocomposites showed anode capacity for lithium ion batteries up to 804 mA h g(-1). PMID- 25145781 TI - Co-administration of Wuzhi capsules and tacrolimus in patients with idiopathic membranous nephropathy: clinical efficacy and pharmacoeconomics. AB - PURPOSE: Tacrolimus is an effective (but relatively expensive) immunosuppressant that is used widely in patients with membranous nephropathy. To reduce the tacrolimus dose while maintaining an equivalent therapeutic effect, we studied the clinical efficacy and pharmacoeconomic impact of co-administration of Wuzhi capsules (WZC that protects against damage to liver cells) and tacrolimus. METHODS: Sixty patients with membranous nephropathy were divided randomly into two groups: experimental (tacrolimus + WZC + corticosteroids) and control (tacrolimus + corticosteroids). Each group received treatments continuously for >6 months. Liver function; renal function; and whole-blood concentrations of tacrolimus, sugars, lipids, as well as 24-h urinary protein levels were used in the clinical evaluation. The cost of drugs was calculated, and the pharmacoeconomic cost-effectiveness analyses were carried out to compare indices between the two groups. RESULTS: Doses and costs of tacrolimus differed significantly between experimental and control groups (p < 0.01 or p < 0.05). Costs in the experimental group were 13,702.62 +/- 1,458.6 CNY (2,194.10 +/- 233.56 USD) and those in the control group were 17,796.87 +/- 2,469.27 CNY (2,849.69 +/- 395.39 USD), with clinical efficacy of 93.3 and 90.0 %, respectively. The cost-effectiveness ratios were 146.86 +/- 15.63 and 197.73 +/- 27.44, respectively. Compared with the experimental group, the control group showed an incremental cost-effectiveness ratio of 1,240.68 +/- 306.25 CNY (198.66 +/- 49.04 USD), whereas remission between the two groups was similar. CONCLUSION: Co-administration of WZCs and tacrolimus can reduce the dose of tacrolimus and decrease the costs incurred by patients within the same therapeutic window to that seen for treatment with tacrolimus alone. PMID- 25145782 TI - Ocular and systemic factors associated with glaucoma in chronic kidney disease patients. AB - The goal of this study was to examine, the relationship between chronic kidney disease (CKD) and glaucomatous optic disc neuropathy in a cohort of patients from the south-east Serbia and to determine whether limited screening for glaucoma in specific subgroups of patients with CKD is reasonable and justifiable. This cross sectional study included 328 subjects with various stages of CKD. All patients had visited the Outpatient Department of the Nephrology Clinic, Clinical Center Nis, Serbia. All patients underwent routine ophthalmic examinations. Glaucoma diagnosis based on elevated intraocular pressure (IOP), the presence of excavation of the optic nerve head (C/D ratio), and characteristic glaucomatous visual field loss (MD-mean deviation, PSD-pattern standard deviation). CKD was defined as kidney damage or glomerular filtration rate (GFR) of <60 ml/min/1.73 m(2) for >3 months. A total number of 328 CKD patients, 33 (10.1 %) with primary open angle glaucoma and 28 (8.5 %) with ocular hypertension (OH), were included in the study. Patients with CKD and glaucoma had significantly higher mean values of C/D ratio (0.59), visual field mean deviations (dB)-MD (p < 0.001), and visual field pattern standard deviations (dB)-PSD (p < 0.001) than patients with CKD and OH. Stepwise multivariate linear regression analysis confirmed that the most significant factors related to IOP are age (p < 0.05), AHT (p = 0.01), and eGFR (p = 0.001). Multivariate regression analysis also confirmed that the most significant factors related to cup-to-disc ratio are number of years of smoking (p < 0.05), AHT, and sCr (p < 0.01). In conclusion, the prevalence of glaucoma among CKD patients in the cohort from south-east Serbia is 10.1 %. Patients with CKD and glaucoma, eGFR and current cigarette smoking are associated with IOP level, MD, and PSD of visual field and C/D ratio. PMID- 25145783 TI - Asymptomatic hyponatremia in peritoneal dialysis patients: an algorithmic approach. PMID- 25145784 TI - Loss of hepatitis B surface antigen in a real-life clinical cohort of patients with chronic hepatitis B virus infection. AB - BACKGROUND & AIMS: Hepatitis B surface antigen (HBsAg) clearance is the main indicator of viral cure in patients infected with the hepatitis B virus (HBV). We sought to identify the parameters associated with HBsAg loss in a well characterized real-life clinical cohort of chronically HBV-infected patients. METHODS: Patients with chronic HBV infection were prospectively included, classified according to the disease stage, and followed up to determine parameters associated with HBsAg clearance. RESULTS: In total, 315 patients were followed up for a mean of almost 6 years. At study entry, 109 (34.6%) were inactive HBsAg carriers, 204 (64.8%) had chronic active hepatitis (CAH), and two (0.6%) were immune-tolerant carriers. During follow-up, 128 (62.7%) of the 204 patients with CAH received antiviral therapy. Sixty-nine had HBeAg-positive CAH: 55 (79.7%) were treated and 14 (20.3%) untreated. One hundred thirty-five had HBeAg-negative CAH: 73 (54.1%) were treated and 62 (45.9%) untreated. Inactive carriers showed an annual HBsAg clearance incidence rate of 23.4 cases per 1000 persons-years, which was higher than that of CAH groups. The clearance incidence rates (in cases per 1000 persons-years) of CAH groups were: treated HBeAg positive (20.7), untreated HBeAg-positive (19.1), treated HBeAg-negative (10.1), and untreated HBeAg-negative (8.1). Older age (P = 0.001) and inactive carrier status (P = 0.019) were independent predictors of HBsAg clearance. CONCLUSION: In a well-characterized real-life clinical cohort of chronically HBV-infected patients in various disease phases, older age, and inactive HBsAg carrier status were the only predictors of HBsAg clearance, whereas anti-HBV therapy only marginally increased annual incidence of HBsAg loss. PMID- 25145786 TI - DNA: adding injury to insult. PMID- 25145785 TI - Significance of serum procalcitonin as biomarker for detection of bacterial peritonitis: a systematic review and meta-analysis. AB - BACKGROUND: Bacterial peritonitis is serious disease and remains a diagnostic challenge for clinicians. Many studies have highlighted the potential usefulness of procalcitonin (PCT) for identification of bacterial peritonitis, however, the overall diagnostic value of PCT remains unclear. Therefore, we performed a meta analysis to assess the accuracy of PCT for detection of bacterial peritonitis. METHODS: We performed a systematic searched in MEDLINE, EMBASE, SCOPUS, China Biology Medicine Database (CBM), China National Knowledge Infrastructure Database (CNKI) and Cochrane databases for trials that evaluated the diagnostic role of PCT for bacterial peritonitis. Sensitivity, specificity and other measures of accuracy of PCT were pooled using bivariate random effects models. RESULTS: Eighteen studies involving 1827 patients were included in the present meta analysis. The pooled sensitivity and specificity of serum PCT for the diagnosis bacterial peritonitis were 0.83 (95% CI: 0.76-0.89) and 0.92 (95% CI: 0.87-0.96), respectively. The positive likelihood ratio was 11.06 (95% CI: 6.31-19.38), negative likelihood ratio was 0.18 (95% CI: 0.12-0.27) and diagnostic odds ratio (DOR) was 61.52 (95% CI: 27.58-137.21). The area under the receiver operating characteristic curve (AUROC) was 0.94. Use of a common PCT cut-off value could improve the DOR to 75.32 and the AUROC to 0.95. Analysis of the seven studies that measured serum C-reactive protein (CRP) indicated that PCT was more accurate than CRP for the diagnosis of bacterial peritonitis. CONCLUSIONS: Our results indicate that PCT determination is a relatively sensitive and specific test for the diagnosis of bacterial peritonitis. However, with regard to methodological limitations and significant heterogeneity, medical decisions should be based on both clinical findings and PCT test results. PMID- 25145787 TI - Promotion of survival and differentiation of neural stem cells with fibrin and growth factor cocktails after severe spinal cord injury. AB - Neural stem cells (NSCs) can self-renew and differentiate into neurons and glia. Transplanted NSCs can replace lost neurons and glia after spinal cord injury (SCI), and can form functional relays to re-connect spinal cord segments above and below a lesion. Previous studies grafting neural stem cells have been limited by incomplete graft survival within the spinal cord lesion cavity. Further, tracking of graft cell survival, differentiation, and process extension had not been optimized. Finally, in previous studies, cultured rat NSCs were typically reported to differentiate into glia when grafted to the injured spinal cord, rather than neurons, unless fate was driven to a specific cell type. To address these issues, we developed new methods to improve the survival, integration and differentiation of NSCs to sites of even severe SCI. NSCs were freshly isolated from embryonic day 14 spinal cord (E14) from a stable transgenic Fischer 344 rat line expressing green fluorescent protein (GFP) and were embedded into a fibrin matrix containing growth factors; this formulation aimed to retain grafted cells in the lesion cavity and support cell survival. NSCs in the fibrin/growth factor cocktail were implanted two weeks after thoracic level-3 (T3) complete spinal cord transections, thereby avoiding peak periods of inflammation. Resulting grafts completely filled the lesion cavity and differentiated into both neurons, which extended axons into the host spinal cord over remarkably long distances, and glia. Grafts of cultured human NSCs expressing GFP resulted in similar findings. Thus, methods are defined for improving neural stem cell grafting, survival and analysis of in vivo findings. PMID- 25145788 TI - Integrating Anisakis spp. parasites data and host genetic structure in the frame of a holistic approach for stock identification of selected Mediterranean Sea fish species. AB - The unique environment of the Mediterranean Sea makes fish stock assessment a major challenge. Stock identification of Mediterranean fisheries has been based mostly from data on biology, morphometrics, artificial tags, otolith shape and fish genetics, with less effort on the use of parasites as biomarkers. Here we use some case studies comparing Mediterranean vs Atlantic fish stocks in a multidisciplinary framework. The generalized Procrustes Rotation (PR) was used to assess the association between host genetics and larval Anisakis spp. datasets on demersal (hake) and pelagic (horse mackerel, swordfish) species. When discordant results emerged, they were due to the different features of the data. While fish population genetics can detect changes over an evolutionary timescale, providing indications on the cohesive action of gene flow, parasites are more suitable biomarkers when considering fish stocks over smaller temporal and spatial scales, hence giving information of fish movements over their lifespan. Future studies on the phylogeographic analysis of parasites suitable as biomarkers, and that of their fish host, performed on the same genes, will represent a further tool to be included in multidisciplinary studies on fish stock structure. PMID- 25145790 TI - Peri-implant bone organization surrounding zirconia-microgrooved surfaces circularly polarized light and confocal laser scanning microscopy study. AB - OBJECTIVES: To study the peri-implant bone organization pattern of immediately loaded (IL) zirconia implants with microgrooved surfaces. MATERIALS AND METHODS: Forty-eight dental implants of 4 mm diameter and 10 mm length were inserted after two months postextraction healing in the edentulous mandible of six dogs. Three groups of sixteen implants were used, titanium implants (Control), zirconia implants (test A), and zirconia-microgrooved implants (test B), which were loaded immediately. After 4-month healing period, implant-bone samples were processed and analyzed by circularly polarized light (CPL) and confocal laser scanning microscopy (CLSM) in two regions of interest ROI1 (to evaluate the interthread bone) and ROI2 (to evaluate the bone adjacent to the threads) of 1 mm thickness * 10 mm length each one. RESULTS: Bone organization differs near to the test B, compared with test A and control surfaces, active remodeling was detected surrounding test B implants, with alternancy of organized zones, meanwhile controls and test A areas showed organized areas mainly at 2 mm of implant surfaces. Transverse collagen fibers were significatively higher at ROI1 for test B implants (60.34 +/- 4.34%), compared with controls (47.25 +/- 3.51%) and test A (43.78 +/- 2.78%) groups (P < 0.05). Meanwhile, it was not found any significant difference between groups in ROI2 (P > 0.05). CLSM confirmed the presence of collagen mineralized matrix inside microgrooves of test B groups. 3D reconstruction showed blood vessels in direct contact with the implant surfaces of all groups and bone and blood vessels penetration inside the microgrooves in test B group. CONCLUSION: The organized pattern of the microgrooved surfaces is able to induce transverse collagen fiber microenvironment reaction to the load, being positive to promote and to maintain the bone remodeling; in addition blood vessels and bone cells are able to penetrate microgrooved surfaces. PMID- 25145789 TI - Reversible changes in pancreatic islet structure and function produced by elevated blood glucose. AB - Diabetes is characterized by hyperglycaemia due to impaired insulin secretion and aberrant glucagon secretion resulting from changes in pancreatic islet cell function and/or mass. The extent to which hyperglycaemia per se underlies these alterations remains poorly understood. Here we show that beta-cell-specific expression of a human activating KATP channel mutation in adult mice leads to rapid diabetes and marked alterations in islet morphology, ultrastructure and gene expression. Chronic hyperglycaemia is associated with a dramatic reduction in insulin-positive cells and an increase in glucagon-positive cells in islets, without alterations in cell turnover. Furthermore, some beta-cells begin expressing glucagon, whilst retaining many beta-cell characteristics. Hyperglycaemia, rather than KATP channel activation, underlies these changes, as they are prevented by insulin therapy and fully reversed by sulphonylureas. Our data suggest that many changes in islet structure and function associated with diabetes are attributable to hyperglycaemia alone and are reversed when blood glucose is normalized. PMID- 25145791 TI - Mood, behavior, testosterone, cortisol, and interleukin-6 in adults during immune activation: a pilot study to assess sickness behaviors in humans. AB - OBJECTIVES: Sickness behavior, a suite of behavioral changes subsequent to infection that includes depression, decreased social behaviors, and sleep disturbances, has been well described in model organisms. The phenomenon is relatively unexplored in humans due to methodological difficulties, and hormonal correlates of sickness behavior have not been studied. We therefore attempted to use a vaccine to elicit sickness behaviors outside of a clinical setting and uncover any correlations among testosterone, cortisol, and sickness behavior. METHODS: Eleven participants (five male, six female, mean age 22.8 years) naive to the rabies vaccine were recruited from the School of Veterinary Medicine at Purdue University. Participants provided daily saliva and urine samples and completed questionnaires to assess mood and social behaviors for a period of 6 weeks. Saliva samples were assayed for cortisol and testosterone. Urine samples were assayed for interleukin-6 and creatinine. RESULTS: Analysis revealed an expected decrease in testosterone and an increase in cortisol. While mood did not differ, other behaviors, such as physical activity and hours slept, showed expected changes following vaccination. However, none of these results achieved statistical significance. CONCLUSION: Our results, while generally confirming previous research on sickness behavior and hormone changes during infection, are suggestive, but not statistically significant and so neither confirm nor contradict our hypotheses. We attribute this lack of significance to both the small sample size, as well as possible confounding factors, including the psychosocial stress of entering an intensive study program. PMID- 25145792 TI - Plasticity in ploidy underlies plant fitness compensation to herbivore damage. AB - How plants mitigate damage by animal herbivores is a fundamental ecological and evolutionary question of plant-animal interactions. Some plants can increase their fitness when damaged in a phenomenon termed 'overcompensation'. Despite overcompensation being observed in a variety of plant species, its mechanistic basis remains elusive. Recent research has shown that the Arabidopsis thaliana genotype Columbia-4 employs endoreduplication, the replication of the genome without mitosis, following damage and that it overcompensates for seed yield. The related genotype Landsberg erecta, in contrast, does not increase its endoreduplication following damage and suffers reduced seed yield. While these results suggest that a plant's ability to plastically increase its ploidy during regrowth may promote its mitigation of damage, no studies have explicitly linked the endoreduplication genetic pathway to the regrowth and fitness of damaged plants. By comparing fitness and ploidy between undamaged and damaged plants of Columbia-4, Landsberg erecta and their offspring, we provide evidence that endoreduplication is directly involved in compensatory performance. We then overexpressed an endoreduplication regulator and compared this mutant's endoreduplication and compensation with its background genotype Columbia-0, an undercompensator. Enhancing Columbia-0's ability to endoreduplicate during regrowth led to the complete mitigation of the otherwise detrimental effects of damage on its fitness. These results suggest that the ability of these plants to increase their ploidy via endoreduplication directly impacts their abilities to compensate for damage, providing a novel mechanism by which some plants can mitigate or even benefit from apical damage with potential across the wide range of plant taxa that endoreduplicate. PMID- 25145793 TI - Prevalence of and risk factors for coccidiosis in kiwi between 1977 and 2011. AB - AIMS: To identify risk factors associated with coccidiosis in kiwi (Apteryx spp.) using a retrospective analysis of historical data from kiwi examined post-mortem, and to determine the prevalence of coccidial oocysts in the droppings of wild and captive kiwi. METHODS: Necropsy reports were examined from kiwi submitted to the National Wildlife Mortality Database of New Zealand (Huia) between February 1977 and May 2011. All cases that reported histological examination of one or more hepatic, intestinal or renal tissues were included in the study (n=372). Data collated for analysis included the presence or absence of coccidiosis in one or more tissues, age, host species, habitat, and season of submission. Fisher's exact test was used to determine the association between each independent variable and the prevalence of coccidiosis. Droppings opportunistically collected from wild and captive kiwi between January 2008 and June 2010 were also examined for the presence of coccidial oocysts. RESULTS: Coccidiosis was evident in 47/372 (12.6%) kiwi examined post-mortem and was considered the primary cause of death in 12/47 (26%) infected cases. Examination of 412 droppings from wild and captive kiwi collected over a 29-month period revealed that 98 (23.8%) samples contained coccidia at the time of sampling. Enteric (n=27) coccidiosis was the most common form diagnosed using histology, followed by renal (n=19) and hepatic (n=11), with splenic (n=2) and pulmonary (n=1) infections infrequently seen. Many kiwi demonstrated infections in multiple tissues. The prevalence of coccidiosis was greater in juvenile kiwi (36/148, 24.3%) than adults (8/133, 6.0%) or chicks (2/83, 2.4%) (p<0.001), although there was no difference in mortality between age groups. Season of year was also associated with overall prevalence (p=0.05), with most cases being diagnosed in the autumn and winter. Coccidiosis was histologically evident in four of five species of kiwi examined, and in all host species upon analysis of droppings. Host species or habitat (captive vs. wild) did not influence the prevalence of disease detected histologically. CONCLUSIONS: Age and season were the only factors that influenced the prevalence of coccidiosis in kiwi in this study. Coccidiosis was present in all species of kiwi, and this is the first report of coccidiosis in rowi (Apteryx rowi). PMID- 25145795 TI - High yield, controlled synthesis of graphitic networks from dense micro emulsions. AB - We report on the production of Carbon Nano Networks (CNNs) from dense microemulsions in which catalyst nanoparticles have been synthesized. CNNs are 3D carbon networks, consisting of branches and junctions, and are mesoporous, graphitic, and conductive being suitable as electrode materials. PMID- 25145794 TI - Investigating the physiological roles of low-efficiency D-mannonate and D gluconate dehydratases in the enolase superfamily: pathways for the catabolism of L-gulonate and L-idonate. AB - The sequence/function space in the D-mannonate dehydratase subgroup (ManD) of the enolase superfamily was investigated to determine how enzymatic function diverges as sequence identity decreases [Wichelecki, D. J., et al. (2014) Biochemistry 53, 2722-2731]. That study revealed that members of the ManD subgroup vary in substrate specificity and catalytic efficiency: high-efficiency (kcat/KM = 10(3) 10(4) M(-1) s(-1)) for dehydration of D-mannonate, low-efficiency (kcat/KM = 10 10(2) M(-1) s(-1)) for dehydration of D-mannonate and/or D-gluconate, and no activity. Characterization of high-efficiency members revealed that these are ManDs in the D-glucuronate catabolic pathway {analogues of UxuA [Wichelecki, D. J., et al. (2014) Biochemistry 53, 4087-4089]}. However, the genomes of organisms that encode low-efficiency members of the ManDs subgroup encode UxuAs; therefore, these must have divergent physiological functions. In this study, we investigated the physiological functions of three low-efficiency members of the ManD subgroup and identified a novel physiologically relevant pathway for L-gulonate catabolism in Chromohalobacter salexigens DSM3043 as well as cryptic pathways for L-gulonate catabolism in Escherichia coli CFT073 and L-idonate catabolism in Salmonella enterica subsp. enterica serovar Enteritidis str. P125109. However, we could not identify physiological roles for the low-efficiency members of the ManD subgroup, allowing the suggestion that these pathways may be either evolutionary relics or the starting points for new metabolic potential. PMID- 25145798 TI - Development of ultrafine multichannel microfluidic mixer for synthesis of bimetallic nanoclusters: catalytic application of highly monodisperse AuPd nanoclusters stabilized by poly(N-vinylpyrrolidone). AB - On account of their novel properties, bimetallic nanoparticles and nanoclusters (NCs) are strong potential candidates for optical, magnetic, and catalytic functional materials. These properties depend on the chemical composition and size (number of constituent atoms) of the NCs. Control of size, structure, and composition is particularly important for fabricating highly functional materials based on bimetallic NCs. Size- and structure-controlled synthesis of two-element alloys can reveal their intrinsic electronic synergistic effects. However, because synergistic enhancement of activity is strongly affected by composition as well as by size and structure, controlled synthesis is a challenging task, particularly in catalytic applications. To investigate catalytic synergistic effects, we have synthesized highly monodisperse, sub-2 nm, solid-solution AuPd NCs stabilized with poly(N-vinylpyrrolidone) (AuPd:PVP) using a newly developed ultrafine microfluidic mixing device with 15 MUm wide multiple lamination channels. The synergistic enhancement for catalytic aerobic oxidation of benzyl alcohol exhibited a volcano-shaped trend, with a maximum at 20-65 at. % Pd. From X-ray photoelectron spectroscopic measurements, we confirmed that the enhanced activity originates from the enhanced electron density at the Au sites, donated by Pd sites. PMID- 25145796 TI - Information and decision-making needs among people with mental disorders: a systematic review of the literature. AB - BACKGROUND: Assessment of users' information and decision-making needs is one key step in the development of decision-support interventions. OBJECTIVE: To identify patients' information and decision-making needs as a pre-requisite for the development of high-quality web-based patient decision aids (PtDAs) for common mental disorders. SEARCH STRATEGY: A systematic MEDLINE search for papers published until December 2012 was conducted, and reference lists of included articles and relevant reviews were searched. INCLUSION CRITERIA: Original studies containing data on information or decision-making needs of adults with depression, anxiety disorders, somatoform disorders, alcohol-related disorders and schizophrenia were included. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed using a standardized form, and data synthesis was conducted using a theory-based deductive approach by two independent reviewers. Studies were quality assessed using the Mixed Methods Appraisal Tool. MAIN RESULTS: Twelve studies were included focusing on information needs or the identification of decisions patients with depression and schizophrenia were facing. No studies were found for the other mental disorders. Overall, seven information needs categories were identified with the topics 'basic facts', 'treatment' and 'coping' being of major relevance. Six decision categories were identified of which decisions on 'medication' and 'treatment setting' were most often classified. CONCLUSIONS: This review reveals that patients with schizophrenia and depression show extensive information and decision-making needs. The identified needs can initially inform the design of PtDAs for schizophrenia and depression. However, there is an urgent need to investigate information and decision-making needs among patients with other mental disorders. PMID- 25145797 TI - In situ detection of autoreactive CD4 T cells in brain and heart using major histocompatibility complex class II dextramers. AB - This report demonstrates the use of major histocompatibility complex (MHC) class II dextramers for detection of autoreactive CD4 T cells in situ in myelin proteolipid protein (PLP) 139-151-induced experimental autoimmune encephalomyelitis (EAE) in SJL mice and cardiac myosin heavy chain-alpha (Myhc) 334-352-induced experimental autoimmune myocarditis (EAM) in A/J mice. Two sets of cocktails of dextramer reagents were used, where dextramers(+) cells were analyzed by laser scanning confocal microscope (LSCM): EAE, IA(s)/PLP 139-151 dextramers (specific)/anti-CD4 and IA(s)/Theiler's murine encephalomyelitis virus (TMEV) 70-86 dextramers (control)/anti-CD4; and EAM, IA(k)/Myhc 334-352 dextramers/anti-CD4 and IA(k)/bovine ribonuclease (RNase) 43-56 dextramers (control)/anti-CD4. LSCM analysis of brain sections obtained from EAE mice showed the presence of cells positive for CD4 and PLP 139-151 dextramers, but not TMEV 70-86 dextramers suggesting that the staining obtained with PLP 139-151 dextramers was specific. Likewise, heart sections prepared from EAM mice also revealed the presence of Myhc 334-352, but not RNase 43-56-dextramer(+) cells as expected. Further, a comprehensive method has also been devised to quantitatively analyze the frequencies of antigen-specific CD4 T cells in the 'Z' serial images. PMID- 25145799 TI - A review of the methodological challenges in assessing the cost effectiveness of pharmacist interventions. AB - Pharmacists' roles are shifting away from medicines supply and the provision of patient education involving acute medications towards consultation-type services for chronic medications. Determining the cost effectiveness of pharmacist interventions has been complicated by methodological challenges. A critique of 31 economic evaluations carried out alongside comparative studies of pharmacist interventions published between 2003 and 2013 (12 from the UK, six from the USA) found a range of disease-specific and cross-therapeutic interventions targeting both patients and prescribers in a range of settings evaluated through a variety of study designs. Only ten were full economic evaluations, five of which were based on randomized controlled trials (RCTs). The intervention was usually quite well described, but the comparator was not always clearly described, and some interventions are very context specific due to the variability in pharmacist services available in different countries and practice settings. Complex multidirectional aims of most pharmacist interventions have led to many process, intermediate and longer-term outcomes being included in any one study. Quality of resource use and cost data varied. Most incremental cost-effectiveness ratios (ICERs) were generated from process indicators such as errors and adherence, with only four studies reporting cost per quality-adjusted life-year (QALY). Very few studies examined the effect of uncertainty, and methods used were not very clear in some cases. The principal finding from our critique is that poor RCT study design or analysis precludes many studies from finding pharmacist interventions effective or cost effective. We conclude with a set of recommendations for future study design. PMID- 25145801 TI - Healthy decisions: towards uncertainty tolerance in healthcare policy. PMID- 25145802 TI - Some inconsistencies in NICE's consideration of social values. AB - The UK's National Institute for Health and Care Excellence (NICE) recently proposed amendments to its methods for the appraisal of health technologies. Previous amendments in 2009 and 2011 placed a greater value on the health of patients at the "end of life" and in cases where "treatment effects are both substantial in restoring health and sustained over a very long period". Drawing lessons from these previous amendments, we critically appraise NICE's proposals. The proposals repeal "end of life" considerations but add consideration of the "proportional" and "absolute" quality-adjusted life-year (QALY) loss from illness. NICE's cost-effectiveness threshold may increase from L20,000 to L50,000 per QALY on the basis of these and four other considerations: the "certainty of the ICER [incremental cost-effectiveness ratio]"; whether health-related quality of life is "inadequately captured"; the "innovative nature" of the technology; and "non-health objectives of the NHS". We demonstrate that NICE's previous amendments are flawed; they contain logical inconsistencies which can result in different values being placed on health gains for identical patients, and they do not apply value weights to patients bearing the opportunity cost of NICE's recommendations. The proposals retain both flaws and are also poorly justified. Applying value weights to patients bearing the opportunity cost would lower NICE's threshold, in some cases to below L20,000 per QALY. Furthermore, this baseline threshold is higher than current estimates of the opportunity cost. NICE's proposed threshold range is too high, for empirical and methodological reasons. NICE's proposals will harm the health of unidentifiable patients, whilst privileging the identifiable beneficiaries of new health technologies. PMID- 25145800 TI - The humanistic burden of head and neck cancer: a systematic literature review. AB - BACKGROUND: Head and neck cancer (HNC) and its treatment can affect communication, nutrition, and physical appearance, and the global impact of this disease on patients' quality of life may be substantial. OBJECTIVE: The aim of this systematic literature review was to describe the impact of HNC and its treatment on the physical, emotional, and social well-being of patients over time, by examining longitudinal studies of patient-reported outcomes (PRO) evaluating these domains. METHODS: Databases (MEDLINE and Embase) were searched to identify studies published in English between January 2004 and January 2014 analyzing the humanistic aspects of HNC in adult patients. Additional relevant publications were identified through manual searches of abstracts from recent conference proceedings. RESULTS: Of 1,566 studies initially identified, 130 met the inclusion criteria and were evaluated in the assessment. Investigations using a variety of PRO instruments in heterogeneous patient populations consistently reported that PRO scores decrease significantly from diagnosis through the treatment period, but generally recover to baseline in the first year post treatment. This trend was observed for many functional domains, although some side effects, such as xerostomia, persisted well beyond 1 year. In addition, considerable evidence exists that baseline PRO scores can predict clinical endpoints such as overall and progression-free survival. CONCLUSIONS: Many aspects of HNC, both disease and treatment specific, profoundly affect patients' quality of life. Improved knowledge of these effects on PRO may allow for more informed treatment decisions and can help physicians to better prepare patients for changes they may experience during therapy. Furthermore, the predictive value of baseline PRO data may enable healthcare providers to identify at-risk patients in need of more intensive intervention. PMID- 25145803 TI - Bidirectional citation searching to completion: an exploration of literature searching methods. AB - Literature reviews underpin the majority of research projects in the health sciences, and yet relatively little analysis has been published as to the most appropriate method to identify relevant literature, outside of specialist information journals. The method of applying keyword search queries to bibliographic databases using Boolean logic dominates literature reviews due to its easy application to the major online databases. However, it is recognised increasingly as being problematic where the research question cannot be clearly defined or requires an element of exploration, due to its reliance on author's use of titling and keywords and is unable to identify topics other than those defined in the search query. This paper discusses the relative merits of a systematic citation searching approach as both an alternative and a concurrent method to keyword searching. A method of citation searching, both forwards and backwards, which is iterated to form a closed loop solution, is discussed. An illustrative example is presented of both methods, applying them to the topic of the UK National Institute for Health and Care Excellence (NICE) cost effectiveness threshold. The case study finds the citation searching approach dominates the traditional keyword searching approach, finding 76 papers of relevance, including all 15 found by the alternative approach. Conceptually, and in the example presented, it is demonstrated that the proposed method can represent a dominant strategy to the more traditional approach in some situations, highlighting that, wherever possible, it is preferential to employ multiple methods of searching. However, it is clear that a better understanding is required as to how we can most efficiently search the ever-growing sea of literature. PMID- 25145804 TI - Biotransformation of the mycotoxin zearalenone by fungi of the genera Rhizopus and Aspergillus. AB - Zearalenone (ZEN) is a nonsteroidal estrogenic mycotoxin biosynthesized by various Fusarium fungi. These fungal species frequently infest grains; therefore, ZEN represents a common contaminant in cereal products. The biotransformation of ZEN differs significantly from species to species, and several metabolites are known to be formed by animals, plants, and microorganisms. The aim of the present study was to investigate the microbial conversion of ZEN by species of the genera Rhizopus and Aspergillus representing relevant fungi for food processing (e.g. fermentation). To monitor the ZEN metabolism, ZEN was added to liquid cultures of the different fungal species. After a period of 3 days, the media were analyzed by HPLC-MS/MS for metabolite formation. Two Aspergillus oryzae strains and all seven Rhizopus species were able to convert ZEN into various metabolites, including ZEN-14-sulfate as well as ZEN-O-14- and ZEN-O-16-glucoside. Microbial transformation of ZEN into the significantly more estrogenic alpha-zearalenol (alpha-ZEL) was also observed. Additionally, a novel fungal metabolite, alpha-ZEL sulfate, was detected. Semi-quantification of the main metabolites indicates that more than 50% of initial ZEN may be modified. The results show that fungal strains have the potential to convert ZEN into various metabolites leading to a masking of the toxin, for example in fermented food. PMID- 25145805 TI - Maternal stress and family quality of life in response to raising a child with autism: from preschool to adolescence. AB - While the impact of raising a child with an Autism Spectrum Disorder (ASD) is well documented, with mothers reporting higher levels of stress than mothers of children with other disabilities, positive maternal outcomes have also been identified. What remains unclear, however, is the role of child age on maternal outcomes. We sought to clarify the role of child age in maternal stress and family quality of life (FQoL) in mothers raising a child with ASD. Participants included 140 mothers of children aged 3-16 years grouped to represent four key stages of childhood (preschool, early school years, middle school, early high school). Using a cross-sectional design, mothers completed questionnaires assessing potential risk (e.g., child problem behaviour, symptom severity) and protective (e.g., family characteristics) factors attributed to maternal outcomes. The results revealed significant age related group differences in child internalising behaviour and ASD symptomatology between the early and middle school years. Lower levels of adaptive social behaviour in older age groups were also found. Although mothers of older children reported significantly less support from professionals than mothers of younger children, no significant age effects were found to contribute to maternal reports of stress or FQoL. The current findings support the view that mothers appear to demonstrate stable levels of stress and FQoL despite fluctuations in key child variables and a reduction in supports, across age, highlighting the ongoing nature of maternal needs and heightened levels of child symptomatology during adolescence. PMID- 25145806 TI - Deficient motor timing in children with neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is one of the most common single-gene disorders affecting fine and visual-motor skills. This case-control study investigated motor timing as a possible related performance deficit in children with NF1. A visual-motor reaction time (VRT) test was administered in 20 NF1 children (mean age 9 years 7 months) and 20 age- and gender-matched typically developing (TD) children. Copying and tracing performance were evaluated using the Beery Buktenica Developmental Test of Visual-Motor Integration (Beery VMI). Children with NF1 responded with an increased reaction time (RT) to temporally predictive stimuli compared to TD children, whereas RT at unpredictive stimuli did not differ between groups. Motor timing indexed by the RT decrease at predictive stimuli significantly associated with the Beery VMI copy and tracing outcomes. Deficient motor timing as an actual symptom may add to further research on the pathogenesis of NF1-associated motor impairment and the development of more effective treatment. PMID- 25145807 TI - Cognitive and linguistic predictors of reading comprehension in children with intellectual disabilities. AB - A considerable number of children with intellectual disabilities (ID) are able to acquire basic word reading skills. However, not much is known about their achievements in more advanced reading comprehension skills. In the present study, a group of 49 children with ID and a control group of 21 typically developing children with word decoding skills in the normal ranges of first grade were compared in lower level (explicit meaning) and higher level (implicit meaning) reading comprehension abilities. Moreover, in the group of children with ID it was examined to what extent their levels of lower level and higher level reading comprehension could be predicted from their linguistic skills (word decoding, vocabulary, language comprehension) and cognitive skill (nonverbal reasoning). It was found that children with ID were weaker than typically developing children in higher level reading comprehension but not in lower level reading comprehension. Children with ID also performed below the control group on nonverbal reasoning and language comprehension. After controlling for nonverbal reasoning, linguistic skills predicted lower level reading comprehension but not higher level reading comprehension. It can be concluded that children with ID who have basic decoding skill do reasonably well on lower level reading comprehension but continue to have problems with higher level reading comprehension. PMID- 25145808 TI - Serotonin transporter availability in impulsive aggressive personality disordered patients: a PET study with [11C]DASB. AB - Serotonin (5-HT) has consistently been implicated in the pathophysiology of impulsive aggression. In the current study, we tested the hypothesis that 5-HT transporter (5-HTT) binding is reduced in the anterior cingulate cortex (ACC) in impulsive aggressive patients. Additionally, we characterized pathological personality dimensions, with a specific focus on callousness (i.e. emotional indifference, a facet of psychopathy). Callousness is putatively positively correlated with presynaptic 5-HT, and thus could potentially confound the hypothesized negative relation between 5-HTT levels and trait aggression. We determined 5-HTT binding with positron emission tomography and [(11)C]DASB in 29 patients with intermittent explosive disorder (IED-IR) and 30 controls. We assessed group differences in 5-HTT binding in the pregenual ACC, amygdala and subcortical regions and examined correlations between 5-HTT binding and clinical measures. There were no significant differences in 5-HTT binding between IED-IR patients and controls. Trait callousness exhibited a significant, positive correlation with ACC 5-HTT availability. Among IED-IR patients, a trend-level negative partial correlation was observed between trait aggression and ACC 5-HTT availability, while covarying for callousness and age. Exploratory analyses revealed a significant negative correlation between state aggression levels and 5 HTT availability in subcortical regions, namely striatum and thalamus. We did not confirm our hypothesis of lower ACC 5-HTT availability in impulsive aggressive patients, however, the positive correlation between callousness and ACC 5-HTT availability likely played a confounding role. Subtypes of aggression (e.g., reactive vs. proactive aggression), which are differentially associated with pathological personality dimensions such as callousness, may contribute to variability between 5-HT functioning and aggression. PMID- 25145809 TI - The effects of epistaxis on health-related quality of life in patients with hereditary hemorrhagic telangiectasia. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease mainly characterized by epistaxis in more than 96% of patients. Recently, a validated questionnaire known as the HHT Epistaxis Severity Score (ESS) was developed. However, little is known about the relationship between epistaxis and quality of life. We hypothesize that epistaxis severity is a major factor predicting health-related quality of life (HR-QoL) in HHT patients. METHODS: This is a cross-sectional study. The ESS questionnaire and Medical Outcomes Study 36 item short form (SF-36) were administered to subjects through an Internet survey. All participants had a definitive diagnosis of HHT through Curacao criteria or genetic testing. Demographic information, genetics, and extensive histories were also collected. Descriptive analyses were performed with calculations of means and standard deviations (SDs) for continuous variables and proportions for categorical variables. Linear regressions were then performed to assess the association between HR-QoL and ESS. RESULTS: A total of 604 subjects participated between April and August 2008. All patients reported epistaxis, 285 (47.2%) had telangiectasias, and 545 (90.2%) had a family history of HHT; 167 (27.6%) patients had mild epistaxis (ESS <4), 285 (47.2%) reported moderate epistaxis (>=4 ESS <7), and 152 (25.2%) reported severe epistaxis (ESS >=7). Patients with severe epistaxis had lower scores for both the Physical Component Summary (PCS) and the Mental Component Summary (MCS) of HR-QoL when compared to those with mild epistaxis (p < 0.001, p < 0.001). CONCLUSION: The ESS is a major determinant of HR-QoL and should be considered as a measurement of treatment efficacy in HHT related epistaxis. PMID- 25145810 TI - Localized strain measurements of the intervertebral disc annulus during biaxial tensile testing. AB - Both inter-lamellar and intra-lamellar failures of the annulus have been described as potential modes of disc herniation. Attempts to characterize initial lamellar failure of the annulus have involved tensile testing of small tissue samples. The purpose of this study was to evaluate a method of measuring local surface strains through image analysis of a tensile test conducted on an isolated sample of annular tissue in order to enhance future studies of intervertebral disc failure. An annulus tissue sample was biaxial strained to 10%. High resolution images captured the tissue surface throughout testing. Three test conditions were evaluated: submerged, non-submerged and marker. Surface strains were calculated for the two non-marker conditions based on motion of virtual tracking points. Tracking algorithm parameters (grid resolution and template size) were varied to determine the effect on estimated strains. Accuracy of point tracking was assessed through a comparison of the non-marker conditions to a condition involving markers placed on tissue surface. Grid resolution had a larger effect on local strain than template size. Average local strain error ranged from 3% to 9.25% and 0.1% to 2.0%, for the non-submerged and submerged conditions, respectively. Local strain estimation has a relatively high potential for error. Submerging the tissue provided superior strain estimates. PMID- 25145811 TI - Real-time DC-dynamic biasing method for switching time improvement in severely underdamped fringing-field electrostatic MEMS actuators. AB - Mechanically underdamped electrostatic fringing-field MEMS actuators are well known for their fast switching operation in response to a unit step input bias voltage. However, the tradeoff for the improved switching performance is a relatively long settling time to reach each gap height in response to various applied voltages. Transient applied bias waveforms are employed to facilitate reduced switching times for electrostatic fringing-field MEMS actuators with high mechanical quality factors. Removing the underlying substrate of the fringing field actuator creates the low mechanical damping environment necessary to effectively test the concept. The removal of the underlying substrate also a has substantial improvement on the reliability performance of the device in regards to failure due to stiction. Although DC-dynamic biasing is useful in improving settling time, the required slew rates for typical MEMS devices may place aggressive requirements on the charge pumps for fully-integrated on-chip designs. Additionally, there may be challenges integrating the substrate removal step into the back-end-of-line commercial CMOS processing steps. Experimental validation of fabricated actuators demonstrates an improvement of 50x in switching time when compared to conventional step biasing results. Compared to theoretical calculations, the experimental results are in good agreement. PMID- 25145812 TI - Dioxetane scission products unchanged by mechanical force. AB - Dioxetane-based force-induced light emission from polymers, or mechanoluminescence, is a powerful new way of characterizing the behavior of polymeric materials under stress. Here, we reveal that breaking the dioxetane mechanically gives strikingly similar products to those formed on thermal activation, with a singlet/triplet ratio of 1:9.9 and a total quantum yield of 9.8%. A sensitized relay scheme ensured high reproducibility in the detection of the short-lived triplet products. In addition to guiding the design of more sensitive mechanoluminescent probes, the similarity in the scission products indicates that once mechanical force releases the steric lock between the adamantyl groups, the dioxetane undergoes scission in a pathway that resembles the thermal process. Excited states are formed only after the main transition state in a region in which the excited- and ground-state surfaces are nearly degenerate, which, thus, accounts for the remarkable similarity in the scission products. PMID- 25145813 TI - Assessment of murine exercise endurance without the use of a shock grid: an alternative to forced exercise. AB - Using laboratory mouse models, the molecular pathways responsible for the metabolic benefits of endurance exercise are beginning to be defined. The most common method for assessing exercise endurance in mice utilizes forced running on a motorized treadmill equipped with a shock grid. Animals who quit running are pushed by the moving treadmill belt onto a grid that delivers an electric foot shock; to escape the negative stimulus, the mice return to running on the belt. However, avoidance behavior and psychological stress due to use of a shock apparatus can interfere with quantitation of running endurance, as well as confound measurements of postexercise serum hormone and cytokine levels. Here, we demonstrate and validate a refined method to measure running endurance in naive C57BL/6 laboratory mice on a motorized treadmill without utilizing a shock grid. When mice are preacclimated to the treadmill, they run voluntarily with gait speeds specific to each mouse. Use of the shock grid is replaced by gentle encouragement by a human operator using a tongue depressor, coupled with sensitivity to the voluntary willingness to run on the part of the mouse. Clear endpoints for quantifying running time-to-exhaustion for each mouse are defined and reflected in behavioral signs of exhaustion such as splayed posture and labored breathing. This method is a humane refinement which also decreases the confounding effects of stress on experimental parameters. PMID- 25145814 TI - Red blood cell microparticles in hemoglobin E disorders. PMID- 25145815 TI - Mutual ownership: privatisation under a different name? PMID- 25145816 TI - Impact of regional striatal dopaminergic function on kinematic parameters of Parkinson's disease. AB - Among the cardinal parkinsonian motor deficits, the severity of bradykinesia correlates with striatal dopamine loss. However, the impact of regional striatal dopamine loss on specific components of bradykinesia remains unknown. Using gyroscopes, we measured the amplitude, speed, and frequency of finger tapping in 24 untreated patients with Parkinson's disease (PD) and 28 healthy controls. Using positron emission tomography (PET) studies and [(18)F]-N-3-fluoropropyl-2 beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane (FP-CIT) in PD patients, we investigated the relationship between the mean values, variability and decrements of various kinematic parameters of finger tapping on one side (e.g. the mean, variability and decrement) and contralateral striatal FP-CIT binding. Compared with controls, PD patients had reduced amplitudes and speeds of tapping and showed greater decrement in those parameters. PD patients also exhibited greater irregularity in amplitude, speed, and frequency. Putaminal FP-CIT uptake levels correlated with the mean speed and amplitude, and caudate uptake levels correlated with mean amplitude. The variability of amplitude and speed correlated only with the caudate uptake levels. Neither caudate nor putaminal uptake correlated with frequency-related parameters or decrement in amplitude or speed. Reduced amplitude and speed of repetitive movement may be related to striatal dopaminergic deficit. Dopaminergic action in the caudate nucleus is required to maintain consistency of amplitude and speed. Although decrement of amplitude and speed is known to be specific for PD, we found that it did not mirror the degree of striatal dopamine depletion. PMID- 25145817 TI - Primary fascial closure with laparoscopic ventral hernia repair: systematic review. AB - Laparoscopic ventral hernia repair (LVHR) has grown in popularity. Typically, this procedure is performed with a mesh bridge technique that results in high rates of seroma, eventration (bulging), and patient dissatisfaction. In an effort to avoid these complications, there is growing interest in the role of laparoscopic primary fascial closure with intraperitoneal mesh placement. This systematic review evaluated the outcomes of closure of the central defect during LVHR. A literature search of PubMed, Cochrane databases, and Embase was conducted using PRISMA guidelines. MINORS was used to assess the methodologic quality. Primary outcome was hernia recurrence. Secondary outcomes were surgical-site infection, seroma formation, bulging, and patient-centered items (satisfaction, chronic pain, functional status). Eleven studies were identified, eight of which were case series (level 4 data). Three comparative studies examined the difference between closure and nonclosure of the fascial defect during laparoscopic ventral incisional hernia repairs (level 3 and 4 data). These studies suggested that primary fascial closure (n = 138) compared to nonclosure (n = 255) resulted in lower recurrence rates (0-5.7 vs. 4.8-16.7 %) and seroma formation rates (5.6-11.4 vs. 4.3-27.8 %). Follow-up periods for both groups were similar (1-108 months). Only one study evaluated patient function and clinical bulging. It showed better outcomes with primary fascial closure. Closure of the central defect during LVHR resulted in less recurrence, bulging, and seroma than nonclosure. Patients with closure were more satisfied with the results and had better functional status. The quality of the data was poor, however. A randomized controlled trial to evaluate the role of closure of the central defect during LVHR is warranted. PMID- 25145818 TI - Accurate use of neutrophil to lymphocyte ratio in predicting prognosis of papillary thyroid carcinoma. PMID- 25145819 TI - ALPPS: Adverse Outcomes Demand Clear Justification in an Era of Improving Survival for Colorectal Liver Metastases. PMID- 25145820 TI - Clinical outcome in acute small bowel obstruction after surgical or conservative management. AB - BACKGROUND: Small bowel obstruction (SBO) is characterized by a high rate of recurrence. In the present study, we aimed to compare the outcomes of patients managed either by conservative treatment or surgical operation for an episode of SBO. METHODS: The outcomes of all patients hospitalized at a single center for acute SBO between 2004 and 2007 were assessed. The occurrence of recurrent hospitalization, surgery, SBO symptoms at home, and mortality was determined. RESULTS: Among 221 patients admitted with SBO, 136 underwent a surgical procedure (surgical group) and 85 were managed conservatively (conservative group). Baseline characteristics were similar between treatment groups. The median follow up time (interquartile range) was 4.7 (3.7-5.8) years. Nineteen patients (14.0 %) of the surgical group were hospitalized for recurrent SBO versus 25 (29.4 %) of the conservative group [hazard ratio (HR), 0.5; 95 % CI, 0.3-0.9]. The need for a surgical management of a new SBO episode was similar between the two groups, ten patients (7.4 %) in the surgical group and six patients (7.1 %) in the conservative group (HR, 1.1; 95 % CI, 0.4-3.1). Five-year mortality from the date of hospital discharge was not significantly different between the two groups (age and sex-adjusted HR, 1.1; 95 % CI, 0.6-2.1). A follow-up evaluation was obtained for 130 patients. Among them, 24 patients (34.8 %) of the surgical group and 35 patients (57.4 %) of the conservative group had recurrent SBO symptoms (odds ratio, 0.4; 95 % CI, 0.2-0.8). CONCLUSIONS: The recurrence of SBO symptoms and new hospitalizations were significantly lower after surgical management of SBO compared with conservative treatment. PMID- 25145821 TI - Application of a three-dimensional print of a liver in hepatectomy for small tumors invisible by intraoperative ultrasonography: preliminary experience. AB - BACKGROUND: Hepatectomy for an invisible small tumor using intraoperative ultrasonography requires technical ingenuity. We used a 3D print of a liver to perform a hepatectomy on two patients with synchronous multiple liver metastases from colorectal cancer. Because of preoperative chemotherapy, one of the tumors became smaller and invisible to ultrasonography in each case. We present our procedure here. METHODS: Multidetector-row computed tomography images of anatomical structures were digitally segmented using the original software "PLUTO," which was developed at the Graduate School of Information Science, Nagoya University. After converting the final segmentation data to stereolithography files, a 3D printed liver at a 70 % scale was produced. The support material was washed and the mold charge was removed from the 3D-printed hepatic veins. The surface of the 3D-printed model was abraded and coated with urethane resin paint. After air-drying, the 3D-printed hepatic veins were colored by injecting a dye. The 3D printed portal veins were whitish because mold charge remained. All procedures after 3D printing were performed by hand. RESULTS: Hepatectomy for the small tumor that is invisible to intraoperative ultrasonography was performed by referring to a 3D-printed model. The planned resections were successful with histologically negative surgical margins. CONCLUSIONS: The application of a 3D-printed liver to perform a hepatectomy for a small tumor that is invisible to intraoperative ultrasonography is an easy and feasible procedure. Use of 3D-printing technology in hepatectomy requires further improvement and automation of hand work after the 3D print has been made. PMID- 25145823 TI - A proposed matrix for planning global surgery interventions. AB - The concept of surgery and global health is gaining acceptance; however, a great deal of confusion still exists as to what constitutes global surgery. To facilitate the overall view of how surgical care in a low resource setting can be integrated into a health system, a matrix for planning global surgery interventions has been developed. The key components of this tool are treatment locations and disease time course. The matrix also allows for the inclusion of information on surgical capacity for personnel, infrastructure, procedure, equipment, and supplies. This simple tool can assist researchers, program implementers, policy makers, and donors understand how to improve the delivery of surgical care to the billions of people around the world in need. PMID- 25145822 TI - Minimally invasive esophagectomy for dysplastic Barrett's esophagus. AB - A substantial portion of patients diagnosed preoperatively with high grade dysplasia (HGD) alone will have occult esophageal adenocarcinoma on analysis of the surgical specimen. Therefore, because of an increased risk of disease progression and malignancy, patients with HGD should be referred for esophagectomy promptly when endoscopic therapy has failed. The required extent of lymphadenectomy in this cohort of patients is unknown because of the variable incidence of submucosal cancer observed. Improvements in perioperative care, adoption of a minimally invasive surgical approach, and centralization of esophageal cancer services have substantially reduced the rates of mortality and morbidity associated with esophagectomy in recent years. Minimally invasive esophagectomy should be considered the treatment of choice in patients with dysplastic Barrett's esophagus that is refractory to endoscopic therapy or those at high risk of invasive cancer. PMID- 25145824 TI - Killer activity of Saccharomyces cerevisiae strains: partial characterization and strategies to improve the biocontrol efficacy in winemaking. AB - Killer yeasts are considered potential biocontrol agents to avoid or reduce wine spoilage by undesirable species. In this study two Saccharomyces cerevisiae strains (Cf8 and M12) producing killer toxin were partially characterized and new strategies to improve their activity in winemaking were evaluated. Killer toxins were characterized by biochemical tests and growth inhibition of sensitive yeasts. Also genes encoding killer toxin were detected in the chromosomes of both strains by PCR. Both toxins showed optimal activity and production at conditions used during the wine-making process (pH 3.5 and temperatures of 15-25 degrees C). In addition, production of both toxins was higher when a nitrogen source was added. To improve killer activity different strategies of inoculation were studied, with the sequential inoculation of killer strains the best combination to control the growth of undesired yeasts. Sequential inoculation of Cf8-M12 showed a 45 % increase of killer activity on sensitive S. cerevisiae and spoilage yeasts. In the presence of ethanol (5-12 %) and SO2 (50 mg/L) the killer activity of both toxins was increased, especially for toxin Cf8. Characteristics of both killer strains support their future application as starter cultures and biocontrol agents to produce wines of controlled quality. PMID- 25145829 TI - Is clinical performance adversely affected by wearing gloves during paediatric peripheral intravenous cannulation? AB - OBJECTIVE: To investigate if wearing protective gloves during paediatric intravenous cannulation affects performance of the procedure. METHODS: This was a prospective observational study. Peripheral intravenous cannulation (PIVC) performed within the Paediatric ED was observed and recorded over a 12 month period. Data were compared between those clinicians wearing gloves and those not wearing gloves during PIVC. RESULTS: One thousand and twenty paediatric cannulations were recorded during the observed period. The mean age of the children was 5.79 years. The overall success rate of cannulation was 86.18% and first attempt success rate 76.08%. Overall, gloves were used by 54.31% of clinicians to establish vascular access; glove use was lowest in the registrar group (41.11% compliance rate). The glove-wearing group had comparable overall success rate of 85.74% (475/554) to the no-gloves group of 86.70% (404/466). The difference was not statistically significant (P > 0.05). Higher incidence of significant blood spillage during the procedure was observed among clinicians wearing no gloves (16.74%) in comparison with their glove-wearing counterparts (9.03%, P < 0.05). One needlestick injury was recorded in the present study period. There was no difference in blood culture contamination rate between glove wearing group and no-gloves group (3.94% vs 3.76%, P > 0.05). CONCLUSIONS: The present study shows that the use of protective gloves was not associated with adverse outcomes of clinical performance during paediatric cannulation. The low compliance rate of gloves use is alarming, and many clinicians might be exposed to potential blood-borne infections. Clinicians should be encouraged and supported to use gloves for paediatric cannulation. PMID- 25145831 TI - The solvent dynamics at pore surfaces in molecular gels studied by field-cycling magnetic resonance relaxometry. AB - The molecular dynamics of the solvent molecules at liquid-solid interfaces in low molecular mass gels and in bulk solvents have been identified and characterized with the aid of field-cycling NMR relaxometry. The gels are formed using ethylene glycol (EG) and 1,3-propanediol (PG) with different concentrations of 4,6,4',6'-O terephthalylidene-bis(methyl alpha-D-glucopyranoside) (gelator 1). The spin lattice relaxation times of bulk solvents measured in the function of Larmor frequency were analyzed assuming the intramolecular and intermolecular dipole dipole interactions. For analysis of the relaxation data for confined solvents the two-phase fast-exchange model was assumed. It was found that in a low frequency range a dominating NMR relaxation mechanism of solvent interacting with internal surfaces of pores in studied molecular gels is reorientation mediated by translational displacements (RMTD). This dynamic process allows us to explain a very long correlation time of the order of 10(-5) s calculated for confined EG molecules and an even longer one for PG. The RMTD contribution to the relaxation is described by power-law frequency dependence. In the 1/EG gels the exponent is equal to 0.5 for all gelator concentrations suggesting the equipartition of the diffusion modes with different wavelengths. In this gel the relaxation dispersion data were transformed to a susceptibility representation and a "master-like" curve was constructed. In the 1/PG gel the exponent varies in the function of gelator concentration. Different behavior of the relaxation dispersion shape is due to the relative sizes of the ordered (at surface) and bulk-like phase. In the 1/EG gel the surface layer of the ordered molecules is always much smaller than the dimensions of the gel cavities whereas it differs in the 1/PG gel as a consequence of the disruption of the PG aggregates due to the solvent-gelator interaction. PMID- 25145830 TI - Relationships between reduced heart rate variability and pre-clinical cardiovascular disease in patients with type 2 diabetes. AB - AIMS: Reduced heart rate variability (HRV), an early sign of diabetic cardiovascular autonomic neuropathy (CAN), is associated with worse cardiovascular outcomes. The objective was to evaluate relationships between HRV parameters and three pre-clinical cardiovascular disease markers (left ventricular hypertrophy [LVH], aortic stiffness and carotid atherosclerosis) in type 2 diabetes. METHODS: In a cross-sectional study, 313 patients with type 2 diabetes performed 24-h Holter monitoring, carotid ultrasonography (intima-media thickness and plaques measurements), aortic pulse wave velocity measurement and echocardiography (left ventricular mass index [LVMI] measurement). Time-domain HRV parameters were the standard deviation of all normal RR intervals (SDNN), the standard deviation of the averaged normal RR intervals for all 5min segments (SDANN), the root mean square of differences between adjacent R-R intervals (rMSSD), and the percentage of adjacent R-R intervals that varied by >50ms (pNN50). Multivariate linear and logistic regressions assessed associations between HRV parameters and the three markers of pre-clinical cardiovascular disease. RESULTS: Patients with reduced HRV had longer diabetes duration, greater prevalences of microvascular complications, lower physical fitness, and higher heart rate, glycated hemoglobin, albuminuria and LVMI than patients with normal HRV. On multivariate regressions, after adjustments for several confounders, reduced SDNN and SDANN were independently associated with LVH and aortic stiffness. No HRV parameter was associated with carotid atherosclerosis. CONCLUSIONS: Two reduced HRV parameters, SDNN and SDANN, which reflect cardiovascular autonomic imbalance, were associated with LVH and aortic stiffness, markers of pre-clinical cardiovascular disease. These findings may offer insights into physiopathological mechanisms linking CAN to worse cardiovascular prognosis. PMID- 25145828 TI - Visualization of the spatial and temporal dynamics of MAPK signaling using fluorescence imaging techniques. AB - Conserved mitogen-activated protein kinase (MAPK) signaling pathways are major mechanisms through which cells perceive and respond properly to their surrounding environment. Such homeostatic responses maintain the life of the organism. Since errors in MAPK signaling pathways can lead to cancers and to defects in immune responses, in the nervous system and metabolism, these pathways have been extensively studied as potential therapeutic targets. Although much has been studied about the roles of MAPKs in various cellular functions, less is known regarding regulation of MAPK in living organisms. This review will focus on the latest understanding of the dynamic regulation of MAPK signaling in intact cells that was revealed by using novel fluorescence imaging techniques and advanced systems-analytical methods. These techniques allowed quantitative analyses of signal transduction in situ with high spatio-temporal resolution and have revealed the nature of the molecular dynamics that determine cellular responses and fates. PMID- 25145832 TI - Examining the association between late-life depressive symptoms, cognitive function, and brain volumes in the context of cognitive reserve. AB - OBJECTIVE: The present study aimed to investigate whether cognitive reserve moderated the association between depressive symptoms and cognition, as well as brain volumes in a sample of older adults. METHODS: Non-demented participants (n = 3484) were selected from the Washington Heights/Hamilton Heights Inwood Columbia Aging Project (Northern Manhattan). A subsample of these participants without dementia (n = 703), who had brain imaging data, was also selected for a separate analysis. Depressive symptomatology was assessed with the 10-item Center for Epidemiologic Studies Depression Scale. Reading level and years of education were used as measures of cognitive reserve. Four distinct cognitive composite scores were calculated: executive function, memory, visual-spatial, and language. RESULTS: Multiple regression analysis revealed interaction effects between both measures of cognitive reserve and depressive symptoms on all the cognitive outcome measures except for visual-spatial ability. Those with greater reserve showed greater cognitive decrements than those with lower levels of reserve as depressive symptoms increased. A borderline interaction effect was revealed between reading level and depressive symptoms on total brain volumes. Those with lower reading scores showed greater volume loss as depressive symptoms increased than those with higher reading scores. CONCLUSIONS: Our findings indicate that the association between late-life depressive symptoms and core aspects of cognition varies depending on one's level of cognitive reserve. Those that had greater levels of education and/or reading ability showed a greater decrease in memory, executive, and language performances as depressive symptoms increased than those with lower years of education and reading ability. PMID- 25145834 TI - Authors' response: Origin of the 24-h rest arm. PMID- 25145835 TI - The oncogenic JUNB/CD30 axis contributes to cell cycle deregulation in ALK+ anaplastic large cell lymphoma. AB - Anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in expression of NPM1(NPM)-ALK oncogenic kinase. The latter is capable of activating ERK kinase, which upregulates JUNB expression through ETS1. JUNB, in turn, interacts with the TNFRSF8 (CD30) gene promoter and induces CD30 (TNFRSF8) overexpression. However, the role of CD30 overexpression in ALK+ ALCL oncogenesis remains unknown. Here we show that the JUNB gene is frequently amplified in ALK+ ALCL, suggesting gene amplification as an additional underlying mechanism for JUNB overexpression. Silencing of JUNB resulted in reduced cell growth and colony formation associated with decreased activator protein-1 activity and G1/S and G2/M cell cycle arrest. These effects were linked to decreased CD30 levels, downregulation of CCNA2 (Cyclin A), CCND2 (Cyclin D2) and CCND3 (Cyclin D3) and upregulation of cyclin dependent kinase inhibitors CDKN2A (p14) and CDKN1A (p21), but not CDKN1B (p27). Similar cell cycle changes were observed following the knock-down of TNFRSF8 gene or blockade of its function using anti-CD30 antibodies, which were associated with upregulation of CDKN2A and CDKN1A, but not CDKN1B. These findings indicate that JUNB may partly operate through CD30 signalling. Silencing of JUNB also sensitized NPM1-ALCL+ cells to standard chemotherapeutic agents. Our findings uncover the oncogenic role of the JUNB/CD30 axis and its potential as therapeutic target in ALK+ ALCL. PMID- 25145833 TI - Calcium-dependent energetics of calmodulin domain interactions with regulatory regions of the Ryanodine Receptor Type 1 (RyR1). AB - Calmodulin (CaM) allosterically regulates the homo-tetrameric human Ryanodine Receptor Type 1 (hRyR1): apo CaM activates the channel, while (Ca(2+))4-CaM inhibits it. CaM-binding RyR1 residues 1975-1999 and 3614-3643 were proposed to allow CaM to bridge adjacent RyR1 subunits. Fluorescence anisotropy titrations monitored the binding of CaM and its domains to peptides encompassing hRyR(11975 1999) or hRyR1(3614-3643). Both CaM and its C-domain associated in a calcium independent manner with hRyR1(3614-3643) while N-domain required calcium and bound ~250-fold more weakly. Association with hRyR1(11975-1999) was weak. Both hRyR1 peptides increased the calcium-binding affinity of both CaM domains, while maintaining differences between them. These energetics support the CaM C-domain association with hRyR1(3614-3643) at low calcium, positioning CaM to respond to calcium efflux. However, the CaM N-domain affinity for hRyR(11975-1999) alone was insufficient to support CaM bridging adjacent RyR1 subunits. Other proteins or elements of the hRyR1 structure must contribute to the energetics of CaM-mediated regulation. PMID- 25145837 TI - Duffing oscillation-induced reversal of magnetic vortex core by a resonant perpendicular magnetic field. AB - Nonlinear dynamics of the magnetic vortex state in a circular nanodisk was studied under a perpendicular alternating magnetic field that excites the radial modes of the magnetic resonance. Here, we show that as the oscillating frequency is swept down from a frequency higher than the eigenfrequency, the amplitude of the radial mode is almost doubled to the amplitude at the fixed resonance frequency. This amplitude has a hysteresis vs. frequency sweeping direction. Our result showed that this phenomenon was due to a Duffing-type nonlinear resonance. Consequently, the amplitude enhancement reduced the vortex core-switching magnetic field to well below 10 mT. A theoretical model corresponding to the Duffing oscillator was developed from the Landau-Lifshitz-Gilbert equation to explore the physical origin of the simulation result. This work provides a new pathway for the switching of the magnetic vortex core polarity in future magnetic storage devices. PMID- 25145836 TI - Influenza vaccination among Australian Hajj pilgrims: uptake, attitudes, and barriers. AB - BACKGROUND: Hajj is the largest annual mass gathering where the risk of respiratory infection is high. Although the Saudi Arabian authority recommends influenza vaccination for Hajj pilgrims, the uptake is variable. Influenza vaccine uptake data among Australian Hajj pilgrims is not readily available. Therefore, we aimed to estimate the influenza vaccination uptake rate and identify both attitudes and barriers to vaccine uptake from two consecutives surveys at Hajj in 2011 and 2012. METHODS: Using an anonymous self-administered questionnaire, surveys were conducted in Mecca, Saudi Arabia, among Hajj pilgrims from Australia in 2011 and 2012. Pilgrims staying in "Australian" tents were recruited serially. RESULTS: In 2011, 431 Australian pilgrims completed the survey-median age was 42 (range 7-86) years, 55% were male; 65% reported receiving influenza vaccine. In 2012, 535 pilgrims of median age 43 (range 12-83) years completed the survey, 62% were male; 89% reported receiving the vaccine. Both in 2011 and 2012, common reasons for not receiving the vaccine were the pilgrims' reliance on their "natural immunity" (33 and 26%, respectively, p = 0.4) and believing that they would rarely catch influenza or come in contact with influenza patients (18 and 29%, respectively, p = 0.1). In 2012, when asked why they had received the vaccine, 65% pilgrims responded that it was because of the tour group leaders' recommendation. CONCLUSION: Influenza vaccine uptake among Australian Hajj pilgrims seems satisfactory and increasing but could be better because many pilgrims have misconceptions about vaccines. Tour operators may play a greater role in promoting vaccination. PMID- 25145841 TI - Use of bisphosphonates in children. PMID- 25145838 TI - Medical tourism - an established problem. PMID- 25145842 TI - Response to GEMOX plus erlotinib in pancreatic cancer is associated with ERCC1 overexpression. AB - INTRODUCTION: There are no data about the efficacy of gemcitabine in combination with oxaliplatin (GEMOX) and erlotinib for the treatment of metastatic pancreatic cancer (mPC). Thus, we performed this retrospective analysis in mPC patients to investigate the activity and safety of GEMOX plus erlotinib and correlated the benefit with ERCC1 expression, a potential biomarker for treatment response. PATIENTS AND METHODS: Patients with untreated mPC receiving off-protocol GEMOX plus erlotinib were included. Data collection included baseline demographic, response and toxicity data as well as PFS and OS. Additionally, immunohistochemistry was performed to stain for ERCC1 expression. RESULTS: A total of 51 patients were included. The median age was 62 years and the median ECOG performance score was 1 (range, 0-1). Objective response or disease stabilization was achieved in 54% of the patients. The median PFS was 4.4 months (95% CI 4.4-5.4) and median OS was 8.5 months (95% CI 6.1-10.9). The 27 patients, who benefited from this regimen, had a median PFS of 6.7, a median OS of 11.2 months and an overexpression of ERCC1 (histoscore 10, P <= 0.05) compared to nonresponders (histoscore 7.2). Myelosuppression was the most frequent side effect. The most common severe nonhematological toxicities were diarrhoea and skin toxicity in six (12%) patients each. CONCLUSIONS: These data suggest that the combination of GEMOX plus erlotinib is safe and active in about half of the patients. Patients, who had a higher ERCC1 staining pattern, benefited most from this therapy. Prospective biomarker studies are warranted to confirm these findings. PMID- 25145843 TI - Live birth after 6 years of oocyte vitrification in a survivor with breast cancer. PMID- 25145844 TI - Nuclear envelope: ATR senses mechanical stress. PMID- 25145845 TI - Endocytosis: Unlocking AP2 activity. PMID- 25145850 TI - RNAi screening comes of age: improved techniques and complementary approaches. AB - Gene silencing through sequence-specific targeting of mRNAs by RNAi has enabled genome-wide functional screens in cultured cells and in vivo in model organisms. These screens have resulted in the identification of new cellular pathways and potential drug targets. Considerable progress has been made to improve the quality of RNAi screen data through the development of new experimental and bioinformatics approaches. The recent availability of genome-editing strategies, such as the CRISPR (clustered regularly interspaced short palindromic repeats) Cas9 system, when combined with RNAi, could lead to further improvements in screen data quality and follow-up experiments, thus promoting our understanding of gene function and gene regulatory networks. PMID- 25145849 TI - Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. AB - Membrane protrusions at the leading edge of cells, known as lamellipodia, drive cell migration in many normal and pathological situations. Lamellipodial protrusion is powered by actin polymerization, which is mediated by the actin related protein 2/3 (ARP2/3)-induced nucleation of branched actin networks and the elongation of actin filaments. Recently, advances have been made in our understanding of positive and negative ARP2/3 regulators (such as the SCAR/WAVE (SCAR/WASP family verprolin-homologous protein) complex and Arpin, respectively) and of proteins that control actin branch stability (such as glial maturation factor (GMF)) or actin filament elongation (such as ENA/VASP proteins) in lamellipodium dynamics and cell migration. This Review highlights how the balance between actin filament branching and elongation, and between the positive and negative feedback loops that regulate these activities, determines lamellipodial persistence. Importantly, directional persistence, which results from lamellipodial persistence, emerges as a critical factor in steering cell migration. PMID- 25145853 TI - Polarized immune responses modulated by layered double hydroxides nanoparticle conjugated with CpG. AB - Modulation of the immune response is an important step in the induction of protective humoral and cellular immunity against pathogens. In this study, we investigated the possibility of using a nanomaterial conjugated with the toll like receptor (TLR) ligand CpG to modulate the immune response towards the preferred polarity. MgAl-layered double hydroxide (LDH) nanomaterial has a very similar chemical composition to Alum, an FDA approved adjuvant for human vaccination. We used a model antigen, ovalbumin (OVA) to demonstrate that MgAl LDH had comparable adjuvant activity to Alum, but much weaker inflammation. Conjugation of TLR9 ligand CpG to LDH nanoparticles significantly enhanced the antibody response and promoted a switch from Th2 toward Th1 response, demonstrated by a change in the IgG2a:IgG1 ratio. Moreover, immunization of mice with CpG-OVA-conjugated LDH before challenge with OVA-expressing B16/F10 tumor cells retarded tumor growth. Together, these data indicate that LDH nanomaterial can be used as an immune adjuvant to promote Th1 or Th2 dominant immune responses suitable for vaccination purposes. PMID- 25145852 TI - The promotion of functional urinary bladder regeneration using anti-inflammatory nanofibers. AB - Current attempts at tissue regeneration utilizing synthetic and decellularized biologic-based materials have typically been met in part by innate immune responses in the form of a robust inflammatory reaction at the site of implantation or grafting. This can ultimately lead to tissue fibrosis with direct negative impact on tissue growth, development, and function. In order to temper the innate inflammatory response, anti-inflammatory signals were incorporated through display on self-assembling peptide nanofibers to promote tissue healing and subsequent graft compliance throughout the regenerative process. Utilizing an established urinary bladder augmentation model, the highly pro-inflammatory biologic scaffold (decellularized small intestinal submucosa) was treated with anti-inflammatory peptide amphiphiles (AIF-PAs) or control peptide amphiphiles and used for augmentation. Significant regenerative advantages of the AIF-PAs were observed including potent angiogenic responses, limited tissue collagen accumulation, and the modulation of macrophage and neutrophil responses in regenerated bladder tissue. Upon further characterization, a reduction in the levels of M2 macrophages was observed, but not in M1 macrophages in control groups, while treatment groups exhibited decreased levels of M1 macrophages and stabilized levels of M2 macrophages. Pro-inflammatory cytokine production was decreased while anti-inflammatory cytokines were up-regulated in treatment groups. This resulted in far fewer incidences of tissue granuloma and bladder stone formation. Finally, functional urinary bladder testing revealed greater bladder compliance and similar capacities in groups treated with AIF-PAs. Data demonstrate that AIF-PAs can alleviate galvanic innate immune responses and provide a highly conducive regenerative milieu that may be applicable in a variety of clinical settings. PMID- 25145854 TI - Amphiphilic peptide dendritic copolymer-doxorubicin nanoscale conjugate self assembled to enzyme-responsive anti-cancer agent. AB - Peptide dendrimer drug conjugate based nanoparticles are recently developed as a potential candidate for drug delivery vehicle. In this study, we prepared and characterized the enzyme-sensitive amphiphilc mPEGylated dendron-GFLG-DOX conjugate via two-step highly efficient click reaction. Dynamic light scattering (DLS) and transmission electron microscope (TEM) studies demonstrated the mPEGylated dendron-GFLG-DOX conjugate self-assembled into compact nanoparticles with negatively charged surface. The nanoparticles with 9.62 wt% (weight percent) of DOX showed enzyme-sensitive property by drug release tests. The nanoparticles were shown to effectively kill cancer cells in vitro. The fluorescent image indicated that the nanoparticles could accumulate and retain within tumor for a long time. Moreover, the nanoparticles substantially enhanced antitumor efficacy compared to the free DOX, exhibiting much higher effects on inhibiting proliferation and inducing apoptosis of the 4T1 murine breast cancer model confirmed as the evidences from tumor growth curves, tumor growth inhibition (TGI), immunohistochemical analysis and histological assessment. The nanoparticles reduced DOX-induced toxicities and presented no significant side effects to normal organs of both tumor bearing and healthy mice as measured by body weight shifts and histological analysis. Therefore, the mPEGylated dendron GFLG-DOX conjugate based nanoparticle serves as a potential drug delivery vehicle for breast cancer therapy. PMID- 25145855 TI - Sexual function in women before and after tension-free vaginal tape operation for stress urinary incontinence. AB - OBJECTIVE: To evaluate sexual function in women before and after tension-free vaginal tape operation for stress urinary incontinence. DESIGN: Prospective study. SETTING: Aalborg University Hospital, Department of Gynecology and Obstetrics between November 2008 and June 2010. POPULATION: Sixty-three women who had a tension-free vaginal tape operation performed. METHODS: Patients completed the Pelvic Organ Prolapse Urinary Incontinence Sexual Questionnaire-12 (PISQ-12) and the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) before undergoing surgery and 6 months postoperatively. MAIN OUTCOME MEASURES: Differences in PISQ-12 measures 6 months after the tension-free vaginal tape operation. RESULTS: Twelve women were excluded because of non-completed questionnaires. Preoperatively the PISQ-12 score was 33.7 and postoperatively 36.7, giving a significant difference of 3.0 (p < 0.05). Forty women (78%) scored higher postoperatively, five (10%) scored the same and six (12%) reported lower scores postoperatively. Only PISQ-12 questions in the physical domain were significantly improved. These values were elevated close to the maximum score. Preoperatively 18 women (35%) experienced coital incontinence always, often or sometimes. Postoperatively this was only the case in two women. CONCLUSION: Most women experience an improvement in sexual life after a tension-free vaginal tape procedure mainly because of absence of incontinence during sexual activity or absence of fear of incontinence during sexual activity. PMID- 25145851 TI - The maintenance of chromosome structure: positioning and functioning of SMC complexes. AB - Structural maintenance of chromosomes (SMC) complexes, which in eukaryotic cells include cohesin, condensin and the Smc5/6 complex, are central regulators of chromosome dynamics and control sister chromatid cohesion, chromosome condensation, DNA replication, DNA repair and transcription. Even though the molecular mechanisms that lead to this large range of functions are still unclear, it has been established that the complexes execute their functions through their association with chromosomal DNA. A large set of data also indicates that SMC complexes work as intermolecular and intramolecular linkers of DNA. When combining these insights with results from ongoing analyses of their chromosomal binding, and how this interaction influences the structure and dynamics of chromosomes, a picture of how SMC complexes carry out their many functions starts to emerge. PMID- 25145856 TI - Kinetic resolution of 1,1'-biaryl-2,2'-diols and amino alcohols through NHC catalyzed atroposelective acylation. AB - We present here a highly efficient NHC-catalyzed kinetic resolution of a wide range of 1,1'-biaryl-2,2'-diols and amino alcohols to provide them in uniformly >=99% ee. This represents the first highly enantioselective catalytic acylation of axially chiral alcohols. The aldehyde backbone that is incorporated into the chiral acyl azolium intermediate was found to have a significant effect on the enantioselectivity of the process. PMID- 25145857 TI - Small molecule activation by POC(sp3)OP-nickel complexes. AB - This contribution describes the reactivities of CO2 , CO, O2 , and ArNC with the pincer-type complexes [(kappa(P) ,kappa(C) ,kappa(P') -POC sp 3OP)NiX] (POC sp 3OP=(R2 POCH2 )2 CH; R=iPr; X=OSiMe3 , NArH; Ar=2,6-iPr2 C6 H3 ). Reaction of the amido derivative with CO2 and CO leads to a simple insertion into the Ni?N bond to give stable carbamate and carbamoyl derivatives, respectively, the pincer ligand backbone remaining intact in both cases. In contrast, the analogous reactions with the siloxide derivative produced kinetically labile insertion products that either revert to the starting material (in the case of CO2 ) or react further to give the mixed-valent, dinickel species [(POC sp 3OP)Ni(II) {MU,kappa(O) ,kappa(P) ,kappa(P') -OCOCH(CH2 CH2 OPR2 )2 }Ni(0) (CO)2 ]. The zero valent center in the latter compound is ligated by a new ligand arising from transformation of the POC sp 3OP ligand backbone. The carbonylation and carboxylation of the siloxido derivative also produced minor quantities of a side product identified as the trinickel species, [{(eta(3) -allyl)Ni(MU(O) ,kappa(P) R2 PO)2 }2 Ni], arising from total dismantling of the POC sp 3OP ligand. Similar reactivities were observed with isonitrile, ArNC: reaction with the siloxido derivative resulted in a complex sequence of steps involving initial insertion, a 1,3-hydrogen shift, and an Arbuzov rearrangement to give [Ni(CNAr)4 ] and a methacrylamide based on fragments of the POC sp 3OP ligand. Oxygenation of the amido and siloxido derivatives led to the phosphinate derivative, [(POC sp 3OP)Ni(OP(O)R2 )], arising from oxidative transformation of the original ligand frame; the reaction with the Ni-NHAr derivative also gave ArHNP(O)R2 through a complex N?P bond-forming reaction. PMID- 25145858 TI - Iridium(III)-catalyzed C-H amidation of arylphosphoryls leading to a P stereogenic center. AB - Direct C?H amidation of arylphosphoryl compounds has been developed by using an Ir(III) catalyst system under mild conditions. A wide range of substrates could be employed with high functional-group tolerance. This procedure was successfully applied for the first time to the asymmetric reaction giving rise to a P chirogenic center with a high diastereomeric ratio of up to 19:1 (90 % de). PMID- 25145868 TI - Psychiatric disorders among a sample of internally displaced persons in South Darfur. AB - BACKGROUND: The violent armed conflict in Darfur has been ongoing for years getting the attention of human rights activists and mental health professionals. AIM: The aim of this study was to assess psychiatric disorders in a sample of internally displaced persons (IDPs) in South Darfur. METHOD: A cross-sectional observational study, as a part of the 'Darfur Campaign' organized by Arab Federation of Psychiatrists, assessing psychiatric disorders in a sample of internally displaced women using the Structured Clinical Interview for DSM-IV (SCID-I) (clinical version). RESULTS: Up to 25.7% of participants had lost a close family member or more in the violent clashes. Psychiatric diagnoses were found in 62.2% of the participants. The most frequently reported was post traumatic stress disorder (PTSD) reaching 14.9%, followed by depression 13.5% (among which 2.7% with psychotic features), while comorbid PTSD and depression reached 8.1% of participants. Patients with psychiatric diagnoses had an older age (36.6 years) (p = .024). Suffering from a psychiatric disorder was found to be associated with losing a family member in the conflict (p = .015), being 35.6% in patients with psychiatric diagnoses compared to 10.3% in those without losing a family member in the conflict (odds ratio (OR) = .7, 95% confidence interval (CI) = 1.25-18.28). CONCLUSIONS: This study used a standardized tool for diagnosing psychiatric morbidity among refugees in Darfur to give as much as possible an actual description of the problems and psychiatric morbidity caused by human-made disasters. This study can help to lead to a more detailed and specific mental health service program much needed by this population. PMID- 25145866 TI - Markers of increased cardiovascular risk in patients with chronic kidney disease. AB - BACKGROUND: Epidemiological studies have shown that chronic kidney disease (CKD) is an important risk factor for atherosclerosis and cardiovascular disease (CAD). The aim of the study was to determine markers of increased risk of CAD and to achieve a better understanding of agents implicated in the process of atherosclerosis in CKD patients. METHODS: The study group consisted of a total of 139 patients with CKD while the control group comprised 45 healthy volunteers. Concentrations of osteoprotegerin, osteopontin, osteocalcin, matrix gamma carboxyglutamic acid (Gla) protein (MGP), fetuin A, matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), tissue inhibitor of metalloproteinase-2 (TIMP-2), ATP binding cassette transporter A1 (ABCA1), ATP binding cassette transporter G1 (ABCG1) and renalase were measured by the ELISA method. RESULTS: We observed decreased levels of fetuin A (control vs. CKD group: 37.5 vs. 33.2 ng/ml, p = 0.018), and increased concentrations of osteocalcin (control vs. CKD group: 9.1 +/- 6.0 vs. 13.6 +/- 10.3 ng/ml, p = 0.05), MMP-2 (113.1 +/- 75.0 vs. 166.0 +/- 129.9 ng/ml, p = 0.045), TIMP-2 (22.1 +/- 5.1 vs. 25.4 +/- 7,0 ng/ml, p = 0.005) and renalase (251.0 +/- 157 vs. 316.1 +/- 155.3 ng/ml, p = 0.026). In patients with CKD (in comparison to control group), left ventricle ejection fraction: 53.0 +/- 3,5% vs. 48.5%, p = 0.012) and calcification of the aortic valve (9.5% vs. 39.8%, p = 0.008) were observed more frequently. CONCLUSIONS: Decreased levels of fetuin A and increased concentration of osteocalcin, renalase, MMP-2 and TIMP-2 suggest that these factors may be involved in the pathogenesis of CAD in patients with CKD. Significantly increased indices of cardiac hypertrophy and its dysfunction in patients with CKD are indicators of pathological mechanisms occurring in cardiovascular system in this group of patients. PMID- 25145869 TI - Long-term mental health outcome in post-conflict settings: Similarities and differences between Kosovo and Rwanda. AB - BACKGROUND: Few studies investigated the long-term mental health outcome in culturally different post-conflict settings. This study considers two surveys conducted in Kosovo 8 years after the Balkans war and in Rwanda 14 years after the genocide. METHODS: All participants (n = 864 in Kosovo; n = 962 in Rwanda) were interviewed using the posttraumatic stress disorder (PTSD) and major depressive episode (MDE) sections of the Mini International Neuropsychiatric Interview (MINI) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). RESULTS: Proportions of participants who met diagnostic criteria for either PTSD or MDE were 33.0% in Kosovo and 31.0% in Rwanda, with co-occurrence of both disorders in 17.8% of the Rwandan sample and 9.5% of the Kosovan sample. Among patients with PTSD, patterns of symptoms significantly differed in the two settings, with avoidance and inability to recall less frequent and sense of a foreshortened future and increased startle response more common in Rwanda. Significant differences were also observed in patients with MDE, with loss of energy and difficulties concentrating less frequent and suicidal ideation more common in Rwanda. Comorbid PTSD and MDE were associated with decreased SF-36 subjective mental and physical health scores in both settings, but significantly larger effects in Kosovo than in Rwanda. CONCLUSION: Culturally different civilian populations exposed to mass trauma may differ with respect to their long term mental health outcome, including comorbidity, symptom profile and health perception. PMID- 25145867 TI - Emotions and motivated behavior converge on an amygdala-like structure in the zebrafish. AB - The brain reward circuitry plays a key role in emotional and motivational behaviors, and its dysfunction underlies neuropsychiatric disorders such as schizophrenia, depression and drug addiction. Here, we characterized the neuronal activity pattern induced by acute amphetamine administration and during drug seeking behavior in the zebrafish, and demonstrate the existence of conserved underlying brain circuitry. Combining quantitative analyses of cfos expression with neuronal subtype-specific markers at single-cell resolution, we show that acute d-amphetamine administration leads to both increased neuronal activation and the recruitment of neurons in the medial (Dm) and the lateral (Dl) domains of the adult zebrafish pallium, which contain homologous structures to the mammalian amygdala and hippocampus, respectively. Calbindin-positive and glutamatergic neurons are recruited in Dm, and glutamatergic and gamma-aminobutyric acid (GABAergic) neurons in Dl. The drug-activated neurons in Dm and Dl are born at juvenile stage rather than in the embryo or during adulthood. Furthermore, the same territory in Dm is activated during both drug-seeking approach and light avoidance behavior, while these behaviors do not elicit activation in Dl. These data identify the pallial territories involved in acute psychostimulant response and reward formation in the adult zebrafish. They further suggest an evolutionarily conserved function of amygdala-like structures in positive emotions and motivated behavior in zebrafish and mammals. PMID- 25145870 TI - Comparing a motivational and a self-regulatory intervention to adopt an oral self care regimen: a two-sequential randomized crossover trial. AB - A sequential intervention to facilitate the adoption and maintenance of dental flossing was conducted among 205 students in India, aged 18-26 years. Two experimental groups received different treatment sequences and were observed at three assessment points, 34 days apart. One group received first a motivational intervention (intention, outcome expectancies, and risk perception, followed by a self-regulatory intervention (planning, self-efficacy, and action control). The second group received the same intervention in the opposite order. Both intervention sequences yielded gains in terms of flossing, planning, self efficacy, and action control. However, at Time 2, those who had received the self regulatory intervention first, were superior to their counterparts who had received the motivational intervention first. At Time 3, differences vanished as everyone had then received both interventions. Thus, findings highlight the benefits of a self-regulatory compared to a mere motivational intervention. PMID- 25145872 TI - Efficient red electroluminescent devices with sterically hindered phosphorescent platinum(II) Schiff base complexes and iridium complex codopant. AB - Sterically hindered platinum(II) Schiff base complexes were prepared. Complex 4, which displays red emission with a quantum yield of 0.29 in a thin film and a self-quenching rate constant of 1*10(-7) dm(3) mol(-1) s(-1), was used to fabricate organic light-emitting diodes with single or double emissive layers (EMLs). An iridium(III) complex with a wide band gap was codoped into the electron-dominant EML to act as a deep electron trapper, and red-light-emitting devices with the highest current, power, and external quantum efficiencies of 20.43 cd A(-1) 18.33 Lm W(-1), and 11.7%, respectively, were fabricated. A high current efficiency and EQE of up to 14.69 cd A(-1) and 8.3%, respectively, were achieved at a high brightness of 1000 cd m(-2). The significant delay of efficiency roll-off is attributed to the bulky 3D structure of the norbornene moiety at the periphery of the Schiff base ligand of 4 and to the new device design strategy. The fabricated device had a projected lifetime (LT50) of 18,000 h. PMID- 25145871 TI - Expression of toll-like receptors and co-stimulatory molecules in lymphoid tissue during experimental infection of beef calves with bovine viral diarrhea virus of low and high virulence. AB - The objective of this study was to compare the mRNA expression of Toll-like receptors (TLR3 and TLR7), and costimulatory molecules involved in activation of lymphocytes and antigen presenting cells (CD80, CD86, CD28, and CD40L) after experimental infection of beef calves with low or high virulence noncytopathic (ncp) bovine viral diarrhea virus (BVDV) strains. Thirty BVDV-naive, beef calves were intranasally inoculated with low (LV; n=10, SD-1) or high (HV; n=10, 1373) virulence ncp BVDV or with BVDV-free cell culture medium (Control, n=10). Calves were euthanized on day 5 post-inoculation and tracheo-bronchial lymph node (TBLN) and spleen samples were collected for mRNA expression through quantitative-RT PCR. Levels of mRNA for TLR3 and TLR7 were increased in spleen of HV group (P<0.05), but not in LV group, compared to the control group. Expression of CD86 mRNA was up-regulated in TBLN of both LV and HV groups (P<0.05). A significant up regulation of CD80 mRNA was observed in TBLN for LV calves (P<0.05), but not for HV calves. In conclusion, experimental inoculation with high virulence BVDV-2 1373 stimulated the expression of TLR3, TLR7 and CD86 in spleen and TBLN on day 5 post infection. In contrast, experimental challenge with the low virulence BVDV-1 SD-1 uniquely resulted in up-regulation of both CD80 and CD86 in TBLN samples on day 5 post infection. The observed differential expression during acute infection with high or low virulence BVDV might reflect differences in immune activation by these strains, which could be associated with differences in genotype and/or virulence. PMID- 25145874 TI - Personality as a predictor of depression symptoms in burn patients: a follow-up study. AB - There is empirical evidence that having some personality characteristics increases the risk of developing depression. This is the first study which analyses the role of personality dimensions, assessed by the Alternative Five Factor Model, in the development of depressive symptoms in adult burn survivors across time. Participants were 109 adult burn survivors admitted to a Burns Unit. Personality was assessed by the Zuckerman-Kuhlman Personality Questionnaire and depression symptoms by the Beck Depression Inventory. After adjusting by age, gender and burn size, results showed that high Neuroticism-Anxiety (N-Anx) and Aggression-Hostility (Agg-Host) were related to higher depression scores when compared with low N-Anx and Agg-Host groups along the six months follow-up. Moreover, Activity and Impulsive-Sensation Seeking factors were involved in statistically significant different depressive symptom development trajectories during the six months after burn. These findings suggest that personality factors could be used to identify the most vulnerable patients, who could develop severe mood symptoms at different points in their recovery. PMID- 25145873 TI - The activity of silver nanoparticles (Axonnite) on clinical and environmental strains of Acinetobacter spp. AB - Acinetobacter baumannii isolates are responsible for a high number of wound infections. The reason of this study was to evaluate the activity of silver nanoparticles obtained by microexplosion against wide range of Acinetobacter spp. Susceptibility to silver nanoparticles was tested by microdilution method, susceptibility to antibiotics was evaluated by the disc-diffusion method. All strains of Acinetobacter spp. were sensitive to AgNPs at low concentrations. The values of the MIC for strains of Acinetobacter spp. were 0.39 and 0.78MUg/mL. In general, strains inhibited by 0.78MUg/mL of AgNPs were more resistant to antibiotics than Acinetobacter strains for which MIC=0.39MUg/mL (p=0.023). The AgNPs in Axonnite seems to be a good alternative for other antimicrobials to treat wound infections caused by multidrug resistant Acinetobacter spp. strains because of its high activity. PMID- 25145875 TI - Overgrafting in burns: strategies to avoid going over the top. PMID- 25145876 TI - Water Sorption, Solubility, and Color Stability of Giomer Restoratives. AB - OBJECTIVES: This study compared the color stability, water sorption, and solubility of a giomer composite and two nanohybrid composite resins. MATERIALS AND METHODS: Disc-shaped specimens (1-mm thickness * 15-mm diameter) of a giomer (Beautifil II, Shofu, Kyoto, Japan) and two nanohybrid (Filtek Z550, 3M ESPE, St. Paul, MN, USA; Tetric N-Ceram, Ivoclar Vivadent, Schaan, Liechtenstein) composites (N = 10) were prepared. Baseline color measurements were taken, and specimens were immersed in water for 28 days. Following immersion, color values were remeasured, and color-change values (DeltaE) were calculated. Water sorption and solubility were assessed by mass gain or loss after storage in water for 28 days. Data were analyzed with one-way analysis of variance and Tukey's post-hoc tests (p = 0.05). Pearson's correlation test was used to assess possible correlations between water sorption and solubility, water sorption and color stability, and solubility and color stability (p = 0.05). RESULTS: Water sorbtion (%) and color change (DeltaE) varied significantly among groups, with Beautifil II exhibiting the highest values (p < 0.001). No statistically significant differences were observed in water solubility values among the groups (p = 0.661); however, a linear, positive correlation was detected between solubility and discoloration (r = 0.368, p = 0.046). CONCLUSION: Water sorption and discoloration values of the giomer composite group were significantly higher than those of the nanohybrids tested. CLINICAL SIGNIFICANCE: The high levels of water sorption and discoloration of giomer composites are likely to have an adverse effect on esthetic restorations. PMID- 25145877 TI - Proportion of opioid use due to compensated workers' compensation claims in Manitoba, Canada. AB - BACKGROUND: This study identifies the percentage of opioids prescribed for compensated workplace conditions in Manitoba, Canada and whether Workers Compensation Board (WCB) status is associated with higher prescription opioid doses. METHODS: Opioid prescriptions for WCB recipients were linked with databases housed at the Manitoba Center for Health Policy. Duration of continuous opioid prescription and morphine equivalents (ME) per day (ME/D) were calculated for individuals age 18-65. RESULTS: Over the period from 1998 to 2010, 3.8% of the total opioid dosage of medication prescribed in the study population were prescribed to WCB recipients. WCB recipients accounted for 2.1% of the individuals prescribed opioids. In adjusted analyses WCB recipients were more likely to be prescribed over 120 ME/D (OR 2.06 95% CI, 1.58-2.69). CONCLUSIONS: WCB recipients account for a small, but significant amount of the total opioid prescribed in Manitoba. Manitoba's WCB population is a group at increased risk of being prescribed over 120 ME/day. PMID- 25145879 TI - Masked smoothing using separable kernels for CT perfusion images. AB - BACKGROUND: CT perfusion images have a high contrast ratio between voxels representing different anatomy, such as tissue or vessels, which makes image segmentation of tissue and vascular regions relatively easy. However, grey and white matter tissue regions have relatively low values and can suffer from poor signal to noise ratios. While smoothing can improve the image quality of the tissue regions, the inclusion of much higher valued vascular voxels can skew the tissue values. It is thus desirable to smooth tissue voxels separately from other voxel types, as has been previously implemented using mean filter kernels. We created a novel Masked Smoothing method that performs Gaussian smoothing restricted to tissue voxels. Unlike previous methods, it is implemented as a combination of separable kernels and is therefore fast enough to consider for clinical work, even for large kernel sizes. METHODS: We compare our Masked Smoothing method to alternatives using Gaussian smoothing on an unaltered image volume and Gaussian smoothing on an image volume with vascular voxels set to zero. Each method was tested on simulation data, collected phantom data, and CT perfusion data sets. We then examined tissue voxels for bias and noise reduction. RESULTS: Simulation and phantom experiments demonstrate that Masked Smoothing does not bias the underlying tissue value, whereas the other smoothing methods create significant bias. Furthermore, using actual CT perfusion data, we demonstrate significant differences in the calculated CBF and CBV values dependent on the smoothing method used. CONCLUSION: The Masked Smoothing is fast enough to allow eventual clinical usage and can remove the bias of tissue voxel values that neighbor blood vessels. Conversely, the other Gaussian smoothing methods introduced significant bias to the tissue voxels. PMID- 25145878 TI - Assessment of morphine-induced hyperalgesia and analgesic tolerance in mice using thermal and mechanical nociceptive modalities. AB - Opioid-induced hyperalgesia and tolerance severely impact the clinical efficacy of opiates as pain relievers in animals and humans. The molecular mechanisms underlying both phenomena are not well understood and their elucidation should benefit from the study of animal models and from the design of appropriate experimental protocols. We describe here a methodological approach for inducing, recording and quantifying morphine-induced hyperalgesia as well as for evidencing analgesic tolerance, using the tail-immersion and tail pressure tests in wild type mice. As shown in the video, the protocol is divided into five sequential steps. Handling and habituation phases allow a safe determination of the basal nociceptive response of the animals. Chronic morphine administration induces significant hyperalgesia as shown by an increase in both thermal and mechanical sensitivity, whereas the comparison of analgesia time-courses after acute or repeated morphine treatment clearly indicates the development of tolerance manifested by a decline in analgesic response amplitude. This protocol may be similarly adapted to genetically modified mice in order to evaluate the role of individual genes in the modulation of nociception and morphine analgesia. It also provides a model system to investigate the effectiveness of potential therapeutic agents to improve opiate analgesic efficacy. PMID- 25145880 TI - Male-female communication triggers calcium signatures during fertilization in Arabidopsis. AB - Cell-cell communication and interaction is critical during fertilization and triggers free cytosolic calcium ([Ca2+]cyto) as a key signal for egg activation and a polyspermy block in animal oocytes. Fertilization in flowering plants is more complex, involving interaction of a pollen tube with egg adjoining synergid cells, culminating in release of two sperm cells and their fusion with the egg and central cell, respectively. Here, we report the occurrence and role of [Ca2+]cyto signals during the entire double fertilization process in Arabidopsis. [Ca2+]cyto oscillations are initiated in synergid cells after physical contact with the pollen tube apex. In egg and central cells, a short [Ca2+]cyto transient is associated with pollen tube burst and sperm cell arrival. A second extended [Ca2+]cyto transient solely in the egg cell is correlated with successful fertilization. Thus, each female cell type involved in double fertilization displays a characteristic [Ca2+]cyto signature differing by timing and behaviour from [Ca2+]cyto waves reported in mammals. PMID- 25145882 TI - High-load strength training improves outcome in patients with plantar fasciitis: A randomized controlled trial with 12-month follow-up. AB - The aim of this study was to investigate the effectiveness of shoe inserts and plantar fascia-specific stretching vs shoe inserts and high-load strength training in patients with plantar fasciitis. Forty-eight patients with ultrasonography-verified plantar fasciitis were randomized to shoe inserts and daily plantar-specific stretching (the stretch group) or shoe inserts and high load progressive strength training (the strength group) performed every second day. High-load strength training consisted of unilateral heel raises with a towel inserted under the toes. Primary outcome was the foot function index (FFI) at 3 months. Additional follow-ups were performed at 1, 6, and 12 months. At the primary endpoint, at 3 months, the strength group had a FFI that was 29 points lower [95% confidence interval (CI): 6-52, P = 0.016] compared with the stretch group. At 1, 6, and 12 months, there were no differences between groups (P > 0.34). At 12 months, the FFI was 22 points (95% CI: 9-36) in the strength group and 16 points (95% CI: 0-32) in the stretch group. There were no differences in any of the secondary outcomes. A simple progressive exercise protocol, performed every second day, resulted in superior self-reported outcome after 3 months compared with plantar-specific stretching. High-load strength training may aid in a quicker reduction in pain and improvements in function. PMID- 25145883 TI - Inhibitory effects of Hwang-Ryun-Hae-Dok-Tang on cytochrome P450 in human liver microsomes. AB - 1. The herb-drug interaction potential of Hwang-Ryun-Hae-Dok-Tang (HR) extracts mediated by cytochrome P450 (CYP) inhibition was determined using human liver microsomes. 2. HR strongly inhibited CYP1A2 and moderately inhibited CYP2C19, CYP2D6, and CYP3A4 (testosterone) but not CYP2A6, CYP2B6, CYP2C8, CYP2C9, and CYP3A4 (midazolam). 3. The enzyme kinetic results suggest that CYP1A2 inhibition is competitively reversible (Ki, 13.4+/-1.8 MUg/ml), and CYP2D6 inhibition is quasi-irreversible (KI, 0.234+/-0.138 MUg/ml; kinact, 0.067+/-0.006 min(-1)). 4. Fermentation using Lactobacillus acidophilus attenuated the HR-induced inhibition of CYP2D6, but not the other isoforms. 5. Neither CYP1A2 nor CYP3A4 was markedly inhibited by berberine, palmatine, and geniposide-major components in HR-and CYP2D6 was inhibited by berberine (IC50, 13.8 MUg/ml) in a metabolism-dependent manner. 6. The results suggest the possibility of HR-drug interaction through inhibition of CYP-particularly CYP2D6-which may be attenuated by fermentation using L. acidophilus. PMID- 25145881 TI - Plasma vitamin D is associated with fasting insulin and homeostatic model assessment of insulin resistance in young adult males, but not females, of the Jerusalem Perinatal Study. AB - OBJECTIVE: To examine cross-sectional relationships between plasma vitamin D and cardiometabolic risk factors in young adults. DESIGN: Data were collected from interviews, physical examinations and biomarker measurements. Total plasma 25 hydroxyvitamin D (25(OH)D) was measured using LC-tandem MS. Associations between 25(OH)D and cardiometabolic risk factors were modelled using weighted linear regression with robust estimates of standard errors. SETTING: Individuals born in Jerusalem during 1974-1976. SUBJECTS: Participants of the Jerusalem Perinatal Study (n 1204) interviewed and examined at age 32 years. Participants were oversampled for low and high birth weight and for maternal pre-pregnancy obesity. RESULTS: Mean total 25(OH)D concentration among participants was 21.7 (sd 8.9) ng/ml. Among males, 25(OH)D was associated with homeostatic model assessment of insulin resistance (natural log-transformed, beta=-0.011, P=0.004) after adjustment for BMI. However, these associations were not present among females (P for sex interaction=0.005). CONCLUSIONS: We found evidence for inverse associations of 25(OH)D with markers of insulin resistance among males, but not females, in a healthy, young adult Caucasian population. Prospective studies and studies conducted on other populations investigating sex-specific effects of vitamin D on cardiometabolic risk factors are warranted. PMID- 25145885 TI - The group trend of lanthanides binding to DNA and DNAzymes with a complex but symmetric pattern. AB - Using sensitized Tb(3+) luminescence spectroscopy as a tool, binding of 14 lanthanides to a lanthanide-dependent DNAzyme is studied, where the binding affinity is symmetric across the series and the tightest binding occurs with Nd(3+) and Ho(3+). This trend does not correlate with DNAzyme activity, suggesting that metal binding may not be the rate-limiting step of the DNAzyme catalysis. PMID- 25145886 TI - Microscale vortex-assisted electroporator for sequential molecular delivery. AB - Electroporation has received increasing attention in the past years, because it is a very powerful technique for physically introducing non-permeant exogenous molecular probes into cells. This work reports a microfluidic electroporation platform capable of performing multiple molecule delivery to mammalian cells with precise and molecular-dependent parameter control. The system's ability to isolate cells with uniform size distribution allows for less variation in electroporation efficiency per given electric field strength; hence enhanced sample viability. Moreover, its process visualization feature allows for observation of the fluorescent molecular uptake process in real-time, which permits prompt molecular delivery parameter adjustments in situ for efficiency enhancement. To show the vast capabilities of the reported platform, macromolecules with different sizes and electrical charges (e.g., Dextran with MW of 3,000 and 70,000 Da) were delivered to metastatic breast cancer cells with high delivery efficiencies (>70%) for all tested molecules. The developed platform has proven its potential for use in the expansion of research fields where on-chip electroporation techniques can be beneficial. PMID- 25145887 TI - Case of primary hepatic gastrinoma: Diagnostic usefulness of the selective arterial calcium injection test. AB - Gastrinomas mainly occur in the duodenum and pancreas. Primary hepatic gastrinoma is rare and difficult to diagnose because the liver is a frequent site of metastatic gastrinomas. Clinical factors were assessed in a 28-year-old man with diarrhea and heartburn who was hospitalized for recurrent duodenal ulcers. Abdominal ultrasound, endoscopic ultrasound and computed tomography (CT) could not detect a tumor in the duodenum or pancreas. His gastrin level was 846 pg/mL and magnetic resonance imaging showed a mass 12 mm in diameter in the right robe of the liver. A selective intra-arterial calcium injection (SACI) test and 68 gallium edotreotide positron emission tomography CT (Ga-DOTATOC PET-CT) were therefore performed. Calcium gluconate injection into the proper hepatic artery resulted in a marked increase in serum gastrin concentration in the right hepatic vein, with Ga-DOTATOC PET-CT showing uptake only by the liver mass. Following a diagnosis of primary hepatic gastrinoma, the tumor was resected. A histopathological examination indicated gastrinoma. Six months postoperatively, he has no symptoms, is not taking proton-pump inhibitors and his gastrin level remains within the normal range. The SACI test and the clinical course of this patient strongly suggest that the tumor was a primary hepatic gastrinoma. The SACI test is helpful in the diagnosis of primary hepatic gastrinoma. PMID- 25145888 TI - Author's reply to Noe et al.: "Reference selection influences the reliability of conclusions". PMID- 25145889 TI - Niemann-Pick disease type C: introduction and main clinical features. PMID- 25145890 TI - The genetics of ataxia: through the labyrinth of the Minotaur, looking for Ariadne's thread. AB - Among the hereditary cerebellar ataxias (CAs), there are at least 36 different forms of autosomal dominant cerebellar ataxia (ADCAs), 20 autosomal recessive cerebellar ataxias (ARCAs), two X-linked ataxias, and several forms of ataxia associated with mitochondrial defects. Despite the steady increase in the number of newly discovered CA genes, patients, especially those with putative ARCAs, cannot yet be genotyped. Moreover, in daily clinical practice, ataxia may present as an isolated cerebellar syndrome or, more often, it is associated with a broad spectrum of neurological manifestations including pyramidal, extrapyramidal, sensory, and cognitive dysfunction. Furthermore, non-neurological symptoms may also coexist. A close integration between clinical records, neurophysiological, neuroradiological and, in some instances, biochemical findings will help physicians in the diagnostic work-up (including selection of the correct genetic tests) and may lead to timely therapy. Some inherited CAs are in fact potentially treatable, and the efficacy of the therapy is directly related to the severity of the cerebellar atrophy and to the time of onset of the disease. Most cases of CA are sporadic, and the diagnostic work-up remains a challenge. Detailed anamnesis and deep investigation of the family pedigree are usually enough to discriminate between acquired and genetic conditions. In the case of ADCA, molecular testing should be guided by taking into account the main associated symptoms. In sporadic cases, a multi-disciplinary approach is needed and should consider the following points: (1) onset and clinical course; (2) associated features; (3) neurophysiological parameters, with special attention to the occurrence of peripheral neuropathy; (4) neuroimaging results; and (5) laboratory findings. A late-onset sporadic ataxia, in which other possible causes have been excluded by following the proposed steps, might be attributable to metabolic disorders, which in some instances may be treatable. In this review, we will guide the reader through the labyrinth of CAs, and we propose a diagnostic flow chart. PMID- 25145892 TI - Psychiatric signs and symptoms in treatable inborn errors of metabolism. AB - Possible underlying organic causes of psychiatric symptoms can be overlooked in the clinical setting. It is important to increase awareness amongst psychiatric and neurological professionals with regard to certain inborn errors of metabolism as, in some cases, disease-specific therapies are available that can, for instance, treat underlying metabolic causes. The following article describes the basic pathophysiology, clinical and neurological features, and available diagnostic procedures of six treatable metabolic diseases that are associated with neuropsychiatric symptoms: Wilson's disease, cerebrotendinous xanthomatosis, porphyrias, homocysteinemia, urea cycle disorders, and Niemann-Pick disease type C (NP-C). NP-C is taken as a particularly relevant example because, while it is traditionally considered to be a condition that presents with severe neurological and systemic manifestations in children, an increasing number of patients are being detected who have the adolescent- or adult-onset form, which is frequently associated with neuropsychiatric signs. A notable proportion of adult-onset cases have been reported where NP-C has mistakenly been diagnosed and treated as a psychiatric condition, usually based on patients' initial presentation with psychotic or schizophrenia-like symptoms. Underlying organic causes of psychiatric disorders such as psychosis should be considered among patients with atypical symptoms and/or resistance to standard therapy. Alongside improved frameworks for additional multidisciplinary diagnostic work in patients with suspected organic disease, the development of convenient and affordable biochemical screening and/or diagnostic methods has enabled new ways to narrow down differential diagnoses. PMID- 25145891 TI - Central ocular motor disorders, including gaze palsy and nystagmus. AB - An impairment of eye movements, or nystagmus, is seen in many diseases of the central nervous system, in particular those affecting the brainstem and cerebellum, as well as in those of the vestibular system. The key to diagnosis is a systematic clinical examination of the different types of eye movements, including: eye position, range of eye movements, smooth pursuit, saccades, gaze holding function and optokinetic nystagmus, as well as testing for the different types of nystagmus (e.g., central fixation nystagmus or peripheral vestibular nystagmus). Depending on the time course of the signs and symptoms, eye movements often indicate a specific underlying cause (e.g., stroke or neurodegenerative or metabolic disorders). A detailed knowledge of the anatomy and physiology of eye movements enables the physician to localize the disturbance to a specific area in the brainstem (midbrain, pons or medulla) or cerebellum (in particular the flocculus). For example, isolated dysfunction of vertical eye movements is due to a midbrain lesion affecting the rostral interstitial nucleus of the medial longitudinal fascicle, with impaired vertical saccades only, the interstitial nucleus of Cajal or the posterior commissure; common causes with an acute onset are an infarction or bleeding in the upper midbrain or in patients with chronic progressive supranuclear palsy (PSP) and Niemann-Pick type C (NP-C). Isolated dysfunction of horizontal saccades is due to a pontine lesion affecting the paramedian pontine reticular formation due, for instance, to brainstem bleeding, glioma or Gaucher disease type 3; an impairment of horizontal and vertical saccades is found in later stages of PSP, NP-C and Gaucher disease type 3. Gaze evoked nystagmus (GEN) in all directions indicates a cerebellar dysfunction and can have multiple causes such as drugs, in particular antiepileptics, chronic alcohol abuse, neurodegenerative cerebellar disorders or cerebellar ataxias; purely vertical GEN is due to a midbrain lesion, while purely horizontal GEN is due to a pontomedullary lesion. The pathognomonic clinical sign of internuclear ophthalmoplegia is an impaired adduction while testing horizontal saccades on the side of the lesion in the ipsilateral medial longitudinal fascicule. The most common pathological types of central nystagmus are downbeat nystagmus (DBN) and upbeat nystagmus (UBN). DBN is generally due to cerebellar dysfunction affecting the flocculus bilaterally (e.g., due to a neurodegenerative disease). Treatment options exist for a few disorders: miglustat for NP-C and aminopyridines for DBN and UBN. It is therefore particularly important to identify treatable cases with these conditions. PMID- 25145893 TI - Genetic and laboratory diagnostic approach in Niemann Pick disease type C. AB - Niemann Pick disease type C (NP-C) is a rare autosomal recessive disorder that results from mutations in either the NPC1 or the NPC2 gene. The estimated incidence of NP-C is 1 in 120,000 live births, although the frequency of cases is higher in some isolated populations. More than 350 different NPC1 and NPC2 gene mutations have been reported in patients with confirmed diagnoses. Approximately 95 % of patients harbour mutations in NPC1, with most of the remaining patients having NPC2 mutations. The traditional methods for diagnosing patients with NP-C include histopathological analysis of bone marrow aspirate, liver and skin biopsies, fluorescent and electron microscopy, and cholesterol esterification assays. New laboratory methods that use mass spectroscopy for detection of cholesterol metabolism products are promising to become part of the routine diagnostic and screening tests in the near future, but further evaluation is required to determine the sensitivity and specificity of these analyses in patients with different age-at-onset forms of NP-C. Although filipin staining and cholesterol esterification studies performed in patient skin fibroblasts can, in experienced hands, provide a robust approach to diagnosing NP-C, they are only available in a few specialist laboratories. Thus, sequencing of NPC1 and NPC2 is currently the most universally accessible diagnostic technique in this disorder. PMID- 25145894 TI - Reverse transcription polymerase chain reaction-based method for selectively detecting vegetative cells of toxigenic Clostridium difficile. AB - The laboratory diagnostic methods for Clostridium difficile infection (CDI) include toxigenic culture, enzyme immunoassays (EIAs) to detect the toxins of C. difficile, and nucleic acid amplification tests (NAATs) to detect C. difficile toxin genes, but each of these methods has disadvantages; toxigenic cultures require a long time to produce results, EIAs have low sensitivity, and NAATs that target DNA cannot distinguish vegetative cells from spores and dead cells. Here we report a new detection method that uses reverse transcription polymerase chain reaction to target the toxin-gene transcripts. This method was able to specifically detect the vegetative cells of toxigenic C. difficile in fecal samples in spike tests, with a minimum detection limit of 5 * 10(2) colony forming units per 100 mg of stool specimen. The performance of this method was also demonstrated in a pilot scale evaluation using clinical fecal specimens, which showed that this method may be more sensitive than EIA and requires a shorter time than toxigenic culture. This method could potentially be applied in the clinical laboratory to detect C. difficile in fecal specimens. The ability of this method to discriminate the presence of vegetative cells from spores and dead cells could help to further the understanding of CDI. PMID- 25145896 TI - Paratesticular sarcomas: two cases with different evolutions. AB - Paratesticular sarcomas are rare and account for less than 1% of all adult sarcomas. Intrascrotal tumours can be testicular or paratesticular, paratesticular tumours being rarer (7-10%). Only 30% of paratesticular tumours are malignant and 90% of these are sarcomas. Histological subtypes include leiomyosarcoma, rhabdomyosarcoma, liposarcoma and undifferentiated high-grade pleomorphic sarcoma. Recurrence is frequent in this type of tumour and can occur years from initial diagnosis. These reports show two cases of paratesticular sarcoma with very distinct evolutions. The first case concerns a patient who presented with low-grade leiomyosarcoma with two local recurrences treated with surgery, and distance recurrence with cutaneous, subcutaneous, pulmonary and hepatic metastasis 30 years after surgery of the primary tumour. The second case reports of a patient who presented with high-grade myxoid liposarcoma with local and distance recurrence 3 years after surgery of the primary tumour, which progressed after chemotherapy; the patient died 7 months after diagnosis of recurrence. PMID- 25145895 TI - Isolated oedema of the uvula induced by intense snoring and ACE inhibitor. AB - A case of snoring-induced angioedema of uvula is described in a patient who was treated with ACE inhibitor. The patient partially responded to complement C1 inhibitor concentrate and did not suffer any recurrences after the medication was withdrawn. When encountering a patient suffering from swellings of the orofacial area it should be considered whether the mechanism is mast-cell associated or not, as classical antiallergic treatment is ineffective in non-mast-cell associated disease (ie, bradykinin-mediated angioedema). Other causes of uvular oedema are also discussed. PMID- 25145897 TI - Intravascular lymphoma: an unusual cause of rapid cognitive decline and the role of brain biopsy. AB - Intravascular lymphoma (IVL) is a rare extra nodal variant of non Hodgkin's lymphoma characterised by neoplastic lymphoid cells growing inside the lumina of medium and small vessels. IVL limited to the central nervous system (CNS) is an extremely rare condition as IVL is usually found with systemic lesions. Most cases of IVL are not diagnosed until post mortem because of variable clinical presentation and non-specific laboratory findings. Even if diagnosed early the disease is clinically aggressive and usually fatal, even with early detection and treatment. We present a case of a 37-year-old woman with a short history of behavioural abnormality, rapidly progressive cognitive decline and seizures. There were no cutaneous manifestations. Diagnosis was established only after the brain biopsy. The case is presented for the rarity of its presentation and role of brain biopsy in diagnosis. PMID- 25145899 TI - Rare delayed complication of laparoscopic sacrocervicopexy with synthetic mesh. PMID- 25145898 TI - Ewing's sarcoma of the hand. PMID- 25145900 TI - When do the risks of repeated courses of corticosteroids exceed the risks of surgery? AB - BACKGROUND: The management of chronic rhinosinusitis with nasal polyposis (CRSwNP) becomes unclear when patients require multiple courses of corticosteroids to maintain quality of life. Repeated courses of corticosteroids carry increased risks to patients. Although endoscopic sinus surgery (ESS) is an effective therapeutic modality, it also carries inherent risks. This study aims to identify the threshold at which the risks of repeated courses of corticosteroid exceed the risks of surgery. METHODS: An evidence-based risk analysis was simulated using literature-reported complication rates, quality of life changes, and Medicare costs. Simulations were performed from the Medicare patient perspective, societal perspective, and the universal healthcare patient perspective. RESULTS: All 3 simulations demonstrate a breakeven threshold favoring surgery over medical therapy when patients require oral corticosteroids (OCS) more often than once every 2 years in CRSwNP, once per year in CRSwNP/asthma, or twice per year for Samter's triad patients. CONCLUSION: This represents the first rationalized evidence-based analysis for when surgery should be considered in place of repeated courses of oral corticosteroids. This threshold provides a guide for otolaryngologists to use when making clinical decisions with patients. PMID- 25145901 TI - Role of heat shock proteins in oxygen radical-induced gastric apoptosis. AB - BACKGROUND: The generation of reactive oxygen species (ROS) and their resultant oxidative damage is a common pathway for gastric mucosal injury. Developing strategies to protect the gastric epithelium against oxygen free radical damage is of profound pathophysiological interest. We have previously shown caspase mediated apoptosis as a major cause of ROS-induced cell death in gastric mucosa. Because heat shock proteins (Hsps) confer protection against many cytotoxic agents, this study was undertaken to determine whether modulation of Hsps was protective against oxidative damage. MATERIALS AND METHODS: AGS cells (human gastric mucosal cell line) received either no pretreatment, heat shock pretreatment (1 h at 42 +/- 1 degrees C), or pretreatment with an Hsp modulating drug (geldanamycin or quercetin). Cells were then exposed to hydrogen peroxide (H2O2), a representative ROS (1 mM, a physiologically relevant concentration), for 24 h. Caspase-3 activation and Poly ADP Ribose Polymerase (PARP) inactivation, as well as DNA-histone complex formation were used as measures of apoptosis. Inducible Hsps (Hsp70 and Hsp90) were detected using Western blot analysis. RESULTS: Results showed heat shock pretreatment induced increased expression of Hsp70 without change in Hsp90. In response to H2O2 exposure alone, there was significant increase in DNA-histone complex formation as well as caspase-3 activation and PARP cleavage in gastric epithelium. Heat shock pretreatment resulted in statistically significant prevention in these measures of apoptosis. Geldanamycin increased Hsp70, but elicited cleavage of Hsp90 and subsequently resulted in an increase in H2O2-induced apoptosis. Quercetin decreased Hsp70 and resulted again in increased H2O2-induced apoptosis. CONCLUSIONS: These findings indicate that heat shock pretreatment protects gastric mucosal cells against H2O2-induced apoptosis and that Hsp70 and Hsp90 may play key roles in this process. These results further suggest that perturbations in Hsp metabolism may induce mucosal injury in response to oxygen free radicals. PMID- 25145902 TI - Effects of glutamine alone on the acute necrotizing pancreatitis in rats. AB - BACKGROUND: The effects of the glutamine on the acute pancreatitis are controversial in the clinical and experimental studies. The aim of this study was to investigate the influence of glutamine alone on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. MATERIAL AND METHODS: Fifty-two male Sprague-Dawley rats weighing 300-350 g were used. Rats were divided into four groups as sham + saline, sham + glutamine, ANP + saline and ANP + glutamine. ANP in rats was induced by glycodeoxycholic acid. The extent of acinar cell injury, mortality, systemic cardiorespiratory variables, functional capillary density, renal/hepatic functions, and changes in some enzyme markers for pancreatic and lung tissue were investigated during ANP in rats. RESULTS: The induction of ANP resulted in a significant increase in the mortality rate, pancreatic necrosis, and serum activity of amylase, alanine aminotransferase, interleukin-6, lactate dehydrogenase in bronchoalveolar lavage fluid, serum concentration of urea, and tissue activity of myeloperoxidase and malondialdehyde in the pancreas and lung, and a significant decrease in concentrations of calcium, blood pressure, urine output, pO2, and functional capillary density. The use of glutamine alone improved these changes. CONCLUSIONS: Glutamine demonstrated beneficial effect on the course of ANP in rats. Therefore, it may be used by itself in the treatment of acute pancreatitis. PMID- 25145903 TI - Laser-induced drug release for local tumor control--a proof of concept. AB - BACKGROUND: The systemic palliative chemotherapy of locally extended gastrointestinal and hepatobiliary tumors is associated with a considerable burden for the patient. The aim of this project was to develop a new drug release system to improve the local stent therapy in these patients as a proof of concept study. For this purpose, polymer filaments were modified with drug-loaded polymer microgels that allow selective release of the active substance by photochemical triggering using laser radiation. Integrated into a stent system, the better local tumor control could thus contribute to a significant increase in the quality of life of patients. METHODS: A standard mammalian cell line and two carcinoma cell lines were established. By Fluorescence activated cell sorting (FACS), the cytotoxicity of the different materials was determined in vitro before and after drug loading with the chemotherapeutic agent 5-Fluorouracil (5 FU). For this purpose, the locally applied 5-FU concentration was previously determined by Bromdesoxyuridin assay. 5-FU dimer was synthesized by photo-induced dimerization of 5-FU in the presence of benzophenone in methanol. The chemical structure of 5-FU dimer was confirmed with Hydrogen-1 nuclear magnetic resonance and Fluorine-19 nuclear magnetic resonance. 5-FU dimer is nonsoluble in water and can be easily incorporated in polymer microgels modified with hydrophobic binding domains (cyclodextrin). After laser irradiation, 5-FU dimer decomposes and 5-FU can be released from microgels. Finally, the measurements were repeated after this laser-induced drug release. RESULTS: In FACS analysis, neither the microgels nor the microgel cumarin complexes showed a significant difference in comparison with the negative control with H2O and therefore no toxic effect on the cell lines. After loading with the 5-FU dimer, there was no significant cell death (contrary to the pure 5-FU monomer, which dose had been previously tested as highly toxic). After laser-induced dissociation back to monomer and the associated drug release, FACS analysis showed cytotoxicity. CONCLUSIONS: It was possible to develop 5-FU dimerloaded microgels, which show no cytotoxic effect on cell lines before laser irradiation. After dissociation back to 5-FU monomer by selective photochemical triggering using laser irradiation, the active substance was released. Thus, a new drug release system has been created and tested in vitro. For further development, integration into a stent system and for in vivo follow-up evaluation more studies need to be conducted. PMID- 25145904 TI - Application of radiofrequency ablation for splenic preservation. AB - BACKGROUND: Traditional splenic preservation surgery involves considerable difficulties, high risks, and numerous postoperative complications. In this study, we applied radiofrequency ablation (RFA) to splenic preservation and explored its clinical value. METHODS: The clinical data of 129 patients with traumatic splenic rupture who received surgery in our hospital from September 2008-June 2013 were retrospectively analyzed. According to the operation methods, these patients were divided into three groups: 35 patients received splenic preservation surgery with RFA-assisted technique (RFA + suture repair group), 78 patients received splenic preservation surgery without RFA (traditional operation group), and 46 patients received splenectomy (splenectomy group). Preoperative, intraoperative, and postoperative-related parameters of the former two groups were compared. The postoperative complications and immunologic parameters of patients with preserved spleens were compared with those of patients who underwent splenectomy. RESULT: In the RFA + suture repair group, 34 cases successfully underwent splenic preservation surgery. Meanwhile, 49 cases successfully underwent spleen preservation surgery in the traditional operation group. RFA + suture repair group had shorter mean operation time (79 +/- 22 versus 119 +/- 26 min, P < 0.05), less bleeding during surgery (115 +/- 67 versus 235 +/- 155 mL, P < 0.05), and less intraoperative transfusion (14% versus 36%, P < 0.05). The postoperative bleeding and hospital-stay duration were remarkably lower than those in the traditional operation group (100 +/- 52 versus 219 +/- 93 mL and 7.1 +/- 1.4 d versus 11.7 +/- 2.8 d, respectively, P < 0.05). The spleen preserving patients showed better results than the splenectomy group did for some parameters related to complications and immunology. CONCLUSIONS: Compared with traditional splenic preservation, RFA is simple and feasible, and it can greatly benefit the spleen preservation operation. PMID- 25145905 TI - Replacement of the esophagus with fascial flap-wrapped allogenic aorta. AB - BACKGROUND: Segmental replacement of the esophagus (SRE) is challenging. Allogenic aorta (AA) has shown promising remodeling abilities when used as an esophageal substitute. The aim of this study was to evaluate the feasibility and results of esophageal replacement with fascial flap-wrapped AA segments in a novel rabbit model. MATERIALS AND METHODS: Seven Geant des Flandres rabbits and one New Zealand rabbit served as thoracic aorta donors, and 25 New Zealand rabbits were used as recipients. One to 3 wk before esophageal replacement either cryopreserved or fresh thoracic aortic segments were wrapped in thoracic wall fascia to generate revascularization. In an attempt to optimize the model, step by-step modifications concerning perioperative and postoperative management of the recipients were made as results accumulated. Microscopic evaluation was focused on the viability of aortic segments and neoangiogenesis originating from the fascia. RESULTS: Survival after SRE was poor. Most recipients died within 1 wk, mainly from upper digestive tract hypomotility. Microscopically, AAs were severely necrosed. In one recipient sacrificed on day 16, the edges of the graft became evanescent. In these areas, esophageal reepithelialization directly covered the fascia, in which unexpected smooth muscle cells were found, suggestive of the first stages of esophageal remodeling of the graft. CONCLUSIONS: Results for SRE using fascial-wrapped AAs in rabbits were disappointing. The transposition of this approach to larger animals might result in longer survival, increasing the possibility for more complete graft remodeling. PMID- 25145906 TI - Upper lesser curvature skeletonization in radical distal gastrectomy. AB - BACKGROUND: To investigate the metastatic status of lymph nodes numbers (no.) 1, 3a, and 3b groups in radical distal gastrectomy with upper lesser curvature skeletonization and the risk factors for lesser curvature regional node (LCRN) metastasis. METHODS: Data on patients who underwent radical distal gastrectomy were retrospectively collected between May 2010 and September 2013. Clinicopathologic features and surgical outcomes were compared between the LCRN (+) and (-) groups. The correlations among the no. 1, 3a and 3b groups, and other groups were analyzed. Univariate and multivariate analyses were performed to identify the independent risk factors for LCRN metastasis. RESULTS: A total of 112 patients were analyzed. In all, 45.5% had metastatic LCRNs, and 59.8% were node positive overall. The LCRN (+) and (-) groups had significantly different features, including gender; tumor size; histologic grade; Lauren classification; gross type; and T, N, and TNM stages. The positivity rates of the no. 1, 3a, and 3b groups were 4.5%, 38.4%, and 32.1%, respectively, and the no. 1, 3a, and 3b groups were comprehensively correlated with the D2-tier groups. In the univariate and multivariate analyses, only stage T3-4 and positive no. 4d nodes were documented as independent risk factors, whereas no. 5 and 11p nodes trended toward a positive correlation. CONCLUSIONS: LCRNs have high frequencies of metastasis in lower gastric cancers, and in the present study, these groups of lymph nodes tended to be associated with each other as an entity in the lesser curvature region. Upper lesser curvature skeletonization can be recommended as a standard procedure in radical distal gastrectomy to thoroughly clear the gastric stump, especially in the case of stage T3-4 or suspicious no. 4d nodes. PMID- 25145907 TI - Isolation of CA1 nuclear enriched fractions from hippocampal slices to study activity-dependent nuclear import of synapto-nuclear messenger proteins. AB - Studying activity dependent protein expression, subcellular translocation, or phosphorylation is essential to understand the underlying cellular mechanisms of synaptic plasticity. Long-term potentiation (LTP) and long-term depression (LTD) induced in acute hippocampal slices are widely accepted as cellular models of learning and memory. There are numerous studies that use live cell imaging or immunohistochemistry approaches to visualize activity dependent protein dynamics. However these methods rely on the suitability of antibodies for immunocytochemistry or overexpression of fluorescence-tagged proteins in single neurons. Immunoblotting of proteins is an alternative method providing independent confirmation of the findings. The first limiting factor in preparation of subcellular fractions from individual tetanized hippocampal slices is the low amount of material. Second, the handling procedure is crucial because even very short and minor manipulations of living slices might induce activation of certain signaling cascades. Here we describe an optimized workflow in order to obtain sufficient quantity of nuclear enriched fraction of sufficient purity from the CA1 region of acute hippocampal slices from rat brain. As a representative example we show that the ERK1/2 phosphorylated form of the synapto-nuclear protein messenger Jacob actively translocates to the nucleus upon induction of LTP and can be detected in a nuclear enriched fraction from CA1 neurons. PMID- 25145909 TI - Who cares about continuity? PMID- 25145908 TI - Tracking conformational dynamics of polypeptides by nonlinear electronic spectroscopy of aromatic residues: a first-principles simulation study. AB - The ability of nonlinear electronic spectroscopy to track folding/unfolding processes of proteins in solution by monitoring aromatic interactions is investigated by first-principles simulations of two-dimensional (2D) electronic spectra of a model peptide. A dominant reaction pathway approach is employed to determine the unfolding pathway of a tetrapeptide, which connects the initial folded configuration with stacked aromatic side chains and the final unfolded state with distant noninteracting aromatic residues. The pi-stacking and excitonic coupling effects are included through ab initio simulations based on multiconfigurational methods within a hybrid quantum mechanics/molecular mechanics scheme. It is shown that linear absorption spectroscopy in the ultraviolet (UV) region is unable to resolve the unstacking dynamics characterized by the three-step process: T-shaped->twisted offset stacking >unstacking. Conversely, pump-probe spectroscopy can be used to resolve aromatic interactions by probing in the visible region, the excited-state absorptions (ESAs) that involve charge-transfer states. 2D UV spectroscopy offers the highest sensitivity to the unfolding process, by providing the disentanglement of ESA signals belonging to different aromatic chromophores and high correlation between the conformational dynamics and the quartic splitting. PMID- 25145911 TI - EURACT statement on family medicine undergraduate teaching EURACT: European Academy of Teachers in general practice/family medicine. PMID- 25145912 TI - Developing essential interventions towards full access of rural population to health care: a proposal of collaboration between occupational health physicians and rural GPs. EURIPA: the European Rural and Isolated Practitioners Association. PMID- 25145915 TI - Killer artificial antigen presenting cells (KaAPC) for efficient in vitro depletion of human antigen-specific T cells. AB - Current treatment of T cell mediated autoimmune diseases relies mostly on strategies of global immunosuppression, which, in the long term, is accompanied by adverse side effects such as a reduced ability to control infections or malignancies. Therefore, new approaches need to be developed that target only the disease mediating cells and leave the remaining immune system intact. Over the past decade a variety of cell based immunotherapy strategies to modulate T cell mediated immune responses have been developed. Most of these approaches rely on tolerance-inducing antigen presenting cells (APC). However, in addition to being technically difficult and cumbersome, such cell-based approaches are highly sensitive to cytotoxic T cell responses, which limits their therapeutic capacity. Here we present a protocol for the generation of non-cellular killer artificial antigen presenting cells (KaAPC), which allows for the depletion of pathologic T cells while leaving the remaining immune system untouched and functional. KaAPC is an alternative solution to cellular immunotherapy which has potential for treating autoimmune diseases and allograft rejections by regulating undesirable T cell responses in an antigen specific fashion. PMID- 25145916 TI - Synthesis, growth and spectral, optical and thermal characterization studies on L Tryptophan p-nitrophenol (LTPN) single crystals for NLO applications. AB - The novel nonlinear optical single crystal of L-Tryptophan p-nitrophenol (LTPN) has been successfully synthesized by taking the appropriate amount of L Tryptophan and p-nitrophenol. The single crystals have been grown by slow evaporation solution growth technique. The single crystal XRD studies confirmed that the grown crystal belongs to the monoclinic system. The various functional groups presented in the crystal were confirmed by FT-IR and (1)H NMR spectroscopic studies. The absorptions of the grown crystals were analyzed using UV-Vis-NIR spectral studies. The thermal analysis was performed to study the thermal stability of the grown crystals. The second harmonic generation behavior of L-Tryptophan p-nitrophenol crystal was tested by Kurtz-Perry powder technique. PMID- 25145917 TI - Accurate spectroscopic calculations of the 17 Lambda-S and 59 Omega states of the AsP molecule including the spin-orbit coupling effect. AB - The potential energy curves (PECs) of 59 Omega states generated from the 17 Lambda-S states (X(1)Sigma(+), a(3)Sigma(+), 1(5)Sigma(+), b(3)Delta, c(3)Pi, 1(5)Pi, 2(5)Sigma(+), 2(3)Delta, 2(3)Pi, 3(3)Sigma(+), A(1)Pi, 2(3)Sigma(+), 3(5)Sigma(+), 1(7)Sigma(+), 1(5)Delta, 2(5)Delta, and 2(5)Pi) of AsP molecule are studied for the first time for internuclear separations from about 0.10 to 1.10nm. All the Lambda-S states are contributed to the first three dissociation channels of AsP molecule except for the A(1)Pi. The 2(3)Sigma(+), 3(5)Sigma(+), 1(7)Sigma(+), 1(5)Delta, 2(5)Delta, and 2(5)Pi are found to be the repulsive states. The a(3)Sigma(+), 1(5)Pi, b(3)Delta, 1(7)Sigma(+), 1(5)Delta, 2(5)Delta, and 2(5)Pi are found to be the inverted states. Each of the 3(3)Sigma(+), c(3)Pi, 2(3)Pi, 1(5)Pi, and 1(5)Sigma(+) states has one potential barrier. The PECs are calculated by the CASSCF method, which is followed by the internally contracted MRCI approach with Davidson correction. Core-valence correlation and scalar relativistic corrections are included. The convergent behavior of present calculations is discussed with respect to the basis set and level of theory. The spin-orbit coupling effect is accounted for. All these PECs are extrapolated to the complete basis set limit. The spectroscopic parameters are evaluated for the bound states involved, and are compared with available measurements. Excellent agreement has been found between the present results and the measurements. It shows that the spectroscopic parameters reported in this paper can be expected to be reliably predicted ones. The conclusion is gained that the effect of spin orbit coupling on the spectroscopic parameters is not obvious for all the Lambda S bound states except for few ones such as 1(5)Sigma(+) and c(3)Pi. PMID- 25145918 TI - Influence of charge and metal coordination of meso-substituted porphyrins on bacterial photoinactivation. AB - The photodynamic effect of meso-substituted porphyrins with different charges and metal ions: meso-tetraphenylporphyrin tetrasulfonate 1, its nickel 2 and zinc complexes 3; meso-tetranaphthylporphyrin tetrasulfonate 4, and its zinc complex Zn 5; and tetra piridyl ethylacetate porphirins 6 and their nickel 7 and zinc 8 complexes, were synthesized and studied their antimicrobial activity against Escherichia coli. Fluorescence quantum yields (PhiF) were measured in water using reference TPPS4, obtaining higher values for complexes 3 and 4. The singlet oxygen PhiDelta were measured using histidine as trapping singlet oxygen and Rose Bengal as a reference standard. Complexes 1, 2 and 6 have the highest quantum yields of singlet oxygen formation, showing no relation with the peripheral charges and efficiency as Type II photosensitizers. Meanwhile complexes 3, 8 and 4 were the most efficient in producing radical species, determined with their reaction with NADH. The photoinduced antibacterial activity of complex was investigated at different concentrations of the photosensitizers with an irradiation time of 30 min. The higher antibacterial activities were obtained for the complexes 1-3 that are those with greater production of ROS and minor structural deformations. Complexes 7 and 8 had moderate activity, while 4-6 a low activity. Thus, in this work demonstrates that the production of ROS and structural deformations due to peripheral substituents and metal coordination, influence the activity of the complexes studied. Therefore, is important to perform comprehensive study physics and structurally when predicting or explain such activity. PMID- 25145919 TI - Phylogeny of cultivated and wild wheat species using ATR-FTIR spectroscopy. AB - Within the last decade, an increasing amount of genetic data has been used to clarify the problems inherent in wheat taxonomy. The techniques for obtaining and analyzing these data are not only cumbersome, but also expensive and technically demanding. In the present study, we introduce infrared spectroscopy as a method for a sensitive, rapid and low cost phylogenetic analysis tool for wheat seed samples. For this purpose, 12 Triticum and Aegilops species were studied by Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) spectroscopy. Hierarchical cluster analysis and principal component analysis clearly revealed that the lignin band (1525-1505 cm(-1)) discriminated the species at the genus level. However, the species were clustered according to their genome commonalities when the whole spectra were used (4000-650 cm(-1)). The successful differentiation of Triticum and its closely related genus Aegilops clearly demonstrated the power of ATR-FTIR spectroscopy as a suitable tool for phylogenetic research. PMID- 25145920 TI - Paragangliomas: presentation and management by radiotherapy at the Prince of Wales Hospital. AB - INTRODUCTION: Paragangliomas are commonly treated with surgery, while radiotherapy is reserved for those that are inoperable or have relapsed. However, this retrospective study aims to determine whether radiotherapy is a viable initial treatment for paragangliomas. METHODS: Of 73 tumours researched, 44 were diagnosed and treated from January 1967 to December 2012 at the Radiation Oncology Department at the Prince of Wales Hospital and thus were eligible for analysis. Median follow-up time was 3.5 years with a range of 1 to 40 years. Thirty-four tumours were treated with radiotherapy only, and 10 tumours were treated with both surgical resection and radiotherapy. Local control and cause specific survival were the primary end points measured. RESULTS: Five-year local control rate for the population of 44 lesions was 89%; it was 100% in the group treated by radiotherapy alone, but only 50% in the group treated by surgery followed by radiotherapy, with radiation used for salvage. The difference in control rates between these two subset groups was found to be statistically significant (P < 0.001). Cause-specific survival rates for this eligible population at 5 and 10 years were 98% and 90%, respectively. After initial radiotherapy, 4 patients had improved cranial nerve function, there was clinical improvement in tinnitus, and one new cranial nerve deficit developed where a high dose was used. CONCLUSIONS: Radiotherapy has high local control rates and few complications. The local control and complication rates compare favourably to surgery. PMID- 25145921 TI - Autophagy and amino acid metabolism in the brain: implications for epilepsy. AB - Autophagy is a catabolic pathway responsible for the maintenance of the tissue and organism homeostasis. Several amino acids regulate autophagic activity in different tissues, such as liver and muscle, but much less is known about this regulation in the brain. The lack of autophagy in neurons leads to a strong neurodegenerative phenotype and epileptic disorders. We summarize the current knowledge about the regulation of autophagy mediated by amino acids and how macroautophagy could serve as source of amino acids. We review the contribution of macroautophagy in the brain physiology and pathology emphasizing the relevancy of the proper control of amino acid levels such as glutamate and GABA in the brain due to its role as neurotransmitters and energy source. Furthermore, we discuss how malfunction in autophagy may result in pathological consequences, because many genetic epileptic disorders are related to signaling or metabolic pathways controlling both macroautophagy and amino acid metabolism in the brain. PMID- 25145922 TI - Selective Embolization of Systemic Collaterals for the Treatment of Recurrent Hemoptysis Secondary to the Unilateral Absence of a Pulmonary Artery in a Child. AB - The unilateral absence of the pulmonary artery (UAPA) is a rare anomaly. Hemoptysis due to systemic collaterals is one of the most common complications of UAPA. To the best of the authors' knowledge, the utility of selective embolization for the treatment of this condition in children has not been reported previously. This report describes a 6-year-old girl with isolated UAPA (IUAPA) admitted for a 10-month history of recurrent hemoptysis that had worsened during the previous 2 months. Selective embolization of the bronchial systemic collaterals was performed. The patient remained asymptomatic with no recurrence of hemoptysis 8 months after the procedure. PMID- 25145923 TI - Thromboembolic complications after Zenith(r) Low Profile Endovascular Graft for infrarenal abdominal aneurysms. AB - PURPOSE: The purpose of this study was to objectify and evaluate risk factors for thromboembolic complications after treatment with a Zenith((r)) Low Profile Endovascular Graft (Zenith LP). Results were compared with those in the recent literature on endovascular aortic repair (EVAR) and with the thromboembolic complications in the patient group treated with a Zenith Flex Endovascular Graft in our institute in the period before the use of the Zenith LP. MATERIALS AND METHODS: All consecutive patients who were suitable for treatment with a Zenith LP endograft between October 2010 and December 2011 were included. The preprocedural computed tomography scan (CT), procedural angiographic images, and the postprocedural CT scans were evaluated for risk factors for and signs of thromboembolic complications. All patients treated between December 2007 and November 2012 with a Zenith Flex endograft were retrospectively evaluated for thromboembolic complications. RESULTS: In the study period 17 patients were treated with a LP Zenith endograft. Limb occlusion occurred in 35 % of the patients. Limb occlusions occurred in 24 % of the limbs at risk (one limb occluded twice). In one patient two risk factors for limb occlusion were identified. Between December 2007 and November 2012, a total of 43 patients were treated with a Zenith Flex endograft. No limb occlusion or distal embolization occurred. CONCLUSION: Despite that this was a small retrospective study, the Zenith LP endograft seems to be associated with more frequent thromboembolic complications compared with the known limb occlusion rates in the literature and those of the patients treated with a Zenith Flex endograft in our institute. PMID- 25145924 TI - Broadening horizons: holistic viewpoints from the Biology of Genomes. AB - A report on the Cold Spring Harbor Laboratory 27th annual meeting on the Biology of Genomes, held in Cold Spring Harbor, New York, USA, 6-10 May 2014. PMID- 25145926 TI - Barriers to supported education implementation: implications for administrators and policy makers. AB - The economic impact of a lack of educational achievement for individuals with psychiatric disabilities is profound. Current poor economic conditions exacerbate the effects of low educational levels. This article presents the current educational barriers faced by individuals with psychiatric disabilities and introduces one potential solution: supported education. Supported education is an emerging best practice which holds promise for helping individuals with psychiatric disabilities in their pursuit of educational goals. However, additional barriers stand in the way of widespread supported education implementation. Recommendations are included for policymakers and community mental health centers to help increase the penetration of this much-needed service. PMID- 25145925 TI - Ebstein anomaly: assessment, management, and timing of intervention. AB - OPINION STATEMENT: Ebstein anomaly is a developmental abnormality of the tricuspid valve and right ventricle that results in tricuspid regurgitation and right heart enlargement. Because of the variation in clinical severity and associated findings, patients require a detailed, well-tailored evaluation. For these reasons, management of adults with Ebstein anomaly should take place in a center with expertise in adult congenital heart disease. In many patients, the decision regarding if and when to perform surgery remains controversial, largely because of a lack of published data demonstrating improved postoperative symptoms and survival compared to the natural history of the disease. Because standard two dimensional echocardiography and cardiovascular magnetic resonance imaging planes do not provide the necessary data to preoperatively manage patients, comprehensive echocardiography and cardiovascular magnetic resonance imaging protocols by experts trained in congenital heart disease are essential in the preoperative management of patients with Ebstein anomaly. As patients may be unaware of their exercise limitations, and for prognostic value, serial cardiopulmonary exercise stress testing is very useful in the evaluation of Ebstein anomaly patients. Surgical tricuspid valve repair historically has not been highly successful because of the marked distortion of tricuspid valve leaflets and right ventricular pathology. Over the last several years, reports of newer surgical techniques to repair the valve, with concurrent advances in arrhythmia management of patients hold promise for improved long term outcomes of patients with Ebstein anomaly. However, because Ebstein anomaly is rare and tricuspid valve repair remains technically challenging, the newer valve repair techniques have not yet gained widespread acceptance throughout the adult congenital heart disease community. PMID- 25145927 TI - Surface-confined single-layer covalent organic framework on single-layer graphene grown on copper foil. AB - The integration of 2D covalent organic frameworks (COFs) with atomic thickness with graphene will lead to intriguing two-dimensional materials. A surface confined covalently bonded Schiff base network was prepared on single-layer graphene grown on copper foil and the dynamic reaction process was investigated with scanning tunneling microscopy. DFT simulations provide an understanding of the electronic structures and the interactions between the surface COF and graphene. Strong coupling between the surface COF and graphene was confirmed by the dispersive bands of the surface COF after interaction with graphene, and also by the experimental observation of tunneling condition dependent contrast of the surface COF. PMID- 25145928 TI - The cardiovascular effect of the uremic solute indole-3 acetic acid. AB - In CKD, uremic solutes may induce endothelial dysfunction, inflammation, and oxidative stress, leading to increased cardiovascular risk. We investigated whether the uremic solute indole-3 acetic acid (IAA) predicts clinical outcomes in patients with CKD and has prooxidant and proinflammatory effects. We studied 120 patients with CKD. During the median study period of 966 days, 29 patients died and 35 experienced a major cardiovascular event. Kaplan-Meier analysis revealed that mortality and cardiovascular events were significantly higher in the higher IAA group (IAA>3.73 uM) than in the lower IAA group (IAA<3.73 uM). Multivariate Cox regression analysis demonstrated that serum IAA was a significant predictor of mortality and cardiovascular events after adjustments for age and sex; cholesterol, systolic BP, and smoking; C-reactive protein, phosphate, body mass index, and albumin; diastolic BP and history of cardiovascular disease; and uremic toxins p-cresyl sulfate and indoxyl sulfate. Notably, IAA level remained predictive of mortality when adjusted for CKD stage. IAA levels were positively correlated with markers of inflammation and oxidative stress: C-reactive protein and malondialdehyde, respectively. In cultured human endothelial cells, IAA activated an inflammatory nongenomic aryl hydrocarbon receptor (AhR)/p38MAPK/NF-kappaB pathway that induced the proinflammatory enzyme cyclooxygenase-2. Additionally, IAA increased production of endothelial reactive oxygen species. In conclusion, serum IAA may be an independent predictor of mortality and cardiovascular events in patients with CKD. In vitro, IAA induces endothelial inflammation and oxidative stress and activates an inflammatory AhR/p38MAPK/NF-kappaB pathway. PMID- 25145929 TI - Deficiency of the planar cell polarity protein Vangl2 in podocytes affects glomerular morphogenesis and increases susceptibility to injury. AB - The planar cell polarity (PCP) signaling pathway is crucial for tissue morphogenesis. Van Gogh-like protein 2 (Vangl2) is central in the PCP pathway; in mice, Vangl2 loss is embryonically lethal because of neural tube defects, and mutations in Vangl2 are associated with human neural tube defects. In the kidney, PCP signaling may be important for tubular morphogenesis and organization of glomerular epithelial cells (podocytes) along the glomerular basement membrane. Podocyte cell protrusions (foot processes) are critical for glomerular permselectivity; loss of foot process architecture results in proteinuria and FSGS. Previously, we showed a profound effect of PCP signaling on podocyte shape, actin rearrangement, cell motility, and nephrin endocytosis. To test our hypothesis that the PCP pathway is involved in glomerular development and function and circumvent lethality of the ubiquitous Vangl2 mutation in the Looptail mouse, we generated a mouse model with a podocyte-specific ablation of the Vangl2 gene. We report here that podocyte-specific deletion of Vangl2 leads to glomerular maturation defects in fetal kidneys. In adult mice, we detected significantly smaller glomeruli, but it did not affect glomerular permselectivity in aging animals. However, in the context of glomerular injury induced by injection of antiglomerular basement membrane antibody, deletion of Vangl2 resulted in exacerbation of injury and accelerated progression to chronic segmental and global glomerular sclerosis. Our results indicate that Vangl2 function in podocytes is important for glomerular development and protects against glomerular injury in adult animals. PMID- 25145930 TI - Subclinical atherosclerosis measures for cardiovascular prediction in CKD. AB - Whether inclusion of the coronary artery calcium score improves cardiovascular risk prediction in individuals with CKD, a population with unique calcium phosphate homeostasis, is unknown. Among 6553 participants ages 45-84 years without prior cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis, coronary artery calcium score was assessed for cardiovascular risk prediction beyond the Framingham predictors in those with (n=1284) and without CKD and contrasted with carotid intima-media thickness and ankle-brachial index (two other measures of subclinical atherosclerosis). During a median follow up of 8.4 years, 650 cardiovascular events (coronary heart disease, stroke, heart failure, and peripheral artery disease) occurred (236 events in subjects with CKD). In Cox proportional hazards models adjusted for Framingham predictors, each subclinical measure was independently associated with cardiovascular outcomes, with larger adjusted hazard ratios (HRs; per 1 SD) for coronary artery calcium score than carotid intima-media thickness or ankle-brachial index in subjects without and with CKD (HR, 1.69; 95% confidence interval [95% CI], 1.45 to 1.97 versus HR, 1.12; 95% CI, 1.00 to 1.25 and HR, 1.20; 95% CI, 1.08 to 1.32, respectively). Compared with inclusion of carotid intima-media thickness or ankle brachial index, inclusion of the coronary artery calcium score led to greater increases in C statistic for predicting cardiovascular disease and net reclassification improvement. Coronary artery calcium score performed best for the prediction of coronary heart disease and heart failure, regardless of CKD status. In conclusion, each measure improved cardiovascular risk prediction in subjects with CKD, with the greatest improvement observed with coronary artery calcium score. PMID- 25145931 TI - Sphingosine 1-phosphate receptor-1 enhances mitochondrial function and reduces cisplatin-induced tubule injury. AB - Sphingosine 1-phosphate (S1P), the natural sphingolipid ligand for a family of five G protein- coupled receptors (S1P1-S1P5Rs), regulates cell survival and lymphocyte circulation. We have shown that the pan-S1PR agonist, FTY720, attenuates kidney ischemia-reperfusion injury by directly activating S1P1 on proximal tubule (PT) cells, independent of the canonical lymphopenic effects of S1P1 activation on B and T cells. FTY720 also reduces cisplatin-induced AKI. Therefore, in this study, we used conditional PT-S1P1-null (PepckCreS1pr1(fl/fl)) and control (PepckCreS1pr1(w/wt)) mice to determine whether the protective effect of FTY720 in AKI is mediated by PT-S1P1. Cisplatin induced more renal injury in PT-S1P1-null mice than in controls. Although FTY720 produced lymphopenia in both control and PT-S1P1-null mice, it reduced injury only in control mice. Furthermore, the increase in proinflammatory cytokine (CXCL1, MCP-1, TNF-alpha, and IL-6) expression and infiltration of neutrophils and macrophages induced by cisplatin treatment was attenuated by FTY720 in control mice but not in PT-S1P1 null mice. Similarly, S1P1 deletion rendered cultured PT cells more susceptible to cisplatin-induced injury, whereas S1P1 overexpression protected PT cells from injury and preserved mitochondrial function. We conclude that S1P1 may have an important role in stabilizing mitochondrial function and that FTY720 administration represents a novel strategy in the prevention of cisplatin-induced AKI. PMID- 25145932 TI - A novel missense mutation of Wilms' Tumor 1 causes autosomal dominant FSGS. AB - FSGS is a clinical disorder characterized by focal scarring of the glomerular capillary tuft, podocyte injury, and nephrotic syndrome. Although idiopathic forms of FSGS predominate, recent insights into the molecular and genetic causes of FSGS have enhanced our understanding of disease pathogenesis. Here, we report a novel missense mutation of the transcriptional regulator Wilms' Tumor 1 (WT1) as the cause of nonsyndromic, autosomal dominant FSGS in two Northern European kindreds from the United States. We performed sequential genome-wide linkage analysis and whole-exome sequencing to evaluate participants from family DUK6524. Subsequently, whole-exome sequencing and direct sequencing were performed on proband DNA from family DUK6975. We identified multiple suggestive loci on chromosomes 6, 11, and 13 in family DUK6524 and identified a segregating missense mutation (R458Q) in WT1 isoform D as the cause of FSGS in this family. The identical mutation was found in family DUK6975. The R458Q mutation was not found in 1600 control chromosomes and was predicted as damaging by in silico simulation. We depleted wt1a in zebrafish embryos and observed glomerular injury and filtration defects, both of which were rescued with wild-type but not mutant human WT1D mRNA. Finally, we explored the subcellular mechanism of the mutation in vitro. WT1(R458Q) overexpression significantly downregulated nephrin and synaptopodin expression, promoted apoptosis in HEK293 cells and impaired focal contact formation in podocytes. Taken together, these data suggest that the WT1(R458Q) mutation alters the regulation of podocyte homeostasis and causes nonsyndromic FSGS. PMID- 25145933 TI - Inactivation of integrin-beta1 prevents the development of polycystic kidney disease after the loss of polycystin-1. AB - Dysregulation of polycystin-1 (PC1) leads to autosomal dominant polycystic kidney disease (ADPKD), a disorder characterized by the formation of multiple bilateral renal cysts, the progressive accumulation of extracellular matrix (ECM), and the development of tubulointerstitial fibrosis. Correspondingly, cystic epithelia express higher levels of integrins (ECM receptors that control various cellular responses, such as cell proliferation, migration, and survival) that are characteristically altered in cystic cells. To determine whether the altered expression of ECM and integrins could establish a pathologic autostimulatory loop, we tested the role of integrin-beta1 in vitro and on the cystic development of ADPKD in vivo. Compared with wild-type cells, PC1-depleted immortalized renal collecting duct cells had higher levels of integrin-beta1 and fibronectin and displayed increased integrin-mediated signaling in the presence of Mn(2+). In mice, conditional inactivation of integrin-beta1 in collecting ducts resulted in a dramatic inhibition of Pkd1-dependent cystogenesis with a concomitant suppression of fibrosis and preservation of normal renal function. Our data provide genetic evidence that a functional integrin-beta1 is required for the early events leading to renal cystogenesis in ADPKD and suggest that the integrin signaling pathway may be an effective therapeutic target for slowing disease progression. PMID- 25145935 TI - WNK1 activates large-conductance Ca2+-activated K+ channels through modulation of ERK1/2 signaling. AB - With no lysine (WNK) kinases are members of the serine/threonine kinase family. We previously showed that WNK4 inhibits renal large-conductance Ca(2+)-activated K(+) (BK) channel activity by enhancing its degradation through a lysosomal pathway. In this study, we investigated the effect of WNK1 on BK channel activity. In HEK293 cells stably expressing the alpha subunit of BK (HEK-BKalpha cells), siRNA-mediated knockdown of WNK1 expression significantly inhibited both BKalpha channel activity and open probability. Knockdown of WNK1 expression also significantly inhibited BKalpha protein expression and increased ERK1/2 phosphorylation, whereas overexpression of WNK1 significantly enhanced BKalpha expression and decreased ERK1/2 phosphorylation in a dose-dependent manner in HEK293 cells. Knockdown of ERK1/2 prevented WNK1 siRNA-mediated inhibition of BKalpha expression. Similarly, pretreatment of HEK-BKalpha cells with the lysosomal inhibitor bafilomycin A1 reversed the inhibitory effects of WNK1 siRNA on BKalpha expression in a dose-dependent manner. Knockdown of WNK1 expression also increased the ubiquitination of BKalpha channels. Notably, mice fed a high K(+) diet for 10 days had significantly higher renal protein expression levels of BKalpha and WNK1 and lower levels of ERK1/2 phosphorylation compared with mice fed a normal-K(+) diet. These data suggest that WNK1 enhances BK channel function by reducing ERK1/2 signaling-mediated lysosomal degradation of the channel. PMID- 25145934 TI - MicroRNA-21 in glomerular injury. AB - TGF-beta(1) is a pleotropic growth factor that mediates glomerulosclerosis and podocyte apoptosis, hallmarks of glomerular diseases. The expression of microRNA 21 (miR-21) is regulated by TGF-beta(1), and miR-21 inhibits apoptosis in cancer cells. TGF-beta(1)-transgenic mice exhibit accelerated podocyte loss and glomerulosclerosis. We determined that miR-21 expression increases rapidly in cultured murine podocytes after exposure to TGF-beta(1) and is higher in kidneys of TGF-beta(1)-transgenic mice than wild-type mice. miR-21-deficient TGF-beta(1) transgenic mice showed increased proteinuria and glomerular extracellular matrix deposition and fewer podocytes per glomerular tuft compared with miR-21 wild-type TGF-beta(1)-transgenic littermates. Similarly, miR-21 expression was increased in streptozotocin-induced diabetic mice, and loss of miR-21 in these mice was associated with increased albuminuria, podocyte depletion, and mesangial expansion. In cultured podocytes, inhibition of miR-21 was accompanied by increases in the rate of cell death, TGF-beta/Smad3-signaling activity, and expression of known proapoptotic miR-21 target genes p53, Pdcd4, Smad7, Tgfbr2, and Timp3. In American-Indian patients with diabetic nephropathy (n=48), albumin to-creatinine ratio was positively associated with miR-21 expression in glomerular fractions (r=0.6; P<0.001) but not tubulointerstitial fractions (P=0.80). These findings suggest that miR-21 ameliorates TGF-beta(1) and hyperglycemia-induced glomerular injury through repression of proapoptotic signals, thereby inhibiting podocyte loss. This finding is in contrast to observations in murine models of tubulointerstitial kidney injury but consistent with findings in cancer models. The aggravation of glomerular disease in miR-21 deficient mice and the positive association with albumin-to-creatinine ratio in patients with diabetic nephropathy support miR-21 as a feedback inhibitor of TGF beta signaling and functions. PMID- 25145938 TI - Safer obstetric anesthesia through education and mentorship: a model for knowledge translation in Rwanda. AB - High rates of maternal mortality remain a widespread problem in the developing world. Skilled anesthesia providers are required for the safe conduct of Cesarean delivery and resuscitation during obstetrical crises. Few anesthesia providers in low-resource settings have access to continuing education. In Rwanda, anesthesia technicians with only three years of post-secondary training must manage complex maternal emergencies in geographically isolated areas. The purpose of this special article is to describe implementation of the SAFE (Safer Anesthesia From Education) Obstetric Anesthesia course in Rwanda, a three-day refresher course designed to improve obstetrical anesthesia knowledge and skills for practitioners in low-resource areas. In addition, we describe how the course facilitated the knowledge-to-action (KTA) cycle whereby a series of steps are followed to promote the uptake of new knowledge into clinical practice. The KTA cycle requires locally relevant teaching interventions and continuation of knowledge post intervention. In Rwanda, this meant carefully considering educational needs, revising curricula to suit the local context, employing active experiential learning during the SAFE Obstetric Anesthesia course, encouraging supportive relationships with peers and mentors, and using participant action plans for change, post-course logbooks, and follow-up interviews with participants six months after the course. During those interviews, participants reported improvements in clinical practice and greater confidence in coordinating team activities. Anesthesia safety remains challenged by resource limitations and resistance to change by health care providers who did not attend the course. Future teaching interventions will address the need for team training. PMID- 25145939 TI - Sagittal computed tomography angiogram of the abdomen with contrast. PMID- 25145937 TI - Platelets in early antibody-mediated rejection of renal transplants. AB - Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses. PMID- 25145940 TI - Ill communication: what's wrong with the medical literature and how to fix it. AB - Current conventions for the writing of medical scientific papers impede clear communication of scientific research results. This article discusses the reasons for this and how to ameliorate them. PMID- 25145941 TI - What do mind readers know and what do we know about mind readers? AB - In this commentary, I raise various questions about Kim and Harris's fascinating findings. I ask what kind of knowledge children expect telepathic individuals to have, who children might consider to be good mind readers, why children value telepathy, and how puzzled children are by telepathy. I suggest potential ways to address some of these questions and end by reiterating the importance of probing individual differences in scepticism and credulity. PMID- 25145942 TI - Accountable care organizations in the USA: types, developments and challenges. AB - A historically fragmented U.S. health care system, where care has been delivered by multiple providers with little or no coordination, has led to increasing issues with access, cost, and quality. The Affordable Care Act included provisions to use Medicare, the U.S. near universal public coverage program for older adults, to broadly implement Accountable Care Organization (ACO) models with a triple aim of improving the experience of care, the health of populations, and reducing per capita costs. Private payers in the U.S. are also embracing ACO models. Various European countries are experimenting with similar reforms, particularly those in which coordinated (or integrated) care from a network of providers is reimbursed with bundled payments and/or shared savings. The challenges for these reforms remain formidable and include: (1) overcoming incentives for ACOs to engage in rationing and denial of care and taking on too much financial risk, (2) collecting meaningful data that capture quality and enable rewarding quality improvement and not just volume reduction, (3) creating incentives for ACOs that do not accept much risk to engage in prevention and health promotion, and (4) creating effective governance and IT structures that are patient-centered and integrate care. PMID- 25145936 TI - Urinary tract effects of HPSE2 mutations. AB - Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 non-neurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant. Homozygous Hpse2 mutant mouse bladders contained urine more often than did wild-type organs, phenocopying human UFS. Pelvic ganglia neural cell bodies contained heparanase 1, heparanase 2, and leucine-rich repeats and immunoglobulin like domains-2 (LRIG2), which is mutated in certain UFS families. In conclusion, heparanase 2 is an autonomic neural protein implicated in bladder emptying, but HPSE2 variants are uncommon in urinary diseases resembling UFS. PMID- 25145943 TI - Depression and anxiety symptoms in male veterans and non-veterans: the Health and Retirement Study. AB - OBJECTIVES: We examined whether veteran status was associated with elevated depression and anxiety symptoms in men aged 50 and older after adjusting for sociodemographic factors. METHODS: Participants were 6577 men aged 50 years and older who completed the 2006 wave of the Health and Retirement Study (HRS). Forty nine percent of participants were veterans. A randomly selected subset of participants completed the HRS Psychosocial Questionnaire (N = 2957), which contained the anxiety items. Elevated depression and anxiety symptoms were determined based on brief versions of Center for Epidemiologic Studies- Depression Scale (CES-D total score >= 4) and Beck Anxiety Inventory (BAI total score >= 12). RESULTS: Elevated depression and anxiety symptoms were found in 11.0 and 9.9% of veterans, respectively, compared with 12.8 and 12.3% of non veterans. Veteran status was not associated with increased odds of anxiety or depression symptoms in the multivariable-adjusted logistic regression analyses. Additional analyses indicated that Vietnam War veterans were more than twice as likely as World War II or Korean War veterans to have elevated depression symptoms (OR = 2.15, 95% CI: 1.54-3.00) or anxiety symptoms (OR = 2.12, 95% CI: 1.28-3.51). CONCLUSIONS: In a community-based sample of men aged 50 and older, veteran status was not associated with the presence of elevated depression and anxiety symptoms. Rather, these symptoms were associated with age, ethnicity, education, and medical conditions. Among veterans, cohort effects accounted for differences in psychiatric symptoms. Including younger cohorts from the Global War on Terror may yield different results in future studies. PMID- 25145944 TI - Pectoralis major transfer for treatment of irreparable subscapularis tear: a systematic review. AB - PURPOSE: Irreparable ruptures of the subscapularis tendon lead to impaired function of the shoulder and presents a surgically complex problem. Transfer of the pectoralis major tendon has been reported as a possible treatment option. The purpose of this systematic review is to critically examine the outcomes of pectoralis major transfers for the treatment of irreparable subscapularis tears. METHODS: A systematic review of the literature was performed using search of electronic databases. No language restrictions were applied. Case reports, review articles, and operative techniques without outcome data were excluded. All the outcomes reported by each study were analyzed and when possible, data were pooled to generate frequency-weighted values to summarize outcomes. RESULTS: Eight studies with a total 195 shoulders were included in this systematic review. The mean age of patients was 58.8 years (range 18-81 years) and the mean follow-up was 33.4 months (range 6-80 months). Constant scores improved from a mean pre operative score of 37.8 +/- 6.8, to a mean postoperative score of 61.3 +/- 6.5 (p < 0.0001). Pain scores could not be pooled as different scales were used. Nevertheless, a trend in pain reduction was noted in all papers. Functional outcomes were less favorable in patients with massive rotator cuff tears or previous shoulder replacements. Moreover, the Constant scores were significantly higher in patients following subcoracoid transfer of the pectoralis major tendon compared to patients who received supracoracoid transfer (p < 0.001). The overall reported incidence of postoperative nerve palsy is low (one transient musculocutaneous nerve palsy and one axillary nerve dysfunction out of 195 cases). CONCLUSIONS: The systematic review based on frequency-weighted means demonstrated improvement in shoulder function, strength and pain relief after pectoralis major transfer for irreparable subscapularis tear. LEVEL OF EVIDENCE: IV. PMID- 25145945 TI - Long-term outcome after arthroscopic rotator cuff treatment. AB - PURPOSE: Arthroscopic techniques have become the gold standard in the operative management of several pathologic conditions of the shoulder. The purpose of this systematic review was to present the long-term outcomes following arthroscopic treatment of rotator cuff pathology. METHODS: A comprehensive literature review was performed to identify studies reporting clinical or structural results of arthroscopic rotator cuff repairs (ARCRs) at least 5 years after surgery. RESULTS: Ten articles were selected, which described 483 procedures. Study type, surgical approaches, complications, evidences of structural integrity of the repaired lesions, preoperative and postoperative functional scores are identified, analyzed and discussed. Satisfactory results are presented by all authors, and significant postoperative improvement is reported by all the studies with available preoperative data; 16 of 483 cases were re-operated. CONCLUSION: Although high-level evidences are lacking, ARCR appears to be an effective and safe option to treat the symptoms of rotator cuff tears and to provide successful clinical results durable with time. Current evidences are insufficient to clearly define the relationship between structural integrity of repaired cuffs and long term clinical outcome. The available data do not allow to draw conclusions regarding the long-term superiority of double-row versus single-row repairs. LEVEL OF EVIDENCE: Review of level II, III and IV studies, Level IV. PMID- 25145948 TI - Micronuclei and nuclear budding in chronic lymphocytic leukaemia. PMID- 25145947 TI - Quantification of functional brace forces for posterior cruciate ligament injuries on the knee joint: an in vivo investigation. AB - PURPOSE: Counteracting posterior translation of the tibia with an anterior force on the posterior proximal tibia has been demonstrated clinically to improve posterior knee laxity following posterior cruciate ligament (PCL) injury. This study quantified forces applied to the posterior proximal tibia by two knee braces designed for treatment of PCL injuries. METHODS: The forces applied by two knee braces to the posterior proximal tibia and in vivo three-dimensional knee kinematics of six adult, male, healthy volunteer subjects (mean +/- standard deviation: height, 182.5 +/- 5.2 cm; body mass, 83.2 +/- 9.3 kg; body mass index, 24.9 +/- 1.5 kg/m(2); age, 25.8 +/- 2.9 years) were measured using a custom pressure mapping technique and traditional surface marker motion capture techniques, while subjects performed three functional activities. The activities included seated unloaded knee flexion, squatting, and stair descent in a new generation dynamic force (DF) PCL brace and a static force (SF) PCL brace. RESULTS: During unloaded flexion at the lowest force level setting, the force applied by the DF brace increased as a function of flexion angle (slope = 0.7 N/ degrees ; p < 0.001) compared to the SF brace effect. Force applied by the SF brace did not significantly change as a function of flexion angle (slope = 0.0 N/ degrees ; n.s.). By 45 degrees of flexion, the average force applied by the DF brace (48.1 N) was significantly larger (p < 0.001) than the average force applied by the SF brace (25.0 N). The difference in force continued to increase as flexion angle increased. During stair descent, average force (mean +/- standard deviation) at toe off was significantly higher (p = 0.013) for the DF brace (78.7 +/- 21.6 N) than the SF brace (37.3 +/- 7.2 N). Similar trends were observed for squatting and for the higher force level settings. CONCLUSIONS: The DF brace applied forces to the posterior proximal tibia that dynamically increased with increased flexion angle. Additionally, the DF brace applied significantly larger forces at higher flexion angles compared to the SF brace where the PCL is known to experience larger in situ forces. Clinical studies are necessary to determine whether the loading characteristics of the DF brace, which more closely replicated the in situ loading profile of the native PCL, results in long-term improved posterior knee laxity following PCL injury. LEVEL OF EVIDENCE: II. PMID- 25145949 TI - In appreciation of Albert Z. Kapikian. PMID- 25145946 TI - Effect of patellar thickness on early results of total knee replacement with patellar resurfacing. AB - PURPOSE: Patellar thickness is a concern in total knee replacement with patellar resurfacing because of the risk of patellar fracture or implant loosening. The aim of this study was to evaluate if patellar thickness is related to clinical outcome in the absence of patellar fracture or implant loosening. METHODS: Early results of 169 patients who underwent total knee replacement with patellar resurfacing were reviewed to assess the effect of patellar thickness on clinical outcome. The mean follow-up was 13 months. The range of motion, Knee Society Score, Function Score and WOMAC Score were assessed preoperatively, at day 0, 6 months and 1 year. Radiographs were assessed for patellar fracture or implant loosening. RESULTS: Thirty-one percent of all patients had preoperative thickness <21 mm. Seven percent had <12 mm residual thickness after patellar cut, all were female. Twenty-three percent had >=1 mm increase of thickness after surgery. Radiographs did not show any patellar fracture or implant loosening. However, preoperative patellar thickness <21 mm had poorer gain in range of motion at 1 year. Preoperative range of motion had greater influence on postoperative range of motion than preoperative patellar thickness. Residual thickness <12 mm had lower gain in WOMAC score at 1 year and an increase in thickness >=1 mm postoperatively was associated with lower gain in WOMAC score at 6 months. CONCLUSIONS: Early results of patellar resurfacing with preoperative thickness <21 mm or residual thickness <12 mm were found to be inferior even in the absence of patellar fracture or implant loosening. Conservative cutting resulting in 1 mm increase in thickness was also found to have inferior clinical results. LEVEL OF EVIDENCE: II. PMID- 25145951 TI - Rotigotine transdermal system: developing continuous dopaminergic delivery to treat Parkinson's disease and restless legs syndrome. AB - Rotigotine is a nonergoline dopamine receptor agonist with structural similarity to dopamine. Rotigotine binds to the D1 through D5 dopamine receptors, having several times more affinity than dopamine does to the D2 and D3 receptors. Although rotigotine was demonstrated to restore locomotor activity in animal models of Parkinson's disease (PD), the rapid metabolism of rotigotine limited the development of an orally administered formulation. Rotigotine's high lipid solubility and extended duration of action when applied to the skin in experimental models of PD suggested that rotigotine was a candidate for transdermal application. The constant transdermal delivery of rotigotine over 24 h is hypothesized to approximate continuous agonist-receptor stimulation, which conceptually more closely mimics physiologic striatal dopamine receptor function. Randomized clinical studies have demonstrated rotigotine's efficacy, safety, and tolerability in patients with early- and advanced-stage PD, including improvements in motor symptoms and off-time. Although the etiology is unknown, restless legs syndrome (RLS) is thought to involve dopaminergic dysregulation. Randomized clinical studies also have demonstrated the efficacy of rotigotine in improving the symptoms of moderate-to-severe primary RLS. This review examines rotigotine's developmental history for transdermal administration leading to its approval for the treatment of early- and advanced-stage PD and moderate-to-severe primary RLS. PMID- 25145952 TI - Mapping intermolecular bonding in C60. AB - The formation of intermolecular bonds in C60 has been investigated in detail at pressures below 2.2 GPa and up to 750 K. Fullerene samples were heated in a temperature gradient to obtain data on the formation of dimers and low dimensional polymers along isobars. Intermolecular bonding was analyzed ex situ by Raman scattering, using both intramolecular modes and intermolecular stretching modes. Semi-quantitative reaction maps are given for the formation of dimers and chains. The activation energy for dimer formation decreases by 0.2 meV pm(-1) when intermolecular distances decrease and dimer formation is noticeably affected by the rotational state of molecules. Above 400-450 K larger oligomers are formed; below 1.4 GPa most of these are disordered, with small domains of linear chains, but above this the appearance of stretching modes indicates the existence of ordered one-dimensional polymers. At the highest pressures and temperatures two-dimensional polymers are also observed. PMID- 25145953 TI - Illusions and cloaks for surface waves. AB - Ever since the inception of Transformation Optics (TO), new and exciting ideas have been proposed in the field of electromagnetics and the theory has been modified to work in such fields as acoustics and thermodynamics. The most well known application of this theory is to cloaking, but another equally intriguing application of TO is the idea of an illusion device. Here, we propose a general method to transform electromagnetic waves between two arbitrary surfaces. This allows a flat surface to reproduce the scattering behaviour of a curved surface and vice versa, thereby giving rise to perfect optical illusion and cloaking devices, respectively. The performance of the proposed devices is simulated using thin effective media with engineered material properties. The scattering of the curved surface is shown to be reproduced by its flat analogue (for illusions) and vice versa for cloaks. PMID- 25145954 TI - Reconstruction of cell-electrode-adjacencies on multielectrode arrays. AB - The multichannel recordings of signals of many cells cultivated on a multielectrode array (MEA) impose some challenging problems. A meanwhile classic problem is the separation of the recordings of a single electrode into classes of recordings where each class is caused by a single cell. This is the well-known spike sorting. A "dual" problem is the determination of the set of electrodes that record signals of a single cell. This set is called the neighborhood of the cell and has often more than one element if the MEA has a large number of electrodes with high density. A method for the reconstruction of the neighborhoods from the multichannel recordings is presented. Special effort is directed to a precise peak detection. For the evaluation of the algorithm, artificial data, obtained from an appropriate model of MEA recordings, are used. Because the artificial data provide a ground truth, an evaluation of the accuracy of the algorithm is possible. The algorithm works well for realistic parameters. PMID- 25145955 TI - Switching neuronal state: optimal stimuli revealed using a stochastically-seeded gradient algorithm. AB - Inducing a switch in neuronal state using energy optimal stimuli is relevant to a variety of problems in neuroscience. Analytical techniques from optimal control theory can identify such stimuli; however, solutions to the optimization problem using indirect variational approaches can be elusive in models that describe neuronal behavior. Here we develop and apply a direct gradient-based optimization algorithm to find stimulus waveforms that elicit a change in neuronal state while minimizing energy usage. We analyze standard models of neuronal behavior, the Hodgkin-Huxley and FitzHugh-Nagumo models, to show that the gradient-based algorithm: (1) enables automated exploration of a wide solution space, using stochastically generated initial waveforms that converge to multiple locally optimal solutions; and (2) finds optimal stimulus waveforms that achieve a physiological outcome condition, without a priori knowledge of the optimal terminal condition of all state variables. Analysis of biological systems using stochastically-seeded gradient methods can reveal salient dynamical mechanisms underlying the optimal control of system behavior. The gradient algorithm may also have practical applications in future work, for example, finding energy optimal waveforms for therapeutic neural stimulation that minimizes power usage and diminishes off-target effects and damage to neighboring tissue. PMID- 25145956 TI - Fetoplacental vascular alterations associated with fetal growth restriction. AB - INTRODUCTION: Placental functional impairment in pregnancies with fetal growth restriction (FGR) can arise from fetoplacental vascular abnormalities. We aimed to compare the micro and macrovasculature of placentas from normal pregnancies with those showing late onset FGR. METHODS: Placental arterial casts (n = 12 normal, 6 FGR) were prepared. Chorionic arterial number and inter-branch length were examined. Microvascular features were quantified in CD34-stained tissue sections obtained by systematic (n = 12 normal, 12 FGR) and targeted (n = 6 normal, 6 FGR) sampling from the placental periphery and centre. RESULTS: Adjusted for the weight of the placenta or the surface area of the chorionic plate, the number of chorionic arteries was similar in normal and FGR arterial casts. Inter-branch length per unit placental weight was greater in the first generation of arterial branches in FGR (p < 0.05). Villi in FGR placentas were more poorly vascularised, particularly at the periphery and in grossly visible hypovascular regions. Intermediate and terminal FGR villi in these areas exhibited reduced vessel lumens, loss of CD34, and infilling with CD34-negative cells of what appeared to be previously existing vascular spaces. CONCLUSION: Differences in chorionic arterial branching patterns between normal and FGR placentas arise from differences in placental size. FGR placentas show microvascular regression and extreme hypovascularity in peripheral areas. These features may well limit the ability of the placenta to meet fetal nutrient requirements late in gestation. Targeted sampling is more effective than systematic random sampling in revealing vascular defects. PMID- 25145957 TI - Reduced CD200 and CD200R1 expression in human chorionic villi contributes to early spontaneous abortion. AB - OBJECTIVE: To examine the expression of CD200 and its receptor (CD200R) in human chorionic villi during the first trimester of normal pregnancy and early spontaneous abortion (ESA). DESIGN: Prospective study. METHODS: Expression of CD200 and CD200R in the chorionic villi was determined using streptavidin peroxidase immunohistochemistry, confocal laser scanning microscopy and real-time polymerase chain reaction. POPULATION: Thirty-five women diagnosed with ESA and 30 women experiencing a healthy pregnancy in a medical university hospital in China were enrolled in this study between 2011 and 2013. MAIN OUTCOME MEASURES: CD200 and CD200R expression. RESULTS: The expression of CD200 in syncytiotrophoblast cells was significantly higher during normal pregnancy than in ESA (0.51 +/- 0.05 vs. 0.35 +/- 0.05). In contrast, expression of CD200 in cytotrophoblast cells and CD200R in stromal cells was significantly lower during normal pregnancy when compared with ESA (CD200: 0.16 +/- 0.02 vs. 0.32 +/- 0.03; CD200R: 0.19 +/- 0.03 vs. 0.22 +/- 0.02). In villi, the expression of both CD200 protein and CD200R transcripts were significantly higher in healthy first trimester pregnancy than in ESA (CD200: 156.89 +/- 105.65 vs. 37.51 +/- 17.62). CONCLUSIONS: There is an increase in inhibitory properties of human chorionic villi during normal pregnancy. The mechanism underlying ESA might be associated with enhanced expression of CD200 and CD200R in the trophoblast, leading to an upregulation of the immune response during the first trimester of pregnancy. PMID- 25145958 TI - Facile C-H bond formation by reductive elimination at a dinuclear metal site. AB - The electronically unsaturated dirhenium complex [Re2(CO)8(u-AuPPh3)(u-Ph)] (1) was obtained from the reaction of [Re2(CO)8{u-eta(2)-C(H)=C(H)nBu}(u-H)] with [Au(PPh3)Ph]. The bridging {AuPPh3} group was replaced by a bridging hydrido ligand to yield the unsaturated dirhenium complex [Re2(CO)8(u-H)(u-Ph)] (2) by reaction of 1 with HSnPh3. Compound 2 reductively eliminates benzene upon addition of NCMe at 25 degrees C. The electronic structure of 2 and the mechanism of the reductive elimination of the benzene molecule in its reaction with NCMe were investigated by DFT computational analyses. PMID- 25145959 TI - Photophysical properties of ruthenium(II) polypyridyl DNA intercalators: effects of the molecular surroundings investigated by theory. AB - The environmental effects on the structural and photophysical properties of [Ru(L)2 (dppz)](2+) complexes (L=bpy=2,2'-bipyridine, phen=1,10-phenanthroline, tap=1,4,5,8-tetraazaphenanthrene; dppz=dipyrido[3,3-a:2',3'-c]phenazine), used as DNA intercalators, have been studied by means of DFT, time-dependent DFT, and quantum mechanics/molecular mechanics calculations. The electronic characteristics of the low-lying triplet excited states in water, acetonitrile, and DNA have been investigated to decipher the influence of the environment on the luminescent behavior of this class of molecules. The lowest triplet intra ligand (IL) excited state calculated at lambda~800 nm for the three complexes and localized on the dppz ligand is not very sensitive to the environment and is available for electron transfer from a guanine nucleobase. Whereas the lowest triplet metal-to-ligand charge-transfer ((3)MLCT) states remain localized on the ancillary ligand (tap) in [Ru(tap)2 (dppz)](2+), regardless of the environment, their character is drastically modified in the other complexes [Ru(phen)2 (dppz)](2+) and [Ru(bpy)2 (dppz)](2+) upon going from acetonitrile (MLCTdppz/phen or MLCTdppz/bpy) to water (MLCTdppz) and DNA (MLCTphen and MLCTbpy). The change in the character of the low-lying (3) MLCT states accompanying nuclear relaxation in the excited state controls the emissive properties of the complexes in water, acetonitrile, and DNA. The light-switching effect has been rationalized on the basis of environment-induced control of the electronic density distributed in the lowest triplet excited states. PMID- 25145960 TI - Macrocyclic olefin metathesis at high concentrations by using a phase-separation strategy. AB - Macrocyclic olefin metathesis has seen advances in the areas of stereochemistry, chemoselectivity, and catalyst stability, but strategies aimed at controlling dilution effects in macrocyclizations are rare. Herein, a protocol to promote macrocyclic olefin metathesis, one of the most common synthetic tools used to prepare macrocycles, at relatively high concentrations (up to 60 mM) is described by exploitation of a phase-separation strategy. A variety of macrocyclic skeletons could be prepared having either different alkyl, aryl, or amino acids spacers. PMID- 25145961 TI - Anti-ice coating inspired by ice skating. AB - Accumulation of ice to surfaces brings dangerous and costly problems to our daily life. In this paper, an anti-ice coating inspired by ice skating is reported. Hyaluronic acid is used in the anti-ice coating to form aqueous lubricating layer benefitting from its high water absorbing property. Dopamine, the main component of the mussel adhesive protein, is introduced to anchor the hyaluronic acid to the solid surfaces to render the coating applicable to all types of solid surfaces. At the same time it serves as the crosslinking agent for hyaluronic acid, thus the thickness of the water collecting film could be easily varied. Ice adhesion strength on surfaces coated with such kind of coating could be more than one order of magnitude lower than that of uncoated ones. The results indicate that this anti-ice coating with the aqueous lubricating layer has great potential for fighting against icing problems. PMID- 25145963 TI - The presence of an audience modulates responses to familiar call stimuli in the male zebra finch forebrain. AB - The ability to recognize familiar individuals is crucial for establishing social relationships. The zebra finch, a highly social songbird species that forms lifelong pair bonds, uses a vocalization, the distance call, to identify its mate. However, in males, this ability depends on social conditions, requiring the presence of an audience. To evaluate whether the presence of bystanders modulates the auditory processing underlying recognition abilities, we assessed, by using a lightweight telemetry system, whether electrophysiological responses driven by familiar and unfamiliar female calls in a high-level auditory area [the caudomedial nidopallium (NCM)] were modulated by the presence of conspecific males. Males had experienced the call of their mate for several months and the call of a familiar female for several days. When they were exposed to female calls in the presence of two male conspecifics, NCM neurons showed greater responses to the playback of familiar female calls, including the mate's call, than to unfamiliar ones. In contrast, no such discrimination was observed in males when they were alone or when call-evoked responses were collected under anaesthesia. Together, these results suggest that NCM neuronal activity is profoundly influenced by social conditions, providing new evidence that the properties of NCM neurons are not simply determined by the acoustic structure of auditory stimuli. They also show that neurons in the NCM form part of a network that can be shaped by experience and that probably plays an important role in the emergence of communication sound recognition. PMID- 25145962 TI - Role of laparoscopy in patients with peritoneal metastases considered for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). AB - BACKGROUND: We hypothesized that diagnostic laparoscopy (DL) was feasible for the evaluation of patients with peritoneal carcinomatosis (PC) undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). METHODS: A retrospective review of PC patients treated from January 2010 to April 2013 was conducted. Data on tumor characteristics, treatment details and survival outcomes were extracted and analyzed. RESULTS: Of the 101 PC patients (mean age 52.9 +/- 14.1 years), 73 diagnostic laparoscopies DL (61 concurrent with CRS + HIPEC) were performed in 70 patients whereas 31 patients underwent direct exploratory laparotomy (EL). Complete laparoscopic assessment was possible in 63 cases (86.3%), resulting in 18 exclusions (27.7%) while 10 cases were converted to open due to inadequate laparoscopic visualization. Subsequently, CRS + HIPEC was performed in 85.4% (of 55 selected for HIPEC, DL) versus 74.2% (EL, P value = 0.20). Among those excluded from HIPEC at the initial operation, delayed HIPEC after conversion chemotherapy was achieved in 6 (of 11 with extensive disease, DL). The incidence of grade 3 to 5 complications was 0% DL versus 10% EL (P value = 0.2). There were no port site recurrences at mean follow up of 9.1 +/- 8 months. CONCLUSIONS: Laparoscopy is a feasible technique for selecting patients with PC for CRS + HIPEC, and can help select patients for conversion chemotherapy in the setting of high peritoneal carcinomatosis index (PCI) score. PMID- 25145964 TI - DNA vaccines against tuberculosis. AB - INTRODUCTION: Tuberculosis (TB) remains a major health problem and novel vaccination regimens are urgently needed. AREAS COVERED: DNA vaccines against TB have been tested in various preclinical models and strategies have been developed to increase their immunogenicity in large animal species. DNA vaccines are able to induce a wide variety of immune responses, including CD8(+) T-cell-mediated cytolytic and IFN-gamma responses. DNA vaccination may be valuable in heterologous prime-boost strategies with the currently used bacillus Calmette Guerin (BCG) vaccine. This approach could broaden the antigenic repertoire of BCG and enhance its weak induction of MHC class I-restricted immune responses. EXPERT OPINION: DNA vaccines offer a number of advantages over certain other types of vaccines, such as the induction of robust MHC class I-restricted cytotoxic T lymphocyte (CTL), their generic manufacturing platform and their relatively low manufacturing costs. Because of their strong potential for inducing memory responses, DNA vaccines are particularly suited for priming immune responses. Furthermore, DNA vaccine technology may help antigen discovery by facilitating screening of candidate vaccines. Co-administration of BCG with plasmid DNA coding for immunodominant, subdominant and phase-specific antigens, poorly expressed by BCG, may lead to the development of improved TB vaccines. PMID- 25145967 TI - Controlled dynamic helicity of a folded macrocycle based on a bisterephthalamide with a twofold Z-shaped structure. AB - Dynamic helicity in a folded macrocycle and control of the helical preference are described. We designed macrocycle 1 with a dual mode of folding through the integration of two flexible units that are arranged twice to form a cyclic structure. As a folding unit, we used a terephthalamide skeleton and a Z-shaped hydrocarbon: the former acted as a control unit to induce a preference of a particular sense of dynamic helicity and the latter was just a spacer. A terephthalamide unit provided a binding site for capturing a ditopic hydrogen bonding guest when it adopted helically folded syn forms (M/P). Thus, only the terephthalamide unit controlled the helical sense of dynamic helicity in a folded macrocycle through the supramolecular transmission of chirality upon complexation with a chiral ditopic guest. In addition, chirality on a host could also contribute to the control of the helical preference in a folded macrocycle, which led to exceptionally enhanced chiroptical signals. PMID- 25145965 TI - Human brain imaging of alpha7 nAChR with [(18)F]ASEM: a new PET radiotracer for neuropsychiatry and determination of drug occupancy. AB - PURPOSE: Using the alpha7-nAChR radiotracer, [(18)F]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed alpha7-nAChR drugs confirms the specificity of the radiotracer. PROCEDURES: Five healthy male subjects were imaged for 90 min following IV [(18)F]ASEM. Two subjects were scanned for the second time (test/retest; TRV). Mouse biodistribution of [(18)F]ASEM was carried out in CD1 mice injected with using human equivalent doses of DMXB-A, EVP-6124, and varenicline to block specific binding. RESULTS: [(18)F]ASEM readily entered the brain and peaked at 15 min post-injection with reversible kinetics and a peak %SUV of about 400 %. The regional human brain distribution of [(18)F]ASEM matched previous in vitro data and baboon PET results. The precuneus, parietal, occipital, cingulate cortexes, putamen, and thalamus showed high values of distribution volume (>20 ml/ml) and binding potentials >1 with TRV averaged 10.8 +/- 5.1 %. In mouse distribution studies, there was significant dose-dependent blockade in the mouse brain with DMXB-A as well as the other two alpha7-nAChR drugs. CONCLUSIONS: The characteristics of [(18)F]ASEM are consistent with the ability to quantify alpha7-nAChR in the human brain. [(18)F]ASEM is suitable for imaging neuropsychiatric disorders and target engagement (receptor occupancy) of potential alpha7-nAChR drugs. PMID- 25145969 TI - Reconstruction of 3-dimensional histology volume and its application to study mouse mammary glands. AB - Histology volume reconstruction facilitates the study of 3D shape and volume change of an organ at the level of macrostructures made up of cells. It can also be used to investigate and validate novel techniques and algorithms in volumetric medical imaging and therapies. Creating 3D high-resolution atlases of different organs(1,2,3) is another application of histology volume reconstruction. This provides a resource for investigating tissue structures and the spatial relationship between various cellular features. We present an image registration approach for histology volume reconstruction, which uses a set of optical blockface images. The reconstructed histology volume represents a reliable shape of the processed specimen with no propagated post-processing registration error. The Hematoxylin and Eosin (H&E) stained sections of two mouse mammary glands were registered to their corresponding blockface images using boundary points extracted from the edges of the specimen in histology and blockface images. The accuracy of the registration was visually evaluated. The alignment of the macrostructures of the mammary glands was also visually assessed at high resolution. This study delineates the different steps of this image registration pipeline, ranging from excision of the mammary gland through to 3D histology volume reconstruction. While 2D histology images reveal the structural differences between pairs of sections, 3D histology volume provides the ability to visualize the differences in shape and volume of the mammary glands. PMID- 25145966 TI - Patient-specific dosimetry using pretherapy [124I]m-iodobenzylguanidine ([124I]mIBG) dynamic PET/CT imaging before [131I]mIBG targeted radionuclide therapy for neuroblastoma. AB - PURPOSE: Iodine-131-m-iodobenzylguanidine ([(131)I]mIBG)-targeted radionuclide therapy (TRT) is a standard treatment for recurrent or refractory neuroblastoma with response rates of 30-40 %. The aim of this study is to demonstrate patient specific dosimetry using quantitative [(124)I]mIBG positron emission tomography/X ray computed tomography (PET/CT) imaging with a GEometry ANd Tracking 4 (Geant4) based Monte Carlo method for better treatment planning. PROCEDURES: A Monte Carlo dosimetry method was developed using the Geant4 toolkit with voxelized anatomical geometry and source distribution as input. The presegmented hybrid computational human phantoms developed by the University of Florida and the National Cancer Institute (UF/NCI) were used as a surrogate to characterize the anatomy of a given patient. S values for I-131 were estimated by the phantoms coupled with Geant4 and compared with those estimated by OLINDA|EXM and MCNPX for the newborn model. To obtain patient-specific biodistribution of [(131)I]mIBG, a 10-year-old girl with relapsed neuroblastoma was imaged with [(124)I]mIBG PET/CT at four time points prior to the planned [(131)I]mIBG TRT. The organ- and tumor-absorbed doses of the clinical case were estimated with the Geant4 method using the modified UF/NCI 10-year-old phantom with tumors and the patient-specific residence time. RESULTS: For the newborn model, the Geant4 S values were consistent with the MCNPX S values. The S value ratio of the Geant4 method to OLINDA|EXM ranged from 0.08 to 6.5 of all major organs. The [(131)I]mIBG residence time quantified from the pretherapy [(124)I]mIBG PET/CT imaging of the 10-year-old patient was mostly comparable to those previously reported. Organ-absorbed dose for the salivary glands was 98.0 Gy, heart wall 36.5 Gy, and liver 34.3 Gy, while tumor-absorbed dose ranged from 143.9 to 1,641.3 Gy in different sites. CONCLUSIONS: Patient specific dosimetry for [(131)I]mIBG TRT was accomplished using pretherapy [(124)I]mIBG PET/CT imaging and a Geant4-based Monte Carlo dosimetry method. The Geant4 method with quantitative pretherapy imaging can provide dose estimates to normal organs and tumors with more realistic simulation geometry, and thus may improve treatment planning for [(131)I]mIBG TRT. PMID- 25145970 TI - Antenatal health promotion via short message service at a Midwife Obstetrics Unit in South Africa: a mixed methods study. AB - BACKGROUND: Adequate antenatal care is important to both the health of a pregnant woman and her unborn baby. Given South Africa's high rate of cellphone penetration, mobile health interventions have been touted as a potentially powerful means to disseminate health information. This study aimed to increase antenatal health knowledge and awareness by disseminating text messages about clinic procedures at antenatal visits, and how to be healthy during pregnancy. METHODS: Participants recruited were pregnant women attending a primary health care facility in Cape Town. A controlled clinical trial was carried out where the intervention group (n = 102) received text messages staggered according to the week of pregnancy at the time of recruitment. The control group (n = 104) received no text messages. These text messages contained antenatal health information, and were delivered in English, Xhosa or Afrikaans, according to the preference of each participant. A baseline knowledge questionnaire with nine questions was administered prior to the intervention. The same questionnaire was used with added health-related behaviour questions for the intervention group at exit. A modified intention-to-treat analysis was done. To compare the control and intervention group's knowledge, Fisher's exact tests and two-sample t-tests tests were carried out for binary and continuous outcomes, respectively. A focus group of seven participants from the intervention group was then conducted to gain more insight into how the text messages were perceived. RESULTS: There was substantial loss to follow-up during the study with only 57% of the participants retained at exit. No statistically significant difference was detected between the control and intervention group in any of the nine knowledge questions at exit (all p > 0.05). Responses from the focus group indicated that the text messages acted as a welcome reminder and a source of positive motivation, and were perceived as extended care from the health care provider. CONCLUSIONS: While the intervention failed to improve antenatal health knowledge, evidence from self-reported behaviour and the focus group suggests that text messages have the potential to motivate change in health-seeking behaviour. One should be mindful of loss to follow-up when rolling out mobile health interventions in developing country settings. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201406000841188. Registered 3 June 2014. PMID- 25145971 TI - X-ray holography with a customizable reference. AB - In X-ray Fourier-transform holography, images are formed by exploiting the interference pattern between the X-rays scattered from the sample and a known reference wave. To date, this technique has only been possible with a limited set of special reference waves. We demonstrate X-ray Fourier-transform holography with an almost unrestricted choice for the reference wave, permitting experimental geometries to be designed according to the needs of each experiment and opening up new avenues to optimize signal-to-noise and resolution. The optimization of holographic references can aid the development of holographic techniques to meet the demands of resolution and fidelity required for single shot imaging applications with X-ray lasers. PMID- 25145972 TI - Adherence to a Mediterranean diet and risk of diabetes: a systematic review and meta-analysis. AB - OBJECTIVE: Adherence to a Mediterranean diet is associated with significant improvements in health status. However, to date no systematic review and meta analysis has summarized the effects of Mediterranean diet adherence on the risk of type 2 diabetes mellitus. DESIGN: Electronic searches for randomized controlled trials and cohort studies were performed in MEDLINE, SCOPUS, EMBASE and the Cochrane Trial Register until 2 April 2014. Pooled effects were calculated by an inverse-variance random-effect meta-analysis using the statistical software Review Manager 5.2 by the Cochrane Collaboration. SETTING: Meta-analysis of randomized controlled trials and cohort studies. SUBJECTS: ELIGIBILITY CRITERIA: 19+years of age. RESULTS: One randomized controlled trial and eight prospective cohort studies (122 810 subjects) published between 2007 and 2014 were included for meta-analysis. For highest v. lowest adherence to the Mediterranean diet score, the pooled risk ratio was 0.81 (95 % CI 0.73, 0.90, P<0.0001, I 2=55 %). Sensitivity analysis including only long-term studies confirmed the results of the primary analysis (pooled risk ratio=0.75; 95 % CI 0.68, 0.83, P<0.00001, I 2=0 %). The Egger regression test provided no evidence of substantial publication bias (P=0.254). CONCLUSIONS: Greater adherence to a Mediterranean diet is associated with a significant reduction in the risk of diabetes (19 %; moderate quality evidence). These results seem to be clinically relevant for public health, in particular for encouraging a Mediterranean-like dietary pattern for primary prevention of type 2 diabetes mellitus. PMID- 25145973 TI - High uric acid level associated with increased arterial stiffness in apparently healthy women. AB - OBJECTIVES: Increased serum uric acid level is regarded as a risk factor for cardiovascular disease, and found to be associated with increased arterial stiffness. While previous studies investigated the relationship between serum uric acid and arterial stiffness, most did not exclude the confounding factors, such as history or medications of hypertension, diabetes, dyslipidemia and hyperuricemia. The aim of this study was to explore the association of uric acid with arterial stiffness in an apparently healthy population. METHODS: This cross sectional study enrolled 7025 participants during health examinations from October 2006 to August 2009. A total of 5150 apparently healthy subjects were enrolled in the final analysis. Arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV). Uric acid was divided into quartiles in men (Q1: 59.5-333.1, Q2: 333.2-380.7, Q3: 380.8-428.3, Q4: 428.4-701.9 MUmol/L) and women (Q1: 113.0-236.4, Q2: 236.5-273.6, Q3:273.7-315.2, Q4:315.3-585.0 MUmol/L). RESULTS: Uric acid level was significantly different between women with and without increased arterial stiffness, but not in men. ANCOVA showed that women with Q3 and Q4 of serum uric acid had greater baPWV level. In multiple logistic regression analysis, Q4 (OR = 1.53, 95% CI = 1.04-2.26) of uric acid was positively associated with increased baPWV in women, but not in men. In addition, age and high blood pressure were also independently associated factors of increased arterial stiffness for both genders. CONCLUSION: In apparently healthy women, high-normal serum uric acid or greater was associated with greater risk of arterial stiffness. However, the relationship between hyperuricemia and increased arterial stiffness was not significant in men. PMID- 25145974 TI - Congenital midline cervical cleft: clinical approach to a congenital anterior neck defect. AB - Numerous malformations can affect the anterior part of the neck presenting at birth as a real diagnostic challenge for the pediatrician or the primary care physician who initially evaluate the baby. Congenital midline cervical cleft represents a rare defect of the midline neck, which is sometimes wrongly diagnosed as a thyroglossal duct anomaly, dermoid cyst, branchial cleft anomaly or "birthmark". A prompt clinical diagnosis and surgical treatment during early infancy are essential to ensure both functional and aesthetic outcome. We report a case of a female neonate with a midline cervical cleft diagnosed immediately after birth. The main features of other congenital anomalies of the anterior neck are also discussed referring to their embryologic origin. PMID- 25145976 TI - Non-alcoholic fatty liver disease fibrosis score and FIB-4 scoring system could identify patients at risk of systemic complications. AB - AIM: To investigate the relation between systemic complications of non-alcoholic fatty liver disease (NAFLD) and non-invasive fibrosis scores. METHODS: The NAFLD fibrosis score (NFS) and FIB-4 were measured in 1559 people who underwent a complete medical checkup at our hospital and were followed for more than 3 years. Correlation between these scores and prevalence and new incidence rates of diabetes or cerebral-cardiovascular diseases were analyzed. RESULTS: The 1559 cases were classified into two groups using the low cut-off values of NFS and FIB 4: group 1 (>=low cut-off score with fatty liver) and group 2 (the others). In group 1, the prevalence of diabetes and cerebral-cardiovascular diseases at baseline and additional incidences during the observation period was higher compared with group 2. Diabetes at baseline in group 1 versus group 2 were 31.5% versus 3.1% (NFS, P < 0.0001), 17.0% versus 4.7% (FIB-4, P < 0.0001), and cerebral-cardiovascular diseases at baseline were 7.7% versus 2.3% (NFS, P = 0.002) and 9.0% versus 2.3% (FIB-4, P = 0.0012). New incidences of diabetes were 4.5% versus 1.2% (NFS, P = 0.034) and 3.6% versus 1.2% (FIB-4, P = 0.11), and of cerebral-cardiovascular diseases were 5.0% versus 0.9% (NFS, P = 0.0019) and 5.4% versus 0.9% (FIB-4, P = 0.0034). CONCLUSION: NFS and FIB-4 are useful to extract cases with high risk of systemic complications of NAFLD in the public. PMID- 25145975 TI - Copy number variations could predict the outcome of bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. AB - We performed single nucleotide polymorphism (SNP) array analysis of 35 newly diagnosed symptomatic multiple myeloma (MM) patients who received bortezomib melphalan-prednisone (VMP) to identify collaborating genetic events that could predict the outcome of treatment. A total of 340 copy number variations (CNVs) were identified, with the most frequently identified CNVs being gains on 1q, 19p, 9q, 3q, 9p, 15q, 19q, 5q, 11q, 5p, and 7q and losses on 1p, X, 13q, 14q, and 6q. The number and proportion of detected abnormalities by SNP array were associated with presence of cytogenetic abnormalities and complex karyotype. Moreover, increasing genomic complexity as ascertained by SNP arrays correlated with outcome of the VMP treatment. The frequency of CNVs was significantly different according to achievement of very good partial response (VGPR) to VMP treatment (=VGPR, median 11.7 vs. 7.7, respectively, P = 0.032) or occurrence of progressive disease (PD) after VMP treatment (progression vs. nonprogression, median 11.6 and 6.5, respectively, P = 0.011). The proportion of CNV length was also significantly higher in patients who did not achieve VGPR compared with those with >=VGPR (median 31.9 vs. 19.6%, respectively, P = 0.004) and also higher in patients with PD compared with those without it (median 31.9 vs. 15.8%, respectively, P = 0.005). The patients who did not achieve VGPR tended to have deletion of 1p (P = 0.011) and gain of 3q (P = 0.05). Occurrence of PD was associated with complex karyotype (P = 0.020) and gain of 3q (P = 0.022). Our data show that the occurrence of CNVs correlates with clinical outcomes to first line VMP treatment. PMID- 25145977 TI - A field test of a model for the stability of androdioecy in the freshwater shrimp, Eulimnadia texana. AB - The evolution of hermaphroditism from dioecy is a poorly studied transition. Androdioecy (the coexistence of males and hermaphrodites) has been suggested as an intermediate step in this evolutionary transition or could be a stable reproductive mode. Freshwater crustaceans in the genus Eulimnadia have reproduced via androdioecy for 24+ million years and thus are excellent organisms to test models of the stability of androdioecy. Two related models that allow for the stable maintenance of males and hermaphrodites rely on the counterbalancing of three life history parameters. We tested these models in the field over three field seasons and compared the results to previous laboratory estimates of these three parameters. Male and hermaphroditic ratios within years were not well predicted using either the simpler original model or a version of this model updated to account for differences between hermaphroditic types ('monogenic' and 'amphigenic' hermaphrodites). Using parameter estimates of the previous year to predict the next year's sex ratios revealed a much better fit to the original relative to the updated version of the model. Therefore, counter to expectations, accounting for differences between the two hermaphroditic types did not improve the fit of these models. At the moment, we lack strong evidence that the long term maintenance of androdioecy in these crustaceans is the result of a balancing of life history parameters; other factors, such as metapopulation dynamics or evolutionary constraints, may better explain the 24+ million year maintenance of androdioecy in clam shrimp. PMID- 25145978 TI - Femtosecond time-resolved transient absorption spectroscopy of CH3NH3PbI3 perovskite films: evidence for passivation effect of PbI2. AB - CH3NH3PbI3 perovskite layered films deposited on substrates with and without a titania support structure have been prepared and studied using time-resolved femtosecond transient absorption (fs-TA) spectroscopy in the visible light range (450-800 nm). The electron injection dynamics from the photoexcited perovskite layers to the neighboring film structures could be directly monitored via the transient bleaching dynamics of the perovskite at ~750 nm and thus systematically studied as a function of the layer-by-layer architecture. In addition, for the first time we could spectrally distinguish transient bleaching at ~750 nm from laser-induced fluorescence that occurs red-shifted at ~780 nm. We show that an additional bleach feature at ~510 nm appears when PbI2 is present in the perovskite film. The amplitudes of the PbI2 and perovskite TA peaks were compared to estimate relative amounts of PbI2 in the samples. Kinetic analysis reveals that perovskite films with less PbI2 show faster relaxation rates than those containing more PbI2. These fast dynamics are attributed to charge carrier trapping at perovskite grain boundaries, and the slower dynamics in samples containing PbI2 are due to a passivation effect, in line with other recently reported work. PMID- 25145979 TI - Room temperature vortex fluidic synthesis of monodispersed amorphous proto vaterite. AB - Monodispersed particles of amorphous calcium carbonate (ACC) 90 to 200 nm in diameter are accessible at room temperature in ethylene glycol and water using a vortex fluidic device (VFD). The ACC material is stable for at least two weeks under ambient conditions. PMID- 25145980 TI - Using insect electroantennogram sensors on autonomous robots for olfactory searches. AB - Robots designed to track chemical leaks in hazardous industrial facilities or explosive traces in landmine fields face the same problem as insects foraging for food or searching for mates: the olfactory search is constrained by the physics of turbulent transport. The concentration landscape of wind borne odors is discontinuous and consists of sporadically located patches. A pre-requisite to olfactory search is that intermittent odor patches are detected. Because of its high speed and sensitivity, the olfactory organ of insects provides a unique opportunity for detection. Insect antennae have been used in the past to detect not only sex pheromones but also chemicals that are relevant to humans, e.g., volatile compounds emanating from cancer cells or toxic and illicit substances. We describe here a protocol for using insect antennae on autonomous robots and present a proof of concept for tracking odor plumes to their source. The global response of olfactory neurons is recorded in situ in the form of electroantennograms (EAGs). Our experimental design, based on a whole insect preparation, allows stable recordings within a working day. In comparison, EAGs on excised antennae have a lifetime of 2 hr. A custom hardware/software interface was developed between the EAG electrodes and a robot. The measurement system resolves individual odor patches up to 10 Hz, which exceeds the time scale of artificial chemical sensors. The efficiency of EAG sensors for olfactory searches is further demonstrated in driving the robot toward a source of pheromone. By using identical olfactory stimuli and sensors as in real animals, our robotic platform provides a direct means for testing biological hypotheses about olfactory coding and search strategies. It may also prove beneficial for detecting other odorants of interests by combining EAGs from different insect species in a bioelectronic nose configuration or using nanostructured gas sensors that mimic insect antennae. PMID- 25145981 TI - Spherical micelles assembled from variants of recombinant oleosin. AB - An emerging field in biomaterials is the creation and engineering of protein surfactants made by recombinant biotechnology. Protein surfactants made by recombinant biotechnology allow for complete control of the molecular weight and chemical sequence of the surfactant. The proteins are monodisperse in molecular weight, and functionalization with bioactive amino acid sequences is straightforwardly achieved through genetic engineering. We modified the naturally occurring amphiphilic plant protein oleosin by truncating a large portion of its central hydrophobic block, creating a soluble triblock surfactant. Additional variants were constructed to eliminate secondary structure and create ionic surfactants. Variants of oleosin self-assembled into spherical micelles with a diameter of ~21 nm at concentrations above the critical micelle concentration (cmc). We found that the cmc could be manipulated through changes in the protein backbone and was correlated with changes in the protein secondary structure. Micelle size and shape are characterized with dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryo-TEM). Micelles were functionalized with the integrin-binding domain, RGDS, leading to a 2.9-fold increase in uptake in Ovcar-5 cells after 12 h. Oleosin surfactants present a promising platform for micellar assembly because of the ability to precisely modify the protein backbone through molecular biology, allowing for the control over the cmc and the addition of functional domains into the material. PMID- 25145982 TI - Acute leukocyte, cytokine and adipocytokine responses to maximal and hypertrophic resistance exercise bouts. AB - The purpose of this study was to examine the acute immune response (circulating levels of leukocytes, cytokines and adipocytokines) to maximal resistance (MAX, 15 * 1RM) and hypertrophic resistance (HYP, 5 * 10RM) exercise bouts. Twelve healthy men (age = 28.2 +/- 3.5 years, weight = 78.6 +/- 10.4 kg, height 178.8 +/ 5.0 cm, fat percentage = 16.5 +/- 3.5 %) participated in the study. Blood was sampled before, immediately after and 15 and 30 min after exercise. Leukocytes (WBC) significantly increased immediately after HYP (p < 0.01), whereas in MAX, increases in WBC became significant after 30 min (p < 0.05). Lymphocytes increased only after HYP (p < 0.001), while MAX induced lymphopenia during recovery (p < 0.01). Monocyte chemoattractant protein-1 (MCP-1) decreased (p < 0.05) and interleukin-1 receptor antagonist (IL-1ra) increased after HYP, which were not observed after MAX. Adipsin and resistin decreased after both exercise bouts (p < 0.05), which suggest that heavy resistance exercise is at least transiently beneficial for adipocytokine profile. Immediate mechanical stress seemed similar as no differences in myoglobin response were observed. The higher magnitude of metabolic demand reflected in higher lactate response in HYP could be the reason for the significantly high responses in WBC, IL-1ra and decrease in MCP-1. PMID- 25145983 TI - Nosocomial infection caused by vancomycin-susceptible multidrug-resistant Enterococcus faecalis over a long period in a university hospital in Japan. AB - Compared with other developed countries, vancomycin-resistant enterococci (VRE) are not widespread in clinical environments in Japan. There have been no VRE outbreaks and only a few VRE strains have sporadically been isolated in our university hospital in Gunma, Japan. To examine the drug susceptibility of Enterococcus faecalis and nosocomial infection caused by non-VRE strains, a retrospective surveillance was conducted in our university hospital. Molecular epidemiological analyses were performed on 1711 E. faecalis clinical isolates collected in our hospital over a 6-year period [1998-2003]. Of these isolates, 1241 (72.5%) were antibiotic resistant and 881 (51.5%) were resistant to two or more drugs. The incidence of multidrug resistant E. faecalis (MDR-Ef) isolates in the intensive care unit increased after enlargement and restructuring of the hospital. The major group of MDR-Ef strains consisted of 209 isolates (12.2%) resistant to the five drug combination tetracycline/erythromycin/kanamycin/streptomycin/gentamicin. Pulsed-field gel electrophoresis analysis of the major MDR-Ef isolates showed that nosocomial infections have been caused by MDR-Ef over a long period (more than 3 years). Multilocus sequence typing showed that these strains were mainly grouped into ST16 (CC58) or ST64 (CC8). Mating experiments suggested that the drug resistances were encoded on two conjugative transposons (integrative conjugative elements), one encoded tetracycline-resistance and the other erythromycin/kanamycin/streptomycin/gentamicin-resistance. To our knowledge, this is the first report of nosocomial infection caused by vancomycin-susceptible MDR Ef strains over a long period in Japan. PMID- 25145984 TI - An ESIPT based fluorescent probe for highly selective and ratiometric detection of periodate. AB - Periodate is widely used in organic and bioorganic chemistry, and also related to food and environmental safety. To best of our knowledge, there is no efficient tools reported for simultaneously quantifying periodate with high accuracy and discriminating periodate from other forms of iodine. We have synthesized, characterized and applied a first ratiometric fluorescent probe (PDS-2) for simultaneous monitoring of changes of periodate based on the excited-state intramolecular proton transfer mechanism. This PDS-2 based fluorescent technique may enable for a better understanding of periodate related biological and chemical processes. Also, it is an efficient tool for public health, food safety and environmental protection. PMID- 25145985 TI - A novel signal-off electrochemiluminescence biosensor for the determination of glucose based on double nanoparticles. AB - In this work, a novel facile signal-off electrochemiluminescence (ECL) biosensor has been developed for the determination of glucose based on the integration of chitosan (CHIT), CdTe quantum dots (CdTe QDs) and Au nanoparticles (Au NPs) on the glassy carbon electrode (GCE). Chitosan displays high water permeability, hydrophilic property, strong hydrogel ability and good adhesion to load the double nanoparticles to the glassy carbon electrode surfaces. Au NPs are efficient glucose oxidase (GOx)-mimickess to catalytically oxidize glucose, similar to the natural process. Upon the addition of glucose, the Au NPs catalyzed glucose to produce gluconic acid and hydrogen peroxide (H2O2) based on the consumption of dissolved oxygen (O2), which resulted in a quenching effect on the ECL emission. Therefore, the determination of glucose could be achieved by monitoring the signal-off ECL biosensor. Under the optimum conditions, the ECL intensity of CdTe QDs and the concentration of glucose have a good linear relationship in the range of 0.01-10 mmol L(-1). The limit of detection for glucose was 5.28 MUmol L(-1) (S/N=3). The biosensor showed good sensitivity, selectivity, reproducibility and stability. The proposed biosensor has been employed for the detection of glucose in human serum samples with satisfactory results. PMID- 25145986 TI - Efficacy and safety of house dust mite sublingual immunotherapy in monosensitized and polysensitized children with respiratory allergic diseases. AB - BACKGROUND: The efficacy of single-allergen-specific immunotherapy in polysensitized subjects is a matter of debate. This study aimed to investigate the efficacy of house dust mite (HDM) sublingual immunotherapy (SLIT) in monosensitized and polysensitized children. METHODS: A total of 112 children, aged 4 to 13 years old, with HDM-induced respiratory allergic diseases were allocated to a monosensitized group (n = 56) or a polysensitized group (n = 56). Both groups were treated by standard pharmacotherapy and SLIT with Dermatophagoides farinae (American HDM) extracts for 52 weeks. Symptoms, medications, visual analogue scale (VAS), and presence of adverse events (AEs) were assessed once a month. Skin-prick test (SPT) was done before and after treatment. After treatment, subjects in the polysensitized group who completed the study were further analyzed as subgroup 1 (n = 20) and subgroup 2 (n = 15) according to the number of coexisting allergens. RESULTS: Forty-one subjects in the monosensitized group and 35 subjects in the polysensitized group completed the study. The global clinical parameters had significantly improved after treatment, with no significant difference between the monosensitized and polysensitized group throughout this period (all p > 0.05). The comparison among the monosensitized group, subgroup 1, and subgroup 2 indicated that there was no significant difference in symptoms scores and VAS at each scheduled follow-up visit. There was also no significant difference in total medications score (TMS) in the monosensitized group, subgroup 1, and subgroup 2 after week 24 (all p > 0.05). No severe systemic AEs were reported. CONCLUSION: No significant difference was observed in the clinical effects of HDM SLIT between polysensitized and monosensitized children with respiratory allergic diseases. PMID- 25145987 TI - Osteoblastic cell response to spark plasma-sintered zirconia/titanium cermets. AB - Ceramic/metal composites, cermets, arise from the idea to combine the dissimilar properties in the pure materials. This work aims to study the biocompatibility of new micro-nanostructured 3 Y-TZP/Ti materials with 25, 50 and 75 vol.% Ti, which have been successfully obtained by spark slasma sintering technology, as well as to correlate their surface properties (roughness, wettability and chemical composition) with the osteoblastic cell response. All samples had isotropic and slightly waved microstructure, with sub-micrometric average roughness. Composites with 75 vol.% Ti had the highest surface hydrophilicity. Surface chemical composition of the cermets correlated well with the relative amounts used for their fabrication. A cell viability rate over 80% dismissed any cytotoxicity risk due to manufacturing. Cell adhesion and early differentiation were significantly enhanced on materials containing the nanostructured 3 Y-TZP phase. Proliferation and differentiation of SaOS-2 were significantly improved in their late-stage on the composite with 75 vol.% Ti that, from the osseointegration standpoint, is presented as an excellent biomaterial for bone replacement. Thus, spark plasma sintering is consolidated as a suitable technology for manufacturing nanostructured biomaterials with enhanced bioactivity. PMID- 25145988 TI - Hybrid vitronectin-mimicking polycaprolactone scaffolds for human retinal progenitor cell differentiation and transplantation. AB - Many advances have been made in an attempt to treat retinal degenerative diseases, such as age-related macular degeneration and retinitis pigmentosa. The irreversible loss of photoreceptors is common to both, and currently no restorative clinical treatment exists. It has been shown that retinal progenitor and photoreceptor precursor cell transplantation can rescue the retinal structure and function. Importantly, retinal progenitor cells can be collected from the developing neural retina with further expansion and additional modification in vitro, and the delivery into the degenerative host can be performed as a single cell suspension injection or as a complex graft transplantation. Previously, we have described several polymer scaffolds for culture and transplantation of retinal progenitor cells of both mouse and human origin. This tissue engineering strategy increases donor cell survival and integration. We have also shown that biodegradable poly(E-caprolactone) induces mature photoreceptor differentiation from human retinal progenitor cells. However, poor adhesive properties limit its use, and therefore it requires additional surface modification. The aim of this work was to study vitronectin-mimicking oligopeptides (Synthemax II-SC) poly(E caprolactone) films and their effects on human retinal progenitor cell adhesion, proliferation, and differentiation. Here, we show that the incorporation of vitronectin-mimicking oligopeptide into poly(E-caprolactone) leads to dose dependent increases in cell adhesion; the optimum dose identified as 30 ug/ml. Inhibition of human retinal progenitor cells proliferation was seen on poly(E caprolactone) and was maintained with the hybrid scaffold. This has been shown to be beneficial for driving cell differentiation. Additionally, we observed equal expression of Nrl, rhodopsin, recoverin, and rod outer membrane 1 after differentiation on the hybrid scaffold as compared to the standard fibronectin coating of poly(E-caprolactone). After transplantation into rd1 retina degenerative mice, human retinal progenitor cells were able to migrate to the outer nuclear layer and survive for three weeks. We conclude that Synthemax II-SC can be incorporated into poly(E-caprolactone) to create a hybrid chemically defined scaffold for clinical application. PMID- 25145989 TI - Chondrogenic potential of human articular chondrocytes and skeletal stem cells: a comparative study. AB - Regenerative medicine strategies have increasingly focused on skeletal stem cells (SSCs), in response to concerns such as donor site morbidity, dedifferentiation and limited lifespan associated with the use of articular chondrocytes for cartilage repair. The suitability of SSCs for cartilage regeneration, however, remains to be fully determined. This study has examined the chondrogenic potential of human STRO-1-immunoselected SSCs (STRO-1(+) SSCs), in comparison to human articular chondrocytes (HACs), by utilising two bioengineering strategies, namely "scaffold-free" three-dimensional (3-D) pellet culture and culture using commercially available, highly porous, 3-D scaffolds with interconnected pore networks. STRO-1(+) SSCs were isolated by magnetic-activated cell sorting from bone marrow samples of haematologically normal osteoarthritic individuals following routine hip replacement procedures. Chondrocytes were isolated by sequential enzymatic digestion of deep zone articular cartilage pieces dissected from femoral heads of the same individuals. After expansion in monolayer cultures, the harvested cell populations were centrifuged to form high-density 3 D pellets and also seeded in the 3-D scaffold membranes, followed by culture in serum-free chondrogenic media under static conditions for 21 and 28 days, respectively. Chondrogenic differentiation was determined by gene expression, histological and immunohistochemical analyses. Robust cartilage formation and expression of hyaline cartilage-specific markers were observed in both day-21 pellets and day-28 explants generated using HACs. In comparison, STRO-1(+) SSCs demonstrated significantly lower chondrogenic differentiation potential and a tendency for hypertrophic differentiation in day-21 pellets. Culture of STRO-1(+) SSCs in the 3-D scaffolds improved the expression of hyaline cartilage-specific markers in day-28 explants, however, was unable to prevent hypertrophic differentiation of the SSC population. The advantages of application of SSCs in tissue engineering are widely recognised; the results of this study, however, highlight the need for further development of cell culture protocols that may otherwise limit the application of this stem cell population in cartilage bioengineering strategies. PMID- 25145990 TI - Technique of subnormothermic ex vivo liver perfusion for the storage, assessment, and repair of marginal liver grafts. AB - The success of liver transplantation has resulted in a dramatic organ shortage. In most transplant regions 20-30% of patients on the waiting list for liver transplantation die without receiving an organ transplant or are delisted for disease progression. One strategy to increase the donor pool is the utilization of marginal grafts, such as fatty livers, grafts from older donors, or donation after cardiac death (DCD). The current preservation technique of cold static storage is only poorly tolerated by marginal livers resulting in significant organ damage. In addition, cold static organ storage does not allow graft assessment or repair prior to transplantation. These shortcomings of cold static preservation have triggered an interest in warm perfused organ preservation to reduce cold ischemic injury, assess liver grafts during preservation, and explore the opportunity to repair marginal livers prior to transplantation. The optimal pressure and flow conditions, perfusion temperature, composition of the perfusion solution and the need for an oxygen carrier has been controversial in the past. In spite of promising results in several animal studies, the complexity and the costs have prevented a broader clinical application so far. Recently, with enhanced technology and a better understanding of liver physiology during ex vivo perfusion the outcome of warm liver perfusion has improved and consistently good results can be achieved. This paper will provide information about liver retrieval, storage techniques, and isolated liver perfusion in pigs. We will illustrate a) the requirements to ensure sufficient oxygen supply to the organ, b) technical considerations about the perfusion machine and the perfusion solution, and c) biochemical aspects of isolated organs. PMID- 25145991 TI - Modelling ion-pair geometries and dynamics in a 1-ethyl-1-methylpyrrolidinium based ion-conductive crystal. AB - Full conformational and energy explorations are conducted on an organic ionic plastic crystal, 1-ethyl-1-methylpyrrolidium tetrafluoroborate [C2mpyr][BF4]. The onsets of various stages of dynamic behaviour, which appear to account for low temperature solid-solid phase transitions, are investigated by using quantum chemical simulations. It is suggested that pseudorotation of the pyrrolidine ring occurs in the first instance; the partial rotation of the entire cation subsequently occurs and may be accompanied by reorientation of the ethyl chain as the temperature increases further. A cation-anion configuration, whereby BF4(-) interacts with the C2 mpy cation from the side of the ring, is the most likely structure in the low-temperature phase IV region. These interpretations are supported by (13)C nuclear magnetic resonance chemical-shift analysis. PMID- 25145992 TI - Response to the letter by Prof. Daniel Ninello Polesel "Obstructive sleep apnea as a potential confounding factor in atherosclerosis in the Asian population". PMID- 25145993 TI - Obstructive sleep apnea as a potential confounding factor in atherosclerosis in the Asian population. PMID- 25145994 TI - Associations of a polymorphism in the intercellular adhesion molecule-1 (ICAM1) gene and ICAM1 serum levels with migraine in a Chinese Han population. AB - OBJECTIVE: To investigate the associations of a polymorphism in the intercellular adhesion molecule-1 (ICAM1) gene, and ICAM1 serum levels, with migraine and migraine subtypes in a Han Chinese population. METHOD: We used PCR-restriction fragment length polymorphism (PCR-RFLP) and gene sequencing to analyze the genotype and allelic frequencies of the K469E (rs5498) and G241R (rs1799969) ICAM1 polymorphisms between migraine cases and controls. Serum levels of ICAM1 were tested by enzyme linked immunosorbent assay (ELISA). RESULTS: (1) We found significant higher frequencies of the distribution of the E/E genotype and the E allele of the K469E polymorphism between migraine cases and controls (chi(2) = 4.948 &P<0.05 and chi(2) = 13.990 &P<0.01, respectively), and between a migraine without aura subtype of migraine cases and controls (chi(2) = 5.265 &P<0.05; chi(2 )= 20.501 &P<0.01, respectively). After correction by conditional logistical regression, the frequency distribution difference of the E/E genotype between the migraine cases and controls remained statistically significant (OR = 32.85, 95% CI:4.22-28.79, P = 0.007.) (2) ICAM1 serum levels were significantly higher in migraine cases than in controls (P<0.01) and, within migraine cases, were significantly higher in K469E E allele carriers than in K allele carriers (P<0.01). CONCLUSIONS: Our data indicate that the E/E genotype of the ICAM1 K469E polymorphism may be an important risk factor for migraine in a Han Chinese population, and that this polymorphism affects ICAM1 serum levels. Although the independent risk factor constituted by this polymorphism in other ethnic groups requires further study, our studies raise the possibility of the development of ICAM1 K469E E allele-specific therapeutics for the prevention and treatment of migraine in the Chinese Han population. PMID- 25145995 TI - Membrane stabilisation: a possible anti-inflammatory mechanism for the extracts and compounds from Spathodea campanulata. AB - This study was undertaken to evaluate the efficiency of extract, fractions and pure molecules from Spathodea campanulata (SC) towards inflammation. Polarity based extracts of SC were found active in stabilising red blood cell (RBC) membrane indicating anti-inflammatory potential. Bioactivity-guided isolation of SC produced 1-O-(E)-caffeoyl-beta-gentiobiose and (2S)-1,2-di-O-[(9Z,12Z,15Z) octadeca-9,12,15-trienoyl]-3-O-[alpha-d-galctopyranosyl-(1" -> 6')-O-beta-d galactopyranosyl] glycerol as the active constituents with 65.91% and 67.41% of membrane stability, respectively. Activity of the third compound (verminoside) could not be ascertained owing to extremely low recoverability. Furthermore, the isolated compounds were subjected to in silico studies. The compounds showed good binding affinity towards cyclooxygenase-2. Absorption, distribution, metabolism & excretion (ADME)-toxicity studies illustrated that the isolated compounds are free of toxicity. These observations help us to conclude that SC might exert its anti-inflammatory activity by soothing the RBC membrane as it is the case for non steroidal anti-inflammatory drugs towards lysozomal membranes. Therefore, SC might be considered as a potential candidate for development of anti-inflammatory drugs. PMID- 25145997 TI - Personal development through research. PMID- 25145996 TI - Preparation of rat serum suitable for mammalian whole embryo culture. AB - Mammalian whole embryo culture (WEC) is a widely used technique for examining pharmacological toxicity in developing mouse and rat embryos and for investigating the mechanisms of developmental processes. Immediately centrifuged (IC) rat serum is commonly used for WEC and is essential for the growth and development of cultured mouse and rat embryos ex vivo. For the culture of midgestation embryos (i.e., E8.0-12.5 for the mouse, and E10.0-14.5 for the rat), 100% rat serum is the best media for supporting the growth of the embryo ex vivo. To prepare rat serum suitable for WEC, the collected blood should be centrifuged immediately to separate the blood cells from the plasma fraction. After centrifugation, the fibrin clot forms in the upper layer; this clot should be squeezed gently using a pair of sterile forceps and subsequently centrifuged to completely separate the blood cells from the serum. In this video article, we demonstrate our standard protocol for the preparation of optimal IC rat serum, including blood collection from the abdominal aorta of male rats and extraction of the serum by centrifugation. PMID- 25145998 TI - Clinical and radiological results of locking plate fixation for periprosthetic femoral fractures around hip arthroplasties: a retrospective multi-center study. AB - BACKGROUND: Osteosynthesis of periprosthetic femoral fractures around hip arthroplasties is challenging, and locking plate fixation has been found to be a reasonable treatment. However, there is a paucity of evidence of the extent to which patients recover their activities of daily living (ADL). The purpose of this study was to study the clinical results, particularly recovery of ADL, radiological results, and potential complications arising from the use of locking plate fixation for periprosthetic femoral fractures around hip arthroplasties. METHODS: We conducted a retrospective, multi-center study. Patients with periprosthetic femoral fractures around hip arthroplasties who were treated by osteosynthesis with use of locking plates and who underwent follow-up for at least 6 months postoperatively were enrolled in the study. For each patient, recovery of ADL, in terms of social and ambulatory recovery and Parker mobility score, were compared before fracture and at last follow-up. Postoperative complications were investigated. Bony union, loss of reduction, and malunion were assessed radiologically. RESULTS: Thirty-two patients were enrolled in this study. Mean follow-up was 25.1 months. For 84.4, 68.8, and 53.1% of patients, respectively, social status, ambulation, and Parker mobility score at last follow up were determined to be equal to that before the fracture. Bony union was observed for 30 patients within the follow-up period. Four patients had not achieved bony union 6 months postoperatively. There was no loss of reduction, malunion, or implant breakage, and no infection. For one patient each, partial pullout of the locking screws and a supracondylar fracture at the plate end were observed, and additional surgery was required. CONCLUSIONS: Our results reveal that locking plate fixation provided sufficient stability for satisfactory recovery of ADL for most elderly patients with periprosthetic femoral fractures around hip arthroplasties. PMID- 25145999 TI - Non-specific low back pain in adolescents from the south of Portugal: prevalence and associated factors. AB - BACKGROUND: Low back pain (LBP) is a common condition in children and adolescents, and the prevalence has been increasing over the years. Most cases of LBP are due to non-specific causes; however, the role of these risk factors is still controversial. This study determined the prevalence of LBP in Portuguese adolescents and characterized the associated factors. METHODS: The design of this study was observational, analytical and cross-sectional. The sample included 966 adolescents from southern Portugal, aged between 10 and 16 years. The assessments included a questionnaire to characterize the presence of LBP, postural habits, body mass index (BMI) and backpack weights and to use a scoliometer to evaluate the presence of scoliosis. RESULTS: One hundred fifty-two (15.7 %) students had LPB at the present time, 456 (47.2 %) had experienced it in the last year, and 600 (62.1 %) had lifetime prevalence of LBP. Girls have 2.05 more probability of presenting LBP than boys (95 % CI 1.58-2.65; p < 0.001), and older students have a 1.54 greater probability (95 % CI 1.19-1.99; p = 0.001). Students who sit with the spine incorrectly positioned presented 2.49 greater probability of having LBP (95 % CI 1.91-3.2; p < 0.001), students using improper positions for watching TV or playing games have 2.01 greater probabilities (95 % CI 1.55-2.61; p < 0.001), and those who adopt an incorrect standing posture have a 3.39 greater chance of experiencing LBP (95 % CI 2.19-5.23; p < 0.001). CONCLUSIONS: This study found a high prevalence of LBP in adolescents, with higher values in older students, female students and those who adopted incorrect positions when sitting or standing. PMID- 25146000 TI - Calcitonin treatment is associated with less severe osteoarthritis and reduced toll-like receptor levels in a rat model. AB - BACKGROUND: Studies indicate that inflammation promotes progression of osteoarthritis. Cartilage damage is aggravated by the binding of toll-like receptors and endogenous ligands that release large amounts of cytokines and inflammation mediators. Calcitonin can inhibit degeneration of articular cartilage, by inhibiting activation of toll-like receptors and generation of endogenous ligands. To study the effect of calcitonin in the pathogenesis of osteoarthritis and the underlying molecular mechanism, we monitored levels of toll-like receptors during osteoarthritis progression, and after calcitonin injection. METHODS: Male Sprague-Dawley rats were randomly assigned to either a surgery-only or a calcitonin-treatment group (n = 35, each). To induce osteoarthritis, the anterior cruciate ligament and the medial meniscus were cut in the right knees of both groups. Rats in the calcitonin-treatment group received a subcutaneous injection of 15 IU/kg calcitonin once every other day, starting one day post-surgery, until euthanised. Signs of osteoarthritic changes were noted. The amount of collagen II was measured by antibody staining. The amounts of MMP1 and MMP3 in cartilage were measured by use of ELISA. RNA from operated and matched control knee cartilage was extracted to determine expression levels of Col2a1, ACAN, Tlr2, Tlr3, and Tlr4. RESULTS: Signs of osteoarthritis were less severe in rats treated with calcitonin. In the surgery-only group, Tlr2 levels increased early after surgery and then decreased substantially by the latter stages. Tlr3 levels gradually increased and correlated with the severity of osteoarthritis. Tlr4 levels were high but fluctuated over the experimental period. Calcitonin treatment was associated with lower Tlr3 and Tlr4 levels than in the surgery-only group whereas Tlr2 expression was initially lower but increased 28 days after administration of calcitonin. CONCLUSION: Calcitonin treatment may lessen the severity of osteoarthritis in the rat model, perhaps by inhibition of Tlr expression in cartilage. PMID- 25146001 TI - Reconstruction of intercalary bone defects following bone tumor resection with segmental bone transport using an Ilizarov circular external fixator. AB - AIM: The purpose of this retrospective study was to report the long-term follow up results of the reconstruction of bony defects with Ilizarov distraction osteogenesis using the bone transport method following en bloc resection of bone tumors. MATERIALS AND METHODS: En bloc resection was performed in 13 patients with bone tumors between October 1991 and December 2010 in our clinic. The mean age of the patients was 19.46 years (range 7-42 years) at the time of surgery. Histological diagnosis was osteosarcoma in seven cases, Ewing's sarcoma in three cases, giant cell tumor in one case, osteoblastoma in one case and fibrous dysplasia in one case. In all cases either the femur or tibia was involved. RESULTS: The average follow-up period was 157.23 months (range 32-288 months), and the bone defect after resection was 14.61 cm +/- (9-24 cm). The mean Musculoskeletal Tumor Society score of the patients was 89.46 (83-96) at the final follow-up. The mean Knee Society Scale scores of patients in whom reconstruction was performed around the knee joint were 74.3 (51-84). The mean foot and ankle disability index of patients with a tumor around the ankle joint was 81 (73-95). Quality of life of the patients according to the SF-36 and BQUILI indexes was scored as 104 (88-150) and 4 (0-13), respectively. CONCLUSION: From the long-term follow-up results, reconstruction with distraction osteogenesis seems to be an efficient method in patients with long life expectancies. However, a long external fixation time is a disadvantage of this technique. Problems in patient compliance and possible complications such as nonunion should be managed promptly. PMID- 25146002 TI - Effect of synovial transthyretin amyloid deposition on preoperative symptoms and postoperative recovery of median nerve function among patients with idiopathic carpal tunnel syndrome. AB - BACKGROUND: The clinical characteristics of wild-type transthyretin amyloid deposition among patients with carpal tunnel syndrome (CTS) have not been well investigated. METHODS: One-hundred and seven patients with idiopathic CTS who underwent carpal tunnel release were enrolled. They underwent physical examination of the hand, nerve-conduction study, and magnetic resonance imaging (MRI) study of the wrist, and completed a patient-oriented questionnaire. The tests, except for MRI, were repeated 1, 3, and 6 months postoperatively. Synovial tissue was obtained during surgery and analyzed by Congo red and immunohistochemical staining. Ordinal logistic regression analysis was used to evaluate the significance of different clinical and subjective findings between patients with and without amyloid deposition. Postoperative improvements were also compared. RESULTS: Wild-type transthyretin amyloid deposition was observed for 38 patients. Greater symptom severity and 2-point discrimination scores, and larger cross-sectional areas of the carpal tunnel, were significantly correlated with a larger amount of preoperative amyloid deposition. However, the presence and amount of preoperative amyloid deposition did not affect postoperative improvements in physical findings and nerve-conduction studies. CONCLUSIONS: Although transthyretin amyloid deposition can worsen CTS symptoms, postoperative improvements were similar for patients with and without this deposition. PMID- 25146003 TI - Dosimetric and radiobiologic comparison of 3D conformal, IMRT, VMAT and proton therapy for the treatment of early-stage glottic cancer. AB - BACKGROUND: This study aims to compare dosimetrically and radiobiologically 3D conformal, intensity modulated radiation therapy (IMRT), RapidArc (RA) volumetric modulated arc therapy and proton therapy techniques for early-stage glottic cancer. METHODS: Ten patients were retrospectively selected. Photon treatment planning was performed using Eclipse External Beam Planning, and proton planning was performed using CMS Xio. The minimum, mean and maximum dose values for planning target volume (PTV), mean and maximum dose values for organ at risk, % of volume of PTV receiving at least 95% of the prescription dose, and D20, D50 and D90 of carotid arteries were compared. Biological response models of tumour control probabilities and normal tissue complication probabilities were calculated. RESULTS: IMRT, RA and proton plans versus three-dimensional conformal radiotherapy (3D-CRT) plans consistently provided superior PTV coverage and decreased mean dose to the thyroid and carotid arteries. CONCLUSION: All these three modalities showed superiority with less variation among themselves compared with 3D-CRT plans. Clinical investigation is warranted to determine if these treatment approaches will translate into a reduction in radiation therapy-induced toxicities. PMID- 25146005 TI - Classical swine fever virus and p7 protein induce secretion of IL-1beta in macrophages. AB - Classical swine fever virus (CSFV) has a tropism for vascular endothelial cells and immune system cells. The process and release of pro-inflammatory cytokines, including IL-1beta and IL-18, is one of the fundamental reactions of the innate immune response to viral infection. In this study, we investigated the production of IL-1beta from macrophages following CSFV infection. Our results showed that IL 1beta was upregulated after CSFV infection through activating caspase-1. Subsequent studies demonstrated that reactive oxygen species may not be involved in CSFV-mediated IL-1beta release. Recently, research has indicated a novel mechanism by which inflammasomes are triggered through detection of activity of viroporin. We further demonstrated that CSFV viroporin p7 protein induced IL 1beta secretion which could be inhibited by the ion channel blocker amantadine and also discovered that p7 protein was a short-lived protein degraded by the proteasome. Together, our observations provided an insight into the mechanism of CSFV-induced inflammatory responses. PMID- 25146006 TI - Cell-to-cell transfer of HIV infection: implications for HIV viral persistence. AB - A major research priority for HIV eradication is the elucidation of the events involved in HIV reservoir establishment and persistence. Cell-to-cell transmission of HIV represents an important area of study as it allows for the infection of cell types which are not easily infected by HIV, leading to the establishment of long-lived viral reservoirs. This phenomenon enables HIV to escape elimination by the immune system. This process may also enable HIV to escape suppressive effects of anti-retroviral drugs. During cell-to-cell transmission of HIV, a dynamic series of events ensues at the virological synapse that promotes viral dissemination. Cell-to-cell transmission involves various types of cells of the immune system and this mode of transmission has been shown to have an important role in sexual and mother-to-child transmission of HIV and spread of HIV within the central nervous system and gut-associated lymphoid tissues. There is also evidence that cell-to-cell transmission of HIV occurs between thymocytes and renal tubular cells. Herein, following a brief review of the processes involved at the virological synapse, evidence supporting the role for cell-to-cell transmission of HIV in the maintenance of the HIV reservoir will be highlighted. Therapeutic considerations and future directions for this area of research will also be discussed. PMID- 25146004 TI - Genome-wide DNA methylation profiles in progression to in situ and invasive carcinoma of the breast with impact on gene transcription and prognosis. AB - BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development. RESULTS: We generate genome-wide DNA methylation profiles of 285 breast tissue samples representing progression of cancer, and validate methylation changes between normal and DCIS in an independent dataset of 15 normal and 40 DCIS samples. We also validate a prognostic signature on 583 breast cancer samples from The Cancer Genome Atlas. Our analysis reveals that DNA methylation profiles of DCIS are radically altered compared to normal breast tissue, involving more than 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations. A prognostic signature based on methylation level of 18 CpGs is associated with survival of breast cancer patients with invasive tumors, as well as with survival of patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma. CONCLUSIONS: This work demonstrates that changes in the epigenome occur early in the neoplastic progression, provides evidence for the possible utilization of DNA methylation-based markers of progression in the clinic, and highlights the importance of epigenetic changes in carcinogenesis. PMID- 25146008 TI - High APRIL but not BAFF serum levels are associated with poor outcome in patients with follicular lymphoma. AB - Elevated B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) serum levels have been reported to correlate with worse prognosis in B cell-derived malignancies. However, limited information exists regarding the prognostic significance of BAFF and APRIL serum levels in follicular lymphoma (FL). We measured BAFF and APRIL serum levels for 81 patients with newly diagnosed FL and 12 healthy controls. The mean +/- standard deviation (SD) BAFF serum level (1,193.86 +/- 1,126.51 pg/ml) was higher in patients with FL than that in the controls (477.16 +/- 155.55 pg/ml; P < 0.001). No significant difference in the mean +/- SD serum level of APRIL was found between patients and healthy controls (14.39 +/- 43.33 vs 5.07 +/- 2.52 ng/ml; P = 0.193). When the patients were divided into low- and high-BAFF and low- and high-APRIL groups based on the median value of the BAFF and APRIL serum levels (855.14 pg/ml and 6.35 ng/ml, respectively), a high APRIL, but not a high BAFF, serum level significantly correlated with low complete response rate to initial therapy, high relapse/progression rate, and inferior progression-free survival (PFS; P = 0.019) and overall survival (OS; P = 0.008) rates. A high APRIL serum level was also significantly associated with decreased PFS and OS in patients treated with non rituximab regimens but not in patients treated with rituximab-containing regimens. The APRIL serum level remained an independent predictor for PFS and OS in multivariate analysis. APRIL may be an important prognostic predictor with potential significance as a therapeutic target in FL. PMID- 25146007 TI - Characterization of a novel insect-specific flavivirus from Brazil: potential for inhibition of infection of arthropod cells with medically important flaviviruses. AB - In the past decade, there has been an upsurge in the number of newly described insect-specific flaviviruses isolated pan-globally. We recently described the isolation of a novel flavivirus (tentatively designated 'Nhumirim virus'; NHUV) that represents an example of a unique subset of apparently insect-specific viruses that phylogenetically affiliate with dual-host mosquito-borne flaviviruses despite appearing to be limited to replication in mosquito cells. We characterized the in vitro growth potential and 3' untranslated region (UTR) sequence homology with alternative flaviviruses, and evaluated the virus's capacity to suppress replication of representative Culex spp.-vectored pathogenic flaviviruses in mosquito cells. Only mosquito cell lines were found to support NHUV replication, further reinforcing the insect-specific phenotype of this virus. Analysis of the sequence and predicted RNA secondary structures of the 3' UTR indicated NHUV to be most similar to viruses within the yellow fever serogroup and Japanese encephalitis serogroup, and viruses in the tick-borne flavivirus clade. NHUV was found to share the fewest conserved sequence elements when compared with traditional insect-specific flaviviruses. This suggests that, despite apparently being insect specific, this virus probably diverged from an ancestral mosquito-borne flavivirus. Co-infection experiments indicated that prior or concurrent infection of mosquito cells with NHUV resulted in a significant reduction in virus production of West Nile virus (WNV), St Louis encephalitis virus (SLEV) and Japanese encephalitis virus. The inhibitory effect was most effective against WNV and SLEV with over a 10(6)-fold and 10(4)-fold reduction in peak titres, respectively. PMID- 25146010 TI - Acquisition of anatomic parameters concerning molar pulp chamber landmarks using cone-beam computed tomography. AB - INTRODUCTION: Cone-beam computed tomographic (CBCT) imaging is a valuable tool for endodontic therapy. The aim of this study was to verify whether clinical use of CBCT imaging can accurately acquire parameters concerning molar pulp chamber landmarks, which are important data to help start a successful access cavity and avoid iatrogenic furcation perforations. METHODS: Seventy CBCT images were used to measure 118 maxillary and 104 mandibular molars. The following vertical distances were measured: from the cusp tip/central fossa to the pulp chamber floor, to the pulp chamber ceiling, and to furcation; from the pulp chamber ceiling to furcation; from the pulp chamber floor to furcation; and the pulp chamber height. Measurements were read to the nearest 0.05 mm. RESULTS: The measurements were as follows: the pulp chamber floor to furcation (maxillary molar: 1.97 +/- 0.58 [mean +/- standard deviation, mm], mandibular molar: 2.24 +/ 0.47), the pulp chamber ceiling to furcation (maxillary molar: 4.09 +/- 0.68, mandibular molar: 3.78 +/- 0.70), the central fossa to furcation (maxillary molar: 8.78 +/- 0.79, mandibular molar: 8.53 +/- 0.65), the central fossa to the pulp chamber floor (maxillary molar: 6.81 +/- 0.83, mandibular molar: 6.29 +/- 0.65), the central fossa to the pulp chamber ceiling (maxillary molar: 4.69 +/- 0.59, mandibular molar: 4.75 +/- 0.56); and pulp chamber height (maxillary molar: 2.12 +/- 0.81, mandibular molar: 1.53 +/- 0.68). Measurements showing the least standard deviation were the central fossa to furcation and the central fossa to the pulp chamber floor. CONCLUSIONS: CBCT imaging may be used for precise clinical acquisition of the pulp chamber landmark measurements for molars thereby facilitating successful access cavity. PMID- 25146009 TI - Does the combination of 3% mepivacaine plain plus 2% lidocaine with epinephrine improve anesthesia and reduce the pain of anesthetic injection for the inferior alveolar nerve block? A prospective, randomized, double-blind study. AB - INTRODUCTION: In theory, using 3% mepivacaine initially for an inferior alveolar nerve (IAN) block would decrease the pain of injection, provide faster onset, and increase anesthetic success. The purpose of this prospective, randomized, double blind study was to compare the degree of pulpal anesthesia obtained with a combination of 3% mepivacaine/2% lidocaine (1:100,000 epinephrine) versus a combination of 2% lidocaine (1:100,000 epinephrine)/2% lidocaine (1:100,000 epinephrine) in IAN blocks. Injection pain was also studied. METHODS: One hundred asymptomatic subjects were randomly given a combination of a 1-cartridge volume of 3% mepivacaine plus a 1-cartridge volume of 2% lidocaine with 1:100,000 epinephrine and a combination of a 1-cartridge volume of 2% lidocaine with 1:100,000 epinephrine plus a 1-cartridge volume of 2% lidocaine with 1:100,000 epinephrine for the IAN block at 2 separate appointments. Subjects rated the pain of injection. The molars, premolars, and incisors were tested with an electric pulp tester in 4-minute cycles for 60 minutes. Anesthetic success was defined as the subject achieving 2 consecutive 80 readings within 15 minutes after completion of the IAN blocks and sustaining the 80 reading for 60 minutes. RESULTS: Success was not significantly different (P > .05) between the 2 combinations. No statistical differences in injection pain or onset times were found. CONCLUSIONS: The combination of 3% mepivacaine plus 2% lidocaine with 1:100,000 epinephrine was equivalent to the combination of 2 cartridges of 2% lidocaine with 1:100,000 epinephrine in terms of injection pain, onset time, and pulpal anesthetic success for the IAN block. PMID- 25146011 TI - Comparison of the accuracy of 3-dimensional cone-beam computed tomography and micro-computed tomography reconstructions by using different voxel sizes. AB - INTRODUCTION: Cone-beam computed tomography (CBCT) data are, in principle, metrically exact. However, clinicians need to consider the precision of measurements of dental morphology as well as other hard tissue structures. CBCT spatial resolution, and thus image reconstruction quality, is restricted by the acquisition voxel size. The aim of this study was to assess geometric discrepancies among 3-dimensional CBCT reconstructions relative to the micro-CT reference. METHODS: A total of 37 permanent teeth from 9 mandibles were scanned with CBCT 9500 and 9000 3D and micro-CT. After semiautomatic segmentation, reconstructions were obtained from CBCT acquisitions (voxel sizes 76, 200, and 300 MUm) and from micro-CT (voxel size 41 MUm). All reconstructions were positioned in the same plane by image registration. The topography of the geometric discrepancies was displayed by using a color map allowing the maximum differences to be located. RESULTS: The maximum differences were mainly found at the cervical margins and on the cusp tips or incisal edges. Geometric reconstruction discrepancies were significant at 300-MUm resolution (P = .01, Wilcoxon test). CONCLUSIONS: To study hard tissue morphology, CBCT acquisitions require voxel sizes smaller than 300 MUm. This experimental study will have to be complemented by studies in vivo that consider the conditions of clinical practice. PMID- 25146012 TI - An analysis of moderate sedation protocols used in dental specialty programs: a retrospective observational study. AB - INTRODUCTION: Pain and anxiety control is critical in dental practice. Moderate sedation is a useful adjunct in managing a variety of conditions that make it difficult or impossible for some people to undergo certain dental procedures. The purpose of this study was to analyze the sedation protocols used in 3 dental specialty programs at the Case Western Reserve University School of Dental Medicine, Cleveland, OH. METHODS: A retrospective analysis was performed using dental school records of patients receiving moderate sedation in the graduate endodontic, periodontic, and oral surgery programs from January 1, 2010, to December 31, 2012. Information was gathered and the data compiled regarding the reasons for sedation, age, sex, pertinent medical conditions, American Society of Anesthesiologists physical status classifications, routes of administration, drugs, dosages, failures, complications, and other information that was recorded. RESULTS: The reasons for the use of moderate sedation were anxiety (54%), local anesthesia failures (15%), fear of needles (15%), severe gag reflex (8%), and claustrophobia with the rubber dam (8%). The most common medical conditions were hypertension (17%), asthma (15%), and bipolar disorder (8%). Most patients were classified as American Society of Anesthesiologists class II. More women (63.1%) were treated than men (36.9%). The mean age was 45 years. Monitoring and drugs varied among the programs. The most common tooth treated in the endodontic program was the mandibular molar. CONCLUSIONS: There are differences in the moderate sedation protocols used in the endodontic, periodontic, and oral surgery programs regarding monitoring, drugs used, and record keeping. PMID- 25146013 TI - Biologic activity of porphyromonas endodontalis complex lipids. AB - INTRODUCTION: Periapical infections secondary to pulpal necrosis are associated with bacterial contamination of the pulp. Porphyromonas endodontalis, a gram negative organism, is considered to be a pulpal pathogen. P. gingivalis is phylogenetically related to P. endodontalis and synthesizes several classes of novel complex lipids that possess biological activity, including the capacity to promote osteoclastogenesis and osteoclast activation. The purpose of this study was to extract and characterize constituent lipids of P. endodontalis and evaluate their capacity to promote proinflammatory secretory responses in the macrophage cell line, RAW 264.7, as well as their capacity to promote osteoclastogenesis and inhibit osteoblast activity. METHODS: Constituent lipids of both organisms were fractionated by high-performance liquid chromatography and were structurally characterized using electrospray mass spectrometry or electrospray-mass spectrometry/mass spectrometry. The virulence potential of P. endodontalis lipids was then compared with known biologically active lipids isolated from P. gingivalis. RESULTS: P. endodontalis total lipids were shown to promote tumor necrosis factor alpha secretion from RAW 264.7 cells, and the serine lipid fraction appeared to account for the majority of this effect. P. endodontalis lipid preparations also increased osteoclast formation from RAW 264.7 cells, but osteoblast differentiation in culture was inhibited and appeared to be dependent on Toll-like receptor 2 expression. CONCLUSIONS: These effects underscore the importance of P. endodontalis lipids in promoting inflammatory and bone cell activation processes that could lead to periapical pathology. PMID- 25146014 TI - Temporal-controlled release of bovine serum albumin from chitosan nanoparticles: effect on the regulation of alkaline phosphatase activity in stem cells from apical papilla. AB - INTRODUCTION: The controlled delivery of bioactive molecules is crucial for the regulation of stem cell differentiation. In this study, we examined the effects of temporal-controlled release of bovine serum albumin (BSA) from chitosan nanoparticles (CSnp) to regulate the alkaline phosphatase activity (ALP) in stem cells from apical papilla (SCAP). METHODS: BSA-loaded CSnp were synthesized by 2 methods to achieve the variant temporal-controlled release: (1) the encapsulation technique (BSA-CSnpI) and (2) the adsorption technique (BSA-CSnpII). After characterization of the size, charge, and release kinetics, SCAP were cultured in the presence of these bioactive molecule-loaded nanoparticles. SCAP viability was analyzed at 1, 7, 14, 21, and 28 days, and ALP activity was analyzed every 7 days until 21 days to determine the effect of these bioactive molecule-releasing nanoparticles on the cytotoxicity and differentiation potential, respectively. RESULTS: BSA-CSnpI and BSA-CSnpII presented distinct in vitro release profiles of BSA in a time-controlled manner. Cell viability was significantly enhanced over time in the presence of BSA-CSnpI and BSA-CSnpII (P < .01), when compared with BSA nonloaded CSnp. ALP activity was significantly higher (P < .01) in the presence of BSA-CSnpI after 3 weeks than in BSA-CSnpII. CONCLUSIONS: BSA-loaded CSnps were synthesized and characterized in this study. Based on the physical/chemical interaction of BSA with CSnp (encapsulation or surface adsorption), different time-controlled release profiles were observed that influenced the ALP activity of SCAP in vitro. This study highlighted the potential of temporal-controlled bioactive molecule release technology in the differentiation of stem cells in dentin pulp regeneration. PMID- 25146017 TI - Effects of epinephrine on lidocaine pharmacokinetics and blood volume in the dental pulp. AB - INTRODUCTION: Epinephrine potentiates and prolongs the efficacy of local anesthetics by reducing blood flow. We investigated the effect of epinephrine on the pharmacokinetics of lidocaine and the pulpal blood volume after maxillary infiltration anesthesia in rats. METHODS: We measured the (14)C-radioactivity and (14)C-distribution in the maxilla and the dental pulp after the injection of 2% (14)C-lidocaine with or without 10 MUg/mL epinephrine (n = 7) into the palatine mucosa proximal to the first molar. The blood volume in the pulp was measured using (99m)Tc-pertechnetate (n = 5). RESULTS: When lidocaine was injected together with epinephrine, the lidocaine became widely distributed throughout the maxilla and was observed mainly in the first molar pulp. The lidocaine amount in the dental pulp at 10-60 minutes was more than 2 times higher than that after the injection of lidocaine alone. The relative pulpal blood volume after 20 minutes decreased to 63.1% of the value after the injection of lidocaine alone. CONCLUSIONS: We found that lidocaine had infiltrated into the molar pulp after infiltration anesthesia. Furthermore, our results suggested that epinephrine augmented the retention of lidocaine in the pulp. PMID- 25146015 TI - Effect of conditioned medium from preameloblasts on regenerative cellular differentiation of the immature teeth with necrotic pulp and apical periodontitis. AB - INTRODUCTION: The purpose of this study was to investigate the effect of conditioned medium (CM) from murine preameloblasts on the cellular differentiation of mesenchymal stem cells (MSCs) in immature teeth with necrotic pulp and apical periodontitis. METHODS: Pulp necrosis and apical periodontitis were induced in 30 immature permanent double-rooted premolars of 3 beagles and were randomly assigned to the following treatment groups: group CM (n = 10), revascularization treatment was performed using CM from preameloblasts of C57BL/6 mice apical bud cells; group CR (n = 10), conventional revascularization treatment was performed; positive control group (n = 5), left infected; and negative control group (n = 5), untreated. The dogs were followed up for 12 weeks and assessed for treatment outcomes with radiographic and histologic analyses. The effect of the CM on sequential Runx2 and osterix messenger RNA gene expression during the differentiation of MG63 osteoblastlike cells was analyzed with real-time polymerase chain reaction. RESULTS: The overall treatment outcomes were not significantly different between the 2 treatment groups. However, the teeth in the CM group showed significantly more mature apices and a higher degree of hard tissue formation with projections intercalating into the pre-existing root dentin (P < .05). In CM-treated teeth, regenerated pulplike tissue was more frequently observed (P < .05). During differentiation, the CM induced early peak expression of Runx2 followed by sustained osterix overexpression. CONCLUSIONS: CM from preameloblasts rendered a favorable effect in providing a physiologic microenvironment for the differentiation of MSCs after revascularization treatment. PMID- 25146016 TI - Comparison of pulpal responses to pulpotomy and pulp capping with biodentine and mineral trioxide aggregate in dogs. AB - INTRODUCTION: This study evaluated the pulpal and periapical responses of dogs' teeth after pulpotomy and pulp capping with a new tricalcium silicate-based cement (Biodentine) when compared with mineral trioxide aggregate (MTA) by radiographic, histopathologic, and histomicrobiological analyses. METHODS: Sixty roots (30 teeth) of dogs were divided into 2 groups, Biodentine (n = 36 roots) and ProRoot MTA (control, n = 24 roots). Animals were killed after 120 days, and the teeth were subjected to histotechnical processing (hematoxylin-eosin and Brown and Brenn staining). Qualitative and quantitative histopathologic data were analyzed by Fisher exact and Mann-Whitney tests (alpha = 0.05). RESULTS: Radiographically, mineralized tissue bridge formation was observed in more specimens treated with Biodentine (96.8%) than with MTA (72.2%) (P = .02). Integrity of the lamina dura and absence of periapical bone rarefaction and root resorption (external and internal) were observed in all specimens. Histopathologic and histomicrobiological analyses revealed mineralized tissue bridge formation, pulpal vitality, odontoblast layer integrity, preserved periodontal ligament, and absence of bone or root resorption and microorganisms in both groups. Although the bridges formed at the amputation site had similar morphology, they were significantly thicker in the Biodentine group (P < .0001). Comparison between the radiographic and histopathologic results showed that radiographic visualization of more bridges in the Biodentine group was related to bridge thickness because radiographic diagnosis was flawed for bridges with thickness less than 0.5 mm. Fluorescence microscopy improved the visualization of bridge structure. CONCLUSIONS: Biodentine presented tissue compatibility and allowed for mineralized tissue bridge formation after pulpotomy in all specimens with similar morphology and integrity to those formed with use of MTA. Periapical radiographs failed in detecting mineralized tissue bridges with thickness less than 0.5 mm. PMID- 25146018 TI - TLR4 activation by lipopolysaccharide and Streptococcus mutans induces differential regulation of proliferation and migration in human dental pulp stem cells. AB - INTRODUCTION: Dental pulp stem cells (DPSCs) are suspected to be an important part of the innate immune response of dental pulp, which is triggered by microorganisms that progressively invade the human tooth during the formation of caries. This study was performed to elucidate the expression of toll-like receptor 4 (TLR4) in dental pulp of deep caries and to determine whether TLR4 modulates the proliferation and migration of DPSCs. METHODS: Pulp tissue samples were collected from freshly extracted human wisdom tooth. Immunohistochemistry and immunofluorescence were performed to determine the distribution of TLR4 in healthy dental pulp and dental pulp in deep caries. DPSCs were cultured and purified by collecting multiple colonies. The proliferation and migration of DPSCs were examined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide, scratch test, and transwell migration assay after stimulation with lipopolysaccharide and extracts from Streptococcus mutans. TLR4 messenger RNA (mRNA) and cytokine mRNA were evaluated with real-time polymerase chain reaction; TLR4 protein was examined with Western blot and immunocytochemistry. RESULTS: TLR4 is expressed in the odontoblast layer and areas that colocalize with blood vessels to different levels in healthy teeth and teeth affected by caries. TLR4 mRNA, TLR4 protein, and mRNA of cytokine levels can be elevated with stimulations of LPS and extracts from S. mutans. Lipopolysaccharide and extracts from S. mutans treatment inhibited the proliferation of DPSCs but promoted migration; however, these changes were abolished when TLR4 was blocked by anti-TLR4 antibody. CONCLUSIONS: These results suggest that TLR4 will be activated and regulate the proliferation and migration of DPSCs in deep caries. TLR4 may play an important role in the immune response by DPSCs. PMID- 25146019 TI - Modulatory roles of interferon-gamma through indoleamine 2, 3-dioxygenase induction in innate immune response of dental pulp cells. AB - INTRODUCTION: Marked infiltration of inflammatory cells such as activated T cells producing interferon-gamma (IFN-gamma) is observed in severe pulpitis. However, the roles of IFN-gamma in the innate immune response of dental pulp have not been reported. Indoleamine 2, 3-dioxygenase (IDO) is a regulator of immune responses, and the IDO expression is induced by IFN-gamma in many cells whose expression in dental pulp is unknown. The purpose of this study was to determine the role of IFN-gamma in the immune response through microbial pattern recognition receptors (PRRs) such as Toll-like receptors or nucleotide-binding oligomerization domain like receptors on the production of proinflammatory cytokines such as CXCL10 and interleukin (IL)-6 and the expression of IDO in cultured human dental pulp cells (HDPCs). METHODS: HDPCs were established from explant cultures of healthy pulp tissues. CXCL10 and IL-6 production was determined using enzyme-linked immunosorbent assay. Confirmation of IDO localization in dental pulp tissues was examined using immunohistochemistry. IDO expression in HDPCs was analyzed by immunoblot. RESULTS: IFN-gamma significantly up-regulated CXCL10 and IL-6 production in the HDPCs stimulated with ligands for PRRs in a concentration dependent manner. The expression of IDO was detected in inflamed pulp tissue. In addition, IFN-gamma in combination with the PRR ligands enhanced IDO expression in HDPCs compared with IFN-gamma alone. Moreover, CXCL10 production in IFN-gamma stimulated HDPCs was inhibited by an IDO inhibitor. CONCLUSIONS: This study showed the synergistic effects by IFN-gamma on cytokine production and IDO expression in HDPCs, suggesting that IFN-gamma may modulate the innate immune response of dental pulp. PMID- 25146020 TI - Histologic comparison between platelet-rich plasma and blood clot in regenerative endodontic treatment: an animal study. AB - INTRODUCTION: In regenerative endodontic treatment (RET) for immature permanent tooth, better treatment results could be obtained by applying platelet-rich plasma (PRP) as the scaffold rather than the blood clot. The goal of this study was to compare the histologic differences between using PRP and blood clot in RET. METHODS: Three 6-month-old beagles each carrying 9 premolars with double root canals were randomly assigned to the PRP group, blood clot group, or negative control group. All experimental teeth suffered apical periodontitis, and RET was performed. In the blood clot group, bleeding was induced from the periapical tissues to fill the canal space. In the PRP group, autologous PRP was injected into each root canal. The animals were sacrificed 3 months later. Histologic sections were stained with hematoxylin-eosin. Statistical analysis was performed by the Fisher exact test, with the significance set at 0.05. RESULTS: With the ingrowth of cellular cementumlike tissues, the canal wall was thickened, and the apical apex was closed in both the PRP and blood clot groups. Cementocytelike cells were present in the newly formed tissues. Meanwhile, no statistical difference was found in both experimental groups for the average percentage of apical closure, new tissue formation, and pulplike tissue formation. Noticeably, a large number of inflammatory cells were present in some root canals in both groups although the postoperative radiograph revealed the disappearance of periapical radiolucency. CONCLUSIONS: PRP application could be an option for clinical cases in which little or no bleeding were found when irritating the apical tissue during RET. PMID- 25146021 TI - Histochemical localization of Dickkopf-1 in induced rat periapical lesions. AB - INTRODUCTION: The purpose of this study was to evaluate the expression of Dickkopf-1 (DKK-1), a secreted antagonist of the Wnt (wingless)/beta-catenin signaling pathway, during the development of periapical lesions in rats. METHODS: Periapical lesions were induced in Wistar rats by occlusal exposure of the pulp of their mandibular first molars. The animals were sacrificed randomly at 0, 7, 14, 21, and 28 day after pulpal exposure. Jaws containing the first molar were obtained and routinely prepared for histologic, immunohistochemical, and enzyme histochemical double immunofluorescence analyses. Data were analyzed using 1-way analysis of variance and Pearson correlation test. RESULTS: The expansion of the area of periapical lesions was visible from days 7-21 and slowed down thereafter. A few DKK-1- and receptor activator of nuclear factor kappa B ligand (RANKL) positive cells and osteoclasts were observed on day 7. All positive samples peaked in number on day 14. The expression levels of DKK-1 and RANKL and the number of osteoclasts decreased on days 21 and 28. DKK-1 expression was positively correlated with RANKL expression and osteoclast number from days 7-28. CONCLUSIONS: DKK-1 expression was up-regulated during periapical lesion development. DKK-1 may be associated with the inflammatory response and bone resorption in periapical lesions. PMID- 25146022 TI - Down-regulation of inflammatory mediator synthesis and infiltration of inflammatory cells by MMP-3 in experimentally induced rat pulpitis. AB - INTRODUCTION: Matrix metalloproteinase (MMP)-3 is a member of the MMP family that degrades the extracellular matrix. Application of MMP-3 to injured pulp tissue induces angiogenesis and wound healing, but its anti-inflammatory effects are still unclear. Here, we evaluated the anti-inflammatory functions of MMP-3 in vitro and in vivo. METHODS: Nitric oxide and inflammatory mediator synthesis in macrophages activated by lipopolysaccharide (LPS) was measured in the presence or absence of MMP-3. The mouse Mmp3 (mMmp3) expression vector containing full length cDNA sequence of mMmp3 or cDNA sequence of mMmp3 missing the signal peptide and pro-peptide regions was transfected to RAW264, a mouse macrophage cell line, and NO synthesis and inflammatory mediator expression were evaluated. Pulpal inflammation was histologically and immunohistochemically evaluated in a rat model of incisor pulpitis induced by the application of LPS for 9 hours in the presence or absence of MMP-3. RESULTS: NO and pro-inflammatory mediator synthesis promoted by LPS was significantly down-regulated by MMP-3 in vitro. The full length of mMmp3 down-regulated the LPS-induced NO synthesis and chemical mediator mRNA expression, however the mMmp3 missing the signal peptide failed to block the NO synthesis induced by LPS. The numbers of major histocompatibility complex class II+ and CD68+ cells, which infiltrated into the rat incisor pulp tissues in response to the topical application of LPS, were significantly decreased by the application of MMP-3 in vivo. CONCLUSIONS: These results indicate that MMP-3 possesses anti-inflammatory functions, suggesting its potential utility as an anti-inflammatory agent for pulpal inflammation. PMID- 25146023 TI - Hypoxia modulates the differentiation potential of stem cells of the apical papilla. AB - INTRODUCTION: Stem cells from the apical papilla (SCAP) are a population of mesenchymal stem cells likely involved in regenerative endodontic procedures and have potential use as therapeutic agents in other tissues. In these situations, SCAP are exposed to hypoxic conditions either within a root canal devoid of an adequate blood supply or in a scaffold material immediately after implantation. However, the effect of hypoxia on SCAP proliferation and differentiation is largely unknown. Therefore, the objective of this study was to evaluate the effect of hypoxia on the fate of SCAP. METHODS: SCAP were cultured under normoxia (21% O2) or hypoxia (1% O2) in basal or differentiation media. Cellular proliferation, gene expression, differentiation, and protein secretion were analyzed by live imaging, quantitative reverse-transcriptase polymerase chain reaction, cellular staining, and enzyme-linked immunosorbent assay, respectively. RESULTS: Hypoxia had no effect on SCAP proliferation, but it evoked the up regulation of genes specific for osteogenic differentiation (runt-related transcription factor 2, alkaline phosphatase, and transforming growth factor beta1), neuronal differentiation ( 2'-3'-cyclic nucleotide 3' phosphodiesterase, SNAIL, neuronspecific enolase, glial cell-derived neurotrophic factor and neurotrophin 3), and angiogenesis (vascular endothelial growth factor A and B). Hypoxia also increased the sustained production of VEGFa by SCAP. Moreover, hypoxia augmented the neuronal differentiation of SCAP in the presence of differentiation exogenous factors as detected by the up-regulation of NSE, VEGFB, and GDNF and the expression of neuronal markers (PanF and NeuN). CONCLUSIONS: This study shows that hypoxia induces spontaneous differentiation of SCAP into osteogenic and neurogenic lineages while maintaining the release of the proangiogenic factor VEGFa. This highlights the potential of SCAP to promote pulp dentin regeneration. Moreover, SCAP may represent potential therapeutic agents for neurodegenerative conditions because of their robust differentiation potential. PMID- 25146024 TI - Debris remaining in the apical third of root canals after chemomechanical preparation by using sodium hypochlorite and glyde: an in vivo study. AB - INTRODUCTION: During chemomechanical instrumentation, several liquid or paste substances are used to ease the action of the files and to eliminate debris and the smear layer. The aim of this study was to evaluate whether the use of a paste containing EDTA during cleaning and shaping of the root canal helps to eliminate debris. METHODS: Twenty root canals in dog teeth were instrumented by a crown down technique by using nickel-titanium rotary files. In 10 root canals (group A), sodium hypochlorite was used during instrumentation, followed by a final irrigation with 17% liquid EDTA. In another 10 canals (group B), sodium hypochlorite was again used as the irrigating solution, but Glyde File Prep paste was used with every instrument, and a final irrigation with EDTA was also carried out. Two additional teeth were used as positive and 2 as negative controls. The jaws were prepared for histologic evaluation. RESULTS: In group A where Glyde was not used during cleaning and shaping, little or no debris was found in the apical third of the instrumented root canals; however; in group B in which Glyde File Prep paste was used during chemomechanical instrumentation, moderate to high accumulation of debris was observed in the apical third. CONCLUSIONS: The use of Glyde File Prep paste during rotary mechanical instrumentation favors the accumulation of debris in the apical third of the root canals. Irrigation with NaOCl and a final flush with EDTA by means of a small-gauge needle with simultaneous aspiration led to less accumulation of debris than in the Glyde File Prep group (P < .05). PMID- 25146025 TI - Sealapex Xpress and RealSeal XT feature tissue compatibility in vivo. AB - OBJECTIVE: This study evaluated the response of apical and periapical tissues of dogs' teeth with pulp vitality after root canal filling with the endodontic sealers Sealapex Xpress and Real Seal XT. METHODS: Thirty-eight root canals with vital pulp from dogs' premolars were used. After instrumentation, the canals were filled with Sealapex Xpress and gutta-percha (group SX/GP, n = 16) or Real Seal XT and Resilon cones (group RS/R, n = 22). The animals were killed after 90 days, and the teeth with surrounding tissues were subjected to histotechnical processing. Hematoxylin-eosin-stained sections were examined by conventional light microscopy for a quantitative histopathologic analysis (sealing of apical opening by newly formed mineralized tissue [biological sealing], inflammatory cell infiltrate, root and bone tissue resorption), according to a scoring system. The subsequent sections were evaluated by immunohistochemistry for identification of mineralization markers (osteopontin, alkaline phosphatase, and RUNX2). Data were analyzed by nonparametric Mann-Whitney U test (alpha = 0.05). RESULTS: Complete biological sealing was observed in 50% and 22.7% of the specimens of groups SX/GP and RS/R, respectively. Partial biological sealing was observed in 25% and 54.6% and absence of sealing in 25% and 22.7% of the specimens of groups SX/GP and RS/R, respectively. There were no significant differences (P > .05) between the groups for the scores attributed to the histopathologic parameters. Positive staining for osteopontin, alkaline phosphatase, and RUNX2 was observed in both groups, especially in the periodontal ligament. CONCLUSIONS: Sealapex Xpress and RealSeal XT feature tissue compatibility in vivo and allow for sealing of apical opening by deposition of mineralized tissue. PMID- 25146027 TI - Correlation of root dentin thickness and length of roots in mesial roots of mandibular molars. AB - INTRODUCTION: The purpose of this study was to analyze the relation of tooth length and distal wall thickness of mesial roots in mandibular molars at different locations (ie, 2 mm below the furcation and at the junction between the middle and apical third). METHODS: Forty-five mandibular first molars were taken, and the length of each tooth was measured. Then, specimens were divided into three groups according to their length: group I-long (24.2 mm +/- 1.8), group II medium (21 mm +/- 1.5) and group III-short (16.8 mm +/- 1.8). mesial root of each marked at two levels - at 2 mm below the furcation as well as at junction of apical and middle third of roots. The minimum thickness of the distal root dentine associated with the buccal and lingual canals of the mesial roots was measured, The distance between the buccal and lingual canals and the depth of concavity in the distal surface of the mesial roots were also measured. RESULTS: Statistical analysis was performed by using analysis of variance and the Student Newman-Keuls test. The minimum thickness of the distal wall of the mesiobuccal canal was significantly different (P < .001) between groups 1 (long) and 3 (short). CONCLUSIONS: Distal wall thickness of the mesiobuccal root and distal concavity of the mesial root of mandibular first molars were found to be thinner in longer teeth compared with shorter teeth. PMID- 25146026 TI - Capping a pulpotomy with calcium aluminosilicate cement: comparison to mineral trioxide aggregates. AB - INTRODUCTION: Calcium aluminate cements have shown little affinity for bacterial growth, low toxicity, and immunogenicity when used as a restoration material, but calcium aluminate cements have not been tested in vivo in pulpotomy procedures. METHODS: To address this question, a calcium aluminosilicate cement (Quick-Set) was tested along with 2 mineral trioxide aggregates, ProRoot MTA and MTA Plus. These cements were used as a capping agent after pulpotomy. Control rats had no pulpotomy, or the pulpotomy was not capped. Proinflammatory cytokines interleukin (IL)-1beta and IL-1alpha were measured, and histology was performed at 30 and 60 days after capping. The nociceptive response was determined by measuring the lengthening of the rat's meal duration. RESULTS: and CONCLUSIONS: IL-1beta and IL 1alpha concentrations were reduced in the capped teeth, but no differences were observed among the 3 cements. Dentinal bridging could be detected at both 30 and 60 days with each of the 3 cements, and the pulps were still vital 60 days after capping. Meal duration significantly shortened after placement of the 3 different cements, indicating a nociceptive response, but there were no differences among the materials. Calcium aluminosilicate cement had similar properties to mineral trioxide aggregates and is a viable option for pulpotomy procedures. PMID- 25146028 TI - Efficacy of needle irrigation, EndoActivator, and photon-initiated photoacoustic streaming technique on removal of double and triple antibiotic pastes. AB - INTRODUCTION: Photon-induced photoacoustic streaming (PIPS) is a novel technique used for the removal of material on root canal walls, such as bacteria and the smear layer. This study evaluated the efficacy of needle irrigation, the EndoActivator System (Dentsply Tulsa Dental Specialties, Tulsa, OK), and PIPS on the removal of antibiotic pastes from an artificial groove created in a root canal. METHODS: Root canal preparation was performed up to size #40 on 84 extracted single-rooted teeth using ProTaper rotary instruments (Dentsply Maillefer, Ballaigues, Switzerland). The specimens were then split longitudinally, and 2 standardized grooves were prepared in the coronal and apical part of each segment. Double (DAP) and triple antibiotic pastes (TAP) were placed in the grooves for 4 weeks, and the root halves were reassembled. Needle irrigation, the EndoActivator System, and PIPS were used for the removal of DAP and TAP. The root segments were disassembled, and the amount of remaining antibiotic pastes was evaluated under a stereomicroscope at 20* magnification using a 4-grade scoring system. The data were evaluated statistically using Mann Whitney U tests with a 95% confidence level (P = .05). RESULTS: PIPS removed significantly more antibiotic pastes than the EndoActivator and needle irrigation (P < .001). The EndoActivator was superior to needle irrigation in removing antibiotic pastes (P < .001). There were no statistically significant differences between DAP and TAP and between coronal and apical thirds in their removing from artificially created grooves (P > .05). CONCLUSIONS: PIPS was more effective in removing both DAP and TAP from artificial grooves in root canals than the EndoActivator System and needle irrigation. The EndoActivator was also more effective than needle irrigation. It is difficult to completely remove antibiotic pastes from root canals. PMID- 25146029 TI - Assessment of dentinal damage during canal preparation using reciprocating and rotary files. AB - INTRODUCTION: The role of motion kinematics in creating dentinal damage during instrumentation is not very clear. The purpose of this study was to compare the formation of dentinal cracks with instruments working in continuous rotation and reciprocating motion. METHODS: One hundred twenty extracted human mandibular premolars were selected for the study. Thirty teeth served as controls, and the remaining 90 teeth were divided into 3 groups depending on the root canal preparation technique. Group 1 samples were treated with WaveOne primary files (Dentsply Maillefer, Ballaigues, Switzerland), group 2 samples with single F2 ProTaper (Dentsply Maillefer) working in reciprocating motion, and group 3 samples were prepared with sequential ProTaper (Dentsply Maillefer) until F2 working in continuous rotation motion. Roots were then sectioned at 3, 6, and 9 mm from the apex, and the cut surface was observed under a stereomicroscope for the presence of dentinal microcracks. RESULTS: The control group and WaveOne, single F2 ProTaper in reciprocating motion, and continuous ProTaper groups caused cracks in 0%, 15%, 26%, and 53% of samples, respectively. A statistically significant difference was found between 2 reciprocating file groups (WaveOne and single F2 ProTaper in reciprocating motion) and the continuous rotation group (ProTaper) (P < .05). However, no significant difference was found among the 2 reciprocating file groups (P > .05). CONCLUSIONS: Dentinal cracks are produced irrespective of motion kinematics. Within the limits of this study and the current literature, such incidence is less with instruments working in reciprocating motion compared with those working in continuous rotation. PMID- 25146030 TI - Lack of causal relationship between dentinal microcracks and root canal preparation with reciprocation systems. AB - INTRODUCTION: This study aimed to evaluate the frequency of dentinal microcracks observed after root canal preparation with 2 reciprocating and a conventional full-sequence rotary system using micro-computed tomographic analysis. METHODS: Thirty mesial roots of mandibular molars presenting a type II Vertucci canal configuration were scanned at an isotropic resolution of 14.16 MUm. The sample was randomly assigned to 3 experimental groups (n = 10) according to the system used for the root canal preparation: group A-Reciproc (VDW, Munich, Germany), group B-WaveOne (Dentsply Maillefer, Baillagues, Switzerland), and group C BioRaCe (FKG Dentaire, La-Chaux-de-Fonds, Switzerland). Second and third scans were taken after the root canals were prepared with instruments sizes 25 and 40, respectively. Then, pre- and postoperative cross-section images of the roots (N = 65,340) were screened to identify the presence of dentinal defects. RESULTS: Dentinal microcracks were observed in 8.72% (n = 5697), 11.01% (n = 7197), and 7.91% (n = 5169) of the cross-sections from groups A (Reciproc), B (WaveOne), and C (BioRaCe), respectively. All dentinal defects identified in the postoperative cross-sections were also observed in the corresponding preoperative images. CONCLUSIONS: No causal relationship between dentinal microcrack formation and canal preparation procedures with Reciproc, WaveOne, and BioRaCe systems was observed. PMID- 25146031 TI - Blue treatment enhances cyclic fatigue resistance of vortex nickel-titanium rotary files. AB - INTRODUCTION: The aim of the present study was to evaluate the difference in cyclic fatigue resistance between Vortex Blue (Dentsply Tulsa Dental, Tulsa, OK) and Profile Vortex nickel-titanium (Dentsply Tulsa Dental) rotary instruments. METHODS: Two groups of nickel-titanium endodontic instruments, ProFile Vortex and Vortex Blue, consisting of identical instruments in tip size and taper (15/.04, 20/.06, 25/.04, 25/.06, 30/.06, 35/.06, and 40/.04) were tested. Ten instruments from each system and size were tested for cyclic fatigue resistance, resulting in a total of 140 new instruments. All instruments were rotated in a simulated root canal with a 60 degrees angle of curvature and a 5-mm radius of curvature of a specific cyclic fatigue testing device until fracture occurred. The number of cycles to failure and the length of the fractured tip were recorded for each instrument in each group. The mean values and standard deviation were calculated, and data were subjected to 1-way analysis of variance and a Bonferroni t test. Significance was set at the 95% confidence level. RESULTS: When comparing the same size of the 2 different instruments, a statistically significant difference (P < .05) was noted between all sizes of Vortex Blue and Profile Vortex instruments except for tip size 15 and .04 taper (P = 1.000). No statistically significant difference (P > .05) was noted among all groups tested in terms of fragment length. CONCLUSIONS: Vortex Blue showed a significant increase in cyclic fatigue resistance when compared with the same sizes of ProFile Vortex. PMID- 25146032 TI - Influence of drying protocol with isopropyl alcohol on the bond strength of resin based sealers to the root dentin. AB - INTRODUCTION: This study compared the bond strength, interfacial ultrastructure, and tag penetration of resin-based sealers applied to smear-free radicular dentin using 70% isopropyl alcohol as the active final rinse. METHODS: Eighty root canals were prepared and assigned to 2 groups (n = 40) according to the drying protocol: paper points or 70% isopropyl alcohol. Then, roots were divided into 4 subgroups (n = 10) with respect to the sealer and obturation material: AH Plus (Dentsply De Trey GmbH, Konstanz, Germany) and gutta-percha (AH/GP), Hybrid Root SEAL (Sun Medical, Tokyo, Japan) and gutta-percha (HR/GP), Epiphany SE (Pentron Clinical Technologies, Wallingford, CT) and gutta-percha (EP/GP), and Epiphany SE and Resilon (EP/RS). Roots were sectioned, and the push-out test was performed. Failure modes were examined under stereomicroscopy and sealer penetration into the dentinal tubules under scanning electron microscopy. Data were statistically analyzed by 2-way analysis of variance post hoc Tukey tests with a significant level of 5%. RESULTS: Overall, canals dried with isopropyl alcohol showed significantly higher bond strength values (2.11 +/- 1.74 MPa) than with paper points (1.81 +/- 1.73 MPa) (P < .05). The HR/GP group showed lower bond strength than the AH/GP group (P < .05) but higher than the EP/GP and EP/RS groups (P < .05). The most frequent type of failure was cohesive in the AH/GP and HR/GP groups and adhesive in the EP/GP and EP/RS groups. Scanning electron microscopic evaluation revealed better adaptation of the adhesive interface in the AH/GP and HR/GP groups in comparison with the EP/GP and EP/RS groups. CONCLUSIONS: A final rinse with EDTA and 70% isopropyl alcohol improved the bond strength and penetration of the sealers into dentinal tubules of the root. PMID- 25146033 TI - Immediate shear bond strength of resin cements to sodium hypochlorite-treated dentin. AB - INTRODUCTION: The purpose of this in vitro study was to evaluate the immediate shear bond strength of different categories of resin cements on sodium hypochlorite (NaOCl)-treated dentin and to evaluate if the bond was improved by a subsequent treatment with 10% sodium ascorbate before adhesive procedures. METHODS: This study tested immediate shear bond strengths to human dentin of 5 resin cements: Variolink II (Ivoclar Vivadent, Schaan, Liechtenstein), Multilink (Ivoclar Vivadent), Clearfil Esthetic Cement EX (Kuraray, Tokyo, Japan), SpeedCEM (Ivoclar Vivadent), and Clearfil SA Cement (Kuraray). All cements were tested with no NaOCl pretreatment of the dentin (negative control) and with a 20-minute exposure of the dentin to 6% NaOCl before bonding procedures. The cements found to have decreased bond strengths to NaOCl-treated dentin were tested with the dentin exposed to 10% sodium ascorbate after NaOCl exposure. The sodium ascorbate exposure times tested were 5 seconds and 1 minute. RESULTS: The mean and standard deviation values for immediate shear bond strength (MPa) for the negative control group were as follows: Variolink II, 18.8 +/- 4.2; Multilink, 29.1 +/- 7.1; Clearfil Esthetic Cement EX, 20.7 +/- 4.9; SpeedCEM, 17.8 +/- 4.2; and Clearfil SA Cement, 7.2 +/- 2.8. The results for the NaOCl exposure group were as follows: Variolink II, 24.0 +/- 6.7; Multilink, 34.1 +/- 6.1; Clearfil Esthetic Cement EX, 20.7 +/- 6.8; SpeedCEM, 0.0 +/- 0.0; and Clearfil SA Cement, 0.1 +/- 0.1. The results for the 5-second sodium ascorbate group were the following: SpeedCEM, 8.5 +/- 2.6, and Clearfil SA Cement, 4.3 +/- 2.0. The following results were found for the 1-minute sodium ascorbate group: SpeedCEM, 12.2 +/- 3.2, and Clearfil SA Cement, 4.8 +/- 1.0. CONCLUSIONS: The resin cements tested varied in their capacity to adhere to NaOCl-treated dentin. Some resin cements exhibited equal or improved bond strengths (P < .05), whereas others exhibited significantly decreased bond strengths (P < .05). For the susceptible resin cements, a rinse of 10% sodium ascorbate provided an immediate restoration of at least 50% of the original bond strength (P < .05). The efficacy of sodium ascorbate may vary among resin cements. PMID- 25146034 TI - In vitro comparison in a manikin model: increasing apical enlargement with K3 and K3XF rotary instruments. AB - INTRODUCTION: The aim of the study was to compare the K3 and K3XF systems (SybronEndo, Glendora, CA) after 1 and 2 uses by evaluating apical transportation, working length loss, and working time in a manikin model. METHODS: Mesial canals of 40 extracted first mandibular molars were instrumented. Radiographs taken after instrumentation with #25, #30, #35, and #40 files were superimposed on the preoperative image in both mesiodistal and buccolingual angulations. AutoCAD (Autodesk Inc, San Rafael, CA) was used to measure working length loss and apical transportation at 0, 0.5, and 1 mm from the working length (WL). The working time was measured. Group comparison was analyzed using post hoc Tukey honestly significant difference tests (P < .05). RESULTS: No significant differences were found in apical transportation, working length loss between K3 and K3XF systems, or between the number of uses. Significant differences were found when canal enlargement was performed to a #35-40 (P < .05). K3 instrumentation performed significantly faster (29.6 +/- 15.4) than with the K3XF system (40.2 +/- 17.7) (P < .05). No differences were observed in working time when comparing the number of uses. CONCLUSIONS: K3 and R-phase K3XF rotary systems shaped curved root canals safely with minimal apical transportation, even up to a 40/04 file. PMID- 25146036 TI - Influence of cone-beam computed tomographic scan mode for detection of horizontal root fracture. AB - INTRODUCTION: The purpose of the present study was (1) to test the accuracy of a small-volume cone-beam computed tomographic (CBCT) device in detecting horizontal root fractures (HRFs) in teeth with and without an intracanal metallic post (IMP) and (2) to investigate the use of 2 different acquisition protocols of a CBCT device for HRF diagnosis. METHODS: Forty endodontically treated teeth with and without an IMP were examined using PreXion 3D CBCT scanner (Terarecon, San Mateo, CA) with a 5-cm high and 5-cm diameter cylinder at 0.10-mm voxel reconstruction. Two observers analyzed the samples to determine the presence and location of HRFs. RESULTS: Sensitivity values ranged from 0.40-0.80. The most favorable results were found for the samples with no IMP observed using the protocol of a higher number of x-ray projections (0.70-0.80). Accuracy in the groups with an IMP ranged from 75%-90% in the 1024 x-ray projection protocol (HI-HI group) versus 70%-85% for the same samples examined in the 512 x-ray projection protocol (HI-STD group). Intraobserver agreement ranged from relevant to perfect concordance for both protocols (HI-HI = Kappa: 0.60-1.00 and HI-STD = Kappa: 0.55 0.89). Interobserver agreement ranged from moderate to perfect concordance for both protocols (HI-HI = Kappa: 0.79-0.89 and HI-STD = Kappa: 0.42-0.76). CONCLUSIONS: Even though there are statistically significant differences for the protocol with the higher number of x-ray projections, we found high accuracy, sensitivity, sensibility, and intra- and interobserver agreement in detecting HRFs for both Prexion 3D protocols. PMID- 25146035 TI - Shaping ability of waveone primary reciprocating files and ProTaper system used in continuous and reciprocating motion. AB - INTRODUCTION: The purpose of this study was to compare the shaping effects of Wave One (Dentsply Maillefer, Ballaigues, Switzerland) and full-sequence ProTaper nickel-titanium (NiTi) files (Dentsply Maillefer) used in reciprocating and conventional movements in a simulated canal. METHODS: Seventy-five S-shaped canals in resin blocks were randomly allocated to 3 groups (n = 25): WaveOne (group 1), full sequence of ProTaper Universal files in conventional movements (group 2), and full sequence of ProTaper Universal files in reciprocating movements (group 3). Preoperative and postoperative photographs of the simulated canals were taken under standardized conditions, after which they were accurately superimposed. Two methods were adopted to evaluate the shaping ability of the 3 approaches: measuring the differences in apical and coronal curvature modifications and measuring the amount of resin removed for both curvatures on the right and left sides of the simulated canals. Differences in canal curvature modifications and in the amount of resin removed were analyzed using 1-way analysis of variance (P < .0001) followed by a Tukey-Kramer multiple comparison post hoc test and mixed-effects linear model (P < .05), respectively. METHODS: Group 3 maintained better coronal and apical canal curvature and less straightening of the simulated canals with respect to groups 1 and 2. CONCLUSIONS: When preparing S-shaped canals, full-sequence ProTaper Universal NiTi files used in a reciprocating motion exhibited better shaping effects than full-sequence ProTaper Universal NiTi files used in a conventional motion and WaveOne. PMID- 25146037 TI - Differences in cyclic fatigue resistance between ProTaper Next and ProTaper Universal instruments at different levels. AB - INTRODUCTION: New designs and alloys have been developed to increase cyclic fatigue (CF) resistance of rotary files. The aim of this study was to compare CF resistance of ProTaper Universal (PTU; Dentsply Tulsa Dental, Tulsa, OK) and ProTaper Next (PTN, Dentsply Tulsa Dental) instruments at different points of curvature. METHODS: A total of 420 files (240 PTU, S1, F1, F2, and F3 and 180 PTN, X1, X2, and X3) were divided in 14 groups of 30 instruments each. Instruments in groups S1-5, F1-5, X1-5, F2-5, X2-5, F3-5, and X3-5 were tested at 5 mm from the tip. Groups S1-12, X1-12, and F1-12 were tested at 12 mm from the tip because S1, X1, and F1 instruments have the same diameter at that level. Groups F2-8, X2-8, F3-8, and X3-8 were tested at 8 mm (F2/X2 and F3/X3, respectively, had the same diameter at 8 mm). All files were rotated at 300 rpm until fracture. CF resistance was tested in stainless steel curved canals (60 degrees , r = 3 mm). Time to fracture was recorded. The mean half-life and beta and eta were calculated for each group and were compared with Weibull analysis. RESULTS: PTN instruments will last significantly longer than PTU files with a probability higher than 98% at all tested levels except for S1, which was the significantly the most resistant instrument to CF at 5 mm from the tip. CONCLUSIONS: PTU S1 was significantly the most resistant instrument at 5 mm from the tip. PTN files were significantly more resistant to CF than PTU instruments at all the other tested levels. PMID- 25146038 TI - Effects of ProTaper Universal, ProTaper Next, and HyFlex instruments on crack formation in dentin. AB - INTRODUCTION: The aim of the present study was to investigate the incidence of cracks in root dentin after root canal preparation with ProTaper Next (Dentsply Maillefer, Ballaigues, Switzerland), HyFlex (Coltene-Whaledent, Allstetten, Switzerland), and ProTaper Universal (Dentsply Maillefer) rotary instruments. METHODS: One-hundred mandibular premolars were selected. Twenty-five teeth were left unprepared and served as a negative control; another 25 teeth were instrumented with the ProTaper Universal system up to size F4 as a positive control, and the remaining 50 teeth were shaped with the following experimental groups with an apical size 40 file: ProTaper Next X4 and HyFlex 40/0.4. After root canal preparation, all of the roots were sectioned perpendicular to the long axis at 2, 4, 6, and 8 mm from the apex, and the sections were then observed under a stereomicroscope. The absence/presence of cracks was recorded, and the data were analyzed with a chi-square test. The significance level was set at P = .05. RESULTS: No cracks were observed in the negative control group. Vertical root fractures were not observed in any of the groups. The ProTaper Next and HyFlex instruments caused fewer cracks (28%) than the ProTaper Universal instrument (56%) (P < .05). However, there were no significant differences in crack formation between the ProTaper Next and HyFlex groups (P > .05). CONCLUSIONS: Within the limitations of this in vitro study, all of the instrumentation systems used in this study created cracks in the root dentin. The ProTaper Next and HyFlex instruments tended to cause fewer dentinal cracks compared with the ProTaper Universal instrument. PMID- 25146039 TI - Biocompatibility evaluation of biodentine in subcutaneous tissue of rats. AB - INTRODUCTION: Biodentine (Septodont, St-Maur-des-Fosses, France) is a new material suitable for various clinical situations in endodontics, such as perforation repair, retrograde filling, pulp capping, and others. Because it is a new material, its properties should be analyzed before routine clinical use. Thus, this study evaluated the biocompatibility of Biodentine in the subcutaneous tissue of rats. METHODS: This study was conducted on 15 male rats. Two incisions were made on the dorsal region of each animal for the introduction of 4 tubes. One tube was empty, 1 was filled with zinc oxide-eugenol cement, 1 was filled with mineral trioxide aggregate, and the last tube was filled with Biodentine. After 7, 14, and 30 days, the animals were sacrificed, and the specimens were submitted to histotechnical preparation. The histologic sections were stained with hematoxylin-eosin and analyzed using light microscopy. Scores were established according to the inflammatory process and were statistically compared using the Kruskal-Wallis test (P < .05). RESULTS: The analysis of the histologic sections evidenced a nonsignificant or mild presence of inflammatory reaction in the connective tissue in contact with the empty tube and the tube containing MTA, which was different from the tube containing zinc oxide eugenol. The connective tissue was moderately inflamed at 7 days when in contact with Biodentine; however, at 14 and 30 days, the inflammatory process was mild or nonsignificant. CONCLUSIONS: Biodentine was biocompatible with tissue after the 14th day. PMID- 25146040 TI - Influence of apical root resection on the biomechanical response of a single rooted tooth: a 3-dimensional finite element analysis. AB - INTRODUCTION: Apical root resection is a biologically essential component in endodontic microsurgery. However, because it reduces the total root length and supported root surface, it changes the biomechanical response of the tooth. The purpose of this study was to analyze the biomechanical effect of apical root resection and to compare apical root resection with periodontal bone loss from a biomechanical standpoint. METHODS: Finite element models of the maxillary central incisor were reconstructed. First, preoperative and surgically treated models were generated to assess the factors altering the biomechanical response of the tooth. Then, apically resected models with different amounts of resection (3, 4, 5, 6, 7, and 8 mm) were created to estimate the clinically applicable limit of apical root resection. Periodontally destructed models with varying degrees of bone loss (0.5, 1, 1.5, 2, and 3 mm) were also created to compare the effect of apical root resection with periodontal bone loss. Stress distribution, tooth displacement, and effective crown-to-root ratio (alpha) were analyzed for each condition. RESULTS: Apical root resection did not significantly alter the maximum von Mises stress or tooth displacement until it reached 6 mm (alpha = 0.67) when the tooth was supported by normal periodontium. In contrast, periodontal bone loss had a greater impact on biomechanical response change compared with apical root resection. CONCLUSIONS: For a tooth supported by normal periodontium, 3 mm of apical root resection (alpha = 1.07) appeared to be mechanically acceptable. The biomechanical influence of apical root resection was weak compared with that of periodontal bone loss. PMID- 25146042 TI - Managing endodontic patients with severe gag reflex by glossopharyngeal nerve block technique. AB - INTRODUCTION: Gagging is a protective reflex, but when the gag reflex becomes abnormally active, it poses a difficulty for the dentist because it hinders all aspects of dental procedures including diagnosis, radiography, and any form of active procedure. METHODS: In this case report, to overcome this difficulty the authors used a glossopharyngeal nerve block technique that is used by anesthetists and otolaryngologists, but its endodontic use has gone previously unreported. RESULTS: Response to gag reflex decreases after successful glossopharyngeal nerve block. CONCLUSIONS: The glossopharyngeal nerve block technique is a relatively safe, simple, and easy to master technique as compared with general anesthesia for treating a patient with an exaggerated gag reflex. The glossopharyngeal nerve block technique may be used in dental procedures in patients with an exaggerated gag reflex or when performing procedures in the posterior aspect of the mouth. Due caution should be exercised to prevent inadvertent intravascular administration of local anesthetic when using this procedure. PMID- 25146041 TI - Impact of heat treatments on the fatigue resistance of different rotary nickel titanium instruments. AB - INTRODUCTION: The aim of this study was to assess the influence of M-Wire (Dentsply Tulsa Dental Specialties, Tulsa, OK) and controlled memory technologies on the fatigue resistance of rotary nickel-titanium (NiTi) files by comparing files made using these 2 technologies with conventional NiTi files. METHODS: Files with a similar cross-sectional design and diameter were chosen for the study: new 30/.06 files of the EndoWave (EW; J. Morita Corp, Osaka, Japan), HyFlex (HF; Coltene/Whaledent, Inc, Cuyahoga Falls, OH), ProFile Vortex (PV; Dentsply Tulsa Dental Specialties, Tulsa, OK), and Typhoon (TYP; Clinician's Choice Dental Products, New Milford, CT) systems together with ProTaper Universal F2 instruments (PTU F2; Dentsply Maillefer, Ballaigues, Switzerland). The compositions and transformation temperatures of the instruments were analyzed using x-ray energy-dispersive spectroscopy and differential scanning calorimetry, whereas the mean file diameter values at 3 mm from the tip (D3) were measured using image analysis software. The average number of cycles to failure was determined using a fatigue test device. RESULTS: X-ray energy-dispersive spectroscopy analysis showed that, on average, all the instruments exhibited the same chemical composition, namely, 51% Ni-49% Ti. The PV, TYP, and HF files exhibited increased transformation temperatures. The PTU F2, PV, and TYP files had similar D3 values, which were less than those of the EW and HF files. The average number of cycles to failure values were 150% higher for the TYP files compared with the PV files and 390% higher for the HF files compared with the EW files. CONCLUSIONS: M-Wire and controlled memory technologies increase the fatigue resistance of rotary NiTi files. PMID- 25146044 TI - Bisphosphonate-associated osteonecrosis of jaw reoccurrence after methotrexate therapy: a case report. AB - INTRODUCTION: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well known complication caused by amino-bisphosphonate therapy. We document one case of BRONJ associated with oral administration of methotrexate, a known immunosuppressive drug used to treat rheumatoid arthritis. METHODS: A 66-year-old woman was referred for evaluation and endodontic surgery of recently re-treated tooth 13. Tooth 14 was extracted 3 months prior, and the extraction site had not completely healed. Her medical history revealed rheumatoid arthritis and osteoporosis. She had been taking Fosamax (alendronate) 70 mg daily. Because of adequate root canal therapy of tooth 13, endodontic surgery was performed. Five months after apicoectomy, her symptoms had not changed. Tooth 13 was extracted, and the socket healed without complications. The socket of extracted tooth 14 was also healing. At the 3-month recall visit, bone exposure and purulent discharge at the site of extracted tooth 14 were noted. The patient had recently received methotrexate. The methotrexate was discontinued, and she was given course of amoxicillin. RESULTS: At the 18-month follow-up, the healing progressed, and the wound was closed. CONCLUSIONS: A medication that suppresses the immune system such as methotrexate may complicate the management of BRONJ. Once a diagnosis of BRONJ is made, a closely monitored conservative approach is recommended. PMID- 25146043 TI - The use of cone-beam computed tomography in the preservation of pulp vitality in a maxillary canine with type 3 dens invaginatus and an associated periradicular lesion. AB - INTRODUCTION: Dens invaginatus type 3 is an anomaly characterized by an invagination of enamel and dentin that can extend up to the root apex. It may pose treatment challenges when nonsurgical root canal therapy is deemed necessary. Conventional diagnostic aids such as periapical radiographs play an important role in the assessment of complex root canal morphologies. However, these modalities may sometimes yield insufficient diagnostic information. Cone beam computed tomographic imaging produces 3-dimensional digital images and provides the clinician with a more in-depth understanding of the true morphology of the root canal system. METHODS: This case report describes the diagnosis and conservative treatment of an unusual case of a maxillary canine with an infected type 3 dens invaginatus and an associated periradicular lesion in which the vitality of the surrounding pulp was maintained. Mineral trioxide aggregate was used to fill the entire invagination, whereas the circular true root canal system around the invagination with vital pulp was left untreated. RESULTS: At the 1 year follow-up examination, clinical and radiographic findings showed that a diligent nonsurgical endodontic treatment can result in satisfactory periradicular healing and complete root formation. CONCLUSIONS: The use of cone beam computed tomographic imaging as an auxiliary tool for both diagnosis and planning the treatment of these anomalies is highlighted. PMID- 25146045 TI - The serine protease inhibitor TLCK attenuates intrinsic death pathways in neurons upstream of mitochondrial demise. AB - It is well-established that activation of proteases, such as caspases, calpains and cathepsins are essential components in signaling pathways of programmed cell death (PCD). Although these proteases have also been linked to mechanisms of neuronal cell death, they are dispensable in paradigms of intrinsic death pathways, e.g. induced by oxidative stress. However, emerging evidence implicated a particular role for serine proteases in mechanisms of PCD in neurons. Here, we investigated the role of trypsin-like serine proteases in a model of glutamate toxicity in HT-22 cells. In these cells glutamate induces oxytosis, a form of caspase-independent cell death that involves activation of the pro-apoptotic protein BH3 interacting-domain death agonist (Bid), leading to mitochondrial demise and ensuing cell death. In this model system, the trypsin-like serine protease inhibitor Nalpha-tosyl-l-lysine chloromethyl ketone hydrochloride (TLCK) inhibited mitochondrial damage and cell death. Mitochondrial morphology alterations, the impairment of the mitochondrial membrane potential and ATP depletion were prevented and, moreover, lipid peroxidation induced by glutamate was completely abolished. Strikingly, truncated Bid-induced cell death was not affected by TLCK, suggesting a detrimental activity of serine proteases upstream of Bid activation and mitochondrial demise. In summary, this study demonstrates the protective effect of serine protease inhibition by TLCK against oxytosis induced mitochondrial damage and cell death. These findings indicate that TLCK sensitive serine proteases play a crucial role in cell death mechanisms upstream of mitochondrial demise and thus, may serve as therapeutic targets in diseases, where oxidative stress and intrinsic pathways of PCD mediate neuronal cell death. PMID- 25146046 TI - In this issue of Occupational Medicine. PMID- 25146047 TI - Consent for release of confidential information--ethics in context? PMID- 25146048 TI - Tom Roberts, Shearing the Rams 1890. PMID- 25146049 TI - Factors influencing return to work after hip and knee replacement. AB - BACKGROUND: Return to employment is one of the key goals of joint replacement surgery in the working-age population. There is limited quantitative and qualitative research focusing on return to work after hip and knee replacement. It remains unclear why certain groups of patients are not able to achieve sufficient functional improvement to allow productive return to work while others can. Very little is known about the individual patient and employer perspectives in this regard. AIMS: To review current evidence for the factors influencing employment outcomes in patients undergoing hip and knee replacement. METHODS: Original articles and reviews in Medline, Embase and PsycINFO from 1987 to 2013 were included in the analysis. RESULTS: Age, patient motivation, employment before surgery and type of job were found to be important factors in determining return to work following hip and knee replacement. CONCLUSIONS: There is a need for further qualitative work on how and why these factors influence employment outcomes. PMID- 25146050 TI - Health and safety legislation. PMID- 25146051 TI - The Ontario Workplace Health Champions Program. PMID- 25146052 TI - The raincoat sign. PMID- 25146053 TI - Fifty years ago: 'Occupational health: an employer's view'. 1964. PMID- 25146054 TI - Sensitization to pets in pet shop workers. PMID- 25146055 TI - Bronchiolitis obliterans. PMID- 25146056 TI - The CAGE questionnaire. PMID- 25146057 TI - High incidence of hemiarthroplasty for shoulder osteoarthritis among recently graduated orthopaedic surgeons. AB - BACKGROUND: Primary glenohumeral osteoarthritis is a common indication for shoulder arthroplasty. Historically, both total shoulder arthroplasty (TSA) and hemi-shoulder arthroplasty (HSA) have been used to treat primary glenohumeral osteoarthritis. The choice between procedures is a topic of debate, with HSA proponents arguing that it is less invasive, faster, less expensive, and technically less demanding, with quality of life outcomes equivalent to those of TSA. More recent evidence suggests TSA is superior in terms of pain relief, function, ROM, strength, and patient satisfaction. We therefore investigated the practice of recently graduated orthopaedic surgeons pertaining to the surgical treatment of this disease. QUESTIONS/PURPOSES: We hypothesized that (1) recently graduated, board eligible, orthopaedic surgeons with fellowship training in shoulder surgery are more likely to perform TSA than surgeons without this training; (2) younger patients are more likely to receive HSA than TSA; (3) patient sex affects the choice of surgery; (4) US geographic region affects practice patterns; and (5) complication rates for HSA and TSA are not different. METHODS: We queried the American Board of Orthopaedic Surgery's database to identify practice patterns of orthopaedic surgeons taking their board examination. We identified 771 patients with primary glenohumeral osteoarthritis treated with TSA or HSA from 2006 to 2011. The rates of TSA and HSA were compared based on the treating surgeon's fellowship training, patient age and sex, US geographic region, and reported surgical complications. RESULTS: Surgeons with fellowship training in shoulder surgery were more likely (86% versus 72%; OR 2.32; 95% CI, 1.56-3.45, p<0.001) than surgeons without this training to perform TSA rather than HSA. The mean age for patients receiving HSA was not different from that for patients receiving TSA (66 versus 68, years, p=0.057). Men were more likely to receive HSA than TSA when compared to women (RR 1.54; 95% CI, 1.19 2.00, p=0.0012). The proportions of TSA and HSA were similar regardless of US geographic region (Midwest HSA 21%, TSA 79%; Northeast HSA 25%, TSA 75%; Northwest HSA 16%, TSA 84%; South HSA 27%, TSA 73%; Southeast HSA 24%, TSA 76%; Southwest HSA 23%, TSA 77%; overall p=0.708). The overall complication rates were not different with the numbers available: 8.4% (15/179) for HSA and 8.1% (48/592) for TSA (p=0.7555). CONCLUSIONS: The findings of this study are at odds with the recommendations in the current clinical practice guidelines for the treatment of glenohumeral osteoarthritis published by the American Academy of Orthopaedic Surgeons. These guidelines favor using TSA over HSA in the treatment of shoulder arthritis. Further investigation is needed to clarify if these practice patterns are isolated to recently graduated board eligible orthopaedic surgeons or if the use of HSA continues with orthopaedic surgeons applying for recertification. LEVEL OF EVIDENCE: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 25146058 TI - CORR Insights(r): How do knee implants perform past the second decade? Nineteen- to 25-year followup of the Press-fit Condylar design TKA. PMID- 25146059 TI - Effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy: an experimental pilot study. AB - BACKGROUND: This study explored the effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy. PATIENTS AND METHODS: For this experimental study, 57 subjects were randomly assigned to three groups: acupressure with essential oils (n=17), acupressure only (n=24), and sham acupressure (n=16). Acupoints were Hegu (LI4), Zusanli (ST36), and Sanyingjiao (SP6). All subjects received acupressure once every morning for 5 months, with each acupoint pressed for 1 min. Fatigue, functional status, anxiety, depression, and sleep quality were measured before initial chemotherapy (T0), on Day 1 of third chemotherapy (T1), and on Day 1 of sixth chemotherapy (T2). Outcome differences between groups were analyzed at T0, T1, and T2 by general estimating equations. RESULTS: After controlling for baseline outcome values, age, and adherence to acupressure, subjects who received acupressure with essential oils and acupressure had significantly less fatigue in daily living activities and sleep better quality at T1 than subjects who received sham acupressure. Subjects who received acupressure with essential oils had significantly better sleep quality at T2 than the sham acupressure group. Subjects who received acupressure with or without essential oils had greater odds of better functional status at T1 than the sham group. CONCLUSION: It is plausible that acupressure with or without essential oils helps lung cancer patients undergoing chemotherapy reduce cancer related fatigue and increase activity level. Further study is wanted to test this hypothesis. PMID- 25146060 TI - Pulsed application of focused ultrasound to the LI4 elicits deqi sensations: pilot study. AB - OBJECTIVES: Focused ultrasound (FUS) techniques enable the delivery of acoustic pressure waves to a localized, specific region of anatomy, and mechanically stimulate the sonicated region when given in a train of pulses. The present pilot study examines if the pulsed application of acoustic waves focused to an acupuncture point (LI4, Hegu), i.e. FUS acupuncture, can elicit deqi sensations. DESIGN AND SETTING: The FUS was generated by a single-element ultrasound transducer, and delivered to the LI4 of acupuncture-naive participants (n=10) for a duration of 1s using 2 ms tone-burst-duration and 50 Hz pulse repetition frequency. The subjective ratings of deqi descriptors were obtained across different conditions, i.e. FUS acupuncture using acoustic intensities of 1 and 3 W/cm(2) (spatial-peak temporal-averaged intensity, Ispta), sham sonication condition, tactile stimulation using a von Frey monofilament, and needle-based real and sham acupuncture. We also measured the presence of sharp pain, unpleasantness, and anxiety level during each condition. RESULTS: The FUS acupuncture given at 3 W/cm(2) elicited deqi sensation ratings similar to those acquired during the needle-based acupuncture condition across the subjects, with significantly reduced levels of non-deqi related sensations, such as sharp pain, anxiety and unpleasantness. The lower acoustic intensity also generated deqi sensations, but at a lesser degree than the ones acquired using the higher acoustic intensity. Neither the sham conditions nor the tactile stimulation elicited deqi sensations. CONCLUSIONS: The present data on acoustic acupuncture, with its exquisite spatial and depth control, along with the ability to electronically adjust its intensity, may suggest its potential utilization as an alternative mode of acupuncture, although further study is needed to probe its clinical efficacy. PMID- 25146061 TI - Effect of Royal Jelly on premenstrual syndrome among Iranian medical sciences students: a randomized, triple-blind, placebo-controlled study. AB - BACKGROUND: Premenstrual syndrome (PMS) may have negative effects on women's health and sometimes need therapeutic non-pharmacological management. OBJECTIVES: To determine the effect of oral consumption of 1000 mg Royal Jelly capsule on premenstrual syndrome. METHOD: This is a randomized, triple-blind, placebo controlled clinical trial, which was conducted in Tehran University of Medical Sciences female dormitories between December 2011 and October 2012. The study population comprised 110 medical sciences student with PMS, whom were randomly assigned to an intervention or a control group. Each participant in the intervention group took one Royal jelly capsule orally per day, starting on the first day of menstruation and continued the same treatment daily throughout two consecutive menstrual cycles, while participants in the intervention group took placebo capsules as same method. The outcome measure in this study was PMS score as obtained through the Premenstrual Profile 2005. RESULTS: The mean of personal characteristics and baseline level of the premenstrual score before intervention did not differ between groups. After two consecutive months consumption of Royal Jelly, PMS score had decreased from 23.17 +/- 17.43 to 11.42 +/- 14.58 (mean change: 11.75; 95% confidence interval [CI]: 8.31-15.19) and in Placebo, PMS score changed from 21.48 +/- 16.39 to 20.27 +/- 15.76 (mean change: 1.20; 95% CI: -1.69 to 4.10). Also difference between mean changes was significant (mean difference: 10.54; 95% CI: 6.10-14.98). CONCLUSIONS: The results of the study have demonstrated that 2 months consumption of Royal Jelly was effective in reducing PMS. PMID- 25146062 TI - Seidlitzia rosmarinus for lower urinary tract symptoms associated with benign prostatic hyperplasia: a pilot randomized controlled clinical trial. AB - OBJECTIVE: This study was performed to investigate the effect of Seidlitzia rosmarinus on the clinical symptoms of benign prostatic hyperplasia. METHODS: This single-blind clinical trial included 98 patients with voiding and storage symptoms in Shohada Ashayer Hospital of Khorramabad. The patients were randomly divided into two groups of treatment with prazosin 1mg/day plus Seidlitzia rosmarinus 3g/day and treatment with prazosin 1mg/day. The clinical symptoms were measured using the International Prostate Symptoms Score (IPSS) questionnaire. Serum prostate-specific antigen (PSA) level, prostate volume, and residual urine volume before and 2 months after the intervention were measured. RESULTS: The results of the study before the intervention did not show significant differences between the prazosin and Seidlitzia rosmarinus plus prazosin groups for the scores of clinical symptoms, PSA level, prostate volume, and residual urine volume (p>0.05). However, significant differences were found between the two groups after the intervention for the mean change scores of clinical symptoms (6.8 scores in the Seidlitzia rosmarinus group vs. 2 scores in the control group) (p<0.001), while no significant differences were found for the mean change scores of PSA level, prostate volume, and residual urine volume (p>0.05). CONCLUSION: The results of the study showed that the simultaneous consumption of Seidlitzia rosmarinus and prazosin, compared to the consumption of prazosin alone, results in significant improvements in the clinical symptoms of benign prostatic hyperplasia. PMID- 25146063 TI - Exercise training and music therapy in elderly with depressive syndrome: a pilot study. AB - OBJECTIVE: Recent studies have thrown doubt on the true effectiveness of anti depressants in light and moderate depression. The aim of this study is to evaluate the impact of physical training and music therapy on a sample group of subjects affected by light to moderate depression versus subjects treated with pharmacological therapy only. DESIGN AND SETTING: Randomized controlled study. Patients were randomized into two groups. Subjects in the pharmacotherapy group received a therapy with antidepressant drugs; the exercise/music therapy group was assigned to receive physical exercise training combined with listening to music. The effects of interventions were assessed by differences in changes in mood state between the two groups. MAIN OUTCOME MEASURES: Medically eligible patients were screened with the Hamilton Anxiety Scale and with the Geriatric Depression Scale. We used plasmatic cytokine dosage as a stress marker. RESULTS: We recruited 24 subjects (mean age: 75.5 +/- 7.4, 11 M/13 F). In the pharmacotherapy group there was a significant improvement in anxiety only (p<0.05) at 6-months. In the exercise/music therapy was a reduction in anxiety and in depression at 3-months and at 6-months (p<0.05). We noted an average reduction of the level of TNF-a from 57.67 (+/- 39.37) pg/ml to 35.80 (+/- 26.18) pg/ml. CONCLUSIONS: Our training may potentially play a role in the treatment of subjects with mild to moderate depression. Further research should be carried out to obtain more evidence on effects of physical training and music therapy in depressed subjects. PMID- 25146064 TI - The Making Cases Count intiative. AB - Given the challenges faced, how can homeopaths communicate the power and scope of the therapeutic system of homeopathy? Homeopaths need to communicate to patients, the public and media, other healthcare professionals, healthcare researchers, and funders of healthcare (healthcare insurers, those who commission healthcare services either in publicly funded healthcare systems such as the NHS or charities). Effective communication with these stakeholders requires information that is: (a) easily understood, (b) credible, and (c) relevant. The patient's voice is the trusted, indisputable and easily understood common ground in homeopathy. Yet, the experiences of patients are rarely heard outside the profession of homeopathy. Homeopaths are in a unique position to make these voices heard by disseminating the results of their routine practice cases incorporating their patients' voices. The 'Making Cases Count' initiative has been created in order to bring about a culture where easily understood, trusted and salient information is regularly made available to all stakeholders in homeopathy. The Making Cases Count initiative supports, guides and incentives homeopaths to collect routine data with the aim of bringing about a culture where a significant proportion of homeopaths collect routine data from their patients in a format which will then be able to be transformed (i.e. anonymised, summarised and counted). This routine data requires numbers and categories to report the behavior and the perspective of patients receiving homeopathic treatment. This can be strengthened through the use of validated outcome measures in hearing patients' voices. When transformed, this routine data will then be able to inform homeopaths and more importantly other key stakeholders. It is now time to make patient cases count. PMID- 25146065 TI - Quality of life in patients referring to private osteopathic clinical practice: a prospective observational study. AB - BACKGROUND: Health improvement is one of the main priorities of both public and private health systems. In recent years, more attention has been given to the use of complementary and alternative medicines, including osteopathic manipulative treatment (OMT), as possible effective interventions in increasing patients' health reported outcomes. With regard to OMT, very little research was focused on its effectiveness in enhancing health in the general population. OBJECTIVES: To explore the extent to which OMT is effective in improving quality of life in referring patients. DESIGN: Cohort study. SETTING: Private osteopathic clinical practices in Italy. INTERVENTIONS: 25 osteopaths from Central and Southern Italy participated in the study. Self-referred patients, with a diagnosed musculo skeletal disorder and older than 18 years of age, who did not undergo any OMT session in the previous 12 months and/or contemporarily additional manual therapies were enrolled. MAIN OUTCOME MEASURES: Changing from baseline SF36 general health sub-domain scores was used as the study primary outcomes. RESULTS: 1000 patients with primary diagnosis of musculo-skeletal disorder were initially enrolled. 988 patients completed the study. After 4 weeks, mean general health score was 14.7 points higher (95% CI 13.9-15.6; Cohen's d=0.84). Similarly, physical and mental component scores increased (11.5; 95% CI 10.8-12.1; d=0.87 and 9.6; 95% CI 8.6-10.5; d=0.61 respectively). No association between SF36 domains and socio-demographic exposures was found to be statistically significant. CONCLUSIONS: Positive changes on various quality of life dimensions were reported by patients receiving osteopathic treatment. The trial was registered on clinicaltrials.gov (identifier NCT01965678). PMID- 25146066 TI - Reduction of surgery rate in endometriosis patients who take Chinese medicine: a population-based retrospective cohort study. AB - OBJECTIVES: Female patients have frequently utilized Chinese medicine (CM) to treat symptoms that could possibly be related to endometriosis. The objective of this population-based retrospective cohort study was to evaluate the relationship between CM use and subsequent surgery among patients with endometriosis. DESIGN: A total of 8,283 CM users were identified among the 22,488 endometriosis patients found in the National Health Insurance reimbursement database between 2000 and 2010. A control group was identified and consisted of 8,283 matched nonusers with the same disease. A Cox proportional regression analysis was performed in order to assess risk factors for surgery for the CM users and nonusers. RESULTS: When compared to nonusers, CM users were significantly less likely to undergo surgery, with a hazard ratio of 0.47 (95% CI=0.421, 0.534) after adjusting for age, occupation, childbirth status, hypermenorrhea, iron-deficient anemia, dysmenorrhea, and amount of conventional medications. Among patients who had undergone surgery, the follow-up time was longer for CM users than for CM nonusers (p<0.001). Moreover, the most frequently used CM single and formula were Cyperus rotundus and Gui-zhi-fu-ling-wan, respectively. CONCLUSIONS: These results suggest that whatever the underlying reason, CM provides an alternative option that reduces the incidence rate of surgery in endometriosis patients. PMID- 25146067 TI - The effects of wet cupping on serum high-sensitivity C-reactive protein and heat shock protein 27 antibody titers in patients with metabolic syndrome. AB - INTRODUCTION: It has previously been reported that increased level of serum heat shock proteins (Hsps) antibody in patients with metabolic syndrome. It is possible that the expression of Hsp and inflammatory markers can be affected by cupping and traditional Chinese medicine. There is a little data investigating the effects of cupping on markers of inflammation and Hsp proteins, hence, the objective of this study was evaluation of the effects of wet cupping on serum high-sensitivity C-reactive protein (hs-CRP) and Hsp27 antibody titers in patients with metabolic syndrome. SUBJECTS AND METHODS: Serum Hs-CRP and Hsp27 antibody titers were assessed in samples from 126 patients with metabolic syndrome (18-65 years of age) at baseline, and after 6 and 12 weeks after treatment. One hundred and twenty-six patients were randomly divided into the experimental group treated with wet cupping combined with dietary advice, and the control group treated with dietary advice alone using a random number table. Eight patients in case group and five subjects in control groups were excluded from the study. Data were analyzed using SPSS 15.0 software and a repeated measure ANCOVA. RESULTS: Serum hs-CRP titers did not change significantly between groups (p>0.05) and times (p=0.27). The same result was found for Hsp27 titers (p>0.05). CONCLUSION: Wet-cupping on the interscapular region has no effect on serum hs-CRP and Hsp27 patients with metabolic syndrome. PMID- 25146068 TI - Unexpected lumbar abscess due to scarification wet cupping: a case report. AB - OBJECTIVE: This case presents a rare cause of lumbar abscess. METHODS: A 51-year old male patient was admitted to the emergency department with a complaint of lumbar pain. Spinal magnetic resonance imaging revealed a lumbar abscess. RESULTS: The abscess was treated with drainage of the abscess and antibiotic. CONCLUSION: Scarification wet cupping therapy should be taken into consideration as a rare cause of lumbar abscesses in patients who present with skin findings indicative of scarification. Scarification wet cupping therapy practitioners must pay attention to hygienic measures. PMID- 25146069 TI - Effect of herbal medicine use on medication adherence of cardiology patients. AB - PURPOSE: Herbal drug use for cardiovascular disease is frequent and growing rapidly. The aim of this study is to investigate the effect of herbal medicine use on medication adherence of cardiology patients. METHODS: All patients admitted to the outpatient cardiology clinics, who had been prescribed at least one cardiovascular drug before, were asked to complete a questionnaire. Participants were asked if they have used any herbals during the past 12 months with an expectation of beneficial effect on health. Medication adherence was measured by using the Morisky Scale. High adherence was defined as a Morisky score <2 and a score >= 2 was accepted as low adherence in our study. RESULTS: Totally 390 patients (54.9% male and 45.1% female patients, mean age 58.9) participated in our study. 29.7% of them had consumed herbals in the past 12 months. The median Morisky score was significantly higher in herbal users than nonusers (p<0.001). Rate of low adherence, according to the Morisky Scale, was also higher in herbal users (61.2% vs. 29.9%, p<0.001). Number of herbals used was moderately correlated with the Morisky score (rho=0.313, p<0.001). In stepwise, multivariate logistic regression analysis, herbal use was significantly associated with low medication adherence (OR: 3.76, 95% CI 2.36-6.09, p<0.001). CONCLUSION: Herbal use was found to be independently associated with low medication adherence in our study population. Further studies are needed to elucidate the effect of herbal medicine use on medication adherence of cardiology patients. PMID- 25146070 TI - Spa adjuvant therapy improves diabetic lower extremity arterial disease. AB - OBJECTIVE: To investigate the effect of spa adjuvant therapy on diabetic lower extremity arterial disease (LEAD). METHODS: 128 patients with type II diabetes were separated into three groups according to the degree of lower extremity vascular stenosis. Patients within each group were then randomly divided to receive no treatment (control) or spa adjuvant therapy (treatment). Clinical symptoms, blood pressure and hemodynamic analyses were compared between control and treatment groups by Chi square or t-test. RESULTS: After adjuvant therapy with spa, patients' pain, numbness, and cold sensation were significantly improved compared with control groups (P<0.05). Spa adjuvant therapy also significantly increased the dorsalis pedis pulse and systolic peak velocity ratio of patients with mild lower extremity vascular stenosis compared with control groups (P<0.05), while there were no significant differences between the two groups for patients with moderate and severe stenosis (P>0.05). Both in the spa and control groups, there were no significant differences before and after medication for fasting, 2-h postprandial blood glucose and glycosylated hemoglobin (HbA1C) analyses (P>0.05). CONCLUSIONS: Spa adjuvant therapy can significantly alleviate lower extremity pain, numbness, and cold sensory symptoms in diabetic LEAD patients with stenosis. Moreover, in LEAD patients with mild stenosis, spa adjuvant therapy also improves the dorsalis pedis pulse and systolic peak velocity ratio, suggesting a potential role for spa therapy as an early intervention strategy to treat the initial stages of disease. PMID- 25146071 TI - Muscle utilization patterns vary by skill levels of the practitioners across specific yoga poses (asanas). AB - OBJECTIVE: To compare muscle activation patterns in 14 dominant side muscles during different yoga poses across three skill levels. DESIGN: Mixed repeated measures descriptive study. SETTING: University neuromuscular research laboratory, Miami, US. PARTICIPANTS: A group of 36 yoga practitioners (9 M/27 F; mean +/- SD, 31.6 +/- 12.6 years) with at least 3 months yoga practice experience. INTERVENTIONS: Each of the 11 surya namaskar poses A and B was performed separately for 15s and the surface electromyography for 14 muscles were recorded. MAIN OUTCOME MEASURES: Normalized root mean square of the electromyographic signal (NrmsEMG) for 14 muscles (5 upper body, 4 trunk, 5 lower body). RESULTS: There were significant main effects of pose for all fourteen muscles except middle trapezius (p<.02) and of skill level for the vastus medialis; p=.027). A significant skill level * pose interaction existed for five muscles (pectoralis major sternal head, anterior deltoid, medial deltoid, upper rectus abdominis and gastrocnemius lateralis; p<.05). Post hoc analyses using Bonferroni comparisons indicated that different poses activated specific muscle groups; however, this varied by skill level. CONCLUSION: Our results indicate that different poses can produce specific muscle activation patterns which may vary due to practitioners' skill levels. This information can be used in designing rehabilitation and training programs and for cuing during yoga training. PMID- 25146072 TI - Measuring body constitution: validation of the Body Constitution Questionnaire (BCQ) in Hong Kong. AB - BACKGROUND: The Body Constitution Questionnaire (BCQ) was developed in Taiwan to classify people into body constitution (BC) types based on Traditional Chinese Medicine (TCM) theories. Since the culture of Hong Kong is different from Taiwan, the BCQ must be validated before a wider application can be preceded. AIM AND OBJECTIVES: To adapt and validate the Hong Kong version of BCQ in Hong Kong Chinese population. METHODS: The content validity of BCQ was investigated by the cognitive debriefing with 10 patients and 10 Chinese Medicine Practitioners (CMP). A cross-sectional study of 1084 Chinese patients recruited from TCM and Western Medicine (WM) outpatient clinics to confirm the construct validity, reliability, sensitivity and responsiveness of BCQ. 225 of the patients were assessed after 2 weeks for the test-retest reliability. 404 subjects were followed up to evaluate the responsiveness after 3-6 months. RESULTS: Cognitive debriefing confirmed the content validity of the BCQ (HK version) with content validity index of all items ranged from 70 to 100%. 1084 out of 2128 patients (51%) completed the cross-sectional study. The construct validity was confirmed with scaling success rates that ranged from 87.5 to 89.5%, moderate correlations between with SF-12v2 scores, and 3-factors structure with confirmatory factor analysis. The reliability was confirmed by the Cronbach's alphas >0.8 and test retest reliability (intra-class correlation coefficients >0.8). CONCLUSION: BCQ was adapted and validated on Hong Kong Chinese population. Patients with imbalanced BC types had lower health-related quality of life (HRQOL) than those with balanced BC types, which supported the validity and importance of the body constitution under the concept of TCM. PMID- 25146073 TI - The use of complementary and alternative medicine in an Irish cohort of people with an iatrogenic hepatitis C infection: results from a health and lifestyle survey. AB - INTRODUCTION: A cohort of people with iatrogenic HCV infection, current or resolved, in Ireland have access to primary and secondary health care services, including specified complementary and alternative medicine (CAM) services, free of charge. OBJECTIVES: Information about their pattern of CAM usage and its association with various demographic and lifestyle factors, and current HCV status, was sought as part of a health and lifestyle survey, in order to provide information for health service planning. DESIGN AND METHODS: The survey was carried out by self-administered postal questionnaire. The level of CAM usage was compared to an age- and sex-matched sample of the general population. RESULTS: The response was 48% (720/1485). Compared to the general population, the HCV population was significantly more likely to have attended a CAM practitioner (50.1% vs 23.9%, OR 3.2; 95% CI 2.7-3.9). Within the HCV population, multivariate analysis showed that females (OR 3.1; 95% CI 1.9-4.9), those who reported fibromyalgia (OR 2.7; 95% CI 1.8-3.9) and those who reported anxiety (OR 1.4; 95% CI 1.0-2.0) were significantly more likely to have used CAM, and smokers significantly less likely (OR 0.6; 95% CI 0.4-0.8). CAM attendance did not vary by current HCV status. Reflexology, acupuncture and massage were the most commonly used forms of CAM. CONCLUSIONS: This study demonstrates that CAM services are used by a high proportion of people with iatrogenic chronic HCV. A more holistic approach to health care, using a biopsychosocial model framework, may better meet the physical and psychological health needs of this group. PMID- 25146074 TI - How to capture patients' concerns and related changes: comparing the MYCaW questionnaire, semi-structured interview and a priority list of outcome areas. AB - OBJECTIVES: To compare the capacity of the MYCaW questionnaire, a priority list of concerns covered by validated questionnaires, and semi-structured interviews to identify patients' personalized concerns and related changes. DESIGN: In a pragmatic trial on the effectiveness of energy healing as rehabilitation after colorectal cancer, a sub-sample of 31 participants completed the MYCaW questionnaire and the priority list and were interviewed before, during and after the treatment period. SETTING: Treatments were provided in healers' clinics in Denmark. MAIN OUTCOME MEASURES: For each participant convergences and divergences of the outcome measures are identified, and strengths and weaknesses of the three methods in regard to capturing personalized concerns and changes are discussed. RESULTS: Three patterns were identified: (1) in the intervention groups concerns stated in MYCaW were adjusted after experience with the treatment, while concerns stated in interviews and the priority list remained stable throughout the study; (2) emotional concerns were reported more often in interviews than in MYCaW, physical concerns were predominant in MYCaW, and quality of life was marked as a primary concern most frequently on the priority list; (3) participants reported greater improvement in interviews than in MYCaW. CONCLUSIONS: Relevant concerns in the MYCaW questionnaire seem to require that participants are well acquainted with the treatment under study. The priority list directs participants to particular areas of concerns and markings are stable. Interviews are well suited to disclose concerns regarding sensitive issues, e.g. anxiety of relapse, and experiences of subtle, non-specific changes. PMID- 25146075 TI - Health-related self-perceptions over time and provider-based Complementary and Alternative Medicine (CAM) use in people with inflammatory bowel disease or arthritis. AB - OBJECTIVES: To prospectively investigate how health-related self-perceptions are associated with use of provider-based CAM in two chronic inflammatory diseases, arthritis and inflammatory bowel disease (IBD). DESIGN AND SETTING: A prospective online survey was administered to convenience samples of individuals with arthritis or inflammatory bowel disease, and a follow-up survey completed 6 months later. Participants were recruited via online ads, through national organizations, and support groups. MAIN OUTCOME MEASURES: Surveys included measures of demographics, use of provider-delivered CAM, disease-related factors, self-perceptions of having a healthy lifestyle and being able to handle stress, and trait resilience. RESULTS: 325 people (170 with arthritis and 155 with IBD) completed the initial and follow-up surveys. Rates of CAM use were 43.2% and 45.9% for the arthritis and IBD groups, respectively. T-tests revealed significant differences on healthy lifestyle self-perceptions and trait resilience for both illness groups. Differences in self-perceptions about handling stress were only significant in the IBD group. Multivariate logistic regression controlling for demographics and health-related variables revealed that seeing oneself as having a healthy lifestyle predicted CAM use in both illness groups. Being resilient predicted CAM use only in the IBD group, and self perceptions about handling stress predicted CAM use only in the arthritis group. CONCLUSIONS: This study provides insights into how health-related self perceptions are prospectively linked to provider-based CAM use in patients with chronic inflammatory disease. This information is important for both health-care practitioners and researchers as it has implications for maximizing the health promoting aspects of CAM use and understanding CAM adherence. PMID- 25146076 TI - Treatment of women's reproductive health conditions by Australian and New Zealand acupuncturists. AB - BACKGROUND: Acupuncture is used by nine percent of the Australian population; however, we know relatively little about the practice of acupuncture to treat women's reproductive health in Australia and New Zealand. METHODS: This study surveyed acupuncturists to examine their practice with treating women's reproductive health complaints. A cross sectional survey of 3406 Australian and New Zealand acupuncturists was conducted. A self-completion questionnaire explored the areas of acupuncture treatment for gynaecological pregnancy and fertility complaints. RESULTS: Questionnaires were completed by 377 acupuncturists. Ninety-six percent of practitioners reported treating women's reproductive health conditions within the previous year. All three areas of women's reproductive health were commonly treated with 96% treating gynaecological health, 91% treating pregnancy conditions, and 90% fertility conditions. The most commonly treated gynaecological conditions were premenstrual syndrome (90.1%, 95% CI 86.2-93.0), menopause (89.4%, 95% CI 85.4-92.4) and primary dysmenorrhea (89.1%, 95% CI 85.1-92.2). Participants reported treating general fertility not related to assisted reproduction (93%, 95% CI 89.4-95.5), treatment for a diagnosed fertility related conditions (85.8%, 95% CI 81.1-89.4), and to decrease infertility related stress (86%, 95% CI 81.5-89.7). The most common pregnancy related conditions treated were nausea (90.3%, 95% CI 86.3 93.3), back or pelvic pain (89.3%, 95% CI 85.1-92.4), and prebirth labour preparation (86.8%, 95% CI 82.3-90.3). CONCLUSION: Treating women's reproductive health complaints was commonly reported among the groups of acupuncturists in Australia and New Zealand responding to this survey; however, our findings cannot be generalised to the wider acupuncture communities in these two countries. PMID- 25146077 TI - Preventive use of Bach flower Rescue Remedy in the control of risk factors for cardiovascular disease in rats. AB - OBJECTIVES: To evaluate the effect of Bach flower Rescue Remedy on the control of risk factors for cardiovascular disease in rats. DESIGN: A randomized longitudinal experimental study. METHODS: Eighteen Wistar rats were randomly divided into three groups of six animals each and orogastrically dosed with either 200 MUl of water (group A, control), or 100 MUl of water and 100 MUl of Bach flower remedy (group B), or 200 MUl of Bach flower remedy (group C) every 2 days, for 20 days. All animals were fed standard rat chow and water ad libitum. MAIN OUTCOME MEASURES: Urine volume, body weight, feces weight, and food intake were measured every 2 days. On day 20, tests of glycemia, hyperuricemia, triglycerides, high-density lipoprotein (HDL) cholesterol, and total cholesterol were performed, and the anatomy and histopathology of the heart, liver and kidneys were evaluated. Data were analyzed using Tukey's test at a significance level of 5%. RESULTS: No significant differences were found in food intake, feces weight, urine volume and uric acid levels between groups. Group C had a significantly lower body weight gain than group A and lower glycemia compared with groups A and B. Groups B and C had significantly higher HDL-cholesterol and lower triglycerides than controls. Animals had mild hepatic steatosis, but no cardiac or renal damage was observed in the three groups. CONCLUSION: Bach flower Rescue Remedy was effective in controlling glycemia, triglycerides, and HDL cholesterol and may serve as a strategy for reducing risk factors for cardiovascular disease in rats. This study provides some preliminary "proof of concept" data that Bach Rescue Remedy may exert some biological effects. PMID- 25146078 TI - Is acupuncture a placebo therapy? AB - Complementary therapies such as acupuncture are suggested to have enhanced placebo effects. Numerous high quality randomized controlled trials found that acupuncture is no better than its placebo control; however, patients in both real and sham acupuncture groups report clinically meaningful symptom improvements. A possible interpretation of these trials is that acupuncture acts entirely by engaging placebo mechanisms. This article provides further evidence supporting that acupuncture might be a potent placebo, and explains how to address major concerns following this suggestion. PMID- 25146079 TI - Homeopathy in the treatment of fibromyalgia--a comprehensive literature-review and meta-analysis. AB - BACKGROUND: Coping with the complex nature of fibromyalgia symptoms (FMS) still remains a challenge for patients. Taking into account the possible adverse events of pharmacological treatments patients often seek additional treatments for the management of fibromyalgia and turn towards complementary and alternative medicine (CAM). OBJECTIVE: In this review, we aimed to investigate the current state of literature of homeopathy in the treatment of FMS. METHODS: We searched Medline, the Cochrane Register of Controlled Trials, Embase, AMED, PsycInfo and CAMbase for the terms "fibromyalgia AND homeopath$" through February 2013. In addition we searched Google Scholar, the library of the Carstens Foundation and that of the Deutsche Homoopathische Union (DHU). Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated and meta-analyzed using the generic inverse variance method. RESULTS: We found 10 case-reports, 3 observational studies, 1 non-randomized and 4 randomized controlled trials (RCTs) on homeopathy for fibromyalgia. Both case reports and observational studies are naturally predominated by the use of qualitative and not validated outcome measures. Meta-analyses of CCTs revealed effects of homeopathy on tender point count (SMD=-0.42; 95%CI -0.78, -0.05; P=0.03), pain intensity (SMD=-0.54; 95%CI 0.97, -0.10; P=0.02), and fatigue (SMD=-0.47; 95%CI -0.90, -0.05; P=0.03) compared to placebo. CONCLUSION: The results of the studies as well as the case reports define a sufficient basis for discussing the possible benefits of homeopathy for patients suffering from fibromyalgia syndrome although any conclusions based on the results of this review have to be regarded as preliminary. PMID- 25146080 TI - Effects of Tai Chi on health related quality of life in patients with chronic conditions: a systematic review of randomized controlled trials. AB - OBJECTIVES: To determine the effects of Tai Chi practice on health related quality of life in patients with various chronic medical conditions. BACKGROUND: One of the characters of chronic illness is life-long condition with the deterioration in health related quality of life. Tai Chi has become a popular mind-body exercise and self-management strategy for patients with chronic conditions regarding its various physical and psychological effects. METHODS: Eight databases (the Cochrane Library, PubMed, Medline, EBSCO, Web of science and three Chinese databases: CNKI, Wanfang data and VIP) were searched (up to December 2013) for relevant studies. Studies including participants with chronic conditions were selected. All studies were randomized controlled trials reporting the effects of Tai Chi on health related quality of life. Two independent reviewers extracted trial data and assessed risk of bias using the risk of bias tool recommended by the Cochrane Back Review Group. RESULTS: Of the 2021 papers which were screened, 21 studies including 1200 patients met the eligibility criteria. Most studies (18 of 21 studies) found significant improvements on health related quality of life for participants with chronic conditions in Tai Chi group. No evidence was observed to suggest that Tai Chi was more effective than other types of exercise. And objective measures were not always consistent with self-reported quality of life measures. CONCLUSIONS: Tai Chi appears to be safe and has positive effects on health related quality of life in patients with chronic conditions, especially for patients with disorders in Cardio cerebrovascular and respiratory systems, and musculoskeletal system. However, as the delivery mood of Tai Chi provides multiply benefits, which part of the group provides the most benefit in improving quality of life is unclear. Due to the design limitations of previous studies, more larger and well-designed RCTs are needed to confirm the effects. And qualitative researches are warranted to explore how Tai Chi may work exactly from patients' own perspectives. PMID- 25146081 TI - Do asthmatics benefit from music therapy? A systematic review. AB - OBJECTIVE: To determine the effectiveness of music therapy in asthma. METHODS: Searches for experimental and observational studies published between 01.01.92 and 31.12.13 were conducted through electronic databases: Medline/PubMed, Embase, SportDiscus, Cochrane Library, Teacher Reference Centre, Web of Science, Academic Search Complete, PsycINFO, PsycARTICLES, PEDro and Scopus. The selection criteria included any method of music therapy applied to patients with asthma, with respect to asthma symptoms and lung function. Two reviewers screened the records independently. The risk of bias was assessed using the Cochrane Collaboration's tool. Strength of recommendation was graded according to GRADE recommendation. RESULTS: The literature search identified 867 citations, from which 8 (three RCTs and five nRCTs) low and high risk of bias studies were included in the review. All RCTs used music listening as a form of complementary treatment. One RCT of the low risk of bias indicated positive effects on lung function in mild asthma. In two others, despite the decrease in asthma symptoms, music was not more effective than the control condition. In two nRCTs a decrease in asthma symptoms was reported as an effect of playing a brass or wind instrument; in two nRCTs the same effect was observed after music assisted vocal breathing exercises and singing. Mood improvement, decrease of depression and anxiety were also observed. CONCLUSION: The paucity, heterogeneity, and significant methodological limitations of available studies allow for only a weak recommendation for music therapy in asthma. This study highlights the need for further research of mixed methodology. PMID- 25146082 TI - The effectiveness of acupuncture in postoperative gastroparesis syndrome--a systematic review and meta-analysis. AB - BACKGROUND: Postoperative gastroparesis syndrome (PGS) which is mainly manifested as delayed gastric emptying is often caused by upper abdominal and sometimes lower abdominal surgery. In view of the side effects of drugs therapy, the search of supplementary and alternative has been of increasing interest. OBJECTIVE: This paper included a systematic review and meta-analysis on the use of acupuncture and acupoints selection in PGS. Quality for meta-analysis was evaluated using GRADE while each trial was assessed with CONSORT and STRICTA for TCM. METHODS: Randomized controlled trials (RCTs) comparing acupuncture with non-acupuncture treatment were identified from databases PubMed, EBSCO, Ovid, Cochrane, CNKI and Wanfangdata. Meta-analysis on eligible studies was performed using fixed-effects model with RevMan 5.2. Results were expressed as relative risk (RR) for dichotomous data, and 95% confidence interval (CI) were calculated. RESULTS: Of the 348 studies reviewed, 16 RCTs met the inclusion criteria for review while 7 RCTs, 188 patients (intervention) and 182 patients (control) met the criteria for meta-analysis. Both acupuncture and acupuncture combined with medication showed significant higher total effective rate than control (usual care/medication); with (RR 1.27, 95% CI 1.13, 1.44; P<0.0001) and (RR 1.37, 95% CI 1.18, 1.58; P<0.0001) respectively. All included RCTs reported positive effect of acupuncture in PGS treatment. ST36, CV12 and PC6 seemed to be the common acupoints selected. CONCLUSIONS: The results suggested acupuncture might be effective to improve PGS, however, a definite conclusion could not be drawn due to low quality of trials. Further large-scale, high-quality randomized clinical trials are needed to validate this. STUDY REGISTRATION: PROSPERO CRD42013005485. PMID- 25146083 TI - Oral Chinese proprietary medicine for angina pectoris: an overview of systematic reviews/meta-analyses. AB - BACKGROUND: Oral Chinese proprietary medicine (CPM) is commonly used to treat angina pectoris, and many relevant systematic reviews/meta-analyses are available. However, these reviews have not been systematically summarized and evaluated. We conducted an overview of these reviews, and explored their methodological and reporting quality to inform both practice and further research. METHODS: We included systematic reviews/meta-analyses on oral CPM in treating angina until March 2013 by searching PubMed, Embase, the Cochrane Library and four Chinese databases. We extracted data according to a pre-designed form, and assessed the methodological and reporting characteristics of the reviews in terms of AMSTAR and PRISMA respectively. Most of the data analyses were descriptive. RESULTS: 36 systematic reviews/meta-analyses involving over 82,105 participants with angina reviewing 13 kinds of oral CPM were included. The main outcomes assessed in the reviews were surrogate outcomes (34/36, 94.4%), adverse events (31/36, 86.1%), and symptoms (30/36, 83.3%). Six reviews (6/36, 16.7%) drew definitely positive conclusions, while the others suggested potential benefits in the symptoms, electrocardiogram, and adverse events. The overall methodological and reporting quality of the reviews was limited, with many serious flaws such as the lack of review protocol and incomprehensive literature searches. CONCLUSIONS: Though many systematic reviews/meta-analyses on oral CPM for angina suggested potential benefits or definitely positive effects, stakeholders should interpret the findings of these reviews with caution, considering the overall limited methodological and reporting quality. We recommend further studies should be appropriately conducted and systematic reviews reported according to PRISMA standard. PMID- 25146084 TI - The association between blood lipid and phlegm turbidity syndrome of angina pectoris: a systematic review and meta-analysis. AB - BACKGROUND: A series of case-control studies have been conducted to investigate the association between blood lipid and phlegm turbidity syndrome of angina pectoris, but produced inconsistent results. OBJECTIVE: We performed a meta analysis to determine the association between blood lipid and phlegm turbidity syndrome of angina pectoris more precisely. METHODS: Manual screening as well as screening of the China National Knowledge Infrastructure (CNKI), Chinese Journal full-text database (VIP), Wanfang database (WF), ScienceDirect, Pubmed, the Cochrane Library, and Embase were carried out for relevant literature. The formula was translated to calculate the pooled mean value and standard deviation value. The "Newcastle-Ottawa Quality Assessment Scale: Case-Control Studies" (NOS) was taken to assess the quality of the included studies. The Revman 5.2.6 software provided by "The Cochrane Collaboration" was used to analyze the collected data. The subgroup analysis was established according to the sample size proportion between the test group and the control group. Sensitivity analysis was constructed by using two different effect models. Besides, a funnel plot was created to analyze potential publication bias. RESULTS: No statistically meaningful difference existed between the test group and control group of total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) in non-Qi and yin deficiency syndrome (QYDS) and non-Yang deficiency syndrome (YDS) subgroup, whereas the two biotic indicators in the test group were higher than the non phlegm syndrome group in other subgroups. Triglyceride (TG) in phlegm syndrome group showed superior to non-phlegm syndrome group in the rest subgroups except for the non-CCS (Cold coagulating syndrome)-non-YDS subgroup. High-density lipoprotein-cholesterol (HDL-C) levels of the phlegm group were lower than that of the non-phlegm group in all subgroups. CONCLUSION: When comparing with Traditional Chinese Medicine (TCM) syndromes of asthenia nature, such as YDS, QYDS, and heart qi deficiency syndrome), the levels of TG, TC, and LDL-C were higher in phlegm turbidity syndrome. However, for sthenia syndromes such as Qi stagnation syndrome (QSS), heart blood stasis syndrome (HBSS), and CCS, there was no obvious difference. Furthermore, HDL-C levels in the phlegm turbidity group were lower than those of the non-phlegm group. Nevertheless, these results should be confirmed with further studies. PMID- 25146085 TI - The efficacy and safety of Chinese herbal medicine, Rhodiola formulation in treating ischemic heart disease: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Rhodiola formulation is widely used in treating ischemic heart disease (IHD), angina pectoris in China. A number of clinical studies have reported and claimed that Rhodiola formulation can relieve the symptoms of IHD. This study provides the first Preferred Reporting Items for Systematic Reviews (PRISMA)-compliant systematic review to evaluate the efficacy and safety of Rhodiola formulation in treating ischemic heart disease either as a sole agent or in combination with routine western medicine (RWM). METHODS: Search strategy - PubMed, Science Direct, the Cochrane Library, China National Knowledge Infrastructure (CNKI), China Master Theses Full-text Database (CMTD), China Doctor Dissertations Full-text Database (CDMD), Wanfang Data (WF) databases were searched for all relevant studies on Rhodiola formulation that have been published in English and Chinese. The last search of all databases was performed on 31 January 2013. All randomized controlled trials (RCTs) of Rhodiola formulation for patients with IHD were included, and the quality of included RCTs was assessed with Cochrane risk of bias tool. The primary outcomes, including the effective size of symptomatic and electrocardiography (ECG) improvement were calculated as an odds ratio (OR) and 95% confidence intervals (CIs). Because of obvious heterogeneity in the studies with regard to herbal species, herbal formulations, treatment group medicines, control group medicines and outcome measurement, subgroup analysis and sensitivity analysis were performed to evaluate the effects of study characteristics of RCTs, including quality, the role of Rhodiola formulations in treatment group and the different control group medicines. RESULTS: A total of thirteen studies (n=1672) were included. most of included studies were found to be high risk of bias with low quality of methodology. The Rhodiola formulations used alone or in combination with RWM demonstrated a positive effect on both improvement of symptoms and ECG. For the subgroup analysis, the ORs of symptomatic improvement in Rhodiola formulations versus other Chinese herbal medicines (CHMs), Rhodiola formulations versus RWM, and Rhodiola formulations plus RWM versus RWM were 1.51, 2.64, 5.63, respectively. The ORs of symptomatic improvement for Rhodiola formulations versus other CHMs, Rhodiola formulations versus RWM, and Rhodiola formulations plus RWM versus RWM were 1.33, 3.11, 2.27, respectively. Overall, the effectiveness of Rhodiola formulations was higher compared to medicines in control groups, with statistically significant differences observed both in symptomatic improvement (OR=2.40, 95% CI: 1.57-3.66, P<0.0001) and ECG improvement (OR=1.48, 95% CI: 1.17 1.87, P<0.01). However, the sensitivity test indicated that overall effects of Rhodiola formulation versus other CHMs in ECG improvement were not stable (after removing the study by Yin, P=0.05); the differences of CHMs in the control group are a possible source of heterogeneity. CONCLUSION: Rhodiola formulations may have a positive effect on treating IHD alone and in combination with RWM. However, poor quality of methodology and heterogeneity of the included trials means that larger sample size, multi-center, placebo-controlled, double blind studies are needed. PMID- 25146086 TI - Traditional Chinese medicine for chronic fatigue syndrome: a systematic review of randomized clinical trials. AB - BACKGROUND: There is no curative treatment for chronic fatigue syndrome (CFS). Traditional Chinese medicine (TCM) is widely used in the treatment of CFS in China. OBJECTIVE: To evaluate the effectiveness and safety of TCM for CFS. METHODS: The protocol of this review is registered at PROSPERO. We searched six main databases for randomized clinical trials (RCTs) on TCM for CFS from their inception to September 2013. The Cochrane risk of bias tool was used to assess the methodological quality. We used RevMan 5.1 to synthesize the results. RESULTS: 23 RCTs involving 1776 participants were identified. The risk of bias of the included studies was high. The types of TCM interventions varied, including Chinese herbal medicine, acupuncture, qigong, moxibustion, and acupoint application. The results of meta-analyses and several individual studies showed that TCM alone or in combination with other interventions significantly alleviated fatigue symptoms as measured by Chalder's fatigue scale, fatigue severity scale, fatigue assessment instrument by Joseph E. Schwartz, Bell's fatigue scale, and guiding principle of clinical research on new drugs of TCM for fatigue symptom. There was no enough evidence that TCM could improve the quality of life for CFS patients. The included studies did not report serious adverse events. CONCLUSIONS: TCM appears to be effective to alleviate the fatigue symptom for people with CFS. However, due to the high risk of bias of the included studies, larger, well-designed studies are needed to confirm the potential benefit in the future. PMID- 25146087 TI - Post-metallocenes in the industrial production of polyolefins. AB - Research on "post-metallocene" polymerization catalysis ranges methodologically from fundamental mechanistic studies of polymerization reactions over catalyst design to material properties of the polyolefins prepared. A common goal of these studies is the creation of practically useful new polyolefin materials or polymerization processes. This Review gives a comprehensive overview of post metallocene polymerization catalysts that have been put into practice. The decisive properties for this success of a given catalyst structure are delineated. PMID- 25146088 TI - Racial differences in adipose tissue distribution and risk of aggressive prostate cancer among men undergoing radiotherapy. AB - BACKGROUND: Although elevated body mass index (BMI) has been associated with increased risk of aggressive prostate cancer, the importance of adipose tissue distribution is not well understood. We examined associations between overall and visceral obesity and aggressive prostate cancer risk. Moreover, given racial differences in adipose tissue distribution, we examined whether race modified these associations. METHODS: We conducted a cross-sectional analysis of 308 radiotherapy-treated patients with prostate cancer within the Durham VA from 2005 to 2011. Multivariable logistic regression examined the association between BMI categories and tertiles of waist circumference (WC), visceral fat area (VFA), and periprostatic adipose tissue area (PPAT) with high-grade prostate cancer risk (Gleason score >=7 vs. <=6). Models stratified by race examined whether these associations differed between black and nonblack men. RESULTS: Both elevated BMI (Ptrend = 0.054) and WC (Ptrend = 0.040) were associated with increased high grade prostate cancer risk, with similar results between races, although the association with BMI was not statistically significant. In contrast, elevated VFA was associated with increased aggressive prostate cancer risk in black men (Ptrend = 0.002) but not nonblack men (Ptrend = 0.831), with a significant interaction between race and VFA (Pinteraction = 0.035). Though similar patterns were observed for PPAT, none was statistically significant. CONCLUSIONS: Among men undergoing radiotherapy for prostate cancer, visceral obesity is associated with increased aggressive prostate cancer risk, particularly among black men. If confirmed in future studies, these results suggest that adipose tissue distribution differences may contribute to prostate cancer racial disparity. IMPACT: These findings highlight the need to elucidate mechanisms contributing to racial differences in the association between visceral obesity and aggressive prostate cancer. PMID- 25146089 TI - A web tool for age-period-cohort analysis of cancer incidence and mortality rates. AB - BACKGROUND: Age-period-cohort (APC) analysis can inform registry-based studies of cancer incidence and mortality, but concerns about statistical identifiability and interpretability, as well as the learning curves of statistical software packages, have limited its uptake. METHODS: We implemented a panel of easy-to interpret estimable APC functions and corresponding Wald tests in R code that can be accessed through a user-friendly Web tool. RESULTS: Input data for the Web tool consist of age-specific numbers of events and person-years over time, in the form of a rate matrix of paired columns. Output functions include model-based estimators of cross-sectional and longitudinal age-specific rates, period and cohort rate ratios that incorporate the overall annual percentage change (net drift), and estimators of the age-specific annual percentage change (local drifts). The Web tool includes built-in examples for teaching and demonstration. User data can be input from a Microsoft Excel worksheet or by uploading a comma separated-value file. Model outputs can be saved in a variety of formats, including R and Excel. CONCLUSIONS: APC methodology can now be carried out through a freely available user-friendly Web tool. The tool can be accessed at http://analysistools.nci.nih.gov/apc/. IMPACT: The Web tool can help cancer surveillance researchers make important discoveries about emerging cancer trends and patterns. PMID- 25146091 TI - Detection of CoHV-1 by loop-mediated amplification (LAMP). Application of LAMP for CoHV-1 incidence monitoring in domestic pigeons. AB - The occurrence of Columbid herpesvirus-1 (CoHV-1) in domestic pigeons presents a potential threat for their husbandry and trade. CoHV-1 causes Smadel disease among pigeons but may not be manifested by any clinical signs and complicates secondary infections. The material for our study originated from 42 domestic pigeons sent to private veterinary practice in Lublin, Poland, between 2011 and 2013. Some of birds showed clinical signs similar to Smadel disease. The cytological examination also indicated on CoHV-1 infection. The incidence of CoHV 1 was tested in DNA extracted from liver of birds by loop-mediated isothermal amplification (LAMP). LAMP was used for the monitoring of CoHV-1 presence among pigeons in Poland. Our study showed that LAMP was capable of detecting CoHV-1 presence in 8 (19%) of 42 examined birds without the use of any advanced laboratory equipment. The results were confirmed by real-time PCR and virus isolation in chicken embryo fibroblasts. This is the first report on LAMP application for successful detection of CoHV-1 in domestic pigeons. SIGNIFICANCE AND IMPACT OF THE STUDY: The incidence of Columbid herpesvirus-1 (CoHV-1) in pigeons was examined for the first time by loop-mediated isothermal amplification (LAMP). The study showed the presence of CoHV-1 in 8 of 42 examined domestic pigeons. LAMP technique developed within this study may be used by not well equipped veterinary laboratories. PMID- 25146090 TI - Longitudinal assessment of imatinib's effect on the blood-brain barrier after ischemia/reperfusion injury with permeability MRI. AB - Acute ischemic stroke (AIS) often results in degeneration of the blood-brain barrier (BBB), which can lead to vasogenic edema and an increased risk of intracerebral hemorrhage. Imatinib is an agent that may be able to protect the BBB and reduce the risk of the harmful consequences of BBB degeneration. We sought to measure the effect of Imatinib on the BBB after experimental stroke longitudinally in vivo with permeability dynamic contrast-enhanced MRI. Ischemia/reperfusion injury was induced with a transient middle cerebral artery occlusion surgery. Rats were given Imatinib at 2 and 20 h after stroke onset. Post-assessment included neurologic functioning, MR imaging, Evans Blue extravasation, Western blot, and immunohistology assay. Imatinib protected the BBB by 24 h but failed to decrease BBB permeability at an earlier time-point. Imatinib also reduced infarct volume, edema, and improved neurologic functioning by 24 h. Rats treated with Imatinib also had a higher expression of the BBB structural protein Zona ocludens-1 and a reduction in nuclear factor-kappa beta (NF-kappabeta) activation. Imatinib is a promising agent to protect the BBB after AIS, but its effect on the BBB may not become prominent until 24 h after the onset of ischemia. This finding may help elucidate Imatinib's role in the clinical management of AIS and influence future study designs. PMID- 25146093 TI - Rapid access imaging for occult fractured neck of femur. AB - We completed a full audit cycle to assess waiting times for inpatients with suspected occult femoral neck fracture to get MRI scan, identify the causes of delay and implement the changes to reduce the waiting times. We have proved that inpatient MRI waiting times can significantly be reduced by a targeted approach. INTRODUCTION: The timely management of hip fractures is now underpinned by NICE Guidance, June 2011. This includes a statement that magnetic resonance imaging (MRI) should be offered if occult femoral neck fracture is suspected and that MRI should be made available within 24 hours. We completed a full audit cycle: (1) analyse the time taken for inpatient MRI to be performed for suspected occult femoral neck fractures, (2) identify correctable reasons for delay, (3) develop and implement changes and (4) re-audit. METHODS: Data was collected from the computerised radiology information system on consecutive patients between 01/04/2010 and 31/03/2012. This data was presented at a number of directorate audit meetings. Following the development and implementation of targeted improvements, a prospective re-audit was carried out between 01/08/2012 and 31/07/2013. RESULTS: After the initial audit, various reasons of delay were identified. The correctable causes for delay were (1) duty radiologist not directly contacted by clinician to request urgent scan, (2) slow vetting and protocoling of electronic requests, (3) resistance to weekend scanning and (4) delay in completing MRI safety questionnaire. After implementing strategies to address these remediable causes of delay, the re-audit demonstrated a 16% improvement in patients scanned within 24 h. The mean waiting time to get an MRI was 2,025.4 min (SD 2,406.4) for the baseline audit and 1,374 min (SD 1,635.7) for the re-audit. Mean difference is 651.4 min (95% CI 85.21, 1,217.5; p = 0.0243). CONCLUSION: MRI is a useful and sensitive tool to investigate occult femoral neck fracture. Inpatient MRI waiting times can significantly be reduced by a targeted approach which embodies improved team working. PMID- 25146092 TI - Lower P1NP serum levels: a predictive marker of bone loss after 1 year follow-up in premenopausal systemic lupus erythematosus patients. AB - SUMMARY: Predictors of bone mineral density (BMD) loss are additional tools in the management of osteoporosis in premenopausal women with systemic lupus erythematosus (SLE). This study provides original evidence that N-terminal propeptide of type 1 collagen (P1NP), the most specific bone formation marker, is a predictor of BMD loss in this group of women. INTRODUCTION: SLE is associated with a high risk of low bone mass/fractures but this risk is still controversial in premenopausal women. Our aim was to determine the 1 year incidence of BMD loss in premenopausal SLE women and the value of bone turnover markers as predictors of this complication. METHODS: This study enrolled a convenience sample of 63 premenopausal SLE patients. BMD was evaluated by dual X-ray absorptiometry at lumbar spine and hip at baseline and after 12 months. BMD changes above the least significant change were considered significant. Serum levels of P1NP and CTX (electrochemiluminescence), OPG, and RANKL (ELISA) were determined at baseline. RESULTS: Mean age was 31.1+/-6.8 years, and disease duration was 5.25+/-3.8 years. 36.5 % of patients presented BMD loss and 17.5 % BMD gain at lumbar spine and/or hip. Patients were divided in three groups: BMD loss (BL), no BMD change (NC), and BMD gain (BG). Patients with BL and NC received similar cumulative/mean/maximum glucocorticoid doses during the study, but patients with BG received lower doses (p<0.05). Baseline P1NP levels were different in the groups (BL: 36.95+/-23.37 vs. NC: 54.63+/-30.82 vs. BG: 84.09+/-43.85 ng/mL; p=0.031 BL vs. NC, p<0.001 BL vs. BG, and p=0.039 NC vs. BG). There was no difference in CTX, OPG, or RANKL levels. After multivariate analysis, P1NP remained as an independent risk factor for BMD loss (p<0.03). CONCLUSIONS: This study provides original evidence that lower levels of P1NP, the most specific bone formation marker, are predictive of BMD loss over 12 months in premenopausal SLE patients. PMID- 25146095 TI - Demonstrating sucralose as a monitor of full-scale UV/AOP treatment of trace organic compounds. AB - Due to the large number of trace organic compounds (TOrCs) in water and wastewater, their degradation during UV-based advanced oxidation (UV/AOP) is best monitored using a conservative indicator compound. The present study demonstrates the in situ use of sucralose, a widely consumed artificial sweetener, as a conservative probe for UV/AOP degradation of TOrCs. The main qualities of sucralose in this regard are its high concentration in wastewater effluent and surface water (enabling its direct detection), its resistance to direct UV photolysis, and its relatively slow reaction with hydroxyl radical. Degradation of sucralose was compared to the degradation of commonly detected TOrCs, across two AOPs (i.e. UV/H2O2 and UV/NO3), in both lab-scale and pilot-scale systems. In all cases, UV/AOP degradation of sucralose was slower than the degradation of the examined TOrCs, and is expected to be slower than the degradation of the majority of other environmentally relevant TOrCs. These results demonstrate the potential of sucralose as a conservative probe, to monitor the transformation of TOrCs during UV/AOP treatment. Furthermore, degradation of sucralose was slower than the degradation of many transformation products (generated during oxidation of TOrCs), implying that sucralose is also a valuable indicator for the decay of primary transformation products. PMID- 25146096 TI - A novel pre-oxidation method for elemental mercury removal utilizing a complex vaporized absorbent. AB - A novel semi-dry integrative method for elemental mercury (Hg(0)) removal has been proposed in this paper, in which Hg(0) was initially pre-oxidized by a vaporized liquid-phase complex absorbent (LCA) composed of a Fenton reagent, peracetic acid (CH3COOOH) and sodium chloride (NaCl), after which Hg(2+) was absorbed by the resultant Ca(OH)2. The experimental results indicated that CH3COOOH and NaCl were the best additives for Hg(0) oxidation. Among the influencing factors, the pH of the LCA and the adding rate of the LCA significantly affected the Hg(0) removal. The coexisting gases, SO2 and NO, were characterized as either increasing or inhibiting in the removal process, depending on their concentrations. Under optimal reaction conditions, the efficiency for the single removal of Hg(0) was 91%. Under identical conditions, the efficiencies of the simultaneous removal of SO2, NO and Hg(0) were 100%, 79.5% and 80.4%, respectively. Finally, the reaction mechanism for the simultaneous removal of SO2, NO and Hg(0) was proposed based on the characteristics of the removal products as determined by X-ray diffraction (XRD), atomic fluorescence spectrometry (AFS), the analysis of the electrode potentials, and through data from related research references. PMID- 25146097 TI - Interpreting and comparing risks in the presence of competing events. PMID- 25146098 TI - Optimization of the diagnostic management of clinically suspected pulmonary embolism in hospitalized patients. AB - Identical diagnostic algorithms for suspected pulmonary embolism (PE) are used for hospitalized patients and outpatients, while D-dimer levels, risk factors and pre-test probability for PE differ, and the percentage of patients managed without computerized tomography pulmonary angiography (CTPA) is lower in hospitalized patients. We aimed to improve the efficiency of the diagnostic algorithm by increasing the threshold of the D-dimer, the threshold of the Wells rule and by adjustments of the Wells rule. Six-hundred and twenty-four hospitalized patients from two previously performed management studies with a PE prevalence of 26% were studied. Adjustments were considered to be safe when the failure rate remained <2%. By applying standard management, 8% (49/624) were managed without CTPA with a failure rate of 0.0% (0/49; 95% confidence interval [CI] 0.0-7.3), and it was 1.7% (8/465; 95%CI 0.8-3.4) for all patients in whom PE was excluded at baseline. All evaluated adjustments resulted in an increase of the failure rate with very small improvements of the efficiency. Given these potentially small improvements and the increasing complexity of clinical practice if adjusted diagnostic algorithms for specific patient categories were introduced, we do not recommend further evaluation of any of the adjustments; we recommend that the standard diagnostic algorithm should continue to be applied. PMID- 25146099 TI - The construction of hierarchical structure on Ti substrate with superior osteogenic activity and intrinsic antibacterial capability. AB - The deficient osseointegration and implant-associated infections are pivotal issues for the long-term clinical success of endosteal Ti implants, while development of functional surfaces that can simultaneously overcome these problems remains highly challenging. This study aimed to fabricate sophisticated Ti implant surface with both osteogenic inducing activity and inherent antibacterial ability simply via tailoring surface topographical features. Micro/submciro/nano-scale structure was constructed on Ti by three cumulative subtractive methods, including sequentially conducted sandblasting as well as primary and secondary acid etching treatment. Topographical features of this hierarchical structure can be well tuned by the time of the secondary acid treatment. Ti substrate with mere micro/submicro-scale structure (MS0-Ti) served as a control to examine the influence of hierarchical structures on surface properties and biological activities. Surface analysis indicated that all hierarchically structured surfaces possessed exactly the same surface chemistry as that of MS0-Ti, and all of them showed super-amphiphilicity, high surface free energy, and high protein adsorption capability. Biological evaluations revealed surprisingly antibacterial ability and excellent osteogenic activity for samples with optimized hierarchical structure (MS30-Ti) when compared with MS0-Ti. Consequently, for the first time, a hierarchically structured Ti surface with topography-induced inherent antibacterial capability and excellent osteogenic activity was constructed. PMID- 25146100 TI - A case of mixed adenoneuroendocrine carcinoma of the gallbladder arising from an intracystic papillary neoplasm associated with pancreaticobiliary maljunction. AB - A 54-year-old Japanese woman was referred with a gallbladder tumor. Based on the results of the computed tomography scan, endoscopic retrograde cholangiopancreatography, and magnetic resonance cholangiopancreatography, a mucin-producing neoplasm of the gallbladder associated with pancreaticobiliary maljunction was diagnosed. Extended cholecystectomy, extrahepatic bile duct resection, and choledochojejunostomy were performed, and she remains free of recurrence 24 months after resection. Histopathological examination revealed that the papillary component of the lesion was an intracystic papillary neoplasm with diverse characteristics of pancreaticobiliary epithelium and intestinal epithelium including mucin. In this component, most of the papillary lesion was a high-grade intraepithelial neoplasm, but also showed slight invasion into the muscular layer. The nodular component consisted of both poorly differentiated biliary type adenocarcinoma and large cell neuroendocrine carcinoma. We report a rare case of a mixed adenoneuroendocrine carcinoma arising from an intracystic papillary neoplasm associated with pancreaticobiliary maljunction. As for the histogenesis of this tumor, based on the histopathologic appearance, transdifferentiation from poorly differentiated biliary type adenocarcinoma to large cell neuroendocrine carcinoma is considered the most possible histogenesis of this tumor. PMID- 25146101 TI - Gadolinium chloride improves the course of TNBS and DSS-induced colitis through protecting against colonic mucosal inflammation. AB - Inflammatory macrophages in colonic mucosa are the leading drivers of the pathology associated with inflammatory bowel disease (IBD). Here we examined whether gadolinium chloride (GdCl3), a macrophage selective inhibitor, would improve the course of 2,4,6-trinitro benzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS)-induced colitis in mice and the potential mechanisms were investigated. By giving GdCl3 to colitis mice through intravenous or intrarectal route, we found that GdCl3 markedly ameliorated the colitis severity, including less weight loss, decreased disease activity index scores, and improved mucosal damage. To investigate the potential mechanisms, flow-cytometric analysis was performed to detect the proportion of mucosal macrophages in colon. The results showed that GdCl3 had no macrophage depletion effect in colonic mucosa, but significantly suppressed TNBS and DSS-induced TNFalpha, IL-1beta and IL-6 secretions. Also, Western blotting analysis indicated that NF-kappaB p65 expression was significantly attenuated in the mucosa in colitis mice with GdCl3 treatment. Then, the anti-inflammatory activity of GdCl3 was confirmed in LPS stimulated RAW 264.7 cells that GdCl3 might down-regulate the production of proinflammatory cytokines by macrophages through inhibition of the NF-kappaB signaling pathway. Therefore, intervention with mucosal inflammatory macrophages may be a promising therapeutic target in IBD. PMID- 25146104 TI - Organocatalytic enantioselective construction of polyaromatic architectures. PMID- 25146102 TI - Location, location, location: applying spatial statistics to the relationship landscape. AB - The desire to understand relationships is a passion shared by professionals in research, clinical, and educational settings. Questionnaires are frequently used in each of these settings for a multitude of purposes-such as screening, assessment, program evaluation, or establishing therapeutic effectiveness. However, clinical issues arise when a couple's answers on questionnaires do not match clinical judgment or lack clinical utility, while statistical problems arise when data from both partners are put into analyses. This article introduces the use of geospatial statistics to analyze couple data plotted on a two dimensional "relational map." Relationship maps can increase assessment sensitivity, track treatment progress, and remove statistical issues typically associated with couple data. This article briefly introduces core assumptions of spatial models, illustrates the use of spatial models in creating a relational landscape of divorce, offers suggestions for the use of relational maps in a clinical setting, and explores future research ideas. PMID- 25146103 TI - Drug conjugation to cyclic peptide-polymer self-assembling nanotubes. AB - We show for the first time how polymeric nanotubes (NTs) based on self-assembled conjugates of polymers and cyclic peptides can be used as an efficient drug carrier. RAPTA-C, a ruthenium-based anticancer drug, was conjugated to a statistical co-polymer based on poly(2-hydroxyethyl acrylate) (pHEA) and poly(2 chloroethyl methacrylate) (pCEMA), which formed the shell of the NTs. Self assembly into nanotubes (length 200-500 nm) led to structures exhibiting high activity against cancer cells. PMID- 25146105 TI - From policy coherence to 21st century convergence: a whole-of-society paradigm of human and economic development. AB - The 20th century saw accelerated human and economic development, with increased convergence in income, wealth, and living standards around the world. For a large part, owing to the well-entrenched Western-centric linear and siloed industrialization pattern, this positive transformation has also been associated with complex societal challenges at the nexus of agricultural, industrial, and health sectors. Efforts at cross-sectoral policy coherence have been deployed with limited success. To go beyond what has been possible thus far, the whole-of society (WoS) paradigm for human and economic development proposes a 21st century convergence where, instead of the rest (of the world) converging with the West, sectoral and cross-sectoral efforts converge in their single and collective policy and action on a common target of human and economic development. In this paper, we first review and discuss contributions and limitations of policy coherence approaches. We then elaborate the institutional foundation of the WoS paradigm, taking as an anchor the well-established model of polycentric governance that views individuals, and state, market, and community, forming society as part of the same complex adaptive system. Actors within such systems self-organize into nested hierarchies that operate at multiple scales and move toward 21st century convergence of human and economic development. PMID- 25146107 TI - Obstetric anesthesia: not just for cesareans and labor. AB - The scope of obstetric anesthesia practice ranges far beyond the delivery of care to women for vaginal and cesarean deliveries. Increasingly, obstetric anesthesiologists are involved in the management of anesthetics for new procedures and for new indications. Anesthesia is frequently needed for maternal procedures, as well as fetal procedures, and at varying times in the intrapartum period. Maternal-specific procedures include cerclage, external cephalic version (ECV), postpartum bilateral tubal ligation (BTL), and dilation and evacuation (D and E). Fetus-specific procedures include fetoscopic laser photocoagulation and ex-utero intrapartum treatment (EXIT). This review will not include discussion of the anesthetic management of non-obstetric surgery during pregnancy, such as appendectomy or cholecystectomy. PMID- 25146106 TI - Changes in middle cerebral artery velocimetry of fetuses diagnosed postnatally with mild or moderate hemolytic disease. AB - OBJECTIVES: To determine the longitudinal trends of middle cerebral artery peak systolic velocity (MCA PSV) in fetuses with mild or moderate hemolytic disease according to the need for postnatal therapy. DESIGN: Prospective cohort study. SETTING: University referral center. SAMPLE: Twenty-three fetuses from singleton alloimmunized pregnancies. METHODS: Serial measurements of MCA PSV were performed. After delivery, newborns were grouped by the need for postnatal management into mild hemolytic disease, which required no or only phototherapy (n = 14, group 1), and moderate hemolytic disease, where postnatal top-up or exchange transfusions were required (n = 9, group 2). MAIN OUTCOME MEASURES: Serial Doppler MCA PSV data transformed to multiples of the median, analyzed with linear regression and exponential models. RESULTS: We performed 83 measurements in group 1: 3-8 per fetus; mean GA at inclusion, 23 weeks and 65 measurements in group 2: 4-15 per fetus; mean GA at inclusion, 22 weeks. The estimated mean slopes of the MCA PSVs increased with the degree of postnatal therapy required (group 1: MCA PSV = 0.003 GA + 1.298; group 2: MCA PSV = 0.035 GA + 0.436). The relative average increments (RAI) were 4.7% and 7.1%, respectively. The two groups exhibited significant differences in mean slope and RAI (p<0.05). CONCLUSIONS: Fetuses that required postnatal transfusions due to hemolytic disease showed an enhanced progressive increase in MCA PSVs compared to those without transfusion requirement. This information might enable their identification during pregnancy. PMID- 25146108 TI - Post-dural puncture headache: the worst common complication in obstetric anesthesia. AB - Ever since the first spinal anesthetic in the late 19th century, the problem of "spinal headache" or post-dural puncture headache (PDPH) has plagued clinicians, and more importantly, patients. It has long been realized that the headache and other symptoms that often occur after the entry of a needle into the subarachnoid space is somehow related to fluid loss, although the exact pathophysiology of the headache has really never been defined. With the introduction of pencil-point spinal needles for spinal anesthesia in pregnant women over the past 2 decades, the problem of PDPH in obstetrics has been more associated with accidental dural puncture during attempted epidural procedures. Accidental puncture probably occurs in about 1% of procedures, so with over 60% of pregnant women receiving epidural analgesia for labor, there are probably 20,000-50,000 obstetric patients with PDPH in the United States each year. In this article, we will discuss the current state of knowledge in this area, suggesting that the PDPH syndrome is more severe and often more long-lasting, with some potentially life-threatening complications (cerebral hemorrhage) than usually appreciated or admitted. While prevention and treatment options are still limited, with the only clearly effective treatment being the epidural blood patch, recognition of the PDPH syndrome in postpartum women by anesthesiologists and obstetricians, with aggressive follow-up and treatment, may help limit the associated morbidity and mortality. PMID- 25146109 TI - The anesthetic approach to operative delivery of the extremely obese parturient. AB - Extreme obesity (BMI >= 40) is thought to complicate approximately 5% of deliveries in the United States. Extreme obesity puts a pregnant woman at an increased risk for cardiovascular disease, including hypertension, coronary artery disease, and congestive heart failure; respiratory disease, including obstructive sleep apnea and asthma; as well as pregnancy-specific diseases including pregnancy-induced hypertension and gestational diabetes. Extreme obesity also puts a parturient at a significantly increased risk of requiring cesarean delivery. For the anesthesiologist, the physiologic changes of obesity combined with the normal physiologic changes of pregnancy can make for a complex and challenging case. This review will focus on the anesthetic approach to the extremely obese parturient undergoing scheduled operative delivery. With proper planning and a detailed understanding of the patient's comorbidities, a safe and effective anesthetic can be achieved. PMID- 25146110 TI - Salt-assisted high-throughput synthesis of single- and few-layer transition metal dichalcogenides and their application in organic solar cells. PMID- 25146111 TI - Diffusion weighted magnetic resonance imaging demonstrates tumor response following palliative embolization of a recurrent shoulder plasmacytoma. AB - We report the palliative embolization and functional imaging follow-up of a recurrent shoulder plasmacytoma. The multiple myeloma patient complained of severe pain and discomfort, while he could not tolerate further chemotherapy. The left shoulder lesion had earlier received a high dose of irradiation. Thus, the well-vascularized lesion was embolized via feeding arteries branching off from the left subclavian artery in two sessions. The patient's symptoms rapidly improved post-embolization and the serum free light chain ratio stabilized at a lower level. The follow-up magnetic resonance image showed increased diffusivity in previously restricted tumor foci. This has negatively correlated with the decreased fludeoxyglucose uptake on PET, suggesting post-embolization necrosis. PMID- 25146112 TI - Mechanistic insights into the oxidative coupling of N-heterocyclic carbenes within the coordination sphere of copper complexes. AB - The behavior of N-heterocyclic carbene (NHC) ligands in organometallic chemistry is hugely important for catalysis, due to the effect of these ligands on catalytic pathways and their involvement in catalyst decomposition. In this report, a combined experimental and computational study is presented, which provides mechanistic understanding of the unprecedented oxidative coupling of NHCs at Cu. The presence of Cu(I) -, Cu(II) -, and Cu(III) -NHC complexes during the process is postulated, with the unusual Ccarbene -Ccarbene oxidative coupling reaction occurring under extremely mild reaction conditions. This process may represent a novel pathway for the decomposition of Cu-NHC complexes. PMID- 25146114 TI - The cloud and other new computational methods to improve molecular modelling. AB - INTRODUCTION: Industrial, as well as academic, drug discovery efforts are usually supported by computational modelling techniques. Many of these techniques, such as virtual high-throughput docking, pharmacophore-based screening of conformer databases and molecular dynamics simulations, are computationally very demanding. Depending on the parallelisation strategy applicable to the respective method, recent technologies based on central processing units, for example, cloud and grid computing, or graphics processing units (GPUs), can be employed to accelerate their execution times considerably. This allows the molecular modeller to look at larger data sets, or to use more accurate methods. AREAS COVERED: The article introduces the recent developments in grid, cloud and GPU computing. The authors provide an overview of molecular modelling applications running on the above-mentioned hardware platforms and highlight caveats of the respective architectures, both from a theoretical and a practical point of view. EXPERT OPINION: The architectures described can improve the molecular modelling process considerably, if the appropriate technologies are selected for the respective application. Despite these improvements, each of the individual computational platforms suffers from specific issues, which will need to be addressed in the future. Furthermore, current endeavours have focused on improving the performance of existing algorithms, rather than the development of new methods that explicitly harness these new technologies. PMID- 25146113 TI - Frequency matters: beta-band subthalamic nucleus deep-brain stimulation induces Parkinsonian-like blink abnormalities in normal rats. AB - The synchronized beta-band oscillations in the basal ganglia-cortical networks in Parkinson's disease (PD) may be responsible for PD motor symptoms or an epiphenomenon of dopamine loss. We investigated the causal role of beta-band activity in PD motor symptoms by testing the effects of beta-frequency subthalamic nucleus deep-brain stimulation (STN DBS) on the blink reflex excitability, amplitude, and plasticity in normal rats. Delivering 16 Hz STN DBS produced the same increase in blink reflex excitability and impairment in blink reflex plasticity in normal rats as occurs in rats with 6-hydroxydopamine lesions and patients with PD. These deficits were not an artifact of STN DBS because, when these normal rats received 130 Hz STN DBS, their blink characteristics were the same as without STN DBS. To demonstrate that the blink reflex disturbances with 16 Hz STN DBS were frequency specific, we tested the same rats with 7 Hz STN DBS, a theta-band frequency typical of dystonia. In contrast to beta stimulation, 7 Hz STN DBS exaggerated the blink reflex plasticity as occurs in focal dystonia. Thus, without destroying dopamine neurons or blocking dopamine receptors, frequency-specific STN DBS can be used to create PD-like or dystonic-like symptoms in a normal rat. PMID- 25146115 TI - Worldwide Integrated Assessment on systemic pesticides: global collapse of the entomofauna: exploring the role of systemic insecticides. PMID- 25146116 TI - Insights into assessing environmental quality status using potential surrogates of biofilm-dwelling ciliate fauna in coastal waters. AB - To determine potential surrogates of biofilm-dwelling ciliate fauna for assessing water quality, a dataset of coastal waters of the Yellow Sea was studied. Samples were collected monthly at a depth of 1 m from four sampling stations during a 1 year cycle (August 2011-July 2012), northern China. The ciliate communities at low taxonomic resolutions up to family level were significantly correlated with the full ciliate fauna at species-level resolution and represented a significant spatial variation in relation to the environmental changes. The presence/absence resolutions up to genus level maintained sufficient information of the ciliate species-abundance matrix. The vagile and sessile ciliate assemblages were significantly correlated with the full ciliate communities but only the latter maintained sufficient information with a significant spatial variation in response to the environmental stress. Correlation analyses showed that the taxon richness indices of potential surrogates at genus- and family-level resolutions can explain >95 % of the variance in that of the full species pool. Thus, it is suggested that the taxonomic resolutions up to family level may be a robust time efficient surrogate of whole periphytic ciliate communities for assessing water quality status and would allow improving sampling strategies of large spatial scale monitoring programs, using biofilm-dwelling ciliates, in coastal waters. PMID- 25146117 TI - Synthesis of carbon nanospheres using fallen willow leaves and adsorption of Rhodamine B and heavy metals by them. AB - This paper focuses on the synthesis of carbon nanospheres (CNSs) using fallen willow leaves as a low-cost precursor. The scanning electron microscopy (SEM) image and transmission electron microscopy (TEM) image demonstrated that the structure of synthesized CNSs was spherical, with a diameter of 100 nm. The crystal structure and chemical information were characterized by Raman spectrum and energy-dispersive spectrum (EDS), respectively. BET results showed that the CNSs had a larger specific surface area of 294.32 m(2) g(-1), which makes it a potentially superior adsorbent. Rh-B and heavy metal ions such as Cu(2+), Zn(2+), and Cr(6+) were used as targets to investigate the adsorption capacity of the CNSs. The effects of adsorption parameters such as adsorption equilibrium time, dose of CNSs, adsorption kinetics, and effect factors were also studied. These findings not only established a cost-effective method of synthesizing CNSs using fallen willow leaves but also broadened the potential application range of these CNSs. PMID- 25146118 TI - Sorption behavior and modeling of endocrine-disrupting chemicals on natural sediments: role of biofilm covered on surface. AB - The surfaces of natural sediments are ubiquitously coated by biofilms that increase the content of organic matter in sediments. However, it is less understood whether the biofilms act as a sorbent or a barrier of mass transfer from water column to sediment phase. This study focused on the role of biofilms coverage on sediments in the sorption of bisphenol A (BPA), 17alpha-ethinyl estradiol (EE2), and 4-nonylphenols (4-NP) as model compounds for endocrine disrupting chemicals (EDCs). The OC-normalized distribution coefficients (k OC) for BPA, EE2 and 4-NP ranged from 10(1.87) to 10(3.09) l/kg, the k OC of EE2 was slightly higher (10(2.23) l/kg) for sediment after H2O2 oxidation than before (10(1.93) l/kg). A two-stage model with a fast section and slow section was employed to describe the sorption process (r (2) > 0.95). The model results showed that the fast sorption section played a main role in the sorption process, while the slow section determined the extent of the reaction (the second-phase partition coefficient (k p2) ranged from 11.7 to 118.9 l/kg). The ratios of the mass transfer rate constant of the two stages for the natural sediment ranged from 6.0 to 7.2, which were somewhat lower than those for soil samples. These results indicated that the biofilm coverage on sediment may act as a barrier in mass transfer from water to sediment and scarcely increased the sorption capacity of sediments. PMID- 25146119 TI - Pollutant toxicity and detoxification by humic substances: mechanisms and quantitative assessment via luminescent biomonitoring. AB - The paper considers mechanisms of detoxification of pollutant solutions by water soluble humic substances (HSs), natural detoxifying agents. The problems and perspectives of bioassay application for toxicity monitoring of complex solutions are discussed from ecological point of view. Bioluminescence assays based on marine bacteria and their enzymes are of special attention here; they were shown to be convenient tools to study the detoxifying effects on cellular and biochemical levels. The advantages of bioluminescent enzymatic assay for monitoring both integral and oxidative toxicities in complex solutions of model pollutants and HS were demonstrated. The efficiencies of detoxification of the solutions of organic oxidizers and salts of metals (including radioactive ones) by HS were analyzed. The dependencies of detoxification efficiency on time of exposure to HS and HS concentrations were demonstrated. Antioxidant properties of HS were considered in detail. The detoxifying effects of HS were shown to be complex and regarded as 'external' (binding and redox processes in solutions outside the organisms) and/or 'internal' organismal processes. The paper demonstrates that the HS can stimulate a protective response of bacterial cells as a result of (1) changes of rates of biochemical reactions and (2) stabilization of mucous layers outside the cell walls. Acceleration of auto oxidation of NADH, endogenous reducer, by HS was suggested as a reason for toxicity increase in the presence of HS due to abatement of reduction ability of intracellular media. PMID- 25146120 TI - The use of vertical constructed wetland and ultrasound in aquaponic systems. AB - Treatment performance, fish production, crop plant biomass production, water consumption, and water use efficiency of a pilot aquaponic system for small-scale land-based cyprinid fish farms were evaluated. The system consisted of a 36 m(3) Pond A with an initial carp load of 0.6 kg/m(3); of a treatment chain with a lamellar settler, a roughing filter, a vertical constructed wetland filled with expanded clay and planted with tomatoes; and of a low power ultrasound unit installed in the corner of the pond. The average circulation of the water in the system was 1.2 times per day. Pond A was compared with Pond B of the same dimensions and fish load but with no treatment chain or ultrasound. The treatment chain was efficient in mass removal of total suspended solids , biochemical oxygen demand, chemical oxygen demand, NH4-N, total nitrogen, and total phosphorous (57, 49, 35, 42, 31, and 25 %, respectively). Negative removal of NO3 N, NO2-N, and PO4-P indicated the need for the introduction of additional hydroponic beds in the system. Pond A had markedly lower nutrient concentrations compared with Pond B. Fish body weight increase and specific growth rate in Pond A were higher than in Pond B (102.6 %, 72.1 %; 0.19 %/day, 0.14 %/day, respectively) indicating better rearing conditions in Pond A. Tomato biomass production was high. Water use efficiency was higher in Pond A compared with Pond B (0.31 kg of produced fish/m(3) inflow water and 0.22 kg of produced fish/m(3) inflow water, respectively). The presented aquaponic system could be useful for semi-natural fish farming with fish loads up to 2 kg/m(3). PMID- 25146121 TI - Evolution of dissolved organic matter during abiotic oxidation of coal tar- comparison with contaminated soils under natural attenuation. AB - In former coal transformation plants (coking and gas ones), the major organic contamination of soils is coal tar, mainly composed of polycyclic aromatic compounds (PACs). Air oxidation of a fresh coal tar was chosen to simulate the abiotic natural attenuation impact on PAC-contaminated soils. Water-leaching experiments were subsequently performed on fresh and oxidized coal tars to study the influence of oxidation on dissolved organic matter (DOM) quality and quantity. The characterization of the DOM was performed using a combination of molecular and spectroscopic techniques (high-performance liquid chromatography size-exclusion chromatography (HPLC-SEC), 3D fluorescence, and gas chromatography coupled with mass spectrometry (GC-MS)) and compared with the DOM from contaminated soils sampled on the field exposed to natural attenuation for several decades. An increase in the oxygenated polycyclic aromatic compound concentrations was observed with abiotic oxidation both in the coal tar and the associated DOM. Polycyclic aromatic hydrocarbon concentrations in the leachates exceeded pure water solubility limits, suggesting that co-solvation with other soluble organic compounds occurred. Furthermore, emission excitation matrix analysis combined with synchronous fluorescence spectra interpretation and size exclusion chromatography suggests that oxidation induced condensation reactions which were responsible for the formation of higher-molecular weight compounds and potentially mobilized by water. Thus, the current composition of the DOM in aged soils may at least partly result from (1) a depletion in lower-molecular weight compounds of the initial contamination stock and (2) an oxidative condensation leading to the formation of a higher-molecular weight fraction. Abiotic oxidation and water leaching may therefore be a significant combination contributing to the evolution of coal tar-contaminated soils under natural attenuation. PMID- 25146122 TI - Olive mill waste biochar: a promising soil amendment for metal immobilization in contaminated soils. AB - The potential use of biochar from olive mill waste for in situ remediation of metal contaminated soils was evaluated. Biochar was mixed with metal contaminated soil originating from the vicinity of an old zinc smelter. Soil-biochar mixtures were equilibrated for 30 and 90 days. At these time points, Ca(NO3)2 exchangeable metals were determined, and effects of the biochar amendment on soil toxicity were investigated using plants, bacteria, and earthworms. Bean (Phaseolus vulgaris) growth, metal content, antioxidative enzymes activities, and soluble protein contents were determined. Furthermore, effects on soil microbial communities (activity, diversity, richness) were examined using Biolog ECOplates. After 120 days of soil-biochar equilibration, effects on weight and reproduction of Eisenia foetida were evaluated. With increasing biochar application rate and equilibration period, Ca(NO3)2 exchangeable metals decreased, and growth of bean plants improved; leaf metal contents reduced, the activities of antioxidative stress enzymes decreased, and soluble protein contents increased. Soil microbial activity, richness, and diversity were augmented. Earthworm mortality lowered, and their growth and reproduction showed increasing trends. PMID- 25146123 TI - Evaluation of the genotoxicity of waters impacted by domestic and industrial effluents of a highly industrialized region of Sao Paulo State, Brazil, by the comet assay in HTC cells. AB - The problems that most affect the quality of the waters of rivers and lakes are associated with the discharges performed in these environments, mainly industrial and domestic effluents inappropriately treated or untreated. The comet assay is a sensitive tool and is recommended for studies of environmental biomonitoring, which aim to determine the genotoxicity potential of water pollutants. This study aimed to assess the genotoxic potential of the Ribeirao Tatu waters, region of Limeira, Sao Paulo (SP), by the comet assay with mammalian cells (hepatoma tissue culture (HTC)). Water samples were collected along the Ribeirao Tatu at three distinct periods: November 2008, February 2009 and August 2009, and five collection sites were established: P1, source of the stream; P2, site located downstream the urban perimeter of the municipality of Cordeiropolis and after receiving the pollution load of this city; P3, collection site located upstream the urban perimeter of the city of Limeira; P4, urban area of Limeira; and P5, rural area of Limeira, downstream the discharges of the city sewage. The results showed that for the November 2008 collection, there was no water sample-induced genotoxicity; for the February 2009 collection, the sites P1 and P2 were statistically significant in relation to the negative control (NC), and for the August 2009 collection, the site P5 was statistically significant. These results could be explained by the content of different metals during the different seasons that are under the influence of domestic, industrial and agricultural effluents and also due to the seasonality, since the water samples collected in the period of heavy rain (February 2009) presented a higher genotoxicity possibly due to the entrainment of contaminants into the bed of the stream promoted by the outflow of rainwaters. The comet assay showed to be a useful and sensitive tool in the evaluation of hydric resources impacted by pollutants of diverse origins, and a constant monitoring should be done in order to verify the influence of different factors (season, amount of contaminants) in the water quality. PMID- 25146124 TI - Automated quantification of 18F-flutemetamol PET activity for categorizing scans as negative or positive for brain amyloid: concordance with visual image reads. AB - Clinical trials of the PET amyloid imaging agent (18)F-flutemetamol have used visual assessment to classify PET scans as negative or positive for brain amyloid. However, quantification provides additional information about regional and global tracer uptake and may have utility for image assessment over time and across different centers. Using postmortem brain neuritic plaque density data as a truth standard to derive a standardized uptake value ratio (SUVR) threshold, we assessed a fully automated quantification method comparing visual and quantitative scan categorizations. We also compared the histopathology-derived SUVR threshold with one derived from healthy controls. METHODS: Data from 345 consenting subjects enrolled in 8 prior clinical trials of (18)F-flutemetamol injection were used. We grouped subjects into 3 cohorts: an autopsy cohort (n = 68) comprising terminally ill patients with postmortem confirmation of brain amyloid status; a test cohort (n = 172) comprising 33 patients with clinically probable Alzheimer disease, 80 patients with mild cognitive impairment, and 59 healthy volunteers; and a healthy cohort of 105 volunteers, used to define a reference range for SUVR. Visual image categorizations for comparison were from a previous study. A fully automated PET-only quantification method was used to compute regional neocortical SUVRs that were combined into a single composite SUVR. An SUVR threshold for classifying scans as positive or negative was derived by ranking the PET scans from the autopsy cohort based on their composite SUVR and comparing data with the standard of truth based on postmortem brain amyloid status for subjects in the autopsy cohort. The derived threshold was used to categorize the 172 scans in the test cohort as negative or positive, and results were compared with categorization using visual assessment. Different reference and composite region definitions were assessed. Threshold levels were also compared with corresponding thresholds derived from the healthy group. RESULTS: Automated quantification (using pons as the reference region) demonstrated 91% sensitivity and 88% specificity and gave 3 false-positive and 4 false-negative scans. All 3 false-positive cases were either borderline-normal by standard of truth or had moderate to heavy cortical diffuse plaque burden. In the test cohort, the concordance between quantitative and visual read categorization ranged from 97.1% to 99.4% depending on the selection of reference and composite regions. The threshold derived from the healthy group was close to the histopathology-derived threshold. CONCLUSION: Categorization of (18)F flutemetamol amyloid imaging data using an automated PET-only quantification method showed good agreement with histopathologic classification of neuritic plaque density and a strong concordance with visual read results. PMID- 25146126 TI - Dimeric tetrathiafulvalene linked to pseudo-ortho-[2.2]paracyclophane: chiral electrochromic properties and use as a chiral dopant. AB - A dimeric tetrathiafulvalene installed into a chiral pseudo-ortho [2.2]paracyclophane framework was synthesized as a novel chiral electrochromic material. This compound exhibited pronounced chiroptical properties in the UV-Vis NIR range depending on its redox states without racemization. Each enantiomer was examined as a chiral dopant for nematic liquid crystals (LCs), and the induced helicity of the LC solvent was in accord with that of the tetrathiafulvalene compound. PMID- 25146125 TI - N-terminal modifications improve the receptor affinity and pharmacokinetics of radiolabeled peptidic gastrin-releasing peptide receptor antagonists: examples of 68Ga- and 64Cu-labeled peptides for PET imaging. AB - Gastrin-releasing peptide receptors (GRPrs) are overexpressed on a variety of human cancers, providing the opportunity for peptide receptor targeting via radiolabeled bombesin-based peptides. As part of our ongoing investigations into the development of improved GRPr antagonists, this study aimed at verifying whether and how N-terminal modulations improve the affinity and pharmacokinetics of radiolabeled GRPr antagonists. METHODS: The potent GRPr antagonist MJ9, Pip-d Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH(2) (Pip, 4-amino-1-carboxymethyl piperidine), was conjugated to 1,4,7-triazacyclononane, 1-glutaric acid-4,7 acetic acid (NODAGA), and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and radiolabeled with (68)Ga and (64)Cu. The GRPr affinity of the corresponding metalloconjugates was determined using (125)I-Tyr(4)-BN as a radioligand. The labeling efficiency of (68)Ga(3+) was compared between NODAGA-MJ9 and NOTA-MJ9 in acetate buffer, at room temperature and at 95 degrees C. The (68)Ga and (64)Cu conjugates were further evaluated in vivo in PC3 tumor xenografts by biodistribution and PET imaging studies. RESULTS: The half maximum inhibitory concentrations of all the metalloconjugates are in the high picomolar-low nanomolar range, and these are the most affine-radiolabeled GRPr antagonists we have studied so far in our laboratory. NODAGA-MJ9 incorporates (68)Ga(3+) nearly quantitatively (>98%) at room temperature within 10 min and at much lower peptide concentrations (1.4 * 10(-6) M) than NOTA-MJ9, for which the labeling yield was approximately 45% under the same conditions and increased to 75% at 95 degrees C for 5 min. Biodistribution studies showed high and specific tumor uptake, with a maximum of 23.3 +/- 2.0 percentage injected activity per gram of tissue (%IA/g) for (68)Ga-NOTA-MJ9 and 16.7 +/- 2.0 %IA/g for (68)Ga-NODAGA-MJ9 at 1 h after injection. The acquisition of PET images with the (64)Cu-MJ9 conjugates at later time points clearly showed the efficient clearance of the accumulated activity from the background already at 4 h after injection, whereas tumor uptake still remained high. The high pancreas uptake for all radiotracers at 1 h after injection was rapidly washed out, resulting in an increased tumor-to-pancreas ratio at later time points. CONCLUSION: We have developed 2 GRPr antagonistic radioligands, which are improved in terms of binding affinity and overall biodistribution profile. Their promising in vivo pharmacokinetic performance may contribute to the improvement of the diagnostic imaging of tumors overexpressing GRPr. PMID- 25146127 TI - Simvastatin to modify neutrophil function in older patients with septic pneumonia (SNOOPI): study protocol for a randomised placebo-controlled trial. AB - BACKGROUND: Community-acquired pneumonia (CAP) is considered the leading cause of death from infectious disease in developed countries, while complications of CAP sepsis being the most common and challenging - increase the risk of mortality. During the progression of sepsis, a state of neutrophil 'paralysis' develops resulting in the impairment of neutrophil anti-microbial functions including: chemotaxis, production of reactive oxygen species, and formation of neutrophil extracellular traps (NETs). Mechanisms underlying defective neutrophil function remain elusive although NET formation has been implicated in the immunosuppression and increased rates of sepsis observed in neonates. There is, however, increasing evidence that statins are able to modulate neutrophil function in sepsis as several systematic reviews have concluded that statins have a role in improving infection-related outcomes and mortality while, in vitro, statins have also been shown to boost NET formation in healthy individuals. METHODS/DESIGN: The 'SNOOPI' trial is a phase 4, randomised placebo-controlled trial. The aim of this study is to determine whether oral treatment with simvastatin compared to placebo optimises neutrophil anti-microbial functions in elderly patients with septic pneumonia improving patient outcomes in the elderly. The primary outcome will be NET production within 72 to 96 hours of treatment with simvastatin or placebo measured in response to a number of inflammatory mediators, including IL8, f-Met-Leu-Phe and lipopolysaccharide. Secondary outcomes include neutrophil migratory capacity; reactive oxygen species production; neutrophil phagocytic capacity; safety and tolerability of simvastatin administration within this patient group; biological markers of neutrophil activation, the inflammatory response, alveolar epithelial and endothelial injury; systemic endothelial function biomarkers and pulmonary extracellular matrix degradation. This study aims to recruit 60 patients admitted into Queen Elizabeth Hospital Birmingham NHS-Foundation Trust. DISCUSSION: This study will investigate the ability of in vivo simvastatin therapy to modulate neutrophil anti-microbial functions in CAP-associated sepsis. TRIAL REGISTRATION: EudraCT number: 2012-003343-29 (Trial Registered: 26 November 2012). PMID- 25146129 TI - Biomechanical evaluation of maxillary Lefort Iota fracture with bioabsorbable osteosynthesis internal fixation. AB - The aim of this study was to apply biomechanical analysis model to evaluate the effects of bioabsorbable internal fixation devices on maxillary Lefort Iota fracture. CT scan technology and the finite element software (ansys) were used to establish three-dimensional finite element models of five resorbable internal fixation devices in maxillary Lefort Iota fractures. We used the model to calculate the stress of the upper jaw and internal fixation. We further analyzed the stability of fixation under four occlusions. The fixation using two bioabsorbable plates was not stable. The zygomaticomaxillary pillars fixation is more stable than other fixations. The stability of fracture fixation was influenced with the molar occlusion. The current study developed a functional three-dimensional finite element model of bioabsorbable internal fixation and compared the stability of five fixation methods for maxillary Lefort Iota fractures. The results would facilitate the application of bioabsorbable materials in dental clinic. PMID- 25146128 TI - Smoking-specific experiential avoidance cognition: explanatory relevance to pre- and post-cessation nicotine withdrawal, craving, and negative affect. AB - BACKGROUND: Negative-reinforcement based cognitive processes have been implicated in the maintenance of cigarette smoking. Given the expectation that smoking will attenuate aversive internal experiences, smokers may be particularly unwilling to experience or remain in contact with smoking-related distress (i.e., experiential avoidance). Yet, there is little known about a cognitive-based process termed smoking-specific experiential avoidance with regard to withdrawal, craving, or negative affect during a quit attempt. METHOD: Data were collected from adult daily smokers (n = 259) participating in a larger smoking cessation trial. Pre- and post-quit experiences of nicotine withdrawal, craving, and negative affect were examined in terms of cognitive-based smoking-specific experimental avoidance, measured by the Avoidance and Inflexibility Scale (AIS). RESULTS: Results indicated that baseline smoking-specific experiential avoidance was associated with greater overall levels of withdrawal, craving, and negative affect at treatment initiation (pre-cessation). Reductions in smoking-specific experiential avoidance from baseline to quit day were associated with increased likelihood of quit day abstinence. Such reductions were also predictive of lower levels of nicotine withdrawal, craving, and negative affect on quit day. Also, less reduction in experiential avoidance was associated with experiencing greater withdrawal in the early phase of quitting. DISCUSSION: The impact of cognitive based experiential avoidance pertaining to smoking impacts both pre- and post cessation experiences in terms of negative affect, withdrawal, and smoking cravings and may represent an important treatment target. PMID- 25146131 TI - Complete genome sequence of a mosaic bacteriophage, waukesha92. AB - In this study, we determined the complete genome sequence of a mosaic bacteriophage, Waukesha92, which was isolated from soil using Bacillus thuringiensis as the host organism. This temperate Myoviridae bacteriophage has similarities to phages SpaA1 and BceA1 and the Bacillus thuringiensis plasmid pBMB165. PMID- 25146132 TI - Complete Genome Sequence of Erwinia amylovora Bacteriophage vB_EamM_Ea35-70. AB - The complete genome of an Erwinia amylovora bacteriophage, vB_EamM_Ea35-70 (Ea35 70), is 271,084 bp, encodes 318 putative proteins, and contains one tRNA. Comparative analysis with other Myoviridae genomes suggests that Ea35-70 is related to the Phikzlikevirus genus within the family Myoviridae, since 26% of Ea35-70 proteins share homology to proteins in Pseudomonas phage phiKZ. PMID- 25146130 TI - Laser nanosurgery of cerebellar axons in vivo. AB - Only a few neuronal populations in the central nervous system (CNS) of adult mammals show local regrowth upon dissection of their axon. In order to understand the mechanism that promotes neuronal regeneration, an in-depth analysis of the neuronal types that can remodel after injury is needed. Several studies showed that damaged climbing fibers are capable of regrowing also in adult animals. The investigation of the time-lapse dynamics of degeneration and regeneration of these axons within their complex environment can be performed by time-lapse two photon fluorescence (TPF) imaging in vivo. This technique is here combined with laser surgery, which proved to be a highly selective tool to disrupt fluorescent structures in the intact mouse cortex. This protocol describes how to perform TPF time-lapse imaging and laser nanosurgery of single axonal branches in the cerebellum in vivo. Olivocerebellar neurons are labeled by anterograde tracing with a dextran-conjugated dye and then monitored by TPF imaging through a cranial window. The terminal portion of their axons are then dissected by irradiation with a Ti:Sapphire laser at high power. The degeneration and potential regrowth of the damaged neuron are monitored by TPF in vivo imaging during the days following the injury. PMID- 25146133 TI - Genome Sequence of Salmonella Phage 9NA. AB - The virulent double-stranded DNA (dsDNA) bacteriophage 9NA infects Salmonella enterica serovar Typhimurium and has a long noncontractile tail. We report its complete 52,869-bp genome sequence. Phage 9NA and two closely related S. enterica serovar Newport phages represent a tailed phage type whose molecular lifestyle has not yet been studied in detail. PMID- 25146134 TI - Whole-Genome Sequence of Serratia symbiotica Strain CWBI-2.3T, a Free-Living Symbiont of the Black Bean Aphid Aphis fabae. AB - The gammaproteobacterium Serratia symbiotica is one of the major secondary symbionts found in aphids. Here, we report the draft genome sequence of S. symbiotica strain CWBI-2.3(T), previously isolated from the black bean aphid Aphis fabae. The 3.58-Mb genome sequence might provide new insights to understand the evolution of insect-microbe symbiosis. PMID- 25146136 TI - Draft Genome Sequence of Hawaiian Sea Slug Symbiont Vibrio sp. Strain ER1A. AB - Bacteria belonging to the genus Vibrio are prevalent in the marine environment and are known for forming symbiotic relationships with hosts. Vibrio sp. strain ER1A is a dominant symbiont of the Hawaiian sea slug, Elysia rufescens. Here we report the draft genome sequence of Vibrio sp. ER1A. PMID- 25146135 TI - Genome Sequence of a Xylella fastidiosa Strain Causing Sycamore Leaf Scorch Disease in Virginia. AB - Xylella fastidiosa causes bacterial leaf scorch in landscape trees including sycamore. We determined the draft genome of X. fastidiosa strain Sy-Va, isolated in Virginia from a sycamore tree displaying leaf scorch symptoms. The Sy-VA genome contains 2,477,829 bp, and has a G+C content of 51.64 mol%. PMID- 25146137 TI - Draft Genome Sequence of Brucella abortus S99: Designated Antigenic Smooth Reference Strain Used in Diagnostic Tests in India. AB - Brucella abortus strain S99 is widely used for the preparation of colored, plain, recombinant and smooth lipopolysaccharide antigens for the preparation of Brucella diagnostic kits. The genome of this strain was sequenced and the length of the genome was 3,253,175 bp, with 57.2% G+C content. A total of 3,365 protein coding genes and 53 RNA genes were predicted. PMID- 25146138 TI - Draft Genome Sequence of Falsirhodobacter sp. Strain alg1, an Alginate-Degrading Bacterium Isolated from Fermented Brown Algae. AB - Falsirhodobacter sp. alg1 is an alginate-degrading bacterium, the second species from the nonphototrophic bacterial genus Falsirhodobacter. We report the first draft genome of a bacterium from this genus and point out possible important features related to alginate assimilation and its evolutionary aspects. PMID- 25146139 TI - Genome Sequence of Rhodococcus opacus Strain R7, a Biodegrader of Mono- and Polycyclic Aromatic Hydrocarbons. AB - Rhodococcus opacus strain R7 (CIP107348) degrades several mono- and polycyclic aromatic hydrocarbons. Here, we present the high-quality draft genome sequence of strain R7, consisting of 10,118,052 bp, with a G+C content of 67.0%, 9,602 protein-coding genes, and 62 RNAs genes. PMID- 25146140 TI - Draft Genome Assembly of Acinetobacter baumannii ATCC 19606. AB - Acinetobacter baumannii is an emerging nosocomial pathogen, and therefore high quality genome assemblies for this organism are needed to aid in detection, diagnostic, and treatment technologies. Here we present the improved draft assembly of A. baumannii ATCC 19606 in two scaffolds. This 3,953,621-bp genome contains 3,750 coding regions and has a 39.1% G+C content. PMID- 25146141 TI - Draft Genome Sequence of the Pyridinediol-Fermenting Bacterium Synergistes jonesii 78-1. AB - Here we present the draft genome of Synergistes jonesii 78-1, ATCC 49833, a member of the Synergistes phylum. This organism was isolated from the rumen of a Hawaiian goat and ferments pyridinediols. The assembly contains 2,747,397 bp in 61 contigs. PMID- 25146142 TI - Draft Genome Sequence of the Nominated Type Strain of "Ferrovum myxofaciens," an Acidophilic, Iron-Oxidizing Betaproteobacterium. AB - "Ferrovum myxofaciens" is an iron-oxidizing betaproteobacterium with widespread distribution in acidic low-temperature environments, such as acid mine drainage streams. Here, we describe the genomic features of this novel acidophile and investigate the relevant metabolic pathways that enable its survival in these environments. PMID- 25146143 TI - Genome Sequence of Mycobacterium tuberculosis C2, a Cerebrospinal Fluid Clinical Isolate from Central India. AB - We report the annotated genome sequence of a Mycobacterium tuberculosis clinical isolate from the cerebrospinal fluid of a tuberculous meningitis patient admitted to the Central India Institute of Medical Sciences, Nagpur, India. PMID- 25146144 TI - Complete Genome Sequence of Campylobacter iguaniorum Strain 1485ET, Isolated from a Bearded Dragon (Pogona vitticeps). AB - Campylobacter iguaniorum has been isolated from reptiles. This Campylobacter species is genetically related to Campylobacter fetus and Campylobacter hyointestinalis. Here we present the first whole-genome sequence for this species. PMID- 25146145 TI - Mycolic Acid Biosynthesis Genes in the Genome Sequence of Corynebacterium atypicum DSM 44849. AB - The complete chromosomal sequence of the type strain Corynebacterium atypicum DSM 44849 comprises 2,311,380 bp. A functional annotation revealed the presence of genes involved in the synthesis and export of mycolic acids and in trehalose corynomycolate biosynthesis, supporting the view that the cell envelope of C. atypicum contains mycolic acids. PMID- 25146146 TI - Complete Genome Sequence of a Klebsiella pneumoniae Strain Isolated from a Known Cotton Insect Boll Vector. AB - Klebsiella pneumoniae (associated with bacterial pneumonia) was previously isolated from Nezara viridula, a significant vector of cotton boll-rot pathogens. We provide the first annotated genome sequence of the cotton opportunistic strain K. pneumoniae 5-1. This data provides guidance to study the bases of cotton pathogenesis by bacteria associated with vectors. PMID- 25146147 TI - Whole-Genome Sequence of Weissella ceti Strain WS08, Isolated from Diseased Rainbow Trout in Brazil. AB - We report here the complete genome sequence of Weissella ceti strain WS08, an emerging pathogen to farm-raised rainbow trout. The genome of strain WS08 is composed of a circular chromosome with 1,355,853 bp and a G+C content of 40.78%. PMID- 25146148 TI - Complete Genome Sequence and Annotation of a Campylobacter jejuni Strain, MTVDSCj20, Isolated from a Naturally Colonized Farm-Raised Chicken. AB - Campylobacter jejuni is a major cause of human food-borne illness, with contaminated poultry products serving as a main source of human infection. C. jejuni strain MTVDSCj20 was isolated from the cecal contents of a farm-raised chicken that was naturally colonized with Campylobacter. We present here the complete annotated genome sequence of MTVDSCj20. PMID- 25146149 TI - Central coherence in adolescents with bulimia nervosa spectrum eating disorders. AB - BACKGROUND: Weak central coherence-a tendency to process details at the expense of the gestalt-has been observed among adults with bulimia nervosa (BN) and is a potential candidate endophenotype for eating disorders (EDs). However, as BN behaviors typically onset during adolescence it is important to assess central coherence in this younger age group to determine whether the findings in adults are likely a result of BN or present earlier in the evolution of the disorder. This study examines whether the detail-oriented and fragmented cognitive inefficiency observed among adults with BN is observable among adolescents with shorter illness duration, relative to healthy controls. METHOD: The Rey Osterrieth Complex Figure Test (RCFT) was administered to a total of 47 adolescents with DSM5 BN, 42 with purging disorder (PD), and 25 healthy controls (HC). Performance on this measure was compared across the three groups. RESULTS: Those with BN and PD demonstrated significantly worse accuracy scores compared to controls in the copy and delayed recall condition with a moderate effect size. These findings were exacerbated when symptoms of BN increased. DISCUSSION: Poorer accuracy scores reflect a fragmented and piecemeal strategy that interferes with visual-spatial integration in BN spectrum disorders. This cognitive inefficiency likely contributes to broad difficulties in executive functioning in this population especially in the context of worsening bulimic symptoms. The findings of this study support the hypothesis that poor global integration may constitute a cognitive endophenotype for BN. PMID- 25146151 TI - Observation of monolayer valence band spin-orbit effect and induced quantum well states in MoX2. AB - Transition metal dichalcogenides [corrected] have attracted much attention recently due to their potential applications in spintronics and photonics because of the indirect to direct band gap transition and the emergence of the spin valley coupling phenomenon upon moving from the bulk to monolayer limit. Here, we report high-resolution angle-resolved photoemission spectroscopy on MoSe2 single crystals and monolayer films of MoS2 grown on highly ordered pyrolytic graphite substrate. Our experimental results resolve the Fermi surface trigonal warping of bulk MoSe2, and provide evidence for the critically important spin-orbit split valence bands of monolayer MoS2. Moreover, we systematically image the formation of quantum well states on the surfaces of these materials, and present a theoretical model to account for these experimental observations. Our findings provide important insights into future applications of transition metal dichalcogenides in nanoelectronics, spintronics and photonics devices as they critically depend on the spin-orbit physics of these materials. PMID- 25146152 TI - Ethics education: do we need compassion boot camps? PMID- 25146150 TI - Correlation between ERK1 and STAT3 expression and chemoresistance in patients with conventional osteosarcoma. AB - BACKGROUND: The standard therapy regimen of conventional osteosarcoma includes neoadjuvant chemotherapy followed by surgical resection and postoperative chemotherapy. The percentage of necrotic tissue following induction chemotherapy is assessed by using the Huvos grading system, which classifies patients as "poor responders" (PR) and "good responders" (GR). The aim of this study was to identify molecular markers expressed differentially between good and poor responders to neoadjuvant chemotherapy in order to predict the response to chemotherapy in conventional osteosarcomas before beginning treatment. METHODS: Suppression Substractive Hybridization (SSH) was performed by using cDNA from frozen biopsy specimens. Expression of selected relevant genes identified by SSH was validated by using QRT-PCR. Immunohistochemistry (IHC) on tissue microarray (TMA) sections of 52 biopsies was performed to investigate protein expression in an independent cohort. RESULTS: ERK1 and STAT3 mRNA level were significantly different between PR and GR in an independent cohort. Phosphorylated STAT3 and ERK1 expressions by IHC on TMA were correlated with poor response to chemotherapy. CONCLUSIONS: Our results suggest that ERK1 and STAT3 expression are good predictive markers for chemotherapy response and that inhibitors might be used in combination with common chemotherapeutic drugs in conventional osteosarcomas. PMID- 25146153 TI - Nursing ethics comes of age in India. PMID- 25146155 TI - Commentary on Nursing Ethics article: Facilitating ethics education in nursing students. PMID- 25146156 TI - Response to Commentary. 1: Effectiveness of nursing ethics education: much more research needed. PMID- 25146157 TI - Response to Commentary. 2: A view from sTimul. PMID- 25146159 TI - Prediction of survival for patients with advanced colorectal cancer using (1) H High-resolution magic angle spinning nuclear MR spectroscopy. AB - PURPOSE: To evaluate whether the metabolic profiles of colorectal cancer specimens can be used for prediction of survival. MATERIALS AND METHODS: The metabolic profiles of colorectal cancer tissues were determined using the high resolution magic angle spinning (HR MAS) nuclear magnetic resonance (NMR) technique (16.4 T). HR MAS analysis was performed for 52 tissues taken from patients classified as survivors and nonsurvivors (30). Quantitative analysis was performed for each spectrum. Receiver operating characteristic (ROC) curves were used to evaluate the potential to predict patient survival over 5.5 years. RESULTS: Analysis of (1) H NMR spectra led to the identification and quantitative analysis of 30 metabolites. A significant increase in the Tau/Gly and Tau/MI ratios were associated with long-term survival (P = 0.004 and P = 0.003, respectively). ROC analysis indicated that the Tau/MI ratio had the best predictive value for survival (sensitivity 64.7% and specificity 100%). Good predictive value of survival was found for Tau/Gly ratio (sensitivity 63.6% and specificity 96.3%). Moreover, the Glu/Gln metabolic ratio with a cutoff level of 1.74 was predictive of survival with a sensitivity of 83.3% and a specificity of 85.7%. CONCLUSION: Our results indicate that HR MAS spectroscopy is potentially useful for survival prediction in advanced colorectal cancer. PMID- 25146161 TI - The robustness of the weak selection approximation for the evolution of altruism against strong selection. AB - The weak selection approximation of population genetics has made possible the analysis of social evolution under a considerable variety of biological scenarios. Despite its extensive usage, the accuracy of weak selection in predicting the emergence of altruism under limited dispersal when selection intensity increases remains unclear. Here, we derive the condition for the spread of an altruistic mutant in the infinite island model of dispersal under a Moran reproductive process and arbitrary strength of selection. The simplicity of the model allows us to compare weak and strong selection regimes analytically. Our results demonstrate that the weak selection approximation is robust to moderate increases in selection intensity and therefore provides a good approximation to understand the invasion of altruism in spatially structured population. In particular, we find that the weak selection approximation is excellent even if selection is very strong, when either migration is much stronger than selection or when patches are large. Importantly, we emphasize that the weak selection approximation provides the ideal condition for the invasion of altruism, and increasing selection intensity will impede the emergence of altruism. We discuss that this should also hold for more complicated life cycles and for culturally transmitted altruism. Using the weak selection approximation is therefore unlikely to miss out on any demographic scenario that lead to the evolution of altruism under limited dispersal. PMID- 25146160 TI - Patient reports of health outcome for adults living with sickle cell disease: development and testing of the ASCQ-Me item banks. AB - BACKGROUND: Providers and patients have called for improved understanding of the health care requirements of adults with sickle cell disease (SCD) and have identified the need for a systematic, reliable and valid method to document the patient-reported outcomes (PRO) of adult SCD care. To address this need, the Adult Sickle Cell Quality of Life Measurement System (ASCQ-Me) was designed to complement the Patient Reported Outcome Measurement Information System (PROMIS(r)). Here we describe methods and results of the psychometric evaluation of ASCQ-Me item banks (IBs). METHODS: At seven geographically-disbursed clinics within the US, 556 patients responded to questions generated to assess cognitive, emotional, physical and social impacts of SCD. We evaluated the construct validity of the hypothesized domains using exploratory factor analysis (EFA), parallel analysis (PA), and bi-factor analysis (Item Response Theory Graded Response Model, IRT-GRM). We used IRT-GRM and the Wald method to identify bias in responses across gender and age. We used IRT and Cronbach's alpha coefficient to evaluate the reliability of the IBs and then tested the ability of summary scores based on IRT calibrations to discriminate among tertiles of respondents defined by SCD severity. RESULTS: Of the original 140 questions tested, we eliminated 48 that either did not form clean factors or provided biased measurement across subgroups defined by age and gender. Via EFA and PA, we identified three subfactors within physical impact: sleep, pain and stiffness impacts. Analysis of the resulting six item sets (sleep, pain, stiffness, cognitive, emotional and social impacts of SCD) supported their essential unidimensionality. With the exception of the cognitive impact IB, these item sets also were highly reliable across a broad range of values and highly significantly related to SCD disease severity. CONCLUSION: ASCQ-Me pain, sleep, stiffness, emotional and social SCD impact IBs demonstrated exceptional measurement properties using modern and classical psychometric methods of evaluation. Further development of the cognitive impact IB is required to improve its sensitivity to differences in SCD disease severity. Future research will evaluate the sensitivity of the ASCQ-Me IBs to change in SCD disease severity over time due to health interventions. PMID- 25146162 TI - Clinical and molecular analyses of sporadic acute hepatitis A and E and the specific viral genotypes isolated in Iwate and three neighboring prefectures in the northern part of Honshu, Japan, between 2004 and 2013. AB - AIM: To examine the prevalence and characteristics of hepatitis A virus (HAV) and hepatitis E virus (HEV) infections in the northern part of Honshu, Japan, during the last decade. METHODS: Using the registration system of a prospective cohort study for acute liver injury (ALI) in Iwate and three neighboring prefectures, we examined the prevalence of sporadic acute hepatitis (AH) with HAV (AH-A) and HEV (AH-E) and the distribution of viral genotypes in 487 patients diagnosed with ALI between 2004 and 2013. RESULTS: Among all 487 patients, 135 (28%) had ALI with viral infection. In the cases with viral ALI, the prevalence of hepatitis B virus related AH was highest (55.6%). AH-E was seen in 23 patients (17.0%) and its prevalence was higher than that of AH-A (10 patients, 7.4%). There were no appreciable differences in the prevalence of AH-A and AH-E between 2004-2008 and 2009-2013. However, subgenotype IIIA HAV homologous to Korean strains has recently emerged, and the number of AH-E cases seems to be increasing. HEV genotype 3 was predominant throughout the observation period, but HEV genotype 4 was found in three patients after 2010. The transmission routes of HAV and HEV infections were unknown in approximately 60% of the patients. CONCLUSION: In the northern part of Honshu, Japan, HEV has been more frequently implicated in the development of AH than HAV, and HEV genotype 4 has been recently increasing. To provide an effective prophylactic management for HAV and HEV infections, further clarification of the transmission routes is needed. PMID- 25146163 TI - Real-time impedance-based cell analyzer as a tool to delineate molecular pathways involved in neurotoxicity and neuroprotection in a neuronal cell line. AB - Many brain-related disorders have neuronal cell death involved in their pathophysiology. Improved in vitro models to study neuroprotective or neurotoxic effects of drugs and downstream pathways involved would help gain insight into the molecular mechanisms of neuroprotection/neurotoxicity and could potentially facilitate drug development. However, many existing in vitro toxicity assays have major limitations - most assess neurotoxicity and neuroprotection at a single time point, not allowing to observe the time-course and kinetics of the effect. Furthermore, the opportunity to collect information about downstream signaling pathways involved in neuroprotection in real-time would be of great importance. In the current protocol we describe the use of a real-time impedance-based cell analyzer to determine neuroprotective effects of serotonin 2A (5-HT2A) receptor agonists in a neuronal cell line under label-free and real-time conditions using impedance measurements. Furthermore, we demonstrate that inhibitors of second messenger pathways can be used to delineate downstream molecules involved in the neuroprotective effect. We also describe the utility of this technique to determine whether an effect on cell proliferation contributes to an observed neuroprotective effect. The system utilizes special microelectronic plates referred to as E-Plates which contain alternating gold microelectrode arrays on the bottom surface of the wells, serving as cell sensors. The impedance readout is modified by the number of adherent cells, cell viability, morphology, and adhesion. A dimensionless parameter called Cell Index is derived from the electrical impedance measurements and is used to represent the cell status. Overall, the real-time impedance-based cell analyzer allows for real-time, label free assessment of neuroprotection and neurotoxicity, and the evaluation of second messenger pathways involvement, contributing to more detailed and high throughput assessment of potential neuroprotective compounds in vitro, for selecting therapeutic candidates. PMID- 25146165 TI - Water activation by small free ruthenium oxide clusters. AB - The reactions of ruthenium clusters, Rux(+) (x = 2-5), and ruthenium oxide clusters, RuxOy(+) (x = 2-5, y = 1-2), with water molecules have been investigated by gas phase ion trap mass spectrometry and first principle density functional calculations. The joint experimental and theoretical study reveals that the reactions of the ruthenium oxide clusters with water are considerably more efficient. This is assigned theoretically to the stronger binding of the water molecules to RuxOy(+) and, more importantly, to water activation leading to an efficient hydrogen transfer reaction from the water molecules to the oxygen atoms of the ruthenium oxide clusters. The theoretically predicted hydrogen shift reaction has been confirmed experimentally through (16)O/(18)O isotope exchange experiments. Calculated energy profiles for the reactions of selected oxide clusters with water illustrate that the oxygen isotope exchange relies on the facile transfer of hydrogen atoms via [1,3] shift reactions between the oxygen atoms of the complexes due to the relatively low barriers involved. These findings might open perspectives for the future realization of water oxidation driven by ruthenium oxide clusters. PMID- 25146164 TI - Adipose-derived mesenchymal stem cells transplantation facilitate experimental peritoneal fibrosis repair by suppressing epithelial-mesenchymal transition. AB - BACKGROUND: Prevention or reversal of peritoneal damage is critical in peritoneal dialysis. Although autologous cell transplantation has beneficial effects on tissue repair in various organs, few studies have investigated the effects of transplantation of adipose-derived mesenchymal stem cells (ASCs) on peritoneal fibrosis (PF). Thus, we examined the mechanism of facilitated peritoneal reconstruction induced by ASC transplantation on chlorhexidine gluconate (CG) induced PF in rats. METHODS: To induce PF in rats, continuous-infusion pumps containing 8 % CG were placed in the abdominal cavity for 21 days. The pumps were removed on day 22 and ASCs were immediately injected into the peritoneal cavity. Morphological alterations and mRNA expression levels of fibrosis-related factors were examined on days 29 and 35. RESULTS: ASC transplantation significantly facilitated peritoneal repair. mRNA expression of tumor necrosis factor-alpha, interleukin-1beta, monocyte chemotactic protein-1, and epithelial-mesenchymal transition (EMT) markers such as Snail and alpha-smooth muscle actin were suppressed, whereas that of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-BB (PDGF-BB) were overexpressed after ASC transplantation. Immunofluorescence indicated that some transplanted ASCs expressed VEGF and PDGF-BB and differentiated into vascular cells. CONCLUSIONS: ASC transplantation facilitates peritoneal repair by suppressing EMT and modulating inflammation and angiogenesis during the early phase of tissue repair in experimental PF. PMID- 25146166 TI - Report of the International Equine Influenza Roundtable Expert Meeting at Le Touquet, Normandy, February 2013. PMID- 25146168 TI - Prognostic significance of WNT signaling in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies and is associated with a variety of molecular abnormalities. Although WNT signaling through its canonical/non-canonical pathways is one of the major factors involved in oncogenesis or progression of PDA, the prognostic significance of WNT signaling still remains poorly investigated. In this study, the status of the WNT signaling pathways was immunohistochemically analyzed in 101 PDAs, and its potential association with patient postoperative survival was assessed. Nuclear expression of beta-catenin, a hallmark of the activated canonical pathway, was identified in 59 cases, and was associated with reduced survival compared to the patients lacking nuclear beta-catenin expression (P = 0.002). In contrast, activation of the non-canonical pathway (25 cases), as indicated by co-expression of WNT2/5a and nuclear NFATc1, was not correlated with reduced survival (P = 0.268). Co-activation of both pathways (16 cases) was associated with worse prognosis in comparison with cases with an activated non canonical pathway (P = 0.034). In addition, nuclear beta-catenin expression was an independent unfavorable prognostic factor (P = 0.006). Our data indicate that activated WNT signaling through its canonical pathway has a significantly negative effect on the clinical course of PDA, and the canonical WNT pathway should be considered as a future therapeutic target for PDA. PMID- 25146167 TI - Complex interactions between the components of the PI3K/AKT/mTOR pathway, and with components of MAPK, JAK/STAT and Notch-1 pathways, indicate their involvement in meningioma development. AB - We investigated the significance of PI3K/AKT/mTOR pathway and its interactions with MAPK, JAK/STAT and Notch pathways in meningioma progression. Paraffin embedded tissue from 108 meningioma patients was analysed for the presence of mutations in PIK3CA and AKT1. These were correlated with the expression status of components of the PI3K/AKT/mTOR pathway, including p85alpha and p110gamma subunits of PI3K, phosphorylated (p)-AKT, p-mTOR, p-p70S6K and p-4E-BP1, as well as of p-ERK1/2, p-STAT3 and Notch-1, clinicopathological data and patient survival. A mutation in PIK3CA or AKT1 was found in around 9 % of the cases. Higher grade meningiomas displayed higher nuclear expression of p-p70S6K; higher nuclear and cytoplasmic expression of p-4E-BP1 and of Notch-1; lower cytoplasmic expression of p85alphaPI3K, p-p70S6K and p-ERK1/2; and lower PTEN Histo-scores (H scores). PTEN H-score was inversely correlated with recurrence probability. In univariate survival analysis, nuclear expression of p-4E-BP1 and absence of p ERK1/2 expression portended adverse prognosis, whereas in multivariate survival analysis, p-ERK1/2 expression emerged as an independent favourable prognostic factor. Treatment of the human meningioma cell line HBL-52 with the PI3K inhibitor LY294002 resulted in reduction of p-AKT, p-p70S6K and p-ERK1/2 protein levels. The complex interactions established between components of the PI3K/AKT/mTOR pathway, or with components of the MAPK, JAK/STAT and Notch-1 pathways, appear to be essential for facilitating and fuelling meningioma progression. PMID- 25146169 TI - Thyroid and parathyroid tumours in patients submitted to X-ray scalp epilation during the tinea capitis eradication campaign in the North of Portugal (1950 1963). AB - Tinea capitis attained epidemical proportions in the fifth and sixth decades in Portugal, as in other countries. Before starting the utilization of griseofulvin in 1959, the best approach to treat tinea capitis infection was X-ray scalp epilation combined with topical antimycotic ointments. A long-term side effect of this therapy is thyroid disease, namely thyroid cancer; data on parathyroid lesions (hyperplasia, adenoma and carcinoma) are scarce. We observed clinically 1,375 individuals irradiated in childhood for tinea capitis treatment in the North of Portugal with the main purpose of evaluating thyroid and parathyroid tumours as possible sequelae of the irradiation treatment. For each individual, a cervical ultrasound and a serum calcium measurement were proposed. Fine needle aspiration cytology was suggested whenever ultrasound thyroid nodules presented suspicious features. We observed a 54 % frequency of thyroid nodules and a 2.8 % frequency of thyroid carcinoma (38/1,375). Nineteen of the 38 (50 %) carcinomas were diagnosed by us, whereas the remaining 19 carcinomas had been diagnosed and treated prior to our observation. The carcinomas were significantly more frequent in women than in men. Benign excised lesions were also significantly more frequent in women and in patients irradiated at younger ages. Seven women, considered asymptomatic until our clinical observation, had laboratory signs of hyperparathyroidism. The data we have obtained, namely high thyroid cancer frequency, corroborate previous data from childhood irradiated cohorts and highlight the need for the close follow-up of these populations in order to identify and treat early undiagnosed head and neck lesions. No evidence of increased parathyroid disease was found in this cohort of head and neck X irradiated patients. PMID- 25146171 TI - Ribozymes that can be regulated by external stimuli. AB - Ribozymes have been known for about 30 years, and nowadays are understood well enough to be turned into useful tools for a number of applications in vitro and in vivo. Allosteric ribozymes switch on and off their activity in response to a specific chemical (ligand) or physical (temperature, light) signal. The possibility of controlling ribozyme activity by external stimuli is of particular relevance for applications in different fields, such as environmental and medicinal diagnostics, molecular computing, control of gene expression and others. Herein, we review recent advances and describe selected examples of addressable ribozymes. PMID- 25146170 TI - Visualizing life with ambient mass spectrometry. AB - Since the development of desorption electrospray ionization (DESI), many other ionization methods for ambient and atmospheric pressure mass spectrometry have been developed. Ambient ionization mass spectrometry has now been used for a wide variety of biological applications, including plant science, microbiology, neuroscience, and cancer pathology. Multimodal integration of atmospheric ionization sources with the other biotechnologies, as well as high performance computational methods for mass spectrometry data processing is one of the major emerging area's for ambient mass spectrometry. In this opinion article, we will highlight some of the most influential technological advances of ambient mass spectrometry in recent years and their applications to the life sciences. PMID- 25146172 TI - Pregnancy incidence and outcome before and after cervical intraepithelial neoplasia: a retrospective cohort study. AB - We performed a retrospective cohort study of 3530 women treated for cervical intraepithelial neoplasia (CIN) in Helsinki University Central Hospital, Finland, to investigate whether CIN treatment itself affects pregnancy incidence and outcome. We estimated the incidence of live births, miscarriages, extrauterine pregnancies, molar pregnancies, and termination of pregnancies (TOPs) before and after CIN treatment using nationwide registers. Women were followed up until death, emigration, sterilization, or the end of 2004. The comparison of incidence of pregnancy outcomes before and after the treatment was estimated by calculating hazard ratios (HRs) with conditional Poisson regression. After 76,162 woman-years of follow-up, the incidence of any pregnancy remained constant over CIN treatment, HR 1.02 and 95% confidence interval (CI) 0.97-1.08, but the incidence of the first pregnancy was significantly elevated after treatment, HR 1.13, and 95% CI 1.03-1.23. The incidence of live births was significantly elevated after treatment, HR 1.08 and 95% CI 1.01-1.15. Incidence of miscarriages, TOPs, extrauterine pregnancies, and molar pregnancies was not elevated. TOPs was significantly increased in the first pregnancy, HR 1.40, 95% CI 1.15-1.72 and after treatment by the loop electrosurgical excision procedure (LEEP), HR 1.36, 95% CI 1.15-1.60. CIN treatment did not reduce pregnancy incidence and women had more live births after than before CIN treatment. TOPs was more common in the first pregnancy or after treatment by LEEP. We encourage research on the psychosocial consequences of CIN treatment also in other countries and settings. PMID- 25146173 TI - Synthesis, characterization and anti-inflammatory activity of N-(4- phenyl-1, 3 thiazol-2-yl)-N'-phenylureas. AB - A series of N-(4-phenyl-1, 3-thiazol-2-yl)-N'- phenylureas (5a-z) was synthesized from 2-amino-4-substituted phenylthiazoles and phenylisocyanates. The newly synthesized compounds were characterized by IR, (1)H NMR and Mass spectral data. All the twenty six N-(4-phenyl-1, 3-thiazol-2-yl)-N'-phenylurea derivatives were screened for antiinflammatory activity by following carrageenan induced rat paw edema method. Among the compounds screened, N-[4- (4-methoxy phenyl)-1, 3-thiazol 2-yl)-N'-phenylurea and N-[4-(4-methoxy phenyl-1, 3-thiazol-2-yl)-N'-(4 bromophenyl) urea were found to be more potent. The molecular docking interaction of aforementioned urea compounds revealed the traditional type II p38 kinase inhibitor's interactions in the DFG out active site. PMID- 25146175 TI - Electrodeposition and magnetic characterization of iron and iron-silicon alloys from the ionic liquid 1-butyl-1-methylpyrrolidinium trifluoromethylsulfonate. AB - The electrodeposition of soft magnetic iron and iron-silicon alloys for magnetic measurements is presented. The preparation of these materials in 1-butyl-1 methylpyrrolidinium trifluoromethylsulfonate, [Py1,4]TfO, at 100 degrees C with FeCl2 and FeCl2 +SiCl4 was studied by using cyclic voltammetry. Constant potential electrolysis was carried out to deposit either Fe or FeSi, and deposits of approximately 10 MUm thicknesses were obtained. By using scanning electron microscopy and X-ray diffraction, the microstructure and crystallinity of the deposits were investigated. Grain sizes in the nanometer regime (50-80 nm) were found and the presence of iron-silicon alloys was verified. Frequency-dependent magnetic polarizations, coercive forces, and power losses of some deposits were determined by using a digital hysteresis recorder. Corresponding to the small grain sizes, the coercive forces are around 950-1150 A m(-1) and the power losses were at 6000 J m(-3), which is much higher than in commercial Fe(3.2 wt %)Si electrical steel. Below a polarization of 1.8 T, the power losses are mainly caused by domain wall movements and, above 1.8 T, by rotation of magnetic moments as well as domain wall annihilation and recreation. PMID- 25146178 TI - Micro-masonry for 3D additive micromanufacturing. AB - Transfer printing is a method to transfer solid micro/nanoscale materials (herein called 'inks') from a substrate where they are generated to a different substrate by utilizing elastomeric stamps. Transfer printing enables the integration of heterogeneous materials to fabricate unexampled structures or functional systems that are found in recent advanced devices such as flexible and stretchable solar cells and LED arrays. While transfer printing exhibits unique features in material assembly capability, the use of adhesive layers or the surface modification such as deposition of self-assembled monolayer (SAM) on substrates for enhancing printing processes hinders its wide adaptation in microassembly of microelectromechanical system (MEMS) structures and devices. To overcome this shortcoming, we developed an advanced mode of transfer printing which deterministically assembles individual microscale objects solely through controlling surface contact area without any surface alteration. The absence of an adhesive layer or other modification and the subsequent material bonding processes ensure not only mechanical bonding, but also thermal and electrical connection between assembled materials, which further opens various applications in adaptation in building unusual MEMS devices. PMID- 25146174 TI - Network analysis of the default mode network using functional connectivity MRI in Temporal Lobe Epilepsy. AB - Functional connectivity MRI (fcMRI) is an fMRI method that examines the connectivity of different brain areas based on the correlation of BOLD signal fluctuations over time. Temporal Lobe Epilepsy (TLE) is the most common type of adult epilepsy and involves multiple brain networks. The default mode network (DMN) is involved in conscious, resting state cognition and is thought to be affected in TLE where seizures cause impairment of consciousness. The DMN in epilepsy was examined using seed based fcMRI. The anterior and posterior hubs of the DMN were used as seeds in this analysis. The results show a disconnection between the anterior and posterior hubs of the DMN in TLE during the basal state. In addition, increased DMN connectivity to other brain regions in left TLE along with decreased connectivity in right TLE is revealed. The analysis demonstrates how seed-based fcMRI can be used to probe cerebral networks in brain disorders such as TLE. PMID- 25146179 TI - From question-behaviour effects in trials to the social psychology of research participation. AB - The 'question-behaviour effect' (QBE) has attracted much recent attention within health psychology, where it has also been referred to as the 'mere measurement' effect. There are other conceptualisations of similar phenomena in related disciplines. This paper explores the implications of the QBE for the safety of inferences about intervention effectiveness within the context of randomised controlled trials evaluating health behaviour change interventions. It draws attention to poorly understood mechanisms by which bias is introduced with conventional thinking about trial design and analysis. The threat to valid inference on intervention effectiveness posed by the QBE applies even when its effects are small and regardless of the specific content of the QBE. The nature of the resulting bias does not fit well within existing bias classification schemes, such as that proposed by the Cochrane Collaboration. The QBE is one possible consequence of research participation and it is suggested that the social psychology of research participation is very much underdeveloped. Possible future directions for health psychology research in this area are considered. PMID- 25146180 TI - Retentive characteristics of a vinylpolysiloxane overdenture attachment system. AB - OBJECTIVES: Numerous different attachments are used to retain overdentures on implants. The purpose of this study was to evaluate a new chairside attachment system based on polyvinylsiloxane (PVS). MATERIAL AND METHODS: A total of 250 specimens were fabricated (n = 10) to measure the retention force (RF) in dependence of the following parameters: fatigue (after 100, 200, 500, 1,000, and 5,000 cycles of dislodging), thermal undulation (10,000 cycles between 5 and 55 degrees C), implant angulation (0 degrees , 5 degrees , and 10 degrees ), and disinfection (three different agents). Three different PVS materials (shore hardness (SH), SH25, SH50, and SH65) were evaluated; locator attachments (LR blue) served as controls. Data were imported into a statistical program and analyzed at a 5 % level of significance. RESULTS: Initial RFs were dependent on the shore hardness (p <= 0.001, ANOVA). No changes in RFs were observed for PVS groups after repeated dislodging and thermal undulation. Locator attachments revealed a significant decrease in retention force of up to 58 % (p <= 0.001, Fig. 3). No significant changes in RFs were induced by implant angulation. Retention force was decreased in some PVS groups after storage in disinfection solution. CONCLUSIONS: Polyvinylsiloxane attachments provide an alternative to locator attachments, exhibiting better stability of the retention force. CLINICAL RELEVANCE: The presented directly fabricated chairside attachment system represents RFs superior to existing attachment systems after artificial aging. PMID- 25146183 TI - Spoke ring and anchorage of nuclear pore complex revealed by high resolution transmission electron microscopy. AB - Using several different methods, the nuclear pore complex (NPC) was shown to be anchored in the nuclear envelope into the specific curved region, called pore membrane. Three transmembrane nucleoporins in the equatorial region of NPC contain hydrophobic stretches, which exhibit the ability to intersect the phospholipid bilayer. Using transmission electron microscopy, we observed three different evaluable morphological situations in the section through the NPC spoke ring (SR). We suppose that some sections are directed through one type of subunit that is responsible for anchoring. Other sections are directed through the second type of subunit that may provide pore membrane bending. Finally, the spoke ring is sectioned between aforementioned subunits where the pore membrane is best preserved. The proposed anchor is represented by the chains of protein complexes which replace phospholipid bilayer in a relatively large area. Second subunit, presumed bending module is represented by the bundles of chains copying the shape of the pore membrane from the side of the NPC. This work is based on very high resolution resulting in unique and complicated images of tangled and cut off protein chains, nevertheless, it provides insight into how some proteins interact with or replace the membrane. PMID- 25146181 TI - Type IV collagen is a novel DEJ biomarker that is reduced by radiotherapy. AB - The dental basement membrane (BM) is composed of collagen types IV, VI, VII, and XVII, fibronectin, and laminin and plays an inductive role in epithelial mesenchymal interactions during tooth development. The BM is degraded and removed during later-stage tooth morphogenesis; however, its original position defines the location of the dentin-enamel junction (DEJ) in mature teeth. We recently demonstrated that type VII collagen is a novel component of the inner enamel organic matrix layer contiguous with the DEJ. Since it is frequently co-expressed with and forms functional complexes with type VII collagen, we hypothesized that type IV collagen should also be localized to the DEJ in mature human teeth. To identify collagen IV, we first evaluated defect-free erupted teeth from various donors. To investigate a possible stabilizing role, we also evaluated extracted teeth exposed to high-dose radiotherapy--teeth that manifest post-radiotherapy DEJ instability. We now show that type IV collagen is a component within the morphological DEJ of posterior and anterior teeth from individuals aged 18 to 80 yr. Confocal microscopy revealed that immunostained type IV collagen was restricted to the 5- to 10-um-wide optical DEJ, while collagenase treatment or previous in vivo tooth-level exposure to > 60 Gray irradiation severely reduced immunoreactivity. This assignment was confirmed by Western blotting with whole tooth crown and enamel extracts. Without reduction, type IV collagen contained macromolecular alpha-chains of 225 and 250 kDa. Compositionally, our results identify type IV collagen as the first macromolecular biomarker of the morphological DEJ of mature teeth. Given its network structure and propensity to stabilize the dermal-epidermal junction, we propose that a collagen-IV-enriched DEJ may, in part, explain its well-known fracture toughness, crack propagation resistance, and stability. In contrast, loss of type IV collagen may represent a biochemical rationale for the DEJ instability observed following oral cancer radiotherapy. PMID- 25146182 TI - Projections of U.S. Edentulism prevalence following 5 decades of decline. AB - After decades of decline in prevalence of complete tooth loss (edentulism), the trend continues to be misinterpreted, producing flawed projections and misdirected health goals. We investigated population trends in edentulism among U.S. adults aged >= 15 yr by creating time-series data from 5 national cross sectional health surveys: 1957-1958 (n ~ 100,000 adults), 1971-1975 (n = 14,655 adults), 1988-1998 (n = 18,011 adults), 1999-2002 (n = 12,336 adults), and 2009 2012 (n = 10,522 adults). Birth cohort analysis was used to isolate age and cohort effects. Geographic and sociodemographic variation in prevalence was investigated with a sixth U.S. survey of 432,519 adults conducted in 2010. Prevalence through 2050 was projected with age-cohort regression models using Monte-Carlo simulation of prediction intervals. Across the 5-decade observation period, edentulism prevalence declined from 18.9% in 1957-1958 (95% confidence limits: 18.4%, 19.4%) to 4.9% in 2009-2012 (95% confidence limits: 4.0%, 5.8%). The most influential determinant of the decline was the passing of generations born before the 1940s, whose rate of edentulism incidence (5%-6% per decade of age) far exceeded later cohorts (1%-3% per decade of age). High-income households experienced a greater relative decline, although a smaller absolute decline, than low-income households. By 2010, edentulism was a rare condition in high-income households, and it had contracted geographically to states with disproportionately high poverty. With the passing of generations born in the mid 20th century, the rate of decline in edentulism is projected to slow, reaching 2.6% (95% prediction limits: 2.1%, 3.1%) by 2050. The continuing decline will be offset only partially by population growth and population aging such that the predicted number of edentulous people in 2050 (8.6 million; 95% prediction limits: 6.8 million, 10.3 million) will be 30% lower than the 12.2 million edentulous people in 2010. PMID- 25146184 TI - Biotransformation and nitroglycerin-induced effects on antioxidative defense system in rat erythrocytes and reticulocytes. AB - The effects of nitroglycerin (glyceryl trinitrate - GTN) are mediated by liberated nitric oxide (NO) and formed reactive nitrogen species, which induces oxidative stress during biotransformation in red blood cells (RBCs). The aim of this study was to evaluate effects of GTN on antioxidative defense system (AOS) in rat erythrocytes (without) and reticulocytes (with functional mitochondria). Rat erythrocyte and reticulocyte-rich RBC suspensions were aerobically incubated (2 h, 37 degrees C) without (control) or in the presence of different concentrations of GTN (0.1-1.5 mM). After incubation, concentrations of non enzymatic components of AOS, activities of antioxidative enzymes and oxidative pentose phosphate (OPP) pathway activity were followed in RBC suspensions. In rat reticulocytes, GTN decreased the activity of mitochondrial MnSOD and increased the activity of CuZnSOD. In rat RBCs, GTN induced increase of Vit E concentration (at high doses), but decreased glutathione content and activities of all glutathione-dependent antioxidative enzymes; the OPP pathway activity significantly increased. GTN biotransformation and induction of oxidative stress were followed by general disbalance of antioxidative capacities in both kinds of RBCs. We suggest that oxidative stress, MnSOD inhibition and depletion of glutathione pool in response to GTN treatment lead to decreased bioavailability of NO after GTN biotransformation in rat reticulocytes. PMID- 25146185 TI - The crystal structure of oxy hemoglobin from high oxygen affinity bird emu (Dromaius novaehollandiae). AB - Hemoglobin is an honorary enzyme, a two-way respiratory carrier, transporting oxygen from the lungs to the tissues and facilitating the return transport of carbon dioxide. Hemoglobin has high affinity for oxygen and low affinity for carbon dioxide and other substances in the arterial circulation, whereas in the venous circulation these relative affinities are upturned. The oxygen affinity of hemoglobin increases with the fall in temperature and decreases with the increase in pH and 2, 3-bisphosphoglycerate; point mutations also affect the tetrameric arrangement and alter the oxygen affinity. Though several studies have revealed the specific reasons for the adaptation of increased oxygen affinity of avian hemoglobins at high-altitudes, further structural insights on hemoglobins from high oxygen affinity species are required to understand the detailed oxygen adaptation at the molecular level. Herein, we describe the structural investigation of hemoglobin from emu (Dromaius novaehollandiae), a high oxygen affinity bird. Hemoglobin from emu was purified using anion-exchange chromatography, crystallized and determined the structure in the oxy form at a resolution of 2.3 A; the R-factor of the model was 19.2%. The structure was compared with other oxy hemoglobins of high oxygen affinity avian species; significant changes are noted at intra-subunit contacts which provide the clues for increased oxygen affinity of emu hemoglobin. PMID- 25146186 TI - The effect of cupric and ferric ions on antioxidant properties of human serum albumi. AB - The interaction of both ferric (Fe3+) and cupric (Cu2+) ions with human serum albumin (HSA) was assayed at a temperature of 27 degrees C in aqueous solution using isothermal titration calorimetry. The association equilibrium constant and the molar enthalpy for one binding is 1.7 * 105 M-1 and -31.37 kJ * M-1, respectively. To obtain the binding parameters of metal ion-protein interaction over the whole range of Fe3+ concentrations, the extended solvation model was applied. The solvation parameters obtained from this model were attributed to the structural change of HSA. The binding parameters obtained from the extended solvation model indicate that the stability of HSA was decreased as a result of its binding with ferric ions, which cause dampening the antioxidant property of HSA. Cuperic ion increases the stability of HSA considerably, indicating that the antioxidant property of human serum albumin are increased as a result of its interaction with cupric ion. PMID- 25146187 TI - Genetic and functional characterization of the hyaluronate lyase HylB and the beta-N-acetylglucosaminidase HylZ in Streptococcus zooepidemicus. AB - Hyaluronic acid (hyaluronan) is a high molecular weight glycosaminoglycan composed of repeating disaccharides of glucuronic acid and N-acetylglucosamine. The molecular weight of hyaluronan is important for its rheological property, biological function, and application. However, genes important for regulation of hyaluronan production or molecular weight remain poorly understood. Here, we address the roles of two predicated hyaluronate lyase-encoding genes, hylB and hylZ in Streptococcus zooepidemicus. Semi-quantitative RT-PCR assays showed that hylZ was constitutively expressed while the expression level of hylB was growth phase dependent. Using recombinantly expressed 6His-HylB and -HylZ protein, enzyme assays revealed that HylB was a hyaluronate lyase, and its K(m) and V(max) were 0.57 MUM and 1.43 mM min(-1), respectively. 6His-HylZ showed no activity against hyaluronan while it hydrolyzed pNp-beta-GlcNAc suggesting that HylZ was a beta-N-acetylglucosaminidase. Under the optimal conditions (pH 6.0 and 50 degrees C), the K(m) and V(max) for 6His-HylZ to degrade pNp-beta-GlcNA were 1.16 mM and 26.18 MUmol min(-1) mg(-1), respectively. Characterization of DeltahylB and DeltahylZ demonstrated that loss of hylB or/and hylZ had no significant effects on cell growth, lactic acid, and hyaluronan yields. Significantly, as compared to the wild type, DeltahylB produced hyaluronan with an 18 % increase in molecular weight. Our results strongly suggest that hylB encodes a hyaluronate lyase while hylZ encodes a beta-N-acetylglucosaminidase. hylB-deficient strain has the potential to produce high molecular weight hyaluronan. PMID- 25146188 TI - High-throughput DNA microarray detection of pathogenic bacteria in shallow well groundwater in the Kathmandu Valley, Nepal. AB - Because of heavy dependence on groundwater for drinking water and other domestic use, microbial contamination of groundwater is a serious problem in the Kathmandu Valley, Nepal. This study investigated comprehensively the occurrence of pathogenic bacteria in shallow well groundwater in the Kathmandu Valley by applying DNA microarray analysis targeting 941 pathogenic bacterial species/groups. Water quality measurements found significant coliform (fecal) contamination in 10 of the 11 investigated groundwater samples and significant nitrogen contamination in some samples. The results of DNA microarray analysis revealed the presence of 1-37 pathogen species/groups, including 1-27 biosafety level 2 ones, in 9 of the 11 groundwater samples. While the detected pathogens included several feces- and animal-related ones, those belonging to Legionella and Arthrobacter, which were considered not to be directly associated with feces, were detected prevalently. This study could provide a rough picture of overall pathogenic bacterial contamination in the Kathmandu Valley, and demonstrated the usefulness of DNA microarray analysis as a comprehensive screening tool of a wide variety of pathogenic bacteria. PMID- 25146189 TI - The roles of FoxOs in modulation of aging by calorie restriction. AB - FoxO activity and modifications, such as its phosphorylation, acetylation, and methylation, may help drive the expression of genes involved in combating oxidative stress by causing the epigenetic modifications, and thus, preserve cellular function during aging and age-related diseases, such as diabetes, cancer, and Alzheimer disease. Insulin signaling has been postulated to influence the aging process by increasing resistance to oxidative stress, and slowing the accumulation of oxidative damage. Some antioxidative effects are mediated by a conserved family of forkhead box transcription factors (FoxOs), which in the absence of insulin signaling freely bind to promoters of antioxidant enzymes, superoxide dismutase, and catalase. On the other hand, calorie restriction (CR) extends the lifespans of several species via the insulin pathway, and extends longevity and healthspan in diverse species via a conserved mechanism. CR enhances adaptive stress responses at the cellular and organism levels and extends lifespan in a FoxO-independent manner. Thus, increased modification of FoxO is modulated via the hyperinsulinemia-induced PI3K/Akt pathway during aging, and CR reverses this process. Accordingly, FoxO plays an important role in maintenance of metabolic homeostasis and removal of oxidative stress in the aging process and in the effect of CR on lifespan. PMID- 25146190 TI - Up-regulation of nicotinamide phosphoribosyltransferase and increase of NAD+ levels by glucose restriction extend replicative lifespan of human fibroblast Hs68 cells. AB - Calorie restriction (CR) extends lifespan in a remarkable range of organisms. However, the mechanisms of CR related to the longevity effects are not fully elucidated to date. Using human fibroblast Hs68 (Hs68) cells cultured at a lower level of medium glucose (i.e., glucose restriction; GR) to mimic CR, we investigated the crucial role of nicotinamide phosphoribosyltransferase (Nampt), nicotinamide adenine dinucleotide (NAD(+)), and nicotinamide (NAM) in GR-extended replicative lifespan of Hs68 cells. We found that GR extended the lifespan of Hs68 cells, in parallel to significantly increased expression of Nampt, intracellular NAD(+) levels, and SIRT1 activities, and to significantly decreased NAM levels. The lifespan-extending effects of GR were profoundly diminished by FK866 (a noncompetitive inhibitor of Nampt) and blocked by sirtinol (a noncompetitive inhibitor of sirtuins). However, the steady-state intracellular NAM level (averaged 2.5 MUM) was much lower than the IC50 of NAM on human SIRT1 (about 50 MUM). All these results suggest that up-regulation of Nampt play an important role in GR-extended lifespan of Hs68 cells by increasing the intracellular NAD(+) levels followed by activating SIRT1 activity in Hs68 cells. In contrast, the role of NAM depletion is limited. PMID- 25146192 TI - Occupational asthma to fish. PMID- 25146191 TI - Long-term exposure to outdoor air pollution and the incidence of chronic obstructive pulmonary disease in a national English cohort. AB - OBJECTIVES: The role of outdoor air pollution in the incidence of chronic obstructive pulmonary disease (COPD) remains unclear. We investigated this question using a large, nationally representative cohort based on primary care records linked to hospital admissions. METHODS: A cohort of 812 063 patients aged 40-89 years registered with 205 English general practices in 2002 without a COPD diagnosis was followed from 2003 to 2007. First COPD diagnoses recorded either by a general practitioner (GP) or on admission to hospital were identified. Annual average concentrations in 2002 for particulate matter with an aerodynamic diameter <10 um (PM10) and <2.5 um (PM2.5), nitrogen dioxide (NO2), ozone and sulfur dioxide (SO2) at 1 km(2) resolution were estimated from emission-based dispersion models. Hazard ratios (HRs) per interquartile range change were estimated from Cox models adjusting for age, sex, smoking, body mass index and area-level deprivation. RESULTS: 16 034 participants (1.92%) received a COPD diagnosis from their GP and 2910 participants (0.35%) were admitted to hospital for COPD. After adjustment, HRs for GP recorded COPD and PM10, PM2.5 and NO2 were close to unity, positive for SO2 (HR=1.07 (95% CI 1.03 to 1.11) per 2.2 ug/m(3)) and negative for ozone (HR=0.94 (0.89 to 1.00) per 3 ug/m(3)). For admissions HRs for PM2.5 and NO2 remained positive (HRs=1.05 (0.98 to 1.13) and 1.06 (0.98 to 1.15) per 1.9 ug/m(3) and 10.7 ug/m(3), respectively). CONCLUSIONS: This large population-based cohort study found limited, inconclusive evidence for associations between air pollution and COPD incidence. Further work, utilising improved estimates of air pollution over time and enhanced socioeconomic indicators, is required to clarify the association between air pollution and COPD incidence. PMID- 25146193 TI - Bioremediation of hydrocarbons contaminating sewage effluent using man-made biofilms: effects of some variables. AB - Biofilm samples were established on glass slides by submerging them in oil-free and oil-containing sewage effluent for a month. In batch cultures, such biofilms were effective in removing crude oil, pure n-hexadecane, and pure phenanthrene contaminating sewage effluent. The amounts of the removed hydrocarbons increased with increasing biofilm surface area exposed to the effluent. On the other hand, addition of the reducing agent thioglycollate dramatically inhibited the hydrocarbon bioremediation potential of the biofilms. The same biofilm samples removed contaminating hydrocarbons effectively in three successive batch bioremediation cycles but started to become less effective in the cycles thereafter, apparently due to mechanical biofilm loss during successive transfers. As major hydrocarbonoclastic bacteria, the biofilms harbored species belonging to the genera Pseudomonas, Microvirga, Zavarzinia, Mycobacterium, Microbacterium, Stenotrophomonas, Gordonia, Bosea, Sphingobium, Brachybacterium, and others. The nitrogen fixer Azospirillum brasilense and the microalga Ochromonas distigma were also present; they seemed to enrich the biofilms, with nitrogenous compounds and molecular oxygen, respectively, which are known to enhance microbiological hydrocarbon degradation. It was concluded that man-made biofilms based upon sewage microflora are promising tools for bioremediation of hydrocarbons contaminating sewage effluent. PMID- 25146194 TI - Effect of nitric oxide on Lachnum YMU50 extracellular polyphenol accumulation and antioxidant defense system. AB - The effect of sodium nitroprusside (SNP) of different concentrations (0.05, 0.1, 0.2 mM) on biomass and extracellular polyphenol accumulation and antioxidant defense system of Lachnum YMU50 had been studied in this article. Results showed that, when the NO donor was SNP, both 0.05 and 0.1 mM SNP could promote the biomass accumulation of Lachnum YMU50 and activate the phenylalanine ammonia lyase, thus promoting its extracellular polyphenol accumulation and activate and induce its antioxidant defense system by activating the activities of catalase, superoxide dismutase, and ascorbate peroxidase, and 0.1 mM SNP has a stronger effect than 0.05 mM SNP. SNP 0.2 mM was adverse to the accumulation of the biomass and extracellular polyphenol of Lachnum YMU50, decreasing the activities of catalase, superoxide dismutase, and ascorbate peroxidase and increasing the contents of hydrogen peroxide and malondialdehyde, which indicated that 0.2 mM SNP damaged the antioxidant defense system of Lachnum YMU50. PMID- 25146195 TI - Improvement of the fermentative activity of lactic acid bacteria starter culture by the addition of Mn2+. AB - Production of lactic acid bacteria (LAB) starter with raw material has received much scientific investigation, but little information is available on the influences of some trace elements on the growth and fermentative activity of LAB. Based on this fact, this paper aimed to investigate the effects of Mn(2+) on the performance of Lactobacillus plantarum CX-15 starter with Jerusalem artichoke (JA) as the main medium substrate. The results showed that Mn(2+) addition had a significant beneficial affect on the fermentative activity of L. plantarum CX-15 starter. In contrast, the lack of Mn(2+) would cause the subsequent fermentation significantly slower, whether the cell density in starter culture was higher or lower. The possible mechanism of these phenomenons was further elucidated by the time course analysis of the specific activities of metabolism key enzymes during the culture processes of L. plantarum CX-15 starter. Compared to the fermentation processes without Mn(2+) addition, it was found that Mn(2+) addition would enhance the lactate dehydrogenase (LDH) activity but reduce the activities of pyruvate dehydrogenase (PDH) and ATPase activity. Therefore, it could be concluded that the improvement of L. plantarum starter fermentative activity was probably a consequence of Mn(2+) acting as "metabolic switch," which regulated the metabolic flux from pyruvic acid to lactic acid and other metabolism pathway. PMID- 25146196 TI - Fatty acid content and profile of the aerial microalga Coccomyxa sp. isolated from dry environments. AB - Aerial algae are considered to be highly tolerant of and adaptable to severe conditions including radiation, desiccation, high temperatures, and nutrient deficiency, compared with those from aquatic habitats. There are considerable variations in the fatty acid (FA) composition of aerial microalgae from dry environments. A new species with a high lipid level was found on concrete surfaces and was identified as Coccomyxa sp. KGU-D001 (Trebouxiophyceae). This study characterized its FA content and profile in a bath culture. The alga showed a constant specific growth rate (0.26 day(-1)) ranging in light intensity from 20 to 80 MUmol photons m(-2) s(-1). The algal cells started to form oil bodies in the early stationary phase of growth, and oil bodies occupied most of the cells during the late stationary phase when the cells accumulated 27 % total fatty acids (TFA). The process of lipid body formation accumulating large amounts of triacylglycerols (TAG) appeared to be very unusual in response to stress conditions persisting for a relatively long culture time (50 days). This study could indicate that aerial microalgae will be a candidate for biodiesel production when a new cultivation method is developed using extreme stresses such as nutritional deficiency and/or desiccation. PMID- 25146197 TI - [Therapeutic monitoring of intravenous vancomycin in a pediatric critical care unit]. AB - BACKGROUND: In critically ill pediatric patients vancomycin distribution and elimination is altered underscoring the need for pharmacokinetic monitoring; however the therapeutic trough ranges have not been validated for children. OBJECTIVE: To describe the pharmacokinetics of intravenous vancomycin in critically ill pediatric patients using plasmatic vancomycin monitoring. METHODS: Retrospective, descriptive study performed in a paediatric critical care unit. Vancomycin serum levels (Cmin and Cpeak), t 1/2 and Vd were determined in 1 month to 12 year old patients receiving >= 40 mg per-kg-per day. Plasmatic levels were measured at therapy onset and during follow up, evaluating the proportion of trough level determinations within therapeutic range, the average trough concentration, and the Cpeak achieved. RESULTS: A total of 65 plasmatic vancomycin monitorings were analysed in 45 patients. The average values for Ctrough, Cpeak, t1/2 and Vd were 10.4 MUg/mL, 22.7 MUg/mL, 3,1 h and 0.7 L/kg, respectively. An average dose of 47,1 mg/kg/day achieved initial Ctrough levels < 10 mg/mL in 60% of patients (n = 27), between 10 and 14,9 MUg/mL in 22,2% (n = 10), between 15 to 20 MUg/mL in 4% (n: 2), and > 20 MUg/mL in 13,3% (n: 6). CONCLUSIONS: Vancomycin doses of 40 mg/kg/day are insufficient for critically ill paediatric patients without renal failure. A higher starting dose and monitoring of plasma levels must be considered in this population. PMID- 25146198 TI - [Latent tuberculosis infection screening in healthcare workers in four large hospitals in Santiago, Chile]. AB - BACKGROUND: It is currently unknown which is the prevalence of latent tuberculosis infection in healthcare workers in Chile, but this group has been described as at higher risk of developing active tuberculosis than general population. OBJECTIVES: To determine the prevalence of latent tuberculosis infection in a sample of healthcare workers from at risk areas. METHODOLOGY: A cross-sectional, descriptive study, conducted in health care workers from clinical laboratories or respiratory care areas in four hospitals in Santiago. Latent tuberculosis infection detection was determined by Quantiferon(r) TB Gold In Tube testing (QFT). RESULTS: QFT resulted positive in 20 of 76 (26.3%) of the individuals tested. Test positivity reached 62.5% among the personnel that reported history of past TB contact in the community, 50% among the personnel who belonged to the national tuberculosis control program and 38% among those doing induced sputum, acid fast smear or mycobacterial cultures. The proportion of individuals with positive QFT was significantly lower in those personnel who had no such risk factors (15.7%, p = 0.03). The proportion of latent tuberculosis infection also increased in direct relation to the age of the subject. CONCLUSION: Latent tuberculosis infection as detected by QFT testing was highly prevalent in healthcare workers included in the present study. Further exploring the limitations and possible scenarios for this new diagnostic tool is needed, with emphasis on health personnel at higher-risk and younger individuals. PMID- 25146199 TI - An outbreak of Pseudomonas aeruginosa infective endocarditis subsequent to coronary angiography. AB - OBJECTIVES: To describe an endocarditis outbreak affecting three patients due to Pseudomonas aeruginosa infection post coronary angiography performed in the Cardiovascular Surgery and Cardiology Medical Center of a private hospital. METHODS: After recognition of an infection cluster within a onemonth period, the outbreak was reported to Antalya Department of Health and a broad investigation was initiated in order to determine the most probable cause and/or source of nosocomial pseudomonal endocarditis. Patient data were obtained by medical record review as well as interviews with patients or their next of kin. Thirty-six surveillance samples for P. aeruginosa were collected from various locations within the coronary angiography unit. The outbreak research team reviewed the private hospital's Cardiovascular Surgery and Cardiology Medical Center's infection control procedures. The epidemiology of P. aeruginosa was studied through analysis of phenotypic markers, including antimicrobial sensitivity profiles. RESULTS: The infection control audit revealed multiple breaches of infection control procedures. Only 1/36 environmental samples yielded, which was isolated from a radio-opaque solution within an angiography injector pump. P. aeruginosa from the radio-opaque solution had an identical antimicrobial susceptibility pattern to the strain isolated from patients. Both samples were susceptible to all antipseudomonal agents. This outbreak could have been successfully controlled by instituting combined infection control measures. CONCLUSIONS: This outbreak emphasizes the important of adherence to infection control standards and practices for cardiac catheterization, as well as the need for closer collaboration between the Infection Control Committee and coronary angiography personnel. PMID- 25146201 TI - [Implementation of the strategy "Clean Care is Safer Care" in a third level hospital in Medellin, Colombia]. AB - INTRODUCTION: Hand hygiene is the most cost-effective and simple measure of preventing healthcare associated infections (HAI). The approach to improve low compliance must be through multimodal interventions such as the "Clean Care is Safer Care" strategy (WHO). AIM: To estimate the efficacy of a multimodal strategy in improving hand hygiene in five wards of a tertiary care hospital in Medellin, Colombia (2008-2010). METHODS: Quasi-experimental before-after study. RESULTS: Hand hygiene compliance significantly increased after the intervention (82 to 89%, p = 0.007). The knowledge score increased from a median of 26 (IQR=22 28) to 30 (IQR=26-32, p = 0.001). Alcohol-based hand rub consumption increased significantly from 10.5 liters to 58.1 liters per 1000 patient-days [incidence ratio (IR) = 2.39, 95% CI = 1.99; 2.88]. Monthly HAI rates showed no significant variations during the same period [IR = 0.90, 95% CI = 0.71; 1.13]. DISCUSSION: This and other recent studies demonstrate that implementing a multimodal strategy for hand hygiene significantly increases compliance with this measure, irrespective of type of health worker or hospital department. CONCLUSIONS: Implementing a multimodal strategy we achieved significant increases in hand hygiene compliance but mild or no significant variations in monthly HAI rates. PMID- 25146200 TI - [Impact of copper in the reduction of hospital-acquired infections, mortality and antimicrobial costs in the Adult Intensive Care Unit]. AB - We conducted a clinical trial to determine the impact of coating surfaces with copper in reducing hospital-acquired infections, mortality associated with nosocomial infections and antimicrobial costs in the UCI. The study took place at Carlos Van Buren Hospital, Valparaiso, Chile. No differences in the frequency of nosocomial infections were found. Not in rates of ventilator-associated pneumonia (p = 0.9), nor in catheter- associated urinary tract infection (p = 0.9) or in central venous catheter associated bacteremia (p = 0.3). There were no differences in infection-free survival (p = 0.9). There were less costs of antimicrobials in patients in which copper was used. The fact that the sample size was not completed could explain that no significant differences in infections were found. CONCLUSION: The use of copper as a surface in the ICU showed no statistically significant differences in rates of nosocomial infections during the study period, however, these results could be related to the sample size. PMID- 25146202 TI - [Higher risk for health care associated infections in hospitalized children with special health needs]. AB - BACKGROUND: Nosocomial infections (NIs) represent an important public health issue, being associated with high morbidity, mortality and costs. OBJECTIVES: To identify risk factors of NIs in a cohort of hospitalized pediatric patients, with emphasis in children with special health care needs (CSHCN). PATIENTS AND METHODS: We studied patients hospitalized in Sotero del Rio Pediatric Hospital at Santiago-Chile, between September and December, 2009. Relative Risk (RR) was calculated between CSHCN-3 (children attended by three or more health care professionals) versus non CSHCN-3, and between children with medical complexity (CMC) versus non CMC, using log-binomial models. RESULTS: 920 patients were included. Prevalence of NIs was 12.7%. The most frequent diagnoses were gastrointestinal and respiratory viral infections. Both crude and adjusted by confounders (age and sex), CSHCN-3 and CMC presented significantly higher risk of NIs compared to patients without these conditions (RR 2.91 and RR 2.16, respectively). CONCLUSION: CSHCN-3 and CMC represent independent conditions associated to a 2-3 fold risk of NIs. PMID- 25146203 TI - [Laboratory methods in the diagnosis of coccidioidomycosis]. AB - Coccidioides immitis and Coccidioides posadasii, the two recognized causes of coccidioidomicosis, may be diagnosed by direct microscopy, culture, serologic and the skin-test with mycelial coccidioidin. Identification of spherules by direct examination of secretions after addition of KOH, is more rapid and may speed diagnosis. Histopathology of infected tissue demonstrates acute and chronic granulomatous inflammation and in the section strained with hematoxylin-eosine (HE) or Grocott metamine-silver (GMS). Isolation of Coccidioides spp. by culture is not difficult, the fungus grows well on most mycologic media after 5-7 days of incubation and the laboratory should maintain a biological safety level 2 or 3. Phenotypic identification to genus level may be achieved by visualization of arthroconidia in culture. Isolates may be confirmed as Coccidioides ssp. by molecular probes, but separation of species is best achieved by specialized molecular techniques, available at the Reference Laboratory. Immune diffusion and enzyme-immune assays (EIA) are commonly used for detection of IgM and IgG antibodies in serum. Sequential complement fixations (CF) for IgG class of antibody are useful for the prognosis of coccidioidomycosis. PMID- 25146204 TI - [Norovirus detection in children with community-acquired or nosocomial diarrhea at Guillermo Grant Benavente Hospital in Concepcion, Chile]. AB - INTRODUCTION: Norovirus (NoV) are RNA viruses highly contagious, stable in the environment, genetically variable, and the most common cause of viral sporadic acute gastroenteritis worldwide. This is the first study carried out in Concepcion, Chile, to investigate the presence of NoV as an etiologic agent of viral diarrheas in hospitalized children. Objective. To detect the presence and genogroup of NoV in children with diarrhea and to compare it with rotavirus (RV) and adenovirus (AdV). MATERIAL AND METHODS: A one year descriptive, prospective study in children 0-14 years old. A single diarrheic stool sample per patient was analyzed for the presence of NoV, RV and AdV. Clinical data were unknown at the moment of sampling. Real time RT-PCR with TaqmanTM probes for NoV and the immunocromatography VIKIATM kit for RoV /AV detection were used. RESULTS: Infection for NoV (25.5%) was significantly higher than for RV (15.9%) and AdV (6.2%). It was even greater in infants younger than 2yr. old (n: 103): NoV 34%, RV 17.5%, AdV 7.8%. Children 2-4 yr. old had 11.8% infection of NoV and RV. Children older than 4, only had 12% RV and 4% AdV. Children hospitalized for diarrhea (n: 92) had: 21.7% of both NoV and RV, and 7.6% AdV; whereas children hospitalized for other causes (n: 53) had 32.1% NoV,5.7% RV and 3.8% AV. The proportion of infection due to NoV was significantly higher in males (31.5%) than in females (19.4%). The average frequency during the year was higher for NoV (30.3%) than for RV (14.7%) except in summer. CONCLUSION: The presence of NoV was higher than RV in children with diarrhea. NoV infection showed defined characteristics regarding age, gender, seasonal occurrence and nosocomial transmission that are important epidemiological features. PMID- 25146206 TI - [The molecular basis of infections associated to orthopedic implants]. AB - Infections associated with the use of orthopedic implants are still the major complication associated with these devices and an unsolved challenge. The frequency of infection associated with orthopedic implant is relatively low, estimated to range between 0.5 to 5%. However, it has devastating consequences for the patient and health institutions. The majority of infections is secondary to gram-positive aerobic microorganisms belonging to the genus Staphylococcus. These bacteria establish chronic infections due to its ability of adhesion and biofilm formation. Biofilms are complex communities in a polysaccharide matrix. This structure retains nutrients and protects the bacteria against the immune response and antimicrobial agents. The study of molecular characteristics and biofilm formation regulation is vital for the understanding of judicious clinical management and the development of novel strategies for the prevention of infection. PMID- 25146205 TI - [Prevalence of anal-vaginal colonization of Streptococcus agalactiae in third trimester of pregnancy and susceptibility to macrolides and lincosamides, in pregnant women controlled at Clinica Alemana Temuco, Southern Chile]. AB - INTRODUCTION: Streptococcus agalactiae (GBS) is the most common agent in early neonatal sepsis. Strategies incorporating universal screening for maternal colonization show the lowest rates of perinatal infection. A significant increase in resistance to erythromycin and clindamycin by GBS has been reported around the world. There are no published data regarding prevalence and antimicrobial resistance in southern regions of Chile. Surveillance of antimicrobial resistance is essential to define the drugs of choice and alternatives, in an institution that applies prevention protocols, as Clinica Alemana Temuco (CAT) does. OBJECTIVES: to determine the prevalence of carriage of GBS in vaginal-anal areas at end of pregnancy, in CAT, Araucania Region, Chile. To determine the susceptibility to erythromycin and clindamycin of GBS strains isolated. RESULTS: 1,181 pregnant women were included; 167 were positive for GBS (14.4% of colonization). Sixteen were resistant to erythromycin (9.5%); 15 of these strains were also clindamycin resistant. Twenty-three of 167 were resistant to clindamycin (13.7%). CONCLUSIONS: The prevalence rate of GBS colonization was lower than previously reported in other regions of Chile. Due to the high rates of resistance to clindamycin and erythromycin it is necessary to widen the study of susceptibility to other antimicrobials to have alternatives in allergy to penicillin (primarily cefazolin and vancomycin). PMID- 25146207 TI - [Depression and HAART adherence in HIV infected patients attending Hospital San Pablo of Coquimbo, Chile]. AB - Despite the good HAART coverage of HIV infected patients in Chile, treatment success is interfered by patient-adherence problems. Moreover, HIV and depression co-morbidity has been shown to impair self-care and medication adherence. With the aim to analyze adherence problems and its relationship with depression in HIV infected patients, we evaluated 119 HIV infected patients, attending Coquimbo's Hospital. Our sample was incidental and transversally evaluated with: Morisky, Green & Levine Medication Adherence Scale, and the Beck - II Depression Inventory. In addition, demographic and health data were obtained from clinical files. Main results showed that 68% patients referred having HAART adherence problems, with differences in sex, age and treatment duration. Logistic regression analysis showed that patients with moderate-severe depressive symptoms have 3,08 (95% IC 1,08-8,80) times higher risk of having adherence problems compared to patients with mild to no depressive symptoms. PMID- 25146208 TI - Origin and importance of the Latin American Kawasaki Disease Network (REKAMLATINA). AB - Kawasaki disease is the leading cause of acquired cardiac disease in children. Although the epidemiology of the disease has been well described in Japan, other Asian countries, Europe, Australia and North America, the epidemiology and disease burden in Latin American children is unknown. For this reason, the idea of establishing a research network on Kawasaki disease in children from Latin America was born, becoming this the largest Kawasaki disease international multinational research network and in which 20 countries of the region will be integrated. PMID- 25146209 TI - [Characterization of episodes of febrile neutropenia in children with acute myeloid leukemia and acute lymphoblastic leukemia]. AB - INTRODUCTION: Leukemia is the most common cancer in Chilean children. Acute lymphoblastic leukemia (ALL) is more prevalent and longer survival compared to acute myeloid leukemia (AML). AIMS: To describe episodes of febrile neutropenia (FN) in children with AML, determining frequency of infections as agent, focus and evolution, comparing children with ALL episodes. METHOD: A prospective multicenter study. Children presenting with FN at six hospitals in Santiago, Chile, were invited to participate in two consecutive FONDECYT projects, from April 2004 to June 2011. All patients were uniformly evaluated, recording epidemiological, clinical and laboratory variables. Information regarding FN episodes of children with LMA and LLA was used to this study. RESULTS: We evaluated 506 episodes of FN in children with leukemia: 173 children with AML and 333 in children with ALL. NF episodes in children with ALML showed significantly greater depth and duration of neutropenia, febrile remained a > period of time and had a worse clinical outcome, as evidenced by > hemodynamic instability, > sepsis, CRP > 90 mg/L for a longer time, more days of hospitalization, > frequency of hospitalization in ICU, > bacteremia, mainly by Streptococcus viridans group, > change of antimicrobial treatment, > use of antifungal therapy. CONCLUSIONS: This study demonstrates that FN episodes in children with ALML further evolve unfavorably, compared with episodes of FN in children with ALL. FN episodes in children with ALML require a more aggressive diagnostic and therapeutic approach, related to its severity. PMID- 25146210 TI - [Lichtheimia corymbifera (Cohn) Vuill]. PMID- 25146211 TI - [Juan Marin Rojas M.D., First Professor of History of Medicine at Universidad de Chile and his "Essay about the origin of syphilis"]. AB - Dr. Juan Marin Rojas, M.D., was the first Professor of History of Medicine at Universidad de Chile, navy doctor, diplomat, writer and literary critic. Member of the International Society of History of Medicine, and Correspondent Member for Chile of the "Office de Documentation de Medecine et Pharmacie Militaire", Liege, Belgium, from which his "Essay about the origin of syphilis" is transcribed with interesting historical facts and little known arguments that affirm the non american origin of syphilis, but "aspire to leave a doubt, given not a contrary conviction". PMID- 25146212 TI - [Cutaneous larva migrans after a trip to the Caribean]. AB - Cutaneous larva migrans is a parasitic disease caused by Ancylostoma braziliense and Ancylostoma caninum larvae, which is transmitted by contact with sand infested with these parasites. Dogs and cats are the definitive hosts. This parasitic disease is endemic in the Caribbean, Africa, Australia, and Asia. We present the case of a 27-year-old woman, who developed skin lesions compatible with cutaneous larva migrans on her right foot after returning from beach vacations in the Mexican Caribbean. After clinical diagnosis, oral ivermectin was administered, with good clinical response. PMID- 25146213 TI - [Bacteremia by a Serratia rubidaea with an atypical quinolones resistance phenotype]. AB - Serratia spp. causes the 2% of nosocomial infections. Serratia marcescens is the pathogenic species for excellence as it causes more than 90% of cases, however, there are very few reported cases of clinical infection caused by other minority species, among which is S. rubidaea. We present a case of nosocomial bacteremia by S. rubidaea, probably related to a peripheral catheter, in a healthy teenager who consulted to the emergency room after suffering a fit while practicing strenuous sport. PMID- 25146214 TI - [A possible gold standard for the diagnosis of loxoscelism and a solution for research]. PMID- 25146215 TI - [Speaking of Latin American guidelines for the diagnosis of tick-transmitted rickettsiosis]. PMID- 25146216 TI - [Tribute to Beatriz Gilabert Fierro, pioneer of modern Clinical Microbiology in Chile]. PMID- 25146221 TI - Cu(I)-NHC-catalyzed silylation of allenes: diastereoselective three-component coupling with aldehydes. AB - Copper-catalyzed silylation of aryl allenes using a silylborane reagent affords vinyl silane building blocks with high efficiency. The use of a seven-membered NHC ligand proved crucial for high regioselectivity. The catalytically generated allylcoppper intermediates were intercepted by aldehydes in a diastereoselective three-component coupling to furnish homoallylic alcohols. PMID- 25146220 TI - Expression of nicotinamide phosphoribosyltransferase-influenced genes predicts recurrence-free survival in lung and breast cancers. AB - Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide biosynthesis. NAMPT protein is a secreted plasma biomarker in inflammation and in cancer. The NAMPT enzymatic inhibitor, FK866, acts as an inducer of apoptosis and is a cancer therapeutic candidate, however, little is known regarding the influence of NAMPT on cancer biological mechanisms or on the prognosis of human cancers. We interrogated known microarray data sets to define NAMPT knockdown-influenced gene expression to demonstrate that reduced NAMPT expression strongly dysregulates cancer biology signaling pathways. Comparisons of gene expression datasets of four cancer types generated a N39 molecular signature exhibiting consistent dysregulated expression in multiple cancer tissues. The N39 signature provides a significant and independent prognostic tool of human recurrence-free survival in lung and breast cancers. Despite the absence of clear elucidation of molecular mechanisms, this study validates NAMPT as a novel "oncogene" with a central role in carcinogenesis. Furthermore, the N39 signature provides a potentially useful tool for prediction of recurrence-free survival in lung and breast cancer and validates NAMPT as a novel and effective therapeutic target in cancer. PMID- 25146222 TI - Molecular cloning and expression analysis of the synaptotagmin-1 gene in the hypothalamus and pituitary of Huoyan goose during different stages of the egg laying cycle. AB - BACKGROUND: Synaptotagmin-1 (Syt1) is an abundant, evolutionarily conserved integral membrane protein that plays essential roles in neurotransmitter release and hormone secretion. Neurotransmitters secreted by hypothalamic neurons can alter GnRH (gonadotropin-releasing hormones) neuronal activity by binding to and activating specific membrane receptors in pituitary cells and, in turn, control the release of gonadotropin hormones from the pituitary gland. To reveal the influence of Syt1 on the process of goose egg-laying, we cloned and characterized the cDNA of goose Syt1 originating from hypothalamus and pituitary tissues of Huoyan goose and investigated the mRNA expression profiles during different stages of the egg-laying cycle. METHODS: Hypothalamus and pituitary tissues were obtained from 36 Huoyan geese in the pre-laying period, early laying period, peak laying period, and ceased period. The cDNA sequences of goose Syt1 were cloned and characterized from Huoyan goose tissues using 5'-RACE and 3'-RACE methods. Multiple alignments and phylogenetic analyses of the deduced Syt1 amino acid sequence were conducted using bioinformatics tools. The expression profiles of the Syt1 mRNA in the hypothalamus and pituitary during pre-laying, early laying, peak-laying and ceased period were examined using real-time PCR (qRT-PCR). RESULTS: The cDNA of Syt1 consisted of a 274 bp 5' UTR, a 1266 bp open reading frame (ORF) encoding 421 amino acids, and a 519 bp 3' UTR. The deduced amino acid sequence of goose Syt1 is highly conserved with the sequence from other species, especially with birds (more than 98%), and contains two protein kinase C2 conserved regions (C2 domain) from amino acids residue 157 to 259 and 288 to 402. The results of qRT-PCR demonstrated that the expression of Syt1 mRNA increased from the pre-laying period to the peak-laying period, reached its peak in the peak-laying period, and then decreased in the ceased period. CONCLUSIONS: To the best of our knowledge, this study is the first to obtain full-length cDNA sequences of the goose Syt1 gene, and the results of Syt1 mRNA expression profiling in the hypothalamus and pituitary tissues suggested that Syt1 may play an important role in regulating the secretion of hormones relevant to the reproduction and egg-laying of female geese. PMID- 25146223 TI - Survey of neonatal unit outbreaks in North London: identifying causes and risk factors. AB - BACKGROUND: This survey was undertaken after a number of neonatal unit (NNU) outbreaks were reported to the North London health protection teams (HPTs). AIM: To determine the diversity of the outbreaks, ascertain potential sources and contributing factors, and identify the investigative procedures followed and control measures implemented. METHODS: Using a structured questionnaire, information from the HPT database was collected for all NNU outbreaks reported between January 2010 and February 2011. FINDINGS: Ten outbreaks were identified from seven hospitals in 14 months. There was one para-influenza outbreak, seven Staphylococcus aureus [including six meticillin-resistant S. aureus (MRSA)] outbreaks, and two Gram-negative outbreaks. Potential sources of transmission identified for the MRSA outbreaks were healthcare worker (HCW)-assisted transmission (N = 2) and mother-to-baby transmission with onward HCW-assisted transmission (N = 3). An environmental source with onward HCW-assisted transmission was documented for one of the Gram-negative outbreaks. Interventions included patient screening and enhanced cleaning (N = 10), isolating/cohorting affected neonates (N = 9), barrier nursing (N = 6), staff movement restrictions (N = 5), hand hygiene audits (N = 4), staff screening (N = 4), household contact screening (N = 3) and environmental sampling (N = 3). Potential contributing factors included inadequate staffing levels, cluttered unit, inadequate sterilization of communal milk-expressing equipment and inappropriate follow-up of MRSA results. CONCLUSION: This survey determined the diversity of NNU outbreaks in North London, and highlighted the importance of a multi-faceted approach to outbreak control. These data will assist in the development of clinical standards for the prevention, control and reporting of NNU outbreaks, and guidance for best practice in NNUs. PMID- 25146224 TI - Characterizing the burden of invasive Pseudomonas infection on neonatal units in the UK between 2005 and 2011. AB - Concern about Pseudomonas infection in neonatal units has focused on outbreaks. This study analysed cases of invasive Pseudomonas infection in 18 UK neonatal units participating in the NeonIN Neonatal Infection Surveillance Network from January 2005 to December 2011. Forty-two cases were reported. The majority (35/42, 93%) of cases were late-onset (median 14 days, range 2-262 days), the highest incidence was seen in extremely-low-birthweight infants and all cases were sporadic. One-third of cases were known to be colonized prior to invasive disease. Attributable mortality was 18%. Opportunities for preventing invasive disease due to this important pathogen should be prioritized. PMID- 25146225 TI - Infection prevention in wounds with Surgihoney. PMID- 25146226 TI - Cold atmospheric pressure plasma and decontamination. Can it contribute to preventing hospital-acquired infections? AB - Healthcare-associated infections (HCAIs) affect ~4.5 million patients in Europe alone annually. With the ever-increasing number of 'multi-resistant' micro organisms, alternative and more effective methods of environmental decontamination are being sought as an important component of infection prevention and control. One of these is the use of cold atmospheric pressure plasma (CAPP) systems with clinical applications in healthcare facilities. CAPPs have been shown to demonstrate antimicrobial, antifungal and antiviral properties and have been adopted for other uses in clinical medicine over the past decade. CAPPs vary in their physical and chemical nature depending on the plasma generating mechanism (e.g. plasma jet, dielectric barrier discharge, etc.). CAPP systems produce a 'cocktail' of species including positive and negative ions, reactive atoms and molecules (e.g. atomic oxygen, ozone, superoxide and oxides of nitrogen), intense electric fields, and ultraviolet radiation (UV). The effects of these ions have been studied on micro-organisms, skin, blood, and DNA; thus, a range of possible applications of CAPPs has been identified, including surface decontamination, wound healing, biofilm removal, and even cancer therapy. Here we evaluate plasma devices, their applications, mode of action and their potential role specifically in combating HCAIs on clinical surfaces. PMID- 25146227 TI - Service evaluation of selected risk factors for extended-spectrum beta-lactamase Escherichia coli urinary tract infections: a case-control study. AB - In the context of the increasing incidence of extended-spectrum beta-lactamase (ESBL) Escherichia coli infection, this prospective frequency-matched case control study aimed to identify risk factors that would provide information and guidance for local clinical practice. One hundred and twelve participants were recruited: 54 cases and 58 controls. Univariate analysis indicated that isolation of an ESBL-producing E. coli in the previous 12 months and diabetes were significantly associated with the outcome. This study demonstrates the utility of service evaluation studies for producing epidemiological information to inform clinical practice. PMID- 25146228 TI - The pathological implications of heart transplantation: experience with 50 cases in a single center. AB - Heart transplantation started in Japan in 1999. Since then, 50 transplants have been performed at our center. We performed histopathological analyses of the 50 explanted hearts and the post-transplant biopsy specimens. The median age of recipients was 39 years. The primary diseases before transplant were idiopathic dilated cardiomyopathy in 33 patients (66%), hypertrophic cardiomyopathy in seven (14%), restrictive cardiomyopathy in one, arrhythmogenic right ventricular cardiomyopathy in one, and secondary cardiomyopathy in eight (16%). Before transplantation, 47 patients (94%) had left ventricular assist devices. No severe cardiovascular failure due to allograft rejection occurred. The post-transplant survival rate was 97.6% at 1 year and 93.1% at 10 years. One recipient was lost to sepsis from myelodysplastic syndrome in the fourth year, one died of multiple organ failure and peritonitis 8 months after transplant. Another patient died of recurrent post-transplant lymphoproliferative disorders (PTLD). Mild cardiac dysfunction occurred in seven recipients in the early postoperative period. Moderate acute cellular rejection occurred in six patients (12%), and antibody mediated rejection occurred in three (6%). The number of heart transplants performed in Japan is very small. However, the outstanding 10-year survival rate is due to donor evaluation and post-transplant care resulting in low grade rejection. Pathological evaluation has also greatly contributed to the results. PMID- 25146229 TI - Massive Atenolol, Lisinopril, and Chlorthalidone Overdose Treated with Endoscopic Decontamination, Hemodialysis, Impella Percutaneous Left Ventricular Assist Device, and ECMO. AB - BACKGROUND: Overdose of cardiovascular medications is increasingly associated with morbidity and mortality. We present a case of substantial atenolol, chlorthalidone, and lisinopril overdose treated by multiple modalities with an excellent outcome. CONCLUSION: Aggressive medical intervention did not provide sufficient hemodynamic stability in this patient with refractory cardiogenic and distributive shock. Impella(r) percutaneous left ventricular assist device and extracorporeal membrane oxygenation provided support while the effects of the overdose subsided. We present concentrations demonstrating removal of atenolol with continuous venovenous hemodiafiltration. This is the first report of esophagogastroduo denoscopy decontamination of this overdose with a large pill fragment burden. PMID- 25146230 TI - Unconventional transport through graphene on SrTiO3: a plausible effect of SrTiO3 phase-transitions. AB - High-k dielectric oxides are supposedly ideal gate-materials for ultra-high doping in graphene and other 2D-crystals. Here, we report a temperature-dependent electronic transport study on chemical vapor deposited-graphene gated with SrTiO3 (STO) thin film substrate. At carrier densities away from charge neutrality point the temperature-dependent resistivity of our graphene samples on both STO and SiO2/Si substrates show metallic behavior with contributions from Coulomb scattering and flexural phonons attributable to the presence of characteristic quasi-periodic nano-ripple arrays. Significantly, for graphene samples on STO substrates we observe an anomalous 'slope-break' in the temperature-dependent resistivity for T = 50 to 100 K accompanied by a decrease in mobility above 30 K. Furthermore, we observe an unusual decrease in the gate-induced doping-rate at low temperatures, despite an increase in dielectric constant of the substrate. We believe that a complex mechanism is at play as a consequence of the structural phase transition of the underlying substrate showing an anomalous transport behavior in graphene on STO. The anomalies are discussed in the context of Coulomb as well as phonon scattering. PMID- 25146231 TI - Diatoms: a biotemplating approach to fabricating drug delivery reservoirs. AB - Biotemplating is a rapidly expanding subfield that utilizes nature-inspired systems and structures to create novel functional materials, and it is through these methods that the limitations of current engineering practices may be advanced. The diatom is an exceptional template for drug delivery applications, owing largely to its highly-ordered pores, large surface area, species-specific architecture, and flexibility for surface modifications. Diatoms have been studied in a wide range of biomedical applications and their potential as the next frontier of drug delivery has yet to be fully exploited. In this editorial, the authors aim to review the use of diatoms in the delivery of poorly water soluble drugs as reported in the literature, discuss the progress and advancements that have been made thus far, identify the shortcomings and limitations in the field, and, lastly, present their expert opinion and convey the future outlook on biotemplating approaches for drug delivery. PMID- 25146233 TI - Nifedipine versus terbutaline, tocolytic effectiveness and maternal and neonatal adverse effects: a randomized, controlled pilot trial. AB - Although previous evidence suggests advantages of nifedipine over terbutaline as tocolytic agents, in some jurisdictions, terbutaline is approved for use and nifedipine is not. In women in preterm labour, we compared the impact of terbutaline versus nifedipine on inhibition of uterine contractions, preterm birth, neonatal sepsis, intracranial haemorrhage or necrotizing enterocolitis, death or admission to a neonatal intensive care unit and maternal adverse reactions. We randomized 32 women to nifedipine and 34 to terbutaline. We found no difference between groups in tocolysis or preterm birth. No serious maternal adverse effects or serious neonatal adverse outcome occurred in either group. Less serious maternal adverse effects less common with terbutaline included flushing (2.94% versus 43.7%) and headache (5.9% versus 31.2%). The administration of terbutaline increased tremor (76.4% versus 0%), nausea (58.8% versus 9.4%) and dizziness (29.4% versus 6.25%). The total number of side effects, and the proportion of women experiencing one or more side effects, proved greater with terbutaline. In this study, terbutaline and nifedipine performed similarly in their tocolytic effects. Each drug has specific side effects, although overall, nifedipine was associated with fewer adverse effects. PMID- 25146232 TI - Direct observation of dynamic mechanical regulation of DNA condensation by environmental stimuli. AB - Gene delivery is a promising way to treat hereditary diseases and cancer; however, there is little understanding of DNA:carrier complex mechanical properties, which may be critical for the protection and release of nucleic acids. We applied optical tweezers to directly measure single-molecule mechanical properties of DNA condensed using 19-mer poly-L-lysine (PLL) or branched histidine-lysine (HK) peptides. Force-extension profiles indicate that both carriers condense DNA actively, showing force plateaus during stretching and relaxation cycles. As the environment such as carrier concentration, pH, and the presence of zinc ions changes, DNA:HK complexes showed dynamically regulated mechanical properties at multiple force levels. The fundamental knowledge from this study can be applied to design a mechanically tailored complex which may enhance transfection efficiency by controlling the stability of the complex temporally and spatially. PMID- 25146234 TI - Nonmonotonic response of vitellogenin and estrogen receptor alpha gene expression after octylphenol exposure of Cichlasoma dimerus (Perciformes, Cichlidae). AB - In oviparous vertebrates, vitellogenin (VTG) is mainly produced by the liver in response to estrogen (E2) and its synthesis is traditionally coupled to estrogen receptor alpha induction. Even though VTG is a female-specific protein, chemicals that mimic natural estrogens, known as xenoestrogens, can activate its expression in males causing endocrine disruption to wildlife and humans. Alkylphenols such as nonylphenol (NP) and octylphenol (OP) are industrial additives used in the manufacture of a wide variety of plastics and detergents, and can disrupt endocrine functions in exposed animals. For more than a decade, the freshwater cichlid fish Cichlasoma dimerus has been used for ecotoxicological studies in our laboratory. We recently found an up-regulation of VTG gene expression in livers of male fish exposed to OP, from a silent state to values similar to those of E2 induced fish. To better understand the underlying mechanisms behind the action of xenoestrogens, the aim of this study was to analyze the dose-response relationship of C. dimerus VTG and estrogen receptors (ERs) gene expression after waterborne exposure to 0.15, 1.5, 15, and 150MUg/L OP for up to 1 month (0, 1, 3, 7, 14, 21, and 28 days). At the end of the experiment, histological features of exposed fish included active hepatocytes with basophilic cytoplasm and high eosinophilic content in their vascular system due to augmented expression of VTG. In testis, high preponderance of sperm was found in fish exposed to 150MUg/L OP. A classic dose-response down-regulation of the expression of Na(+)/K(+)-ATPase, a "non-gender specific gene" used for comparison, was found with increasing OP concentrations. No VTG and very low levels of ERalpha were detected in control male livers, but an up-regulation of both genes was found in males exposed to 0.15 or 150MUg/L OP. Moreover, VTG transcripts were significant as early as day 3 or day 1 of exposure to these OP concentrations, respectively. Nearly no response was detected in 1.5 and 15MUg/L OP exposed-fish. Data was curve-fitted evidencing a nonmonotonic dose-response curve. Interestingly, ERbeta2 mRNA expression was augmented above baseline levels only when males were exposed to the lowest OP concentration. We speculate that genomic control of vitellogenesis is under control of multiple steroid receptors with different affinities for ligands. ERbeta isoform, only up-regulated with very low concentrations of ligand, would act as a sensors of OP (or E2) to induce ERalpha and VTG. With high OP concentrations, the expression of ERalpha isoform is promptly augmented, with the concomitant VTG transactivation. PMID- 25146235 TI - Evolutionary ecotoxicology of perfluoralkyl substances (PFASs) inferred from multigenerational exposure: a case study with Chironomus riparius (Diptera, Chironomidae). AB - A multigeneration toxicity test on Chironomus riparius was performed with the aim of investigating the evolutionary consequences of exposure to perfluoralkyl substances (perfluorooctane sulfonic acid, PFOS; perfluorooctanoic acid, PFOA; perfluorobutane sulfonate, PFBS). Six-hundred larvae were bred per treatment and per generation until emergence and egg deposition under a nominal concentration of 10MUg/L of contaminants. Newborn larvae were used to start the next generation. Evolution of genetic variability was evaluated along a total of 10 consecutive generations based on 5 microsatellite loci. Analysis of life-history traits (survival, sex ratio and reproduction) was also carried out. Rapid genetic variability reduction was observed in all treatments, including controls, across generations due to the test conditions. Nevertheless, an increased mutation rate determined a stronger conservation of genetic variability in PFOS and, at minor extent, in PFBS exposed populations compared to controls. No significant effects were induced by exposure to PFOA. Direct mutagenicity or induced stress conditions may be at the base of increased mutation rate, indicating the potential risk of mutational load caused by exposure to PFOS and PFBS. The test provided the opportunity to evaluate the use of approximate Bayesian computation (ABC) and coalescent approaches in evolutionary ecotoxicology. A weak performance was evidenced for ABC, either in terms of bias or dispersion of effective population sizes and of estimates of mutation rate. On the contrary, coalescent simulations proved the sensitivity of traditional genetic endpoints (i.e. heterozygosity and number of alleles) to the alteration of mutation rate, but not to erosion of genetic effective size. PMID- 25146236 TI - Dose-dependent hepatic transcriptional responses in Atlantic salmon (Salmo salar) exposed to sublethal doses of gamma radiation. AB - Due to the production of free radicals, gamma radiation may pose a hazard to living organisms. The high-dose radiation effects have been extensively studied, whereas the ecotoxicity data on low-dose gamma radiation is still limited. The present study was therefore performed using Atlantic salmon (Salmo salar) to characterize effects of low-dose (15, 70 and 280 mGy) gamma radiation after short term (48h) exposure. Global transcriptional changes were studied using a combination of high-density oligonucleotide microarrays and quantitative real time reverse transcription polymerase chain reaction (qPCR). Differentially expressed genes (DEGs; in this article the phrase gene expression is taken as a synonym of gene transcription, although it is acknowledged that gene expression can also be regulated, e.g., at protein stability and translational level) were determined and linked to their biological meanings predicted using both Gene Ontology (GO) and mammalian ortholog-based functional analyses. The plasma glucose level was also measured as a general stress biomarker at the organism level. Results from the microarray analysis revealed a dose-dependent pattern of global transcriptional responses, with 222, 495 and 909 DEGs regulated by 15, 70 and 280 mGy gamma radiation, respectively. Among these DEGs, only 34 were commonly regulated by all radiation doses, whereas the majority of differences were dose-specific. No GO functions were identified at low or medium doses, but repression of DEGs associated with GO functions such as DNA replication, cell cycle regulation and response to reactive oxygen species (ROS) were observed after 280mGy gamma exposure. Ortholog-based toxicity pathway analysis further showed that 15mGy radiation affected DEGs associated with cellular signaling and immune response; 70mGy radiation affected cell cycle regulation and DNA damage repair, cellular energy production; and 280mGy radiation affected pathways related to cell cycle regulation and DNA repair, mitochondrial dysfunction and immune functions. Twelve genes representative of key pathways found in this study were verified by qPCR. Potential common MoAs of low-dose gamma radiation may include induction of oxidative stress, DNA damage and disturbance of oxidative phosphorylation (OXPHOS). Although common MoAs were proposed, a number of DEGs and pathways were still found to be dose-specific, potentially indicating multiple mechanisms of action (MOAs) of low-dose gamma radiation in fish. In addition, plasma glucose displayed an apparent increase with increasing radiation doses, although the results were not significantly different from the control. These findings suggested that sublethal doses of gamma radiation may cause dose dependent transcriptional changes in the liver of Atlantic salmon after short term exposure. The current study predicted multiple MoA for gamma radiation and may aid future impact assessment of environmental radioactivity in fish. PMID- 25146237 TI - Interpretation of NMR relaxation as a tool for characterising the adsorption strength of liquids inside porous materials. AB - Nuclear magnetic resonance (NMR) relaxation times are shown to provide a unique probe of adsorbate-adsorbent interactions in liquid-saturated porous materials. A short theoretical analysis is presented, which shows that the ratio of the longitudinal to transverse relaxation times (T1/T2) is related to an adsorbate adsorbent interaction energy, and we introduce a quantitative metric esurf (based on the relaxation time ratio) characterising the strength of this surface interaction. We then consider the interaction of water with a range of oxide surfaces (TiO2 anatase, TiO2 rutile, gamma-Al2O3, SiO2, theta-Al2O3 and ZrO2) and show that esurf correlates with the strongest adsorption sites present, as determined by temperature programmed desorption (TPD). Thus we demonstrate that NMR relaxation measurements have a direct physical interpretation in terms of the characterisation of activation energy of desorption from the surface. Further, for a series of chemically similar solid materials, in this case a range of oxide materials, for which at least two calibration values are obtainable by TPD, the esurf parameter yields a direct estimate of the maximum activation energy of desorption from the surface. The results suggest that T1/T2 measurements may become a useful addition to the methods available to characterise liquid-phase adsorption in porous materials. The particular motivation for this work is to characterise adsorbate-surface interactions in liquid-phase catalysis. PMID- 25146238 TI - Dearomative indole [5+2] cycloaddition reactions: stereoselective synthesis of highly functionalized cyclohepta[b]indoles. AB - The first dearomative indole [5+2] cycloaddition reaction with an oxidopyrylium ylide resulted in efficient and diastereoselective construction of some highly functionalized and synthetically challenging oxacyclohepta[b]indoles. The protocol proceeds under very mild reaction conditions, thus enabling high functional-group tolerance and unique endo selectivity. PMID- 25146239 TI - Influence of caffeine on the expression of human chorionic gonadotropin and progesterone receptors in human trophoblast cell lines. PMID- 25146240 TI - Genetic diversity and expression profiles of cysteine phytases in the sheep rumen during a feeding cycle. AB - Cysteine phytase is the main phytate-degrading enzyme of ruminant animals. To explore the genetic diversity and dynamic expression profile of cysteine phytase in sheep rumen during a feeding cycle, four transcript (0, 4, 9 and 16 h after feeding) and one DNA (9 h after feeding) clone libraries were constructed, respectively. A total of 46 distinct gene fragments were identified, and most of these sequences had low identities (<60%) with known phytases. Great divergence was found in the constitution and abundance of genes at the genome and transcriptional levels, and the transcript data are more reliable to reflect the information of functional genes. Phylogenetic analysis indicated that the genes from uncultured bacteria instead of Firmicutes played the major phytate-degrading role. Further comparative analysis revealed the dynamic constitution of cysteine phytase genes in rumen at different time points. SIGNIFICANCE AND IMPACT OF THE STUDY: Ruminal phytases, that are cysteine phytases, are novel in sequences and functions. Great divergence in the constitution and abundance of cysteine phytase genes at the genome and transcriptional levels suggested that transcript data are more reliable to reflect the information of functional genes. Phylogenetic and rarefaction analyses indicated that the cysteine phytase genes from uncultured bacteria instead of Firmicutes play the major phytate-degrading role in rumen, and their constitution is dynamic at different time points. This study provides a new insight into ruminal cysteine phytase genes and undermines their expression profiles over a whole feeding cycle. PMID- 25146241 TI - Wraparound Team Composition, Youth Self-determination, and Youth Satisfaction in Transition Services. AB - Wraparound, a team-based planning process for youth and families, has been widely adopted in school-based services for older adolescents and emerging adults with serious mental health conditions transitioning to adulthood. Reservations have been voiced, however, regarding possible drawbacks of teams for these youth, including concerns about difficulties with involving supportive adults, and whether youth might perceive team-based planning as a threat to their developing autonomy. To date, however, no studies have examined the feasibility of involving supports in teams and relationships between team composition and youth's service experiences. The present study examined the relationships between team composition and youth's perceptions of self-determination and service satisfaction among 36 youths in seven school-based programs using a specialized form of wraparound for transition services. Findings showed that meeting participation by caregivers and professionals from both inside and outside of schools was common and that regular participation by combinations of these types of adults was related to youth self-determination and satisfaction. PMID- 25146242 TI - Tobacco control: an issue twinned with oral cancer control. AB - Oral cancer is a silent crisis in India. Thirty per cent of all cancers are oral cancer, and approximately 17% of all cancers in men and 10.5% of all cancers in women are oral cancer. Approximately 70,000 new cases are reported annually and 46,000 oral cancer-related deaths occur each year in India; furthermore, the number of cases is rapidly increasing. With this crescendo there may be an estimated 100,000 new cases by 2020, which is insurmountable, especially in emerging economies like India. This astronomical increase is a direct result of tobacco usage. The Global Adult Tobacco Survey performed in 2010 (GATS-2010) reported that approximately 274.5 million people in India use tobacco in various forms. Increasing use of smokeless tobacco, especially by women and children, is of major concern. The World Health Organisation has identified tobacco control and oral cancer control measures as a health priority. However, prevention of tobacco use in India is a great challenge owing to low overall literacy rates and to greater prevalence among people in lower socio-economic strata. Addressing this problem requires a multidisciplinary approach. This paper presents a situational analysis of oral cancer in India and the role of tobacco in making it the epicentre of the disease, and focuses on the role of dental care-givers in influencing and promoting tobacco-control programmes and early detection of oral cancer. PMID- 25146243 TI - Chirality control of quadruple helixes of metal strings by peripheral chiral ligands. AB - Chirality control of helixes with the Delta (P) or Lambda (M) form is interesting in various fields such as extended metal atom chains (EMACs), in which the metal backbones are helically wrapped by four ligands. Herein, we report two EMACs, Delta-[Ni5((-)camnpda)4] and Lambda-[Ni5((+)camnpda)4], whose chiralities are controlled by chiral ligands with naphthyridine and camphorsulfonyl groups. There is a large energy difference (108 kcal mol(-1)) between the two helical structures with one chiral ligand. Furthermore, the electron communication between [Ni2](3+) units is more pronounced than in [Ni5(bna)4Cl2](2+) (bna=binaphthyridylamido). The results demonstrate control of small-scale helical structure and set the stage for future development of chiral controlled base and nanoelectronic devices. PMID- 25146244 TI - Hydroxycarbamide treatment in sickle cell disease: estimates of possible leukaemia risk and of hospitalization survival benefit. AB - Using health insurance claims databases we compared the frequency/incidence of acute myeloid leukaemia (AML) and inpatient mortality in sickle cell disease (SCD) subjects taking (n = 1051), or not taking (n = 9203) hydroxycarbamide (HC). Patients taking HC were older (median 19 vs. 17 years of age), had a higher proportion of males (53% vs. 38%), and their median hospitalizations per year was five times greater than in SCD patients not on HC (all P < 0.001). No new AML cases occurred in HC-treated paediatric SCD patients. For adults, the new AML incidence with HC exposure was 10.7/10 000 patient years, vs. 4.0/10 000 patient years in subjects not on HC (P = 0.2), a possible AML risk ratio of 3.18. Adjustment for a probable database bias for AML diagnosis/ascertainment lowered the risk ratio to 0.94 (95% confidence interval = 0.16-5.47). Despite their greater disease severity, the inpatient mortality in SCD adults prescribed HC (0.29%) was lower than that of patients not taking the drug (0.42%, P = 0.032). In this SCD population we find no increased risk for AML with HC treatment. If such a risk is eventually proven, it will probably be lower than that for drugs with known AML association. By contrast, HC treatment appears to confer a survival benefit. PMID- 25146245 TI - Neurons in the pigeon nidopallium caudolaterale signal the selection and execution of perceptual decisions. AB - Sensory systems provide organisms with information on the current status of the environment, thus enabling adaptive behavior. The neural mechanisms by which sensory information is exploited for action selection are typically studied with mammalian subjects performing perceptual decision-making tasks, and most of what is known about these mechanisms at the single-neuron level is derived from cortical recordings in behaving monkeys. To explore the generality of neural mechanisms underlying perceptual decision making across species, we recorded single-neuron activity in the pigeon nidopallium caudolaterale (NCL), a non laminated associative forebrain structure thought to be functionally equivalent to mammalian prefrontal cortex, while subjects performed a visual categorisation task. We found that, whereas the majority of NCL neurons unspecifically upregulated or downregulated activity during stimulus presentation, ~20% of neurons exhibited differential activity for the sample stimuli and predicted upcoming choices. Moreover, neural activity in these neurons was ramping up during stimulus presentation and remained elevated until a choice was initiated, a response pattern similar to that found in monkey prefrontal and parietal cortices in saccadic choice tasks. In addition, many NCL neurons coded for movement direction during choice execution and differentiated between choice outcomes (reward and punishment). Taken together, our results implicate the NCL in the selection and execution of operant responses, an interpretation resonating well with the results of previous lesion studies. The resemblance of the response patterns of NCL neurons to those observed in mammalian cortex suggests that, despite differing neural architectures, mechanisms for perceptual decision making are similar across classes of vertebrates. PMID- 25146246 TI - Evaluation of the lipophilicity of selected sunscreens--a chemometric analysis of thin-layer chromatographic retention data. AB - The lipophilicities of 22 selected sunscreens, preservatives, and vitamins used in topical skin products were measured by thin-layer chromatography. Lipophilicity was calculated in silico from the sunscreen molecular structures and compared to the experimental octanol/water partition coefficients found in the literature. The retention of the compounds was investigated on an RP-18 stationary phase with mobile phases consisting of water and one of six organic modifiers (dioxane, tetrahydrofuran, acetone, acetonitrile, methanol, and dimethylformamide) at different concentrations. The theoretical lipophilicities were calculated by several computational algorithms and the results of these calculations were compared using cluster analysis. The results showed that two out of the six investigated organic modifiers (dioxane and acetone) may be used to estimate the octanol/water partition coefficients of highly lipophilic compounds having lipophilicities that cannot be measured directly by the shake flask method. PMID- 25146248 TI - Drug legalisation. PMID- 25146247 TI - Designer's microglia with novel delivery system in neurodegenerative diseases. AB - Neurodegenerative diseases are a group of central nervous system diseases that have a high rate of morbidity and mortality. More disabling than lethal, the pathogenesis of many of these diseases, like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and Multiple sclerosis, (MS) remains to be established. Even after passage of several decades subsequent to their first recognition, these diseases have proven to be notoriously refractory towards drug treatment. Stem cell therapy itself has faced problems like ethical issues with such transplants, difficult and risky implantation routes and immune rejections of the implanted stem cells. Somatic cell nuclear transfer (SCNT) offers a hope to the aforesaid diseases if the cells selected for nuclear donation itself has inherent regenerative and scavenging properties. Here we propose olfactory ensheathing cells (OEC's) as the donor somatic cell that conceivably would attempt regeneration in above mentioned diseases by differentiating into glia, which would have healthy mitochondria and without any fear of immune rejection. Also proposed is a method of delivering these cells after SCNT to the brain by a novel "transcribrial route" through a device that can deliver cells to the brain across the cribriform plate of ethmoid bone. PMID- 25146249 TI - Efficacy and safety of tenofovir in a kidney transplant patient with chronic hepatitis B and nucleos(t)ide multidrug resistance: a case report. AB - INTRODUCTION: Five nucleos(t)ide analogs are used to treat chronic hepatitis B. Ideal nucleos(t)ide analog therapy in chronic hepatitis B patients with kidney transplantation must ensure virological suppression and minimize renal injury. However, resistance to nucleos(t)ide analogs frequently results in virological breakthrough, hepatitis flare, and complicated deterioration of the transplanted kidney. Inappropriate rescue therapy for drug resistance may subsequently cause hepatitis B virus multidrug resistance. Currently, tenofovir is used to treat chronic hepatitis B patients with kidney transplantation. In the field, we first reported combination therapy with tenofovir plus entecavir in a kidney transplant chronic hepatitis B patient with nucleos(t)ide analog multidrug resistance. CASE PRESENTATION: A 50-year-old Chinese man with chronic hepatitis B and kidney transplantation received nucleos(t)ide analog therapy with sequential monotherapy and combination therapy. Virological parameters, hepatic enzymology and renal function were monitored. Drug-resistance mutations were detected by sequence analysis. Our patient received sequential nucleos(t)ide analog monotherapy and inappropriate combination therapy during 132 months, which caused multidrug resistance and renal functional injury. Entecavir plus adefovir was administered in month 106, resulting in decreased hepatitis B virus load, normal hepatic function, and stabilized creatinine clearance. As a result of rebounded viral load and significantly declining creatinine clearance, tenofovir plus entecavir was administered in month 133. After eight weeks, undetectable hepatitis B virus DNA, normal hepatic function and improved creatinine clearance were present. Compared with combination therapy with adefovir plus entecavir, tenofovir plus entecavir showed a potent antiviral effect for multidrug resistance and minimized renal injury. CONCLUSIONS: In chronic hepatitis B patients with kidney transplantation, sequential monotherapy with antiviral agents with low barriers to resistance should be avoided, and initial therapy with entecavir is a better option. Combination therapy with tenofovir plus entecavir in this setting with multidrug resistance is safe and effective. PMID- 25146250 TI - High CXCL-16 levels correlate with symptomatic disease in lung transplant recipients with human cytomegalovirus replication in the allograft. AB - Human cytomegalovirus (HCMV) is an important pathogen in lung transplant recipients (LTRs). In LTRs, HCMV may replicate in the transplanted lung, and this is indicated by HCMV DNA detection in the bronchoalveolar lavage fluid (BALF). Local replication may occur without causing clinical symptoms or, in some patients, it may lead to symptomatic HCMV disease. In the present study, we analyzed whether HCMV replication in the allograft induces CXCL-16, a chemokine that may play a key role in the regulation of mucosal immunity, and investigated whether CXCL-16 levels in BALF can be used to differentiate LTRs with asymptomatic HCMV replication from patients who simultaneously develop disease. In total, BALF samples from 57 LTRs, of whom 8 developed HCMV disease, were assessed for CXCL-16 levels using a quantitative enzyme-linked immunosorbent assay. We found that HCMV replication in the lung triggered a significant rise in CXCL-16 levels in the BALF (p < 0.001, Wilcoxon signed-rank test). Furthermore, the CXCL-16 increase, induced by HCMV, was significantly lower in LTRs who did not develop HCMV disease (p < 0.001, Mann-Whitney U-test). Thus, CXCL-16 is a potential marker that may contribute to identify those LTRs in whom local HCMV replication in the lung remains asymptomatic. PMID- 25146251 TI - Effect of adjuvant radiotherapy on survival in resected pancreatic cancer: a propensity score surveillance, epidemiology, and end results database analysis. AB - BACKGROUND AND OBJECTIVES: The role of adjuvant radiotherapy for resected pancreatic cancer remains controversial. The aim is to demonstrate a survival benefit of adjuvant radiotherapy for resected pancreatic cancer. METHODS: The Surveillance, Epidemiology and End Results database was used to identify patients who were diagnosed with adenocarcinoma of the pancreas from 2004 to 2009, underwent cancer-directed surgery, and received either no radiotherapy or postoperative radiotherapy. Kaplan-Meier and multivariable Cox proportional hazards analyses using a propensity score matching were conducted to determine the effect of adjuvant radiotherapy on overall and disease-specific survival. RESULTS: A total of 2,532 patients were included. The median overall and disease specific survival were significantly longer in the adjuvant radiotherapy group than in no radiotherapy group (overall survival, 20 months vs. 16 months, respectively; disease-specific survival, 22 months vs. 18 months, respectively; both P < 0.0001). In multivariable Cox proportional analyses, adjuvant radiotherapy was associated with a significant overall and disease-specific survival benefit (both P < 0.001). CONCLUSIONS: There is a survival benefit of adjuvant radiotherapy in patients with resected pancreatic cancer. We concluded that adjuvant radiotherapy might be included in the standard treatment for resected pancreatic cancer. PMID- 25146252 TI - Monitoring activation of the antiviral pattern recognition receptors RIG-I and PKR by limited protease digestion and native PAGE. AB - Host defenses to virus infection are dependent on a rapid detection by pattern recognition receptors (PRRs) of the innate immune system. In the cytoplasm, the PRRs RIG-I and PKR bind to specific viral RNA ligands. This first mediates conformational switching and oligomerization, and then enables activation of an antiviral interferon response. While methods to measure antiviral host gene expression are well established, methods to directly monitor the activation states of RIG-I and PKR are only partially and less well established. Here, we describe two methods to monitor RIG-I and PKR stimulation upon infection with an established interferon inducer, the Rift Valley fever virus mutant clone 13 (Cl 13). Limited trypsin digestion allows to analyze alterations in protease sensitivity, indicating conformational changes of the PRRs. Trypsin digestion of lysates from mock infected cells results in a rapid degradation of RIG-I and PKR, whereas Cl 13 infection leads to the emergence of a protease-resistant RIG-I fragment. Also PKR shows a virus-induced partial resistance to trypsin digestion, which coincides with its hallmark phosphorylation at Thr 446. The formation of RIG-I and PKR oligomers was validated by native polyacrylamide gel electrophoresis (PAGE). Upon infection, there is a strong accumulation of RIG-I and PKR oligomeric complexes, whereas these proteins remained as monomers in mock infected samples. Limited protease digestion and native PAGE, both coupled to western blot analysis, allow a sensitive and direct measurement of two diverse steps of RIG-I and PKR activation. These techniques are relatively easy and quick to perform and do not require expensive equipment. PMID- 25146254 TI - Pharmacokinetics of continuous-infusion meropenem in a pediatric patient receiving extracorporeal life support. AB - Meropenem, a broad-spectrum carbapenem, is commonly used for empirical and definitive therapy in the pediatric intensive care unit (ICU). Pharmacokinetic data to guide dosing in children, however, are limited to healthy volunteers or patients who are not in the ICU. Adult data demonstrate that pharmacokinetic parameters such as the volume of distribution and clearance can be significantly altered in individuals receiving extracorporeal membrane oxygenation (ECMO). Alterations in the volume of distribution and clearance of antimicrobials in patients with sepsis and septic shock have also been documented, and these patients have demonstrated lower than expected antimicrobial serum concentrations based on standard dosing regimens. Therefore, an understanding of the pharmacokinetic changes in critically ill children receiving ECMO is crucial to determining the most appropriate dose and dosing interval selection for any antimicrobial therapy. In this case report, we describe the pharmacokinetics of a continuous infusion of meropenem in a pediatric cardiac ICU patient who was receiving concurrent extracorporeal life support. The patient was an 8-month-old male infant who underwent a Glenn procedure and pulmonary artery reconstruction. Postoperatively, he required ECMO with a total run of 21 days. On day 11 of ECMO, a bronchoalveolar lavage was performed, and blood cultures from days 11 and 12 of ECMO grew Pseudomonas aeruginosa, with a meropenem minimum inhibitory concentration (MIC) of 0.5 MUg/ml. On ECMO day 13, meropenem was initiated with a loading dose of 40 mg/kg and infused over 30 minutes, followed by a continuous infusion of 200 mg/kg/day. A meropenem serum concentration measured 8 hours after the start of the infusion was 46 MUg/ml. Repeat levels were measured on days 3 and 9 of meropenem therapy and were 39 and 42 MUg/ml, respectively. Repeat blood and respiratory cultures remained negative. This meropenem regimen (40-mg/kg bolus followed by a continuous infusion of 200 mg/kg/day) was successful in providing a target attainment of 100% for serum and lung concentrations above the MIC for at least 40% of the dosing interval and was associated with a successful clinical outcome. PMID- 25146253 TI - Strategies to promote uptake and use of intimate partner violence and child maltreatment knowledge: an integrative review. AB - BACKGROUND: Intimate partner violence (IPV) and child maltreatment (CM) are major social and public health problems. Knowledge translation (KT) of best available research evidence has been suggested as a strategy to improve the care of those exposed to violence, however research on how best to promote the uptake and use of IPV and CM evidence for policy and practice is limited. Our research asked: 1) What is the extent of IPV/CM-specific KT research? 2) What KT strategies effectively translate IPV/CM knowledge? and 3) What are the barriers and facilitators relevant to translating IPV/CM-specific knowledge? METHODS: We conducted an integrative review to summarize and synthesize the available evidence regarding IPV/CM-specific KT research. We employed multiple search methods, including database searches of Embase, CINAHL, ERIC, PsycInfo, Sociological Abstracts, and Medline (through April, 2013). Eligibility and quality assessments for each article were conducted by at least two team members. Included articles were analyzed quantitatively using descriptive statistics and qualitatively using descriptive content analysis. RESULTS: Of 1230 identified articles, 62 were included in the review, including 5 review articles. KT strategies were generally successful at improving various knowledge/attitude and behavioural/behavioural intention outcomes, but the heterogeneity among KT strategies, recipients, study designs and measured outcomes made it difficult to draw specific conclusions. Four key themes were identified: existing measurement tools and promising/effective KT strategies are underused, KT efforts are rarely linked to health-related outcomes for those exposed to violence, there is a lack of evidence regarding the long-term effectiveness of KT interventions, and authors' inferences about barriers, facilitators, and effective/ineffective KT strategies are often not supported by data. The emotional and sometimes contested nature of the knowledge appears to be an important barrier unique to IPV/CM KT. CONCLUSIONS: To direct future KT in this area, we present a guiding framework that highlights the need for implementers to use/adapt promising KT strategies that carefully consider contextual factors, including the fact that content in IPV/CM may be more difficult to engage with than other health topics. The framework also provides guidance regarding use of measurement tools and designs to more effectively evaluate and report on KT efforts. PMID- 25146256 TI - Cochrane review summary: Face-to-face interventions for informing or educating parents about early childhood vaccination. PMID- 25146255 TI - Nanoscale nickel oxide/nickel heterostructures for active hydrogen evolution electrocatalysis. AB - Active, stable and cost-effective electrocatalysts are a key to water splitting for hydrogen production through electrolysis or photoelectrochemistry. Here we report nanoscale nickel oxide/nickel heterostructures formed on carbon nanotube sidewalls as highly effective electrocatalysts for hydrogen evolution reaction with activity similar to platinum. Partially reduced nickel interfaced with nickel oxide results from thermal decomposition of nickel hydroxide precursors bonded to carbon nanotube sidewalls. The metal ion-carbon nanotube interactions impede complete reduction and Ostwald ripening of nickel species into the less hydrogen evolution reaction active pure nickel phase. A water electrolyzer that achieves ~20 mA cm(-2) at a voltage of 1.5 V, and which may be operated by a single-cell alkaline battery, is fabricated using cheap, non-precious metal-based electrocatalysts. PMID- 25146257 TI - 'Abandoned by medicine'? A qualitative study of women's experiences with lymphoedema secondary to cancer, and the implications for care. AB - BACKGROUND: Lymphoedema secondary to cancer is a relatively neglected and under researched condition. Few studies report people's experiences of care and treatment provision when living with the condition. Current practice focuses on the physical treatment yet psychosocial needs often remain unmet. A previous study examining the patient perspective identified the theme of being 'abandoned by medicine'. Perceived lack of support may result in a delayed adaptation and acceptance of this long-term condition and can significantly impact on psychological well-being. We explore this emerging theme alongside others in order to provide a guide to action for improvements for patient benefit. AIM: The central aim was to explore women's views of their care and treatment following a diagnosis with lymphoedema secondary to cancer. This forms part of a larger study aimed at assessing appropriate screening tools to measure psychosocial distress. METHODS: A mixed-methods approach was used for the main study. Here we report the qualitative component, derived from in-depth semi-structured interviews conducted in the homes of the participants (n = 14) and focus group discussions (n = 15). In addition, qualitative comments from questionnaire data from a large-scale postal survey are included (n = 104). FINDINGS: Participants identified considerable deficiencies in health care workers' knowledge and awareness of lymphoedema, which subsequently impacted on the patients' needs for information, support and understanding. Access to appropriate treatment was patchy and problems were identified with the process of obtaining compression garments, massage and other sources of help. Although lymphoedema is a long-term disfiguring condition, and much is known about how this impacts on patients' emotional well-being, little attention was paid by health professionals to potential psychosocial consequences. In essence women had to become experts of their own condition and cope as best as they could. We provide recommendations to improve service delivery and address these unmet needs. PMID- 25146258 TI - A swan in the making. PMID- 25146260 TI - Political science. Study exposes Chinese censors' deepest fears. PMID- 25146261 TI - Climate change. Is Atlantic holding Earth's missing heat? PMID- 25146262 TI - Public health. A one-two punch against polio. PMID- 25146263 TI - Mathematics. Wheels when you need them. PMID- 25146264 TI - Animal behavior. Wolves cooperate but dogs submit, study suggests. PMID- 25146265 TI - The cancer drug that almost wasn't. PMID- 25146266 TI - Astronomy. Imprint of an ancient conflagration. PMID- 25146267 TI - Biogeochemistry. Carbon cycling in the Arctic. PMID- 25146268 TI - Quantum optics. A photon steers a photon with an atom. PMID- 25146269 TI - Climate change. Glacier retreat crosses a line. PMID- 25146270 TI - Economics. Boosting GDP growth by accounting for the environment. PMID- 25146271 TI - Botany. Making phloem--a near-death experience. PMID- 25146272 TI - RNA. Riboswitch regulates RNA. PMID- 25146274 TI - Ecology. How do coral reefs recover? PMID- 25146273 TI - Evolution. Sensing nectar's sweetness. PMID- 25146275 TI - Retrospective. Joep Lange (1954-2014). PMID- 25146276 TI - Fauna in decline: plight of the pangolin. PMID- 25146277 TI - Fauna in decline: first do no harm. PMID- 25146278 TI - Fauna in decline: global assessments. PMID- 25146279 TI - Ailing academia needs culture change. PMID- 25146280 TI - Let minority-serving institutions lead. PMID- 25146281 TI - Reef ecology. Chemically mediated behavior of recruiting corals and fishes: a tipping point that may limit reef recovery. AB - Coral reefs are in global decline, converting from dominance by coral to dominance by seaweed. Once seaweeds become abundant, coral recovery is suppressed unless herbivores return to remove seaweeds, and corals then recruit. Variance in the recovery of fishes and corals is not well understood. We show that juveniles of both corals and fishes are repelled by chemical cues from fished, seaweed dominated reefs but attracted to cues from coral-dominated areas where fishing is prohibited. Chemical cues of specific seaweeds from degraded reefs repulsed recruits, and cues from specific corals that are typical of healthy reefs attracted recruits. Juveniles were present at but behaviorally avoided recruiting to degraded reefs dominated by seaweeds. For recovery, degraded reefs may need to be managed to produce cues that attract, rather than repel, recruiting corals and fishes. PMID- 25146282 TI - Climate. Varying planetary heat sink led to global-warming slowdown and acceleration. AB - A vacillating global heat sink at intermediate ocean depths is associated with different climate regimes of surface warming under anthropogenic forcing: The latter part of the 20th century saw rapid global warming as more heat stayed near the surface. In the 21st century, surface warming slowed as more heat moved into deeper oceans. In situ and reanalyzed data are used to trace the pathways of ocean heat uptake. In addition to the shallow La Nina-like patterns in the Pacific that were the previous focus, we found that the slowdown is mainly caused by heat transported to deeper layers in the Atlantic and the Southern oceans, initiated by a recurrent salinity anomaly in the subpolar North Atlantic. Cooling periods associated with the latter deeper heat-sequestration mechanism historically lasted 20 to 35 years. PMID- 25146283 TI - Quantum optics. All-optical routing of single photons by a one-atom switch controlled by a single photon. AB - The prospect of quantum networks, in which quantum information is carried by single photons in photonic circuits, has long been the driving force behind the effort to achieve all-optical routing of single photons. We realized a single photon-activated switch capable of routing a photon from any of its two inputs to any of its two outputs. Our device is based on a single atom coupled to a fiber coupled, chip-based microresonator. A single reflected control photon toggles the switch from high reflection (R ~ 65%) to high transmission (T ~ 90%), with an average of ~1.5 control photons per switching event (~3, including linear losses). No additional control fields are required. The control and target photons are both in-fiber and practically identical, making this scheme compatible with scalable architectures for quantum information processing. PMID- 25146284 TI - Helium superfluidity. Shapes and vorticities of superfluid helium nanodroplets. AB - Helium nanodroplets are considered ideal model systems to explore quantum hydrodynamics in self-contained, isolated superfluids. However, exploring the dynamic properties of individual droplets is experimentally challenging. In this work, we used single-shot femtosecond x-ray coherent diffractive imaging to investigate the rotation of single, isolated superfluid helium-4 droplets containing ~10(8) to 10(11) atoms. The formation of quantum vortex lattices inside the droplets is confirmed by observing characteristic Bragg patterns from xenon clusters trapped in the vortex cores. The vortex densities are up to five orders of magnitude larger than those observed in bulk liquid helium. The droplets exhibit large centrifugal deformations but retain axially symmetric shapes at angular velocities well beyond the stability range of viscous classical droplets. PMID- 25146286 TI - Massive stars. A chemical signature of first-generation very massive stars. AB - Numerical simulations of structure formation in the early universe predict the formation of some fraction of stars with several hundred solar masses. No clear evidence of supernovae from such very massive stars has, however, yet been found in the chemical compositions of Milky Way stars. We report on an analysis of a very metal-poor star SDSS J001820.5-093939.2, which possesses elemental-abundance ratios that differ significantly from any previously known star. This star exhibits low [alpha-element Fe] ratios and large contrasts between the abundances of odd and even element pairs, such as scandium/titanium and cobalt/nickel. Such features have been predicted by nucleosynthesis models for supernovae of stars more than 140 times as massive as the Sun, suggesting that the mass distribution of first-generation stars might extend to 100 solar masses or larger. PMID- 25146285 TI - Nanoparticle imaging. Electron microscopy of gold nanoparticles at atomic resolution. AB - Structure determination of gold nanoparticles (AuNPs) is necessary for understanding their physical and chemical properties, but only one AuNP larger than 1 nanometer in diameter [a 102-gold atom NP (Au102NP)] has been solved to atomic resolution. Whereas the Au102NP structure was determined by x-ray crystallography, other large AuNPs have proved refractory to this approach. Here, we report the structure determination of a Au68NP at atomic resolution by aberration-corrected transmission electron microscopy, performed with the use of a minimal electron dose, an approach that should prove applicable to metal NPs in general. The structure of the Au68NP was supported by small-angle x-ray scattering and by comparison of observed infrared absorption spectra with calculations by density functional theory. PMID- 25146287 TI - Nanoparticle growth. Facet development during platinum nanocube growth. AB - An understanding of how facets of a nanocrystal develop is critical for controlling nanocrystal shape and designing novel functional materials. However, the atomic pathways of nanocrystal facet development are mostly unknown because of the lack of direct observation. We report the imaging of platinum nanocube growth in a liquid cell using transmission electron microscopy with high spatial and temporal resolution. The growth rates of all low index facets are similar until the {100} facets stop growth. The continuous growth of the rest facets leads to a nanocube. Our calculation shows that the much lower ligand mobility on the {100} facets is responsible for the arresting of {100} growing facets. These findings shed light on nanocrystal shape-control mechanisms and future design of nanomaterials. PMID- 25146288 TI - Polio eradication. Efficacy of inactivated poliovirus vaccine in India. AB - Inactivated poliovirus vaccine (IPV) is efficacious against paralytic disease, but its effect on mucosal immunity is debated. We assessed the efficacy of IPV in boosting mucosal immunity. Participants received IPV, bivalent 1 and 3 oral poliovirus vaccine (bOPV), or no vaccine. A bOPV challenge was administered 4 weeks later, and excretion was assessed 3, 7, and 14 days later. Nine hundred and fifty-four participants completed the study. Any fecal shedding of poliovirus type 1 was 8.8, 9.1, and 13.5% in the IPV group and 14.4, 24.1, and 52.4% in the control group by 6- to 11-month, 5-year, and 10-year groups, respectively (IPV versus control: Fisher's exact test P < 0.001). IPV reduced excretion for poliovirus types 1 and 3 between 38.9 and 74.2% and 52.8 and 75.7%, respectively. Thus, IPV in OPV-vaccinated individuals boosts intestinal mucosal immunity. PMID- 25146289 TI - Carbon cycle. Sunlight controls water column processing of carbon in arctic fresh waters. AB - Carbon in thawing permafrost soils may have global impacts on climate change; however, the factors that control its processing and fate are poorly understood. The dominant fate of dissolved organic carbon (DOC) released from soils to inland waters is either complete oxidation to CO2 or partial oxidation and river export to oceans. Although both processes are most often attributed to bacterial respiration, we found that photochemical oxidation exceeds rates of respiration and accounts for 70 to 95% of total DOC processed in the water column of arctic lakes and rivers. At the basin scale, photochemical processing of DOC is about one-third of the total CO2 released from surface waters and is thus an important component of the arctic carbon budget. PMID- 25146290 TI - Sensory biology. Evolution of sweet taste perception in hummingbirds by transformation of the ancestral umami receptor. AB - Sensory systems define an animal's capacity for perception and can evolve to promote survival in new environmental niches. We have uncovered a noncanonical mechanism for sweet taste perception that evolved in hummingbirds since their divergence from insectivorous swifts, their closest relatives. We observed the widespread absence in birds of an essential subunit (T1R2) of the only known vertebrate sweet receptor, raising questions about how specialized nectar feeders such as hummingbirds sense sugars. Receptor expression studies revealed that the ancestral umami receptor (the T1R1-T1R3 heterodimer) was repurposed in hummingbirds to function as a carbohydrate receptor. Furthermore, the molecular recognition properties of T1R1-T1R3 guided taste behavior in captive and wild hummingbirds. We propose that changing taste receptor function enabled hummingbirds to perceive and use nectar, facilitating the massive radiation of hummingbird species. PMID- 25146291 TI - Riboswitches. A riboswitch-containing sRNA controls gene expression by sequestration of a response regulator. AB - The ethanolamine utilization (eut) locus of Enterococcus faecalis, containing at least 19 genes distributed over four polycistronic messenger RNAs, appears to be regulated by a single adenosyl cobalamine (AdoCbl)-responsive riboswitch. We report that the AdoCbl-binding riboswitch is part of a small, trans-acting RNA, EutX, which additionally contains a dual-hairpin substrate for the RNA binding response regulator, EutV. In the absence of AdoCbl, EutX uses this structure to sequester EutV. EutV is known to regulate the eut messenger RNAs by binding dual hairpin structures that overlap terminators and thus prevent transcription termination. In the presence of AdoCbl, EutV cannot bind to EutX and, instead, causes transcriptional read through of multiple eut genes. This work introduces riboswitch-mediated control of protein sequestration as a posttranscriptional mechanism to coordinately regulate gene expression. PMID- 25146292 TI - Riboswitches. Sequestration of a two-component response regulator by a riboswitch regulated noncoding RNA. AB - Riboswitches are ligand-binding elements contained within the 5' untranslated regions of bacterial transcripts, which generally regulate expression of downstream open reading frames. Here, we show that in Listeria monocytogenes, a riboswitch that binds vitamin B12 controls expression of a noncoding regulatory RNA, Rli55. Rli55, in turn, controls expression of the eut genes, whose products enable ethanolamine utilization and require B12 as a cofactor. Defects in ethanolamine utilization, or in its regulation by Rli55, significantly attenuate Listeria virulence in mice. Rli55 functions by sequestering the two-component response regulator EutV by means of a EutV-binding site contained within the RNA. Thus, Rli55 is a riboswitch-regulated member of the small group of regulatory RNAs that function by sequestering a protein and reveals a distinctive mechanism of signal integration in bacterial gene regulation. PMID- 25146294 TI - Playing a new tune. PMID- 25146296 TI - Political science. Reverse-engineering censorship in China: randomized experimentation and participant observation. AB - Existing research on the extensive Chinese censorship organization uses observational methods with well-known limitations. We conducted the first large scale experimental study of censorship by creating accounts on numerous social media sites, randomly submitting different texts, and observing from a worldwide network of computers which texts were censored and which were not. We also supplemented interviews with confidential sources by creating our own social media site, contracting with Chinese firms to install the same censoring technologies as existing sites, and--with their software, documentation, and even customer support--reverse-engineering how it all works. Our results offer rigorous support for the recent hypothesis that criticisms of the state, its leaders, and their policies are published, whereas posts about real-world events with collective action potential are censored. PMID- 25146293 TI - Plant genetics. Early allopolyploid evolution in the post-Neolithic Brassica napus oilseed genome. AB - Oilseed rape (Brassica napus L.) was formed ~7500 years ago by hybridization between B. rapa and B. oleracea, followed by chromosome doubling, a process known as allopolyploidy. Together with more ancient polyploidizations, this conferred an aggregate 72* genome multiplication since the origin of angiosperms and high gene content. We examined the B. napus genome and the consequences of its recent duplication. The constituent An and Cn subgenomes are engaged in subtle structural, functional, and epigenetic cross-talk, with abundant homeologous exchanges. Incipient gene loss and expression divergence have begun. Selection in B. napus oilseed types has accelerated the loss of glucosinolate genes, while preserving expansion of oil biosynthesis genes. These processes provide insights into allopolyploid evolution and its relationship with crop domestication and improvement. PMID- 25146297 TI - Predictability rather than amplitude of temperature fluctuations determines stress resistance in a natural population of Drosophila simulans. AB - The adaptability of organisms to novel environmental conditions depends on the amount of genetic variance present in the population as well as on the ability of individuals to adjust their phenotype through phenotypic plasticity. Here, we investigated the phenotypic plasticity induced by a single generation's exposure to three different temperature regimes with respect to several life-history and stress-resistance traits in a natural population of Drosophila simulans. We studied a constant as well as a predictably and an unpredictably fluctuating temperature regime. We found high levels of phenotypic plasticity among all temperature regimes, suggesting a strong influence of both temperature fluctuations and their predictability. Increased heat tolerance was observed for flies developed in both types of fluctuating thermal environments compared with flies developed in a constant environment. We suggest that this was due to beneficial hardening when developing in either fluctuating temperature environment. To our surprise, flies that developed in constant and predictably changing environments were similar to each other in most traits when compared to flies from the unpredictably fluctuating environment. The unpredictably changing thermal environment imposed the most stressful condition, resulting in the lowest performance for stress-related traits, even though the absolute temperature changes never exceeded that of the predictably fluctuating environment. The overall decreased stress resistance of flies in the unpredictably fluctuating environment may be the consequence of maladaptive phenotypic plasticity in this setting, indicating that the adaptive value of plasticity depends on the predictability of the environment. PMID- 25146295 TI - Stem cell therapy. Use of differentiated pluripotent stem cells as replacement therapy for treating disease. AB - Pluripotent stem cells (PSCs) directed to various cell fates holds promise as source material for treating numerous disorders. The availability of precisely differentiated PSC-derived cells will dramatically affect blood component and hematopoietic stem cell therapies and should facilitate treatment of diabetes, some forms of liver disease and neurologic disorders, retinal diseases, and possibly heart disease. Although an unlimited supply of specific cell types is needed, other barriers must be overcome. This review of the state of cell therapies highlights important challenges. Successful cell transplantation will require optimizing the best cell type and site for engraftment, overcoming limitations to cell migration and tissue integration, and occasionally needing to control immunologic reactivity, as well as a number of other challenges. Collaboration among scientists, clinicians, and industry is critical for generating new stem cell-based therapies. PMID- 25146299 TI - Construct validity and responsiveness of the simplified version of Ankylosing Spondylitis Disease Activity Score (SASDAS) for the evaluation of disease activity in axial spondyloarthritis. AB - BACKGROUND: Over the last decade, significant progresses have been achieved in the development and validation of new tools for the evaluation of disease activity in axial spondyloarthritis (SpA). Despite they play a key role in the assessment of these patients, the calculation scores are relatively complex and difficult to be quickly assessed in the busy daily clinical practice. OBJECTIVES: To test the construct validity of the Simplified Ankylosing Spondylitis Disease Activity Score (SADSAS) to define disease activity and compare its internal and external responsiveness with the Ankylosing Spondylitis Disease Activity Score (ASDAS) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in patients with axial SpA. METHODS: The patient cohort comprised 397 consecutive axial SpA patients who had never been treated with tumor necrosis factor (TNF) blockers. Clinical and laboratory outcome assessments were performed at baseline, and at week 24. The following parameters were evaluated: BASDAI, ASDAS-CRP, ASDAS ESR, and SASDAS. Construct convergent validity was evaluated by correlating SASDAS with ASDAS CRP/ESR, BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI) and EuroQol five-dimensional (EQ-5D) questionnaire. One hundred and fifty six patients were observed longitudinally for 6 months. Responsiveness was assessed after six months of treatment with sulfasalazine (SSZ) or biologics. Internal responsiveness was evaluated by using the effect size (ES) and standardized response mean (SRM). External responsiveness was investigated by receiver operating characteristic (ROC) analysis. Change scores were compared by calculating paired t-test statistic for the difference. RESULTS: In testing for convergent validity a strong correlations (p < 0.0001) were observed between both SASDAS and ASDAS-ESR (r = 0.835), and ASDAS-CRP (r = 0.805). Strong correlations (p < 0.0001) were also found between SASDAS and BASDAI score (r = -0.886), SASDAS and BASFI scores (rho = 0.588) and SASDAS and EQ-5D scores (rho = -0.579). The cross-classification showed a significant overall agreement (defined as the percentage of observed exact agreements) for SASDAS vs ASDAS-ESR (weighted k = 0.704) and for SASDAS vs ASDAS-CRP (k = 0.661). The most efficient composite measure in detecting change was the ASDAS-CRP (ES 1.95 and SRM 0.97). The responsiveness of SASDAS was slightly higher to ASDAS-ESR with an ES of 1.62 and 1.33, and an SRM of 0.88 and 0.71, respectively. The BASDAI appear to be the less responsive (ES = 0.93 and SRM = 0.52). The area under ROC curve of the SASDAS gives similar results to those provided by ASDAS CRP/ESR. The score changes of all combinations were highly correlated (p < 0.0001). CONCLUSIONS: The new SASDAS is a highly effective measure in assessing disease activity and it showed comparable internal and external responsiveness with respect to the ASDAS ESR/CRP response criteria in patients with axial SpA. SASDAS is easy to calculate and, therefore, appear suitable for clinical decision making, epidemiologic research, and clinical trials. PMID- 25146298 TI - A meta-analysis of prevalence rates and moderating factors for cancer-related post-traumatic stress disorder. AB - OBJECTIVE: Systematic reviews highlight a broad range of cancer-related post traumatic stress disorder (CR-PTSD) prevalence estimates in cancer survivors. This meta-analysis was conducted to provide a prevalence estimate of significant CR-PTSD symptoms and full diagnoses to facilitate the psychological aftercare of cancer survivors. METHODS: A systematic literature search was conducted for studies using samples of cancer survivors by using validated clinical interviews and questionnaires to assess the prevalence of CR-PTSD (k = 25, n = 4189). Prevalence estimates were calculated for each assessment method using random effects meta-analysis. Mixed-effects meta-regression and categorical analyses were used to investigate study-level moderator effects. RESULTS: Studies using the PTSD Checklist-Civilian Version yielded lower event rates using cut-off [7.3%, 95% confidence intervals (CI) = 4.5-11.7, k = 10] than symptom cluster (11.2%, 95% CI = 8.7-14.4, k = 9). Studies using the Structured Clinical Interview for Diagnostic and Statistical Manual, Fourth Edition (SCID), yielded low rates for lifetime (15.3%, 95% CI = 9.1-25, k = 5) and current CR-PTSD (5.1%, 95% CI = 2.8-8.9, k = 9). Between-study heterogeneity was substantial (I(2) = 54 87%). Studies with advanced-stage samples yielded significantly higher rates with PTSD Checklist-Civilian Version cluster scoring (p = 0.05), and when assessing current CR-PTSD on the SCID (p = 0.05). The effect of mean age on current PTSD prevalence met significance on the SCID (p = 0.05). SCID lifetime prevalence rates decreased with time post-treatment (R(2) = 0.56, p < 0.05). DISCUSSION: The cancer experience is sufficiently traumatic to induce PTSD in a minority of cancer survivors. Post-hoc analyses suggest that those who are younger, are diagnosed with more advanced disease and recently completed treatment may be at greater risk of PTSD. More research is needed to investigate vulnerability factors for PTSD in cancer survivors. (c) 2014 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd. PMID- 25146301 TI - Phytotoxic and antibacterial metabolites from Fusarium proliferatum ZS07 isolated from the gut of long-horned grasshoppers. AB - In the proceeding of screening new bioactive natural products, the ethyl acetate extract of the fermentation broth of Fusarium proliferatum ZS07, a fungus residing in the gut of long-horned grasshoppers (Tettigonia chinensis), was found possessing selective phytotoxic activity against the radicle growth of Amaranthus retroflexus L. Bioactivity-guided fractionation lead to the isolation of six fungal metabolites 1-6, including a new polyketide derivate O-methylated SMA93 (2) and five known compounds SMA93 (1), rhodolamprometrin (3), radicinin (4), dehydroallogibberic acid (5), and 3-methyl-6,8-dihydroxyisocoumarin (6). Their structures were identified on the basis of spectroscopic analysis and by comparison of the corresponding data to those reported in the literature previously. Phytotoxic effects of the four isolated compounds 1-4 on the radicle growth of A. retroflexus L. seeds were investigated under laboratory conditions, and compounds 2 and 4 showed good phytotoxic activity in the concentration of 100 MUg/mL, with the inhibition rates of 83.0 and 65.2%, respectively. Furthermore, the antibacterial activity of compounds 1-5 were evaluated against selected bacteria. Compounds 1-3 were found to possess potent antibacterial activity against Bacillus subtilis (ATCC 6633), with the minimum inhibitory concentration (MIC) values of 3.13-12.50 MUg/mL, while Escherichia coli (ATCC 8739) and Salmonella typhimurium [CMCC(B) 50115] were not susceptible. These results suggest that the new polyketide derivate 2 and known compounds 1, 3, and 4 have potential to be used as biocontrol agents in agriculture. PMID- 25146300 TI - Cobalt-catalyzed, aminoquinoline-directed coupling of sp(2) C-H bonds with alkenes. AB - A method for cobalt-catalyzed, aminoquinoline-directed ortho-functionalization of sp(2) C-H bonds with alkenes has been developed. Reactions proceed at room temperature in trifluoroethanol solvent, use oxygen from air as an oxidant, and require Mn(OAc)3 as a cocatalyst. Benzoic, heteroaromatic, and acrylic acid aminoquinoline amides react with ethylene as well as mono- and disubstituted alkenes affording products in good yields. Excellent functional group tolerance is observed; halogen, nitro, ether, and unprotected alcohol functionalities are compatible with the reaction conditions. PMID- 25146303 TI - Atomic under-coordination fascinated catalytic and magnetic behavior of Pt and Rh nanoclusters. AB - Density functional theory (DFT) calculations with local spin density discrimination have been performed to examine the effect of atomic under coordination on the catalytic and magnetic properties of cuboctahedral (CO) and marks decahedral (MD) structured Pt and Rh nanoclusters. Consistency between theoretical calculations and experimental observations confirmed the predictions based on the framework of bond-order-length-strength (BOLS) correlation and nonbonding electron polarization (NEP) notations. The BOLS-NEP notation suggests that the shorter-and-stronger bonds between under-coordinated atoms induce local densification and quantum entrapment of core electrons, which then polarize the otherwise conducting electrons and result in shifts of the binding energy. Such strong localization resolves the intriguing catalytic and magnetic attributes of Pt and Rh nanoclusters. PMID- 25146302 TI - Stab wound injury of the zebrafish adult telencephalon: a method to investigate vertebrate brain neurogenesis and regeneration. AB - Adult zebrafish have an amazing capacity to regenerate their central nervous system after injury. To investigate the cellular response and the molecular mechanisms involved in zebrafish adult central nervous system (CNS) regeneration and repair, we developed a zebrafish model of adult telencephalic injury. In this approach, we manually generate an injury by pushing an insulin syringe needle into the zebrafish adult telencephalon. At different post injury days, fish are sacrificed, their brains are dissected out and stained by immunohistochemistry and/or in situ hybridization (ISH) with appropriate markers to observe cell proliferation, gliogenesis, and neurogenesis. The contralateral unlesioned hemisphere serves as an internal control. This method combined for example with RNA deep sequencing can help to screen for new genes with a role in zebrafish adult telencephalon neurogenesis, regeneration, and repair. PMID- 25146304 TI - Neuropathological Techniques to Investigate CNS Pathology in Experimental Autoimmune Encephalomyelitis (EAE). AB - Neuropathological techniques such as conventional and immunohistochemical staining of paraffin-embedded tissue sections are instrumental for identification and characterization of aberrations of organ architecture during human inflammatory disorders of the central nervous system (CNS) as in their animal models. Here we describe step-by-step protocols for tissue processing, sectioning, and conventional and immunohistochemical stainings to display as well as quantify CNS inflammation, demyelination, and neuronal damage in experimental autoimmune encephalomyelitis (EAE), an animal model of Multiple Sclerosis (MS). PMID- 25146305 TI - Can FESS combined with submucosal resection (SMR)/septoplasty reduce revision rate? AB - OBJECTIVES: Our study was designed to ascertain the outcomes of functional endoscopic sinus surgery (FESS) combined with submucosal resection (SMR)/septoplasty in reducing FESS revision rates. STUDY DESIGN: Retrospective population-based study. SETTING: Academic tertiary medical center. SUBJECTS AND METHODS: By using the Taiwan Longitudinal Health Insurance Database, we obtained the patients who underwent FESS for chronic rhinosinusitis. These patients were divided into 2 groups: the control group (FESS alone) and the study group (FESS combined with SMR). The primary outcome was the revision operative rate. RESULTS: In total, 4484 patients who had undergone FESS were recruited into this study. The number of patients who underwent revision FESS was 528 (11.78%). In our sample, 80.45% of patients received FESS alone, whereas 19.54% of the patients underwent concurrent SMR/septoplasty during FESS. There are more female patients and older patients in the control group than in the study group. The revision rates of these 2 groups were significantly different (12.36% vs 9.36%, respectively; P = .016). Moreover, logistic regression analysis came out that patients in the control group had a higher revision rates than those in the study group. Male patients and younger patients were found to have higher revision rates. In addition, patients with asthma or allergic rhinitis had higher revision rates compared with those patients without these 2 comorbidities. CONCLUSIONS: This study showed an association between FESS combined with concurrent SMR/septoplasty and less incidence of revision rate of FESS. Patients with asthma or allergic rhinitis have an increased risk of requiring more revision surgeries after FESS. PMID- 25146306 TI - Counting on caveolin for clues in glaucoma. PMID- 25146307 TI - The paradoxical effects of light on photoreceptors. PMID- 25146309 TI - Limbic but not non-limbic kindling impairs conditioned fear and promotes plasticity of NPY and its Y2 receptor. AB - Epileptic seizures negatively affect cognition. However, the mechanisms that contribute to cognitive impairments after seizures are largely unknown. Here, we examined the effects of long-term kindling (i.e., 99 stimulations) of limbic (basolateral amygdala, dorsal hippocampus) and non-limbic (caudate nucleus) brain sites on conditioned fear and hippocampal plasticity. We first showed that kindling had no effect on acquisition of a hippocampal-dependent trace fear conditioning task but limbic kindling impaired the retrieval of these fear memories. To determine the relationship between memory and hippocampal neuronal activity, we examined the expression of Fos protein 90 min after memory retrieval (i.e., 4 days after the last kindling stimulation). We found that limbic kindling, but not non-limbic kindling, decreased Fos expression in the granule cell layer, hilus, CA3 pyramidal cell layer, and CA1 pyramidal cell layer. Next, to investigate a mechanism that could contribute to dampen hippocampal neuronal activity in limbic-kindled rats, we focused on the endogenous anticonvulsant neuropeptide Y (NPY), which is expressed in a subset of GABAergic interneurons and can prevent glutamate release through interactions with its Y2 receptor. We found that limbic kindling significantly decreased the number of NPY immunoreactive cells in several hippocampal subfields despite minimal staining of the neurodegenerative marker Fluoro-Jade B. However, we also noted that limbic kindling enhanced NPY immunoreactivity throughout the mossy fiber pathway. In these same regions, we observed limbic kindling-induced de novo expression of the NPY Y2 receptor. These novel findings demonstrate the site-specific effects of kindling on cognition and NPY plasticity, and they provide evidence that altered hippocampal NPY after limbic seizures coincides with dampened neural activity and cognitive impairments. PMID- 25146308 TI - Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies. AB - Murine sex chromosome aneuploidies (SCAs) provide powerful models for charting sex chromosome influences on mammalian brain development. Here, building on prior work in X-monosomic (XO) mice, we use spatially non-biased high-resolution imaging to compare and contrast neuroanatomical alterations in XXY and XO mice relative to their wild-type XX and XY littermates. First, we show that carriage of a supernumerary X chromosome in XXY males (1) does not prevent normative volumetric masculinization of the bed nucleus of the stria terminalis (BNST) and medial amygdala, but (2) causes distributed anatomical alterations relative to XY males, which show a statistically unexpected tendency to be co-localized with and reciprocal to XO-XX differences in anatomy. These overlaps identify the lateral septum, BNST, ventral group thalamic nuclei and periaqueductal gray matter as regions with replicable sensitivity to X chromosome dose across two SCAs. We then harness anatomical variation across all four karyotype groups in our study--XO, XX, XY and XXY--to create an agnostic data-driven segmentation of the mouse brain into five distributed clusters which (1) recover fundamental properties of brain organization with high spatial precision, (2) define two previously uncharacterized systems of relative volume excess in females vs. males ("forebrain cholinergic" and "cerebelo-pontine-thalamo-cortical"), and (3) adopt stereotyped spatial motifs which delineate ordered gradients of sex chromosome and gonadal influences on volumetric brain development. Taken together, these data provide a new framework for the study of sexually dimorphic influences on brain development in health and disrupted brain development in SCA. PMID- 25146310 TI - Influence of simulated and actual community vaccination clinics on student empowerment and self-efficacy for public health nursing competencies. AB - OBJECTIVES: To examine students' structural empowerment during simulated learning and actual nursing practice, and assess students' self-efficacy for public health nursing competencies (PHNC) after involvement in a mass influenza vaccination clinic as a community practice experience. DESIGN: A nonexperimental survey design was used with a sample of year three baccalaureate nursing students. METHODS: Students completed a demographic form after the simulated clinic experience, they were assessed for perceptions of empowerment after being involved in the simulated and actual clinic settings, and self-efficacy was assessed after the actual clinic experience. RESULTS: Students perceived themselves as structurally empowered after completing the simulated and actual community vaccination clinics. Students reported a high level of self-efficacy for PHNC after their actual community vaccination clinic involvement. There was a significant correlation between empowerment and self-efficacy, which suggests that when students have access to empowering structures, they feel more confident to enact PHNC that align with practice in the clinics. CONCLUSION: This study suggests that nursing students acquired the necessary knowledge and skills for safe vaccination administration through the combination of simulated practice and participating in an actual public health vaccination clinic. PMID- 25146311 TI - Sonication-facilitated immunofluorescence staining of late-stage embryonic and larval Drosophila tissues in situ. AB - Studies performed in Drosophila melanogaster embryos and larvae provide crucial insight into developmental processes such as cell fate specification and organogenesis. Immunostaining allows for the visualization of developing tissues and organs. However, a protective cuticle that forms at the end of embryogenesis prevents permeation of antibodies into late-stage embryos and larvae. While dissection prior to immunostaining is regularly used to analyze Drosophila larval tissues, it proves inefficient for some analyses because small tissues may be difficult to locate and isolate. Sonication provides an alternative to dissection in larval Drosophila immunostaining protocols. It allows for quick, simultaneous processing of large numbers of late-stage embryos and larvae and maintains in situ morphology. After fixation in formaldehyde, a sample is sonicated. Sample is then subjected to immunostaining with antigen-specific primary antibodies and fluorescently labeled secondary antibodies to visualize target cell types and specific proteins via fluorescence microscopy. During the process of sonication, proper placement of a sonicating probe above the sample, as well as the duration and intensity of sonication, is critical. Additonal minor modifications to standard immunostaining protocols may be required for high quality stains. For antibodies with low signal to noise ratio, longer incubation times are typically necessary. As a proof of concept for this sonication-facilitated protocol, we show immunostains of three tissue types (testes, ovaries, and neural tissues) at a range of developmental stages. PMID- 25146312 TI - Effect of temperature and pressure on characteristics and reactivity of biomass derived chars. AB - This study evaluates the influence of pyrolysis temperature (350-450 degrees C) and pressure (0.1-2.0MPa) on product yields and char properties. Spruce chars were produced under slow pyrolysis conditions in a fixed bed reactor. Special attention was devoted to the study of the oxidation reactivity of the produced chars, and its relationship with the evaluated char properties. The obtained results showed that the effect of the pyrolysis condition on char production and in particular on the mechanism of secondary char formation strongly influenced the char reactivity. Additionally it has been observed that the interval of temperature between 350 and 450 degrees C may be key in the mechanism of tar repolymerization. The information provided in this study is of great interest for the determination of optimal operation conditions and the design of new gasification concepts or the development of bioenergy carriers via pyrolysis technologies. PMID- 25146313 TI - Cost analysis of concepts for a demand oriented biogas supply for flexible power generation. AB - With the share of intermittent renewable energies within the electricity system rising, balancing services from dispatchable power plants are of increasing importance. Highlighting the importance of the need to keeping fuel costs for flexible power generation to a minimum, the study aims to identify favourable biogas plant configurations, supplying biogas on demand. A cost analysis of five configurations based on biogas storing and flexible biogas production concepts has been carried out. Results show that additional flexibility costs for a biogas supply of 8h per day range between 2? and 11?MWh(-1) and for a 72h period without biogas demand from 9? to 19?MWh(-1). While biogas storage concepts were identified as favourable short term supply configurations, flexible biogas production concepts profit from reduced storage requirements at plants with large biogas production capacities or for periods of several hours without biogas demand. PMID- 25146314 TI - Direct phosphorus recovery from municipal wastewater via osmotic membrane bioreactor (OMBR) for wastewater treatment. AB - This work reports, for the first time, a new approach to direct phosphorus recovery from municipal wastewater via an osmotic membrane bioreactor (OMBR). In the OMBR, organic matter and NH4(+) were removed by biological activities. PO4(3)(-), Ca(2+), Mg(2+) and unconverted NH4(+) were rejected by the forward osmosis (FO) membrane and enriched within the bioreactor. The resultant phosphorus-rich supernatant was then used for phosphorus recovery. By adjusting the pH to 8.0-9.5, PO4(3)(-) was recovered via precipitation with Ca(2+), Mg(2+) and NH4(+). The OMBR showed up to 98% overall removal of TOC and NH4(+)-N. At pH 9.0, more than 95% PO4(3)(-)-P was recovered without addition of magnesium and calcium. The precipitates were predominantly amorphous calcium phosphate (ACP) with phosphorus content >11.0%. In principal, this process can recover almost all the phosphorus, apart from the portion assimilated by bacteria. The global phosphorus recovery efficiency was shown to be 50% over 84 days. PMID- 25146315 TI - Activated sludge filterability improvement by nitrifying bacteria abundance regulation in an adsorption membrane bioreactor (Ad-MBR). AB - Autotrophic nitrifying bacteria have its intrinsic properties including low EPS production, dense colonial structure and slow-growth rate, favoring the sludge filterability improvement. An adsorption-MBR (Ad-MBR) was developed to enrich nitrifier abundance in the MBR chamber by inlet C/N regulation, and its possible positive effect on sludge filterability and underlying mechanisms were investigated. By DNA extraction, PCR amplification and Illumina high-throughput pyrosequencing, the abundance of nitrifying bacteria was accurately quantified. More than 8.29% nitrifier abundance was achieved in Ad-MBR sludge, which was above three times of that in conventional MBR. Regulated C/N ratio and thereafter nitrifier abundance enrichment improved sludge filterability by altering sludge mixture and its supernatant properties, reflected by a good sludge settleability, a low supernatant viscosity and turbidity, a low supernatant organic substances concentration, and a small amount of strong hydrophobic fractional components, thus to profoundly improve sludge filterability and decelerate membrane fouling. PMID- 25146316 TI - Flocculation of algal cells by amphoteric chitosan-based flocculant. AB - A kind of amphoteric chitosan-based flocculant (quaternized carboxymethyl chitosan, denoted as QCMC) has been prepared. QCMC presented significant improvement of water solubility in the whole pH range. The effects of pH, dosage, temperature and original turbidity of algal water on the flocculation performance were investigated. The optimal dosages of QCMC at pH 5, 9 and 12 with original turbidity of 20NTU at 20 degrees C were 0.1, 0.6 and 2.0mg/L, respectively, which were much less than that of chitosan, PAM, Al2(SO4)3 and FeCl3. The floc properties during grow, breakage and regrow period were also evaluated at different pH values in terms of floc size, strength and density. It was demonstrated that QCMC produced larger, stronger and denser flocs than Al2(SO4)3. There is every indication that QCMC is more suitable for algal harvesting than other traditional coagulants or flocculants. PMID- 25146317 TI - Specific molecular structure changes and radical evolution during biomass polyethylene terephthalate co-pyrolysis detected by (13)C and (1)H solid-state NMR. AB - Co-pyrolysis of biomass with polyethylene terephthalate (PET) was studied as a function of blend ratio and co-pyrolysis temperature by (13)C and (1)H solid state nuclear magnetic resonance (NMR). The (13)C NMR spectra showed that upon heating to 400 degrees C in presence of the biomass, the formation of crystallites in PET was completely suppressed and that at higher temperatures there was increased formation and growth of the polycyclic aromatic hydrocarbons (PAHs). This change in the PET degradation behaviour was attributed to the presence of radicals formed in char from biomass. The measurement of the (1)H-T1 relaxation enabled monitoring the changes in the concentrations of radicals formed, as a function of the blend ratios and the co-pyrolysis temperatures. It indicated that the increase in the radical concentrations correlated well with the increased degradation of the PET and growth of PAHs. PMID- 25146318 TI - SIRT1 expression is associated with a poor prognosis, whereas DBC1 is associated with favorable outcomes in gastric cancer. AB - Clinical trials of histone deacetylase (HDAC) inhibitors as antitumor therapy have been conducted for gastric cancer. Expression of SIRT1, a class III HDAC, is related to poor prognosis in some malignancies. We investigated the correlation between SIRT1 expression and progression and prognosis of gastric cancers comparing with molecules linked to SIRT1 in order to better predict the efficacy of HDAC inhibitors in treating this disease. We evaluated SIRT1 expression by western blot in 51 cases and SIRT1, DBC1, acetylated H4K16 (H4K16Ac), acetylated H3K9 (H3K9Ac), and p53 by immunohistochemistry (IHC) in 557 cases of gastric cancer. Western blotting showed that SIRT1 high expression related with statistics to advanced tumor progression, positive lymphatic invasion, positive venous invasion, and advanced stage but not to poor prognosis. IHC revealed that SIRT1 high expression correlated with worse clinico-pathological prognostic factors as same as in western blotting and related poor prognosis both by univariate and multivariate analyses. By the contrast, DBC1 and H4K16Ac were related to favorable prognostic factors and linked to favorable prognosis by univariate analysis but not by multivariate analysis. H3K16Ac correlated only favorable prognostic factors. Results of p53 were very similar to those of SIRT1. We found that SIRT1 high expression closely correlates with progression and prognosis in gastric cancer patients. And it was also indicated that SIRT1 acts as an oncogene by the results of DBC1, H4K16Ac, and H3K9Ac and might be a target molecule of HDAC inhibitor treatment for gastric cancer patients. PMID- 25146319 TI - Supramolecular interactions of nonsteroidal anti-inflammatory drug in nanochannels of molecular containers: a spectroscopic, thermogravimetric and microscopic investigation. AB - Supramolecular host-guest complexation between the nonsteroidal anti-inflammatory drug indomethacin (IMC) and molecular containers were investigated. The weakly fluorescent drug molecule becomes highly fluorescent on complexation with different molecular containers, and time-resolved fluorescence emission spectroscopy reveals that the lifetime components of IMC significantly increase in the presence of molecular containers, compared with the lifetimes in neat water. The respective solid host-guest complexes were synthesised and characterised by Fourier transform infrared and (1) H nuclear magnetic resonance spectroscopic analysis. Microscopy techniques were used to analyse modifications of the surface morphology, owing to the formation of supramolecular complexes. The effect of the molecular container on the optical properties of IMC has also been investigated to determine the effect of nanochannels of different size and structure. PMID- 25146320 TI - Redo cardiac surgery in a patient with severe kyphoscoliosis and pectus carinatum: a technical challenge. PMID- 25146321 TI - Single plane illumination module and micro-capillary approach for a wide-field microscope. AB - A module for light sheet or single plane illumination microscopy (SPIM) is described which is easily adapted to an inverted wide-field microscope and optimized for 3-dimensional cell cultures, e.g., multi-cellular tumor spheroids (MCTS). The SPIM excitation module shapes and deflects the light such that the sample is illuminated by a light sheet perpendicular to the detection path of the microscope. The system is characterized by use of a rectangular capillary for holding (and in an advanced version also by a micro-capillary approach for rotating) the samples, by synchronous adjustment of the illuminating light sheet and the objective lens used for fluorescence detection as well as by adaptation of a microfluidic system for application of fluorescent dyes, pharmaceutical agents or drugs in small quantities. A protocol for working with this system is given, and some technical details are reported. Representative results include (1) measurements of the uptake of a cytostatic drug (doxorubicin) and its partial conversion to a degradation product, (2) redox measurements by use of a genetically encoded glutathione sensor upon addition of an oxidizing agent, and (3) initiation and labeling of cell necrosis upon inhibition of the mitochondrial respiratory chain. Differences and advantages of the present SPIM module in comparison with existing systems are discussed. PMID- 25146322 TI - Selective Inactivation of Striatal FosB/DeltaFosB-Expressing Neurons Alleviates L DOPA-Induced Dyskinesia. AB - BACKGROUND: DeltaFosB is a surrogate marker of L-DOPA-induced dyskinesia (LID), the unavoidable disabling consequence of Parkinson's disease L-DOPA long-term treatment. However, the relationship between the electrical activity of FosB/DeltaFosB-expressing neurons and LID manifestation is unknown. METHODS: We used the Daun02 prodrug-inactivation method associated with lentiviral expression of beta-galactosidase under the control of the FosB promoter to investigate a causal link between the activity of FosB/DeltaFosB-expressing neurons and dyskinesia severity in both rat and monkey models of Parkinson's disease and LID. Whole-cell recordings of medium spiny neurons (MSNs) were performed to assess the effects of Daun02 and daunorubicin on neuronal excitability. RESULTS: We first show that daunorubicin, the active product of Daun02 metabolism by beta galactosidase, decreases the activity of MSNs in rat brain slices and that Daun02 strongly decreases the excitability of rat MSN primary cultures expressing beta galactosidase upon D1 dopamine receptor stimulation. We then demonstrate that the selective, and reversible, inhibition of FosB/DeltaFosB-expressing striatal neurons with Daun02 decreases the severity of LID while improving the beneficial effect of L-DOPA. CONCLUSIONS: These results establish that FosB/DeltaFosB accumulation ultimately results in altered neuronal electrical properties sustaining maladaptive circuits leading not only to LID but also to a blunted response to L-DOPA. These findings further reveal that targeting dyskinesia can be achieved without reducing the antiparkinsonian properties of L-DOPA when specifically inhibiting FosB/DeltaFosB-accumulating neurons. PMID- 25146323 TI - Triple valve surgery in the modern era: short- and long-term results from a single centre. AB - OBJECTIVES: Triple valve surgery (TVS) is still a challenge for surgeons because of prolonged cardiopulmonary bypass (CPB) and myocardial ischaemic times. The reported operative mortality rate for TVS ranges between 2.5 and 25%; long-term survival is also diminished, with reported survival rates at 5 and 10 years of 75 82 and 61-75%, respectively. The objective of our study is to define early and late clinical outcomes, reporting the initial experience in the treatment of triple valve disease through a minimally invasive approach. METHODS: A retrospective, observational, cohort study was undertaken of prospectively collected data on 106 patients who underwent TVS at our institution between October 2001 and June 2013. A total of 101 procedures were done through the standard median sternotomy; however, in 5 patients, the surgical procedure was carried out through a right minithoracotomy. Univariate analysis was performed to identify predictors of early and late survival. RESULTS: The in-hospital mortality rate was 5.6% (6 of 107 patients). Predictors of early mortality were: previous cardiac surgery [odds ratio (OR) 4, 95% confidence interval (CI) 1.08 5.2, P = 0.04], preoperative left ventricular ejection fraction (LVEF) (OR 0.9, 95% CI 0.8-1.1, P = 0.003), prolonged CPB time (OR 1.02, 95% CI 1.01-1.04, P = 0.01) and postoperative pulmonary complications (OR 8, 95% CI 5.8-41, P = 0.0001). Five- and 10-year survival rates were 85 +/- 3 and 65 +/- 9%, respectively. In univariate analysis, diabetes [hazard ratio (HR) 2.5, 95% CI 1 6.2, P = 0.045], preoperative dialysis (HR 3, 95% CI 2-4.7, P = 0.001), unstable angina (HR 4.8, 95% CI 1-18, P = 0.03), preoperative LVEF (HR 0.9, 95% CI 0.8 1.1, P = 0.02), concomitant coronary artery bypass grafting (CABG) (HR 2.5, 95% CI 1.5-5.7, P = 0.006), prolonged CPB time (HR 1.02, 95% CI 1.01-1.13, P = 0.006), postoperative pacemaker (PMK) implantation (HR 6.2, 95% CI 1.3-18, P = 0.01) and postoperative pulmonary complications (HR 3.3, 95% CI 2.1-7.3, P = 0.002) were found to be significant predictors of late mortality following TVS. The freedom rates from valve-related complications and reoperation at 10 years were 95 +/- 2 and 97 +/- 2%, respectively. The 10-year freedom rates from thromboembolism and anticoagulation-related haemorrhage were 88 +/- 5 and 88 +/- 4%, respectively. CONCLUSIONS: TVS offers encouraging short-term and long-term patient survival; these good results after TVS in patients with advanced valvular heart disease justify aggressive surgical therapy in these patients. TVS with a minimally invasive approach is feasible and could be another treatment option. PMID- 25146324 TI - Improved clinical outcomes and survival following repair of acute type A aortic dissection in the current era. AB - OBJECTIVES: The goal of this study was to compare early postoperative outcomes and actuarial-free survival between patients who underwent repair of acute type A aortic dissection during 2000-2005 and 2006-2010. METHODS: A total of 251 patients from four academic medical centres underwent repair of acute type A aortic dissection between January 2000 and October 2010. Of those, 111 patients underwent repair during 2000-2005, whereas 140 patients underwent repair during 2006-2010. Median ages were 62 years (range 20-83) and 58 years (range 30-80) for patients repaired from 2000-2005 compared with those repaired during 2006-2010, respectively (P = 0.180). Major morbidity, operative mortality and 5-year actuarial survival were compared between groups. Multivariate logistic regression was used to determine predictors of operative mortality. RESULTS: Operative mortality was strongly influenced by surgical era (24% for 2000-2005 vs 12% for 2006-2010, P = 0.013). In multivariable logistic regression analysis, haemodynamic instability [odds ratio (OR) = 17.8, 95% confidence intervals (CIs) = 0.05-0.35, P <0.001], cardiopulmonary bypass time >200 min (OR = 9.5, 95% CI = 0.14-0.64, P = 0.002) and earlier date of surgery (OR = 5.8, 95% CI = 1.18-5.14, P = 0.016) emerged as independent predictors of operative mortality. Actuarial 5 year survival was worse for earlier compared with later date of surgery (64% for 2000-2005 vs 77% for 2006-2010, log-rank P <0.001). CONCLUSIONS: Surgical era significantly impacts early outcomes and actuarial survival following repair of acute type A aortic dissection. PMID- 25146325 TI - Personalized surgical repair of left ventricular aneurysm with computer-assisted ventricular engineering. AB - OBJECTIVES: Although circular ventricular resection techniques are the gold standard of left ventricular (LV) restoration, these techniques can lead to suboptimal results. Postoperative systolic resection can be inadequate, because it must be planned on a heart stopped in diastole. Low cardiac output due to insufficient LV volume results in a potentially unstable condition, and cannot be corrected. Our aim was to find a preoperative method to minimize risk and maximize outcome with ventricular restoration. METHODS: We created a novel method combining surgery with gadolinium-enhanced magnetic resonance to construct a preoperative 3D systolic heart model. The model was utilized to determine resection points that could be intraoperatively used. According to our calculations with the predetermined resection line, the calculated percentage reduction in LV volume was above 30%, and LV volumes were predicted above normal values; thus, performing the operation using these resection points is likely to be safe and effective. We had a mixed, real-life patient group: mitral insufficiency or pulmonary hypertension were not exclusion criteria. RESULTS: Forty-one procedures (12 concomitant mitral valve plasty) were done on consecutive patients in a single-centre experience. The incidence rate of major adverse clinical events was 32% postoperatively (n = 13). Control MRI showed a significant improvement in ejection fraction (18.3 +/- 4.3 vs 31.3 +/- 3.3; P = 0.04). All patients improved their New York Heart Association (NYHA) class postoperatively (40 patients NYHA III/IV versus 40 NYHA I/II). During long-term follow-up, 1 patient died due to end-stage heart failure. CONCLUSIONS: Using this model, we were able to find the optimal resection line providing an excellent postoperative result, thus minimizing the risk of low cardiac output syndrome. PMID- 25146326 TI - A novel genome-wide microsatellite resource for species of Eucalyptus with linkage-to-physical correspondence on the reference genome sequence. AB - Keystone species in their native ranges, eucalypts, are ecologically and genetically very diverse, growing naturally along extensive latitudinal and altitudinal ranges and variable environments. Besides their ecological importance, eucalypts are also the most widely planted trees for sustainable forestry in the world. We report the development of a novel collection of 535 microsatellites for species of Eucalyptus, 494 designed from ESTs and 41 from genomic libraries. A selected subset of 223 was evaluated for individual identification, parentage testing, and ancestral information content in the two most extensively studied species, Eucalyptus grandis and Eucalyptus globulus. Microsatellites showed high transferability and overlapping allele size range, suggesting they have arisen still in their common ancestor and confirming the extensive genome conservation between these two species. A consensus linkage map with 437 microsatellites, the most comprehensive microsatellite-only genetic map for Eucalyptus, was built by assembling segregation data from three mapping populations and anchored to the Eucalyptus genome. An overall colinearity between recombination-based and physical positioning of 84% of the mapped microsatellites was observed, with some ordering discrepancies and sporadic locus duplications, consistent with the recently described whole genome duplication events in Eucalyptus. The linkage map covered 95.2% of the 605.8-Mbp assembled genome sequence, placing one microsatellite every 1.55 Mbp on average, and an overall estimate of physical to recombination distance of 618 kbp/cM. The genetic parameters estimates together with linkage and physical position data for this large set of microsatellites should assist marker choice for genome-wide population genetics and comparative mapping in Eucalyptus. PMID- 25146327 TI - Association between mental health and comorbid obesity and hypertension among children and adolescents in the US. AB - This paper examines the association between mental health and comorbid obesity and hypertension among US children and adolescents using data from the National Health and Nutritional Examination Survey (NHANES). Questionnaires from NHANES were used to assess mental health during the previous 30 days. Respondents were then categorized into two groups namely "poor mental health" and "good mental health" based on their responses to these survey questions. Three multiple logistic regression models, based on these categories, are estimated to compute the odds ratios and 95% confidence intervals in the association of obesity and hypertension and mental health. As a select example, the results of Model 2 reveal that compared with respondents who are not obese, obese respondents have increased odds (OR = 1.24; P < 0.0001) of poor mental health. Furthermore compared with non-hypertensive respondents, hypertensive respondents have higher odds (OR = 2.96; P < 0.0001) of poor mental health. These findings have important implications for mental health management in younger populations. It brings into focus the maintenance of a healthy body mass index and hypertension control in mitigating poor mental health. PMID- 25146328 TI - Exploring a type of central pattern generator based on Hindmarsh-Rose model: from theory to application. AB - This paper proposes the idea that Hindmarsh-Rose (HR) neuronal model can be used to develop a new type of central pattern generator (CPG). Some key properties of HR model are studied and proved to meet the requirements of CPG. Pros and cons of HR model are provided. A CPG network based on HR model is developed and the related properties are investigated. We explore the bipedal primary gaits generated by the CPG network. The preliminary applications of HR model are tested on humanoid locomotion model and functional electrical stimulation (FES) walking system. The positive results of stimulation and experiment show the feasibility of HR model as a valid CPG. PMID- 25146329 TI - Treatment patterns in psoriatic arthritis patients newly initiated on oral nonbiologic or biologic disease-modifying antirheumatic drugs. AB - INTRODUCTION: This study aimed to describe treatment changes (discontinuation, switching, and therapy add-on) following the initiation of biologic or nonbiologic oral disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis (PsA) patients. METHODS: Adult patients with >=2 PsA diagnoses from physician office visits, initiated on a biologic or nonbiologic oral DMARD, were selected from the Truven Health Analytics MarketScan(r) Research Database (2005 to 2009). Patients were required to have continuous insurance coverage >=6 months prior to and >=12 months post index date (first prescription fill date). Treatment discontinuation, treatment switch, and therapy add-on were captured over the 1 year period following the index date. Treatment changes were described separately for patients initiated on nonbiologic and biologic DMARDs. RESULTS: A total of 1,698 and 3,263 patients were initiated on an oral nonbiologic DMARD and biologic DMARD respectively. For patients initiated on nonbiologic DMARDs, 69% had >=1 therapy change over the 12 month study period (median time 85 days). Among patients who had a therapy change, 83% discontinued, 29% switched therapy (64% switched to a biologic DMARD), and 25% had a therapy add-on (76% added-on with a biologic DMARD). For patients initiated on a biologic DMARD, 46% had >=1 therapy change (median time 110 days). Among patients who had a therapy change, 100% discontinued, 25% switched therapy (92% switched to another biologic DMARD), and 7% had a therapy add-on with a nonbiologic DMARD. CONCLUSION: This study suggests that PsA patients newly initiated on a nonbiologic/biologic DMARD do not remain on the index treatment for a long period of time. A better understanding of factors related to these early treatment changes in PsA patients is needed. PMID- 25146330 TI - Analogs of cinnamic acid benzyl amide as nonclassical inhibitors of activated JAK2 kinase. AB - Scaffold-based analogs of cinnamic acid benzyl amide (CABA) exhibit pleiotropic effects in cancer cells, and their exact molecular mechanism of action is under investigation. The present study is part of our systemic analysis of interactions of CABA analogs with their molecular targets. These compounds were shown to inhibit Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and JAK2/signal transducer and activator of transcription 5 (STAT5) signaling and thus are attractive scaffolds for anticancer drug design. To identify the potential mechanisms of action of this class of compounds, direct interactions of the selected CABA analogs with JAK2 kinase were examined. Inhibition of JAK2 enzymatic activity was assessed, and molecular modeling studies of selected compounds-(E)-2-cyano-N-[(S)-1-phenylethyl]-3-(pyridin-2 yl)acrylamide (WP1065), (E)-2-cyano-N-[(S)-1-phenylbutyl]- 3-(3-bromopyridin-2 yl)acrylamide (WP1130), and (E)-2-cyano-N-[(S)-1,4-diphenylbutyl]-3-(3 bromopyridin-2-yl)acrylamide (WP1702)-in the JAK2 kinase domain were used to support interpretation of the experimental data. Our results indicated that the tested CABA analogs are nonclassical inhibitors of activated (phosphorylated) JAK2, although markedly weaker than clinically tested ATP-competitive JAK2 inhibitors. Relatively small structural changes in the studied compounds affected interactions with JAK2, and their mode of action ranged from allosteric noncompetitive to bisubstratecompetitive. These results demonstrated that direct inhibition of JAK2 enzymatic activity by the WP1065 (half-maximal inhibitory concentration [IC50] = 14.8 uM), WP1130 (IC50 = 3.8 uM), and WP1702 (IC50 = 2.9 uM) potentially contributes, albeit minimally, to suppression of the JAK2/STAT signaling pathways in cancer cells and that additional specific structural modifications may amplify JAK2-inhibitory effects. PMID- 25146331 TI - Deregulated expression of miR-224 and its target gene: CD59 predicts outcome of diffuse large B-cell lymphoma patients treated with R-CHOP. AB - miRNAs are non-coding RNA molecules; their deregulations may contribute to cancer pathogenesis. However, the mechanisms of how miRNA dysfunction contributes to the lymphomagenesis of diffuse large B-cell lymphoma (DLBCL) are not well established. In this study, we analyzed the expression of miR-224 in four DLBCL cell lines and 168 patients' specimens. We found that the expression of miR-224 in DLBCL was down-regulated compared with normal B-cell but was not statistically different between the germinal center B-cell-like-type and the activated B-cell like-type. Using bioinformatics prediction and luciferase report assays, we demonstrated that miR-224 directly down-regulated CD59 expression by binding to its 3'-untranslated region. We also used immunohistochemical staining of CD59 in human DLBCL specimens and analyzed the relationship between the expression of miR 224, CD59 and the overall/progress-free survival of DLBCL patients who were uniformly treated with rituximab,cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). We found that miR-224 may contribute to DLBCL pathogenesis. Most importantly, the expression of miR-224 and CD59 can predict the response and outcome of DLBCL patients treated with R-CHOP. PMID- 25146332 TI - GRID2 a novel gene possibly associated with mevalonate kinase deficiency. AB - Mevalonate kinase deficiency (MKD) is a rare autosomal disease caused by mutations in the mevalonate kinase gene (MVK). The genotype-phenotype correlation is sometimes problematic due to the great genetic and clinical heterogeneity; so we hypothesize that genes other than MVK are able to modulate MKD clinical phenotypes. This hypothesis was tested by analyzing the exome of 22 patients with MKD all carrying MVK gene mutations, and 20 patients with recurrent fevers (RF) not carrying MVK mutations. Our preliminary findings suggest a possible role of GRID2 in the susceptibility to develop MKD. GRID2 gene (4q22.2), encoding for human glutamate receptor delta-2, associated with MKD: The rs1450500 SNP was differently distributed in patients with MKD with respect to those with RF. Being aware of the small number of patients analyzed, we hypothesized a possible role for GRID2 as possible phenotype modifier in MKD patients, especially in those with severe phenotypes. PMID- 25146333 TI - Re: "abdominal aortic aneurysm causing lumbar vertebral erosion in Behcet's disease presenting by low back pain". PMID- 25146334 TI - NSCLC metastasis: going with ELMO3. AB - Comment on: Signe Soes, Iben Lyster Daugaard, Brita Singers Sorensen, Andreas Carus, Manuel Mattheisen, Jan Alsner, Jens Overgaard, Henrik Hager, Lise Lotte Hansen, and Lasse Sommer Kristensen. Hypomethylation and increased expression of the putative oncogene ELMO3 are associated with lung cancer development and metastases formation. Oncoscience. 2014; 1(5): 367-7. PMID- 25146335 TI - Preliminary study of pancreatic cancer associated with Helicobacter pylori infection. AB - Little is known about the relationship about Helicobacter pylori (H. pylori) infection and pancreatic, and this study was set to investigate how H. pylori infection is correlated with pancreatic cancer and provide references for the clinical prevention and treatment of pancreatic cancer. 56 cases of pancreatic cancer patients admitted to the hospital from August 2012 to August 2013 were collected as the observation group. The anti-Hp IgG (H. pylori-specific antibodies), Hp IgM (H. pylori antibodies), and CagA-Hp-IgG (H. pylori serotoxin associated protein a antibody) in the serum were measured and compared with the related indicators of control group (60 cases of healthy subjects). The H. pylori infection rate was 64.29% in the observation group, and that in the control group was 46.67%. Our results showed that the H. pylori infection rate in the observation group was significantly higher than that in the control group, which was statistically different (P < 0.01). The positive rate of CagA-Hp in the observation group was 38.88, and 21.53% in the control group, for which the observation group was significantly higher than the control group (P < 0.05). The occurrence of H. pylori infection in patients with pancreatic cancer was also positively correlated with the smoking history and the history of chronic pancreatitis (P < 0.05). Helicobacter pylori infection is one of the risk factors for pancreatic cancer, and the patients with positive CagA-Hp have the higher risk, so the prevention and treatment of H. pylori infection would be beneficial for the prevention and treatment of pancreatic cancer. PMID- 25146336 TI - Oral zinc aspartate treats experimental autoimmune encephalomyelitis. AB - The essential trace element zinc plays a critical role in the regulation of immune homeostasis. Zinc deficiency or excess can cause severe impairment of the immune response, which points to the importance of the physiological and dietary control of zinc levels for a functioning immune system. We previously reported that injection of zinc aspartate suppresses experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), as well as effector T cell functions in vitro. Among the preferred characteristics of novel therapeutics for the treatment of autoimmune diseases such as MS are oral availability and a tolerable effective dose to minimize side effects. In this study, we investigated whether oral administration of zinc aspartate, an approved drug to treat zinc deficiency in humans, is effective in controlling EAE at clinically approved doses. We show that oral administration of 6 ug/day [0.3 mg/kg body weight (BW)] or 12 ug/day [0.6 mg/kg BW] of zinc aspartate reduces clinical and histopathological signs during the relapsing remitting phase of the disease in SJL mice. The clinical effect in mice was accompanied by suppression of IFN-gamma, TNF-alpha, GM-CSF and IL-5 production in stimulated human T cells and mouse splenocytes in a dose-dependent manner. Furthermore, a large array of proinflammatory cytokines was modulated by zinc aspartate exposure in vitro. These data suggest that administration of oral zinc aspartate may have beneficial effects on autoimmune diseases like MS. PMID- 25146337 TI - Assessing parents' attitudes towards ketogenic dietary therapies. AB - We aimed to assess and quantify parental beliefs regarding ketogenic dietary therapies (KDTs). We also aimed to determine whether beliefs were related to response to KDTs. Adapted versions of the Beliefs about Medicine Questionnaire were completed by parents of children following KDTs for epilepsy. Demographic and clinical data were collected from hospital records. Ketogenic dietary therapy response was defined as >=50% seizure reduction compared to baseline. Many parents had a positive perception of KDTs and were convinced of the necessity of KDTs for their children, although beliefs were wide-ranging. Over half of parents reported concerns about the potential long-term effects of KDTs. Parental beliefs about KDTs were significantly correlated with patient response. This was an attempt to quantify parents' beliefs regarding the use of KDTs for their child's epilepsy. The questionnaire may be used to identify individuals with a less positive attitude towards KDTs and who may be less likely to report a favorable response to KDTs. It is unknown whether people who have positive beliefs about KDTs engage in less nonadherent behavior or whether beliefs regarding KDTs simply reflect outcomes. The evidence behind the long-term side effects of KDTs should be emphasized when counseling patients and their families. PMID- 25146338 TI - Three dimensional magnetic abacus memory. AB - Stacking nonvolatile memory cells into a three-dimensional matrix represents a powerful solution for the future of magnetic memory. However, it is technologically challenging to access the data in the storage medium if large numbers of bits are stacked on top of each other. Here we introduce a new type of multilevel, nonvolatile magnetic memory concept, the magnetic abacus. Instead of storing information in individual magnetic layers, thereby having to read out each magnetic layer separately, the magnetic abacus adopts a new encoding scheme. It is inspired by the idea of second quantisation, dealing with the memory state of the entire stack simultaneously. Direct read operations are implemented by measuring the artificially engineered 'quantised' Hall voltage, each representing a count of the spin-up and spin-down layers in the stack. This new memory system further allows for both flexible scaling of the system and fast communication among cells. The magnetic abacus provides a promising approach for future nonvolatile 3D magnetic random access memory. PMID- 25146340 TI - Activation of SO2 and CO2 by trivalent uranium leading to sulfite/dithionite and carbonate/oxalate complexes. AB - The first sulfite [{(((nP,Me) ArO)3 tacn)U(IV) }2 (MU-kappa(1) :kappa(2) -SO3 )] (tacn=triazacyclononane) and dithionite [{(((nP,Me) ArO)3 tacn)U(IV) }2 (MU kappa(2) :kappa(2) -S2 O4 )] complexes of uranium from reaction with gaseous SO2 have been prepared. Additionally, the reductive activation of CO2 was investigated with respect to the rare oxalate [{(((nP,Me) ArO)3 tacn)U(IV) }2 (MU kappa(2) :kappa(2) -C2 O4 )] formation. This ultimately provides the unique S2 O4 (2-) /C2 O4 (2-) and SO3 (2-) /CO3 (2-) complex pairs. All new complexes were characterized by a combination of single-crystal X-ray diffraction, elemental analysis, UV/Vis/NIR electronic absorption, IR vibrational, and (1) H NMR spectroscopy, as well as magnetization (VT SQUID) studies. Moreover, density functional theory (DFT) calculations were carried out to gain further insight into the reaction mechanisms. All observations, together with DFT, support the assumption that SO2 and CO2 show similar (dithionite/oxalate) to analogous (sulfite/carbonate) activation behavior with uranium complexes. PMID- 25146339 TI - Could community pharmacies help to improve youth health? Service availability and views of pharmacy personnel in New Zealand. AB - OBJECTIVES: To investigate the availability of youth-relevant community pharmacy services in New Zealand (NZ), and the opinions of pharmacy personnel on the appropriateness of these services for young people aged 12-24. METHODS: Pharmacist and pharmacy support staff (PSS) questionnaires were developed collaboratively with a Youth Advisory Group (YAG) and were mailed to 500 randomly selected community pharmacies in NZ. RESULTS: Response rates for questionnaires were 50.5 % for pharmacists and 37.0 % for PSS. The majority of community pharmacies in NZ offer public health services relevant to youth health including emergency contraception, condoms, smoking cessation, weight management and harm reduction services for drug use. Not all pharmacy personnel believed these services are appropriate for youth, particularly for those aged 16 or under. PSS appeared less likely than pharmacists to feel services were appropriate. CONCLUSIONS: Community pharmacies are offering an increasing range of youth relevant health services, and may, therefore, be able to improve youth healthcare access. More research is required to investigate the barriers to young people accessing services from pharmacies, and also the challenges for pharmacy personnel in providing services to this age group. PMID- 25146341 TI - Limited segmental rectal resection in the treatment of deeply infiltrating rectal endometriosis: 10 years' experience from a tertiary referral unit. AB - BACKGROUND: The management of symptomatic rectal endometriosis is a challenging condition that may necessitate limited stripping or limited segmental anterior rectal resection (LSARR) depending upon the extent and severity of the disease. OBJECTIVE: To report the efficacy of LSARR in terms of pain, quality of life and short- and long-term complications-in particular, those pertaining to bowel function. METHODS: The case notes of all patients undergoing LSARR were reviewed. The analysed variables included surgical complications, overall symptomatic improvement rate, dysmenorrhoea, dyspareunia, and dyschezia. Chronic pain was measured using a visual analogue scale. Quality of life was measured using the EQ 5D questionnaire. Bowel symptoms were assessed using the Memorial Sloan Kettering Cancer Centre (MSKCC) questionnaire. RESULTS: Seventy-four women who underwent LSARR by both open and laparoscopic approaches were included in this study. Sixty nine (93.2%) women reported improvement in pain and the same percentage would recommend the similar procedure to a friend with the same problem. Approximately 42% of women who wished to conceive had at least one baby. The higher frequency of defecation was a problem in the early post-operative period but this settled in later stages without influencing the quality of life score. Post-operative complications were recorded in 14.9% of cases. CONCLUSIONS: LSARR for rectal endometriosis is associated with a high degree of symptomatic relief. Pain relief achieved following LSARR does not appear to degrade with time. As anticipated, some rectal symptoms persist in few patients after long-term follow-up but LSARR is nonetheless still associated with a very high degree of patient satisfaction. PMID- 25146343 TI - Small bowel malignant melanoma presenting as a perforated jejunal diverticulum: a case report and literature review. AB - Although usually harmless and asymptomatic, jejuno-ileal diverticulae are associated with various non-specific gastrointestinal symptoms, and rarely cause surgical emergencies. This case report describes the presentation and management of a patient with an acute abdomen, whose jejunal diverticulum was perforated. Unexpectedly, histopathological assessment demonstrated malignant melanoma lining the diverticulum. Whether this was primary or metastatic is discussed, together with a synopsis of the literature on small bowel diverticulae. PMID- 25146342 TI - Specimen retrieval approaches in patients undergoing laparoscopic colorectal resections: a literature-based review of published studies. AB - OBJECTIVE: To review the published studies reporting various specimen retrieval incisions being used by colorectal surgeons in patients undergoing laparoscopic colorectal resections (LCR). METHODS: Standard medical electronic databases were searched to find relevant articles and a summary conclusion was generated. RESULTS: There were 43 studies reporting various approaches used for the purpose of specimen retrieval in 2388 patients undergoing LCR. The most common approaches were periumbilical midline incision (1260 reported case in the literature), transverse incision (583 reported cases in the literature) in the right- or left iliac fossa, depending on the side of colonic resection, and Pfannensteil incision (293 reported cases in the literature). Periumbilical midline incision was associated with the higher risk of developing incisional hernia (odds ratio 53.72; 95% confidence interval 7.48-386.04; Z = 3.96; P = 0.0001). In terms of surgical site infection (SSI), there was no difference between the three common approaches to specimen retrieval. Transanal and transvaginal approaches were associated with higher risk of SSI. CONCLUSIONS: Midline, transverse and Pfannensteil incisions were the most commonly used approaches for specimen retrieval following LCR. Midline incision was associated with higher risk of incisional hernia. Risk of SSI was similar in all three common approaches. The transanal and transvaginal approaches pose a higher risk of SSI. These conclusions are based on the combined outcome of published case series, case reports and comparative studies. Randomized, controlled trials with longer follow up are required before recommending the routine use of any approach for specimen retrieval in patients undergoing LCR. PMID- 25146344 TI - Developmental markers of ganglion cells in the enteric nervous system and their application for evaluation of Hirschsprung disease. AB - Hirschsprung disease (HSCR) is a congenital disease resulting from failure of neural crest-derived ganglion cells to colonize the colon. Conventional diagnostic methods are insufficient for evaluating the 'functional' prognosis of HSCR. In order to elucidate the maturation of ganglion cells, 17 immunohistochemical markers were examined. We examined the digestive tracts of 2 human early delivery patients, 2 miniature swine fetuses, 4 little infants, 3 infants, 3 children, 6 adults, and 3 aged individuals. With increasing age, the labeling index (LI) for both calretinin and tyrosine hydroxylase (TH) increased, whereas that for SOX10 decreased. We then examined the 'transitional zone' of HSCR in 21 affected patients and 18 controls for these three markers. The LI of calretinin and TH were significantly lower than in the controls (median: 3.7 in HSCR and 8.2 in controls, P < 0.001, median: 27.9 in HSCR and 44.4 in controls, P < 0.001, respectively). In contrast, the LI for SOX10 showed no significant difference (median: 33.7 in HSCR and 29.2 in controls, P = 0.666) however, hierarchical cluster analysis was able to divide HSCR patients into two groups. These results suggest that immature ganglion cells are present in the transitional zone of HSCR, and that HSCR may have two different pathophysiological processes. PMID- 25146346 TI - Ruthenium-catalyzed reductive methylation of imines using carbon dioxide and molecular hydrogen. AB - The use of the well-defined [Ru(triphos)(tmm)] catalyst, CO2 as C1 source, and H2 as reducing agent enabled the reductive methylation of isolated imines, as well as the direct coupling of amines with aldehydes and the subsequent reductive methylation of the in situ formed imines. The method, which afforded the corresponding N-methyl amines in very good to excellent yields, was also used for the preparation of the antifungal agent butenafine in one step with no apparent waste, thus increasing the atom efficiency of its synthesis. PMID- 25146345 TI - ExCEL in Social Work: Excellence in Cancer Education & Leadership: An Oncology Social Work Response to the 2008 Institute of Medicine Report. AB - ExCEL in Social Work: Excellence in Cancer Education & Leadership was a multi year National Cancer Institute (NCI)-funded grant for the development and implementation of an innovative educational program for oncology social workers. The program's curriculum focused upon six core competencies of psychosocial spiritual support necessary to meet the standard of care recommended by the 2008 Institute of Medicine (IOM) Report: Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs. The curriculum was delivered through a collaborative partnership between the City of Hope National Medical Center and the two leading professional organizations devoted exclusively to representing oncology social workers--the Association of Oncology Social Work and the Association of Pediatric Oncology Social Workers. Initial findings support the feasibility and acceptability of this tailored leadership skills-building program for participating oncology social workers. PMID- 25146347 TI - Inferring human mobility using communication patterns. AB - Understanding the patterns of mobility of individuals is crucial for a number of reasons, from city planning to disaster management. There are two common ways of quantifying the amount of travel between locations: by direct observations that often involve privacy issues, e.g., tracking mobile phone locations, or by estimations from models. Typically, such models build on accurate knowledge of the population size at each location. However, when this information is not readily available, their applicability is rather limited. As mobile phones are ubiquitous, our aim is to investigate if mobility patterns can be inferred from aggregated mobile phone call data alone. Using data released by Orange for Ivory Coast, we show that human mobility is well predicted by a simple model based on the frequency of mobile phone calls between two locations and their geographical distance. We argue that the strength of the model comes from directly incorporating the social dimension of mobility. Furthermore, as only aggregated call data is required, the model helps to avoid potential privacy problems. PMID- 25146348 TI - RNA triplexes: from structural principles to biological and biotech applications. AB - The diverse biological functions of RNA are determined by the complex structures of RNA stabilized by both secondary and tertiary interactions. An RNA triplex is an important tertiary structure motif that is found in many pseudoknots and other structured RNAs. A triplex structure usually forms through tertiary interactions in the major or minor groove of a Watson-Crick base-paired stem. A major-groove RNA triplex structure is stable in isolation by forming consecutive major-groove base triples such as U.A-U and C(+) .G-C. Minor-groove RNA triplexes, e.g., A minor motif triplexes, are found in almost all large structured RNAs. As double stranded RNA stem regions are often involved in biologically important tertiary triplex structure formation and protein binding, the ability to sequence specifically target any desired RNA duplexes by triplex formation would have great potential for biomedical applications. Programmable chemically modified triplex-forming oligonucleotides (TFOs) and triplex-forming peptide nucleic acids (PNAs) have been developed to form TFO.RNA2 and PNA.RNA2 triplexes, respectively, with enhanced binding affinity and sequence specificity at physiological conditions. Here, we (1) provide an overview of naturally occurring RNA triplexes, (2) summarize the experimental methods for studying triplexes, and (3) review the development of TFOs and triplex-forming PNAs for targeting an HIV-1 ribosomal frameshift-inducing RNA, a bacterial ribosomal A-site RNA, and a human microRNA hairpin precursor, and for inhibiting the RNA-protein interactions involving human RNA-dependent protein kinase and HIV-1 viral protein Rev. PMID- 25146349 TI - Danhong enhances recovery from residual dizziness after successful repositioning treatment in patients with benign paroxysmal positional vertigo. AB - OBJECTIVES: Although the repositioning maneuvers are usually very effective in patients with BPPV, some patients still complain residual dizziness. Danhong injection (DHI), a traditional Chinese medicine, can effectively dilate blood vessels and improve microcirculation, and has been proven to be effective in improving cervical vertigo and posterior circulation ischemic vertigo. The aim of this study was to evaluate the effects of DHI on residual dizziness after successful repositioning treatment in patients with BPPV. METHODS: Eighty-six patients with BPPV were randomized into two treatment groups, DHI group and non DHI group. The DHI group received the same repositioning treatment as the non-DHI group, with the addition of DHI therapy. The durations of residual dizziness of DHI group and non-DHI group were compared. In addition, the scores of the dizziness handicap inventory of these two groups were calculated. RESULTS: The durations of residual dizziness of DHI group were shorter than that of non-DHI group. There were no significant differences in the scores of dizziness handicap inventory in the first week between these two groups, and there were much significant differences in the second, the fourth, the sixth and eighth weeks. CONCLUSIONS: The results demonstrate that DHI can significantly improve the residual dizziness after successful repositioning treatment in patients with BPPV. PMID- 25146350 TI - Rare alleles within the CYP2E1 (MEOS system) could be associated with better short-term health outcome after acute methanol poisoning. AB - Genetic polymorphisms influence the metabolism of ethanol and methanol, but the potential effects of genetic predisposition on the clinical course, outcome and short-term health sequelae of acute methanol poisoning are unknown. To evaluate the role of the MEOS system in methanol poisoning, we analysed the effect of three polymorphisms (RsaI - rs2031920; PstI - rs3813867; insertion/deletion I/D) within the CYP2E1 enzyme (MEOS system) in 50 adult survivors of methanol poisoning and compared their genotype frequencies with 460 controls. The minor allele frequencies of all three polymorphisms were below 5% in both groups. We did not detect significant differences in the genotype frequencies between survivors of methanol poisoning and controls (p = 0.34 for the RsaI variant; p = 0.59 for the PstI variant and p = 0.21 for the I/D polymorphism). The carriers of at least one minor allele in the CYP2E1 gene had less severe clinical symptoms and better short-term outcome after acute poisoning. Variants within the CYP2E1 gene are likely not significant genetic determinants of acute methanol poisoning (if survivors are analysed), but they may influence the severity of methanol poisoning and its visual/central nervous system (CNS) outcome. PMID- 25146351 TI - Risk-benefit assessment of the combined oral contraceptive pill in women with a family history of female cancer. AB - INTRODUCTION: Oral contraceptive pills (OCPs) are the most frequently used form of effective, reversible contraception among women of childbearing potential. In the average risk population, OCPs may offer a protective benefit against ovarian, endometrial and colorectal malignancies. In women at high risk for breast, ovarian, endometrial or colorectal malignancies, the risk-benefit profile is less well studied. AREAS COVERED: In this article, we review pertinent literature on the use of OCPs in patients with genetic susceptibilities due to mutations in BRCA1, BRCA2 or mismatch repair genes implicated in hereditary nonpolyposis colorectal cancer as well as those with a strong family history of malignancies associated with these syndromes. EXPERT OPINION: For women at high risk for ovarian, endometrial and/or colorectal malignancies due to genetic susceptibilities or a strong family history, the possibility of chemoprevention with OCPs may be an attractive option; however, the potential increase in breast cancer, although small, must be considered in clinical decision-making. The ultimate decision to use OCPs in a high-risk woman should be based on a consideration of her specific genetic risk, her age, her reproductive plans and her willingness to consider surgical prophylaxis options. PMID- 25146352 TI - Enantiodifferentiation of 3-sec-butyl-2-methoxypyrazine in different species using multidimensional and comprehensive two-dimensional gas chromatographic approaches. AB - With respect to the current hypothesis that natural amino acids may serve as starting material for the biosynthesis of alkyl-methoxypyrazines, the enantiomeric distribution of the potent aroma compound 3-sec-butyl-2 methoxypyrazine (SBMP) was determined in various species using heart-cut multidimensional gas chromatography (H/C MDGC) or comprehensive two-dimensional gas chromatography (GC * GC). Complementary to an earlier described separation on octakis-(6-O-methyl-2,3-di-O-pentyl)-gamma-cyclodextrin used as chiral stationary phase, we found a reversal of the elution order of SBMP enantiomers on heptakis (2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-beta-cyclodextrin, providing further confirmation options for that type of analysis. Optimization of the enantioseparation of SBMP in a single-oven H/C enantio-MDGC system involved the use of a dual-jet cryo modulator for trapping of analytes transferred from the achiral (1)D column to the chiral (2)D column before starting the (2)D enantioseparation with an independent temperature ramp. For the enantiodifferentiation by enantio-GC * GC, the modulation period had to be significantly shortened to avoid loss of chiral resolution gained in (1)D. H/C MDGC with mass spectrometric detection (MS) using selected ion monitoring (SIM) was sufficient for parts per billion level analysis, whereas H/C MDGC-MS/MS or GC * GC time-of-flight (TOF) MS were necessary for parts per trillion level analysis. In various vegetables, lady beetles and Vitis vinifera species analyzed, only (S)-SBMP was detected, supporting the hypothesis of natural amino acids serving as starting material for the biosynthesis of alkyl methoxypyrazines. PMID- 25146353 TI - Online solid phase extraction LC-MS/MS method for the analysis of succinate dehydrogenase inhibitor fungicides and its applicability to surface water samples. AB - A sensitive and selective analytical method, based on online solid phase extraction coupled to LC-MS/MS, was developed and validated to determine traces of several recently introduced fungicides in surface water and wastewater. The list of target analytes included eight succinate dehydrogenase inhibitors (bixafen, boscalid, fluopyram, flutolanil, fluxapyroxad, isopyrazam, penflufen, and penthiopyrad), and two other fungicides with different modes of action, fenpyrazamine and fluopicolide. Detection and quantification limits in various matrices were in the range of 0.1 to 2 and 0.5 to 10 ng/L, respectively. Moderate signal suppression was observed in surface water (<=15%) and wastewater (<=25%) and was well compensated by the selected internal standard. The intra- and inter day precisions were generally <10 and <20%, respectively. The applicability of the method was demonstrated in a study on the occurrence of fungicides in the river Glatt, Switzerland, that drains a catchment area of 419 km(2) with a substantial proportion of agricultural land. Of the studied compounds, only boscalid and fluopicolide were detected in flow-proportional weekly composite samples, generally at low concentrations up to 15 and 5 ng/L, respectively. While fluopicolide was detected in only 30% of the samples above the LOD of 0.5 ng/L, boscalid was detected in all samples analyzed between March and October 2012. PMID- 25146354 TI - Solid-phase extraction and field-amplified sample injection-capillary zone electrophoresis for the analysis of benzophenone UV filters in environmental water samples. AB - A field-amplified sample injection-capillary zone electrophoresis (FASI-CZE) method for the analysis of benzophenone (BP) UV filters in environmental water samples was developed, allowing the separation of all compounds in less than 8 min. A 9- to 25-fold sensitivity enhancement was obtained with FASI-CZE, achieving limits of detection down to 21-59 MUg/L for most of the analyzed BPs, with acceptable run-to-run and day-to-day precisions (relative standard deviations lower than 17%). In order to remove water sample salinity and to enhance FASI sensitivity, an off-line solid-phase extraction (SPE) procedure using a Strata X polymeric reversed-phase sorbent was used and afforded recoveries up to 72-90% for most BPs. With the combination of off-line SPE and FASI-CZE, limits of detection in the range 0.06-0.6 MUg/L in a river water matrix, representing a 2,400- to 6,500-fold enhancement, were obtained. Method performance was evaluated by quantifying a blank river water sample spiked at 1 MUg/L. For a 95% confidence level, no statistical differences were observed between found concentrations and spiked concentrations (probability at the confidence level, p value, of 0.60), showing that the proposed off-line SPE-FASI CZE method is suitable for the analysis of BP UV filters in environmental water samples at low microgram per liter levels. The method was successfully applied to the analysis of BPs in river water samples collected up- and downstream of industrialized and urban areas, and in some drinking water samples. PMID- 25146355 TI - Single-particle speciation of alkylamines in ambient aerosol at five European sites. AB - Alkylamines are associated with both natural and anthropogenic sources and have been detected in ambient aerosol in a variety of environments. However, little is known about the ubiquity or relative abundance of these species in Europe. In this work, ambient single-particle mass spectra collected at five sampling sites across Europe have been analysed for their alkylamine content. The aerosol time of-flight mass spectrometer (ATOFMS) data used were collected in Ireland (Cork), France (Paris, Dunkirk and Corsica) and Switzerland (Zurich) between 2008 and 2013. Each dataset was queried for mass spectral marker ions associated with the following ambient alkylamines: dimethylamine (DMA), trimethylamine (TMA), diethylamine (DEA), triethylamine (TEA), dipropylamine (DPA) and tripropylamine (TPA). The fraction of ambient particles that contained detectable alkylamines ranged from 1 to 17 % depending on location, with the highest fractions observed in Paris and Zurich in the winter months. The lowest fractions were observed at coastal sites, where the influence of animal husbandry-related alkylamine emissions is also expected to be lowest. TMA was the most ubiquitous particle phase alkylamine detected and was observed at all locations. Alkylamines were found to be internally mixed with both sulphate and nitrate for each dataset, suggesting that aminium salt formation may be important at all sites investigated. Interestingly, in Corsica, all alkylamine particles detected were also found to be internally mixed with methanesulphonic acid (MSA), indicating that aminium methanesulphonate salts may represent a component of marine ambient aerosol in the summer months. Internal mixing of alkylamines with sea salt was not observed, however. Alkylamine-containing particle composition was found to be reasonably homogeneous at each location, with the exception of the Corsica and Dunkirk sites, where two and four distinct mixing states were observed, respectively. PMID- 25146357 TI - On copper diffusion in silicon measured by glow discharge mass spectrometry. AB - Copper contamination occurs frequently in silicon for photovoltaic applications due to its very fast diffusion coupled with a low solid solubility, especially at room temperature. The combination of these properties exerts a challenge on the direct analysis of Cu bulk concentration in Si by sputtering techniques like glow discharge mass spectrometry (GDMS). This work aims at addressing the challenges in quantitative analysis of fast diffusing elements in Si matrix by GDMS. N-type, monocrystalline (Czochralski) silicon samples were intentionally contaminated with Cu after solidification and consequently annealed at 900 degrees C to ensure a homogeneous distribution of Cu in the bulk. The samples were quenched after annealing to control the extent of the diffusion to the surface prior to the GDMS analyses, which were carried out at different time intervals from within few minutes after cooling onward. The Cu profiles were measured by high resolution GDMS operating in a continuous direct current mode, where the integration step length was set to ~0.5 MUm over a total sputtered depth of 8-30 MUm. The temperature of the samples during the GDMS analyses was also measured in order to evaluate the diffusion. The Cu contamination of n-type Si samples was observed to be highly material dependent. The practical impact of Cu out diffusion on the calculation of the relative sensitivity factor (RSF) of Cu in Si is discussed. PMID- 25146356 TI - Improvement of derivatized amino acid detection sensitivity in micellar electrokinetic capillary chromatography by means of acid-induced pH-mediated stacking technique. AB - Derivatization is a frequently used sample preparation procedure applicable to the enhancement of analyte detection sensitivity. Amino acids mostly require derivatization prior to electrophoretic or chromatographic analysis, especially if spectrophotometric detection is used. This study presents an on-line preconcentration technique for derivatized amino acids. The sensitivity of the method was improved by the utilization of the proposed acid-induced pH-mediated stacking mechanism. The method is demonstrated by preconcentration of amino acids labeled with 2,4-dinitrofluorobenzene. Use of optimized conditions for a large sample volume injection (40 s, 13.8 kPa) followed by electrokinetic injection of 0.1 M HCl (20 s, 10 kV) gave a 20- to 30-fold enhancement of sensitivity. The significance of the sweeping mechanism and pseudo-isotachophoresis for the on line sample focusing and the influence of parameters on the preconcentration process were discussed. The applicability of the elaborated method was demonstrated using human urine samples. PMID- 25146358 TI - Investigation of volatile metabolites during growth of Escherichia coli and Pseudomonas aeruginosa by needle trap-GC-MS. AB - A new method for the growth-dependent headspace analysis of bacterial cultures by needle trap (NT)-gas chromatography-mass spectrometry (GC-MS) was established. NTs were used for the first time as enrichment technique for volatile organic compounds (VOCs) in the headspace of laboratory cultures. Reference strains of Escherichia coli and Pseudomonas aeruginosa were grown in different liquid culture media for 48 h at 36 degrees C. In the course of growth, bacterial culture headspace was analysed by NT-GC-MS. In parallel, the abiotic release of volatile organic compounds (VOC) from nutrient media was investigated by the same method. By examination of microbial headspace samples in comparison with those of uninoculated media, it could be clearly differentiated between products and compounds which serve as substrates. Specific microbial metabolites were detected and quantified during the stationary growth phase. P. aeruginosa produced dimethyl sulfide (max. 125 MUg L(-1) < limits of quantification (LOQ)), 1 undecene (max. 164 MUg L(-1)) and 2-nonanone (max. 200 MUg L(-1)), whereas E. coli produced carbon disulfide, butanal and indole (max. 149 mg L(-1)). Both organisms produced isoprene. PMID- 25146359 TI - Anion-responsive tunable bulk-phase homochirality and luminescence of a cationic framework. AB - Reaction of a linear bi-chelating N-donor achiral ligand with Zn(II) afforded a homochiral cationic framework with six-fold one-dimensional helical chains. The compound showed selective anion exchange behavior with interesting anion responsive tunable bulk-phase homochirality. The cationic framework also presented anion-driven variable luminescence and sorption behavior. PMID- 25146361 TI - Recrystallization-induced self-assembly for the growth of Cu2O superstructures. AB - The assembly of inorganic nanoparticles (NPs) into 3D superstructures with defined morphologies is of particular interest. A novel strategy that is based on recrystallization-induced self-assembly (RISA) for the construction of 3D Cu2O superstructures and employs Cu2O mesoporous spheres with diameters of approximately 300 nm as the building blocks has now been developed. Balancing the hydrolysis and recrystallization rates of the CuCl precursors through precisely adjusting the experimental parameters was key to success. Furthermore, the geometry of the superstructures can be tuned to obtain either cubes or tetrahedra and was shown to be dependent on the growth behavior of bulk CuCl. The overall strategy extends the applicability of recrystallization-based processes for the guided construction of assemblies and offers unique insights for assembling larger particles into complicated 3D superstructures. PMID- 25146360 TI - Survey of monoclonal antibody disposition in man utilizing a minimal physiologically-based pharmacokinetic model. AB - Minimal physiologically based pharmacokinetic (mPBPK) models provide a simple and sensible approach that incorporates physiological elements into pharmacokinetic (PK) analysis when only plasma data are available. With this modeling concept, a second-generation mPBPK model was further developed with specific accommodations for the unique PK properties of monoclonal antibodies (mAb). This study applied this model to extensively survey mAb PK in man in order to seek general perspectives on mAb distributional and elimination features. Profiles for 72 antibodies were successfully analyzed with this model. The model results provide assessment regarding: (1) predominant clearance site, in plasma or interstitial fluid (ISF); (2) mAb ISF concentrations in two groups of lumped tissues with continuous (V(tight)) or fenestrated (V(leaky)) vascular endothelium; (3) Transcapillary escape rate (TER), an indicator of systemic vascular permeability. For 93% of surveyed mAbs, the model assuming clearance from plasma (CL) produced better or at least equivalent model performance than the model with clearance from ISF and yielded most consistent values of vascular reflection coefficients (sigma1 and sigma2) among all antibodies. The average mAb ISF concentration in V(tight) and V(leaky) at equilibrium was predicted to be about 6.8 and 37.9% of that in plasma. A positive correlation was detected between plasma clearance and TER among most mAbs, which could be interpreted as both parameters having common determinants related to ISF tissue distribution in this model context. The mAbs with relative higher plasma clearance (>0.035 L/h/70 kg) did not reveal such positive correlation between clearance and TER, implying that the factors contributing to high clearance may not necessarily increase tissue distribution and penetration. In conclusion, this mPBPK model offers a more mechanistic approach for analyzing plasma mAb PK than compartment models and generates parameters providing useful intrinsic distributional and elimination insights for a large number of mAbs that were examined in man. PMID- 25146362 TI - Assessments of feline plasma biochemistry reference intervals for three in-house analysers and a commercial laboratory analyser. AB - For each species, the manufacturers of in-house analysers (and commercial laboratories) provide standard reference intervals (RIs) that do not account for any differences such as geographical population differences and do not overtly state the potential for variation between results obtained from serum or plasma. Additionally, biases have been demonstrated for in-house analysers which result in different RIs for each different type of analyser. The objective of this study was to calculate RIs (with 90% confidence intervals [CIs]) for 13 biochemistry analytes when tested on three commonly used in-house veterinary analysers, as well as a commercial laboratory analyser. The calculated RIs were then compared with those provided by the in-house analyser manufacturers and the commercial laboratory. Plasma samples were collected from 53 clinically normal cats. After centrifugation, plasma was divided into four aliquots; one aliquot was sent to the commercial laboratory and the remaining three were tested using the in-house biochemistry analysers. The distribution of results was used to choose the appropriate statistical technique for each analyte from each analyser to calculate RIs. Provided reference limits were deemed appropriate if they fell within the 90% CIs of the calculated reference limits. Transference validation was performed on provided and calculated RIs. Twenty-nine of a possible 102 provided reference limits (28%) were within the calculated 90% CIs. To ensure proper interpretation of laboratory results, practitioners should determine RIs for their practice populations and/or use reference change values when assessing their patients' clinical chemistry results. PMID- 25146363 TI - Associations between 'valentine' heart shape, atrial enlargement and cardiomyopathy in cats. AB - 'Valentine' heart shape is a common qualifier used in veterinary radiology to describe a cardiac silhouette with focal enlargement at the level of the base of the heart in feline patients. Anecdotally, this sign has been thought to be related to biatrial enlargement and also to hypertrophic cardiomyopathy (HCM). However, to our knowledge, there has been no study performed to assess the association between cardiac chamber enlargement and cardiac disease with the 'valentine'-shaped heart. The aim of this study was to verify the association between the 'valentine' heart shape observed in ventrodorsal thoracic radiographs and the presence of singular or combined cardiac chamber enlargement, and also the presence and type of cardiomyopathy (CM) in cats. A search of the database of the Small Animal Veterinary Hospital of the University of Florida for cats with a radiology report of thoracic radiographs that contained the words 'valentine' and 'biatrial', and echocardiography performed within 1 week, was undertaken; 41 cases met the inclusion criteria. Eighty-two percent of the cats of the study sample had some form of CM. The 'valentine' heart shape was associated with biatrial enlargement in 41% of the patients in our study sample that had some form of CM and just 8% of cases diagnosed with HCM, suggesting that the 'valentine' heart shape has a low association with HCM or biatrial enlargement; however, it should be considered a sign of feline CM. PMID- 25146364 TI - The impact of heart failure and left ventricular dysfunction in predicting stroke, thromboembolism, and mortality in atrial fibrillation patients: a systematic review. AB - PURPOSE: Atrial fibrillation (AF) is commonly associated with structural heart disease. Although heart failure (HF) has been proposed as a risk factor for stroke, the coexistence of the 2 diseases increases disproportionally the risk of thromboembolic events. Our objective was to conduct a systematic review to assess the effect of HF on the end points of stroke, systemic embolism (SE), or mortality in patients with AF. METHODS: A literature search was performed to identify studies that examined stroke/ SE in relation to AF and HF. Overall, 405 articles satisfied the preinclusion criteria. FINDINGS: In studies in which HF was based on a clinical diagnosis, HF independently increased stroke/SE in 5 of 13 studies, conferring 1.6- to 3.1-fold increase in risk. When HF was defined as impaired left ventricular (LV) function on echocardiography, the additive risk was evident in 4 of 6 studies, with 1.7- to 2.6-fold increase in the risk of stroke/SE. The data about HF with preserved ejection fraction were less robust, although a recent presentation with acute decompensated HF increased the risk of stroke/SE, irrespective of ejection fraction. IMPLICATIONS: LV systolic impairment as identified by echocardiography is an independent risk factor for stroke/SE, although the magnitude by which it increases the risk of stroke cannot be precisely quantified. Whether a clinical diagnosis of HF is a significant risk factor remains inconclusive, although when the diagnosis is certain (recent decompensation requiring hospitalization), it does seem to be a significant risk factor irrespective of LV systolic function. PMID- 25146366 TI - Cost-effectiveness comparison between monofocal and multifocal intraocular lens implantation for cataract patients in Taiwan. AB - PURPOSE: Our aim was to conduct a cost-effectiveness analysis (CEA) of monofocal and multifocal intraocular lenses (IOLs) for cataract patients in Taiwan. METHODS: This prospective nonrandomized study was designed to evaluate the effectiveness of monofocal and multifocal IOLs by means of visual performance, visual quality, vision-related quality of life, and spectacle-independence rates. The direct costs were calculated using the payment points of the fee schedule for medical services multiplied by the treatment items. The concept of incremental cost effectiveness ratios was used to evaluate the costs of different types of IOLs in cataract surgery and postoperative outcomes in patients. FINDINGS: A total of 61 patients from the monofocal IOL group (n = 21), multifocal IOL group 1 (n = 22), and multifocal IOL group 2 (n = 18) who completed the study were included in the analysis. No significant differences were observed in mean ages or patient to eye ratio. Significant differences in effectiveness after the implantations of monofocal and multifocal IOLs were observed for spectacle-free rate and monocular contrast sensitivity under glare conditions only. The incremental cost-effectiveness ratios of monofocal versus multifocal IOLs indicated that it cost an additional $57 to $58 (US dollars) to increase each 1% of the spectacle-independence rate. IMPLICATIONS: This study's results indicated that multifocal IOLs provided better effectiveness on vision-related indicators like the incremental cost effectiveness ratios of postoperative spectacle independence rate and binocular best-corrected visual acuity measurements at near vision. Our findings suggest that multifocal IOLs can be highly cost effective for patients who prefer to be spectacle free, so it is important to ensure that patients have realistic expectations when making choices between monofocal and multifocal IOLs. PMID- 25146365 TI - Efficacy and tolerability of amlodipine camsylate/losartan 5/100-mg versus losartan/hydrochlorothiazide 100/12.5-mg fixed-dose combination in hypertensive patients nonresponsive to losartan 100-mg monotherapy. AB - PURPOSE: The aim of this study was to determine whether the efficacy and tolerability of amlodipine camsylate/losartan 5/100 mg/d (AML/LOS) are noninferior to those of losartan/hydrochlorothiazide 100/12.5 mg/d (LOS/HCTZ) fixed-dose combination in hypertensive patients unresponsive to losartan 100-mg/d monotherapy. METHODS: Male and female patients aged >= 18 years with hypertension despite 4-week, stable treatment with losartan 100-mg/d monotherapy were eligible for inclusion in this multicenter, randomized, double-blind study. Patients were randomly assigned to receive AML/LOS or LOS/HCTZ once daily for 8 weeks. The primary end point was the change from baseline to week 8 in sitting diastolic blood pressure (DeltasiDBP), and the secondary end points were the changes from baseline to 4 weeks in siDBP and sitting systolic BP (DeltasiSBP) and changes from baseline to 4 and 8 weeks in BP response rate. Tolerability was evaluated by physical examination, including vital sign measurement; laboratory analysis; and ECG. FINDINGS: Of 275 patients screened at 9 cardiovascular centers, 199 were enrolled (AML/LOS, n = 101; LOS/HCTZ, n = 98), and 183 completed the study. The demographic characteristics were similar between the 2 groups (mean age, 51.56 [9.97] years; men, 70.53%). At 8 weeks, the mean DeltasiDBP values were -11.54 (7.89) and -9.05 (6.57) mm Hg in the AML/LOS and LOS/HCTZ groups, respectively (both, P < 0.0001 vs baseline). The mean difference between the 2 groups was 2.57 mm Hg, a nonsignificant difference, meaning that AML/LOS was noninferior to LOS/HCTZ with regard to the primary end point. At 8 weeks, the mean uric acid level was changed significantly from baseline in the LOS/HCTZ group (+0.41 [0.80] mg/dL; P < 0.0001) but not in the AML/LOS group (-0.12 [0.82] mg/dL), representing a significant intergroup difference (P < 0.0001). Nineteen patients each in the AML/LOS (18.81%) and LOS/HCTZ (20.00%) groups experienced >= 1 adverse event, with 4 (3.96%) and 3 (3.16%) patients, respectively, experiencing 1 or more events considered by the investigators to have been treatment related. IMPLICATIONS: The efficacy and tolerability of AML/LOS 5/100 mg/d was found to have been noninferior to those of LOS/HCTZ 100/12.5 mg/d in these hypertensive patients nonresponsive to losartan 100-mg/d monotherapy. PMID- 25146367 TI - A prospective study of screening for hypertensive disorders of pregnancy at 11-13 weeks in a Scandinavian population. AB - OBJECTIVE: To investigate the prediction of preeclampsia and gestational hypertension using maternal characteristics, mean arterial pressure (MAP), uterine artery pulsatility index (UtAPI), pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) at gestational weeks 11-13 in a Scandinavian population with a medium to high prior risk for developing hypertensive disorders of pregnancy. DESIGN: Prospective screening study. SETTING: National Center for Fetal Medicine, Trondheim, Norway. POPULATION: 579 women who were nulliparous or had a previous history of preeclampsia or gestational hypertension. METHODS: Women were examined between 11(+0) and 13(+6) weeks, with interviews for maternal characteristics and measurements of MAP, UtAPI, PAPP-A and PlGF. The tests were evaluated separately and in combined models with receiver operating characteristics (ROC) curves. MAIN OUTCOME MEASURES: Prediction of preeclampsia, severe preeclampsia and gestational hypertension. RESULTS: The best model for severe preeclampsia (MAP+UtAPI+PlGF+PAPP-A) achieved an area under the ROC curve of 0.866 [95% confidence interval (95% CI) 0.756-0.976]. The best models for preeclampsia (MAP+UtAPI+age) achieved 0.738 (0.634-0.841), gestational hypertension (MAP) 0.820 (0.727-0.913) and hypertensive disorders in pregnancy overall (MAP+PlGF+age) 0.783 (0.709-0.856). Using the best model we could identify 61.5% (95% CI 31.6-86.1) of severe preeclampsia, 38.5% (95% CI 20.2-59.4) of preeclampsia and 42.9% (95% CI 21.8-66) of gestational hypertension at a fixed 10% false-positive rate. CONCLUSIONS: Maternal characteristics, MAP, UtAPI, PAPP A and PlGF showed limited value as screening tests. Further research on biochemical and biophysical tests and algorithms combining these parameters is needed before first trimester screening for hypertensive disorders of pregnancy is included in antenatal care in Scandinavia. PMID- 25146368 TI - Predictors of response to infliximab in paediatric perianal Crohn's disease. AB - BACKGROUND: It is reported that 27-54% of paediatric patients with perianal Crohn's disease (CD) do not respond to infliximab (IFX). AIM: To identify predictors of response to IFX in paediatric perianal CD. METHODS: A retrospective cohort study of 101 paediatric patients treated with IFX between 2000 and 2011 for perianal CD in 22 French hospitals of the GETAID pediatrique network was performed. Response was monitored after induction therapy and at 1 year. Complete response was defined by closure of all fistulas and complete healing of ulcers. Associations between baseline characteristics and (i) 1-year response and (ii) time of first relapse among initial responders were tested by logistic regression and Cox model respectively. RESULTS: Eighty-nine patients (88%) responded to induction therapy (36 partial/53 complete). At 1 year, 76 patients (75%) were responders (22 partial/54 complete). Predictors of 1-year response were: number of fistulas <=1 (OR: 3.76, 95% CI: 1.20-11.77, P = 0.03) and baseline Harvey Bradshaw index <5 (OR: 3.72, 95% CI: 1.10-12.60, P = 0.03). Predictors of relapse among initial responders were: CD duration <10 months (OR: 3.31, 95% CI: 1.34 8.19, P = 0.0097) and number of fistulas >1 (OR: 2.79, 95% CI: 1.12-6.95, P = 0.028). Combined therapy with an immunomodulator was not associated with 1-year response or time of relapse. CONCLUSION: Those patients with perianal Crohn's disease have better outcomes if they have less fistulas, a low baseline Harvey Bradshaw Index or a longer duration of Crohn's disease. PMID- 25146369 TI - Novel Striatal GABAergic Interneuron Populations Labeled in the 5HT3a(EGFP) Mouse. AB - Histological and morphological studies indicate that approximately 5% of striatal neurons are cholinergic or gamma-aminobutyric acidergic (GABAergic) interneurons (gINs). However, the number of striatal neurons expressing known interneuron markers is too small to account for the entire interneuron population. We therefore studied the serotonin (5HT) receptor 3a-enhanced green fluorescent protein (5HT3a(EGFP)) mouse, in which we found that a large number of striatal gINs are labeled. Roughly 20% of 5HT3a(EGFP)-positive cells co-express parvalbumin and exhibit fast-spiking (FS) electrophysiological properties. However, the majority of labeled neurons do not overlap with known molecular interneuron markers. Intrinsic electrical properties reveal at least 2 distinct novel subtypes: a late-spiking (LS) neuropeptide-Y (NPY)-negative neurogliaform (NGF) interneuron, and a large heterogeneous population with several features resembling low-threshold-spiking (LTS) interneurons that do not express somatostatin, NPY, or neuronal nitric oxide synthase. Although the 5HT3a(EGFP) NGF and LTS-like interneurons have electrophysiological properties similar to previously described populations, they are pharmacologically distinct. In direct contrast to previously described NPY(+) LTS and NGF cells, LTS-like 5HT3a(EGFP) cells show robust responses to nicotine administration, while the 5HT3a(EGFP) NGF cell type shows little or no response. By constructing a molecular map of the overlap between these novel populations and existing interneuron populations, we are able to reconcile the morphological and molecular estimates of striatal interneuron numbers. PMID- 25146370 TI - The Role of Sonic Hedgehog in the Specification of Human Cortical Progenitors In Vitro. AB - Impaired sonic hedgehog (Shh) signaling is involved in the pathology of cortical formation found in neuropsychiatric disorders. However, its role in the specification of human cortical progenitors is not known. Here, we report that Shh is expressed in the human developing cortex at mid-gestation by radial glia cells (RGCs) and cortical neurons. We used RGC cultures, established from the dorsal (cortical) telencephalon of human brain at mid-gestation to study the effect of Shh signaling. Cortical RGCs in vitro maintained their regional characteristics, expressed components of Shh signaling, and differentiated into Nkx2.1, Lhx6, and calretinin-positive (CalR(+)) cells, potential cortical interneuron progenitors. Treatment with exogenous Shh increased the pool of Nkx2.1(+) progenitors, decreased Lhx6 expression, and suppressed the generation of CalR(+) cells. The blockade of endogenous Shh signaling increased the number of CalR(+) cells, but did not affect Nkx2.1 expression, implying the existence of parallel Shh-independent pathways for cortical Nkx2.1 regulation. These results support the idea that, during human brain development, Shh plays an important role in the specification of cortical progenitors. Since direct functional studies in humans are limited, the in vitro system that we established here could be of great interest for modeling the development of human cortical progenitors. PMID- 25146371 TI - Globally Divergent but Locally Convergent X- and Y-Chromosome Influences on Cortical Development. AB - Owing to their unique evolutionary history, modern mammalian X- and Y-chromosomes have highly divergent gene contents counterbalanced by regulatory features, which preferentially restrict expression of X- and Y-specific genes. These 2 characteristics make opposing predictions regarding the expected dissimilarity of X- vs. Y-chromosome influences on biological structure and function. Here, we quantify this dissimilarity using in vivo neuroimaging within a rare cohort of humans with diverse sex chromosome aneuploidies (SCAs). We show that X- and Y chromosomes have opposing effects on overall brain size but exert highly convergent influences on local brain anatomy, which manifest across biologically distinct dimensions of the cerebral cortex. Large-scale online meta-analysis of functional neuroimaging data indicates that convergent sex chromosome dosage effects preferentially impact centers for social perception, communication, and decision-making. Thus, despite an almost complete lack of sequence homology, and opposing effects on overall brain size, X- and Y-chromosomes exert congruent effects on the proportional size of cortical systems involved in adaptive social functioning. These convergent X-Y effects (i) track the dosage of those few genes that are still shared by X- and Y-chromosomes, and (ii) may provide a biological substrate for the link between SCA and increased rates of psychopathology. PMID- 25146372 TI - Distinct Physiological Effects of Dopamine D4 Receptors on Prefrontal Cortical Pyramidal Neurons and Fast-Spiking Interneurons. AB - Dopamine D4 receptor (D4R), which is strongly linked to neuropsychiatric disorders, such as attention-deficit hyperactivity disorder and schizophrenia, is highly expressed in pyramidal neurons and GABAergic interneurons in prefrontal cortex (PFC). In this study, we examined the impact of D4R on the excitability of these 2 neuronal populations. We found that D4R activation decreased the frequency of spontaneous action potentials (sAPs) in PFC pyramidal neurons, whereas it induced a transient increase followed by a decrease of sAP frequency in PFC parvalbumin-positive (PV+) interneurons. D4R activation also induced distinct effects in both types of PFC neurons on spontaneous excitatory and inhibitory postsynaptic currents, which drive the generation of sAP. Moreover, dopamine substantially decreased sAP frequency in PFC pyramidal neurons, but markedly increased sAP frequency in PV+ interneurons, and both effects were partially mediated by D4R activation. In the phencyclidine model of schizophrenia, the decreasing effect of D4R on sAP frequency in both types of PFC neurons was attenuated, whereas the increasing effect of D4R on sAP in PV+ interneurons was intact. These results suggest that D4R activation elicits distinct effects on synaptically driven excitability in PFC projection neurons versus fast-spiking interneurons, which are differentially altered in neuropsychiatric disorder-related conditions. PMID- 25146373 TI - Kalirin-9 and Kalirin-12 Play Essential Roles in Dendritic Outgrowth and Branching. AB - Proteins derived from the Kalrn gene, encoding 2 Rho guanine nucleotide exchange factor (GEF) domains, affect dendritic and axonal morphogenesis. The roles of endogenous Kalirin-9 (Kal9) and Kalirin-12 (Kal12), the Kalrn isoforms expressed before synaptogenesis, have not been studied in neurite growth and maturation during early development. The Caenorhabditis elegans and Drosophila melanogaster orthologues of Kalrn encode proteins equivalent to Kal9 but, lacking a kinase domain, neither organism expresses a protein equivalent to Kal12. Both in vivo and in vitro analyses of cortical neurons from total Kalrn knockout mice, lacking all major Kalirin isoforms, revealed a simplified dendritic arbor and reduced neurite length. Using isoform-specific shRNAs to reduce Kal9 or Kal12 expression in hippocampal cultures resulted in stunted dendritic outgrowth and branching in vitro, without affecting axonal polarity. Exposing hippocampal cultures to inhibitors of the first GEF domain of Kalirin (ITX3, Z62954982) blunted neurite outgrowth and branching, confirming its essential role, without altering the morphology of neurons not expressing Kalrn. In addition, exogenous expression of the active kinase domain unique to Kal12 increased neurite number and length, whereas that of the inactive kinase domain decreased neurite growth. Our results demonstrate that both endogenous Kal9 and endogenous Kal12 contribute to dendritic maturation in early development. PMID- 25146377 TI - Depth-dependent shear behavior of bovine articular cartilage: relationship to structure. AB - The mechanical behavior of bovine articular cartilage in shear was measured and related to its structure through the depth of the tissue. To make these measurements, we designed an apparatus that could apply controlled shear displacement and measure the resulting shear force on cartilage specimens. Shear displacement and shear strain were obtained from confocal images of photobleached lines on fluorescently stained deformed samples. Depth-dependent collagen structure was obtained using compensated polarized light microscopy. Depth dependent shear behavior and structure of samples from two animals were measured (group A and B). Both animals were 18-24 months old, which is the range in which they are expected reach skeletal maturity. In mature samples (group A), the stiffest region was located beneath the superficial zone, and the most compliant region was found in the radial zone. In contrast, in samples that were in the process of maturing (group B) the most compliant region was located in the superficial zone. Compensated polarized light microscopy suggested that the animal from which the group A samples were obtained was skeletally mature, whereas the animal yielding the group B samples was in the process of maturing. Compensated polarized light microscopy was an important adjunct to the mechanical shear behavior in that it provided a means to reconcile differences in observed shear behavior in mature and immature cartilage. Although samples were harvested from two animals, there were clear differences in structure and shear mechanical behavior. Differences in the depth-dependent shear strain were consistent with previous studies on mature and immature samples and, based on the structural variation between mature and immature articular cartilage, their mechanical behavior differences can be tenable. These results suggest that age, as well as species and anatomic location, need to be considered when reporting mechanical behavior results. PMID- 25146376 TI - Expression of the mannose receptor CD206 in HIV and SIV encephalitis: a phenotypic switch of brain perivascular macrophages with virus infection. AB - We examined the expression of the mannose receptor CD206 by perivascular macrophages (PVM) in normal human and monkey brains and in brains of HIV-infected humans and of monkeys infected with simian immunodeficiency virus (SIV). Depletion of brain PVM in SIV-infected monkeys by intrathecal injection of liposome-encapsulated bisphosphonates eliminated CD206-expressing cells in the brain, confirming their perivascular location and phagocytic capacity. In vivo labeling with bromodeoxyuridine in normal uninfected and SIV-infected macaques in combination with CD206 immunostaining revealed a CD206+-to-CD206- shift within pre-existing PVM during SIV brain infection and neuroinflammation. These findings identify CD206 as a unique marker of human and macaque PVM, and underscore the utility of this marker in studying the origin, turnover and functions of these cells in AIDS. PMID- 25146374 TI - Cross-Modal Decoding of Neural Patterns Associated with Working Memory: Evidence for Attention-Based Accounts of Working Memory. AB - Recent studies suggest common neural substrates involved in verbal and visual working memory (WM), interpreted as reflecting shared attention-based, short-term retention mechanisms. We used a machine-learning approach to determine more directly the extent to which common neural patterns characterize retention in verbal WM and visual WM. Verbal WM was assessed via a standard delayed probe recognition task for letter sequences of variable length. Visual WM was assessed via a visual array WM task involving the maintenance of variable amounts of visual information in the focus of attention. We trained a classifier to distinguish neural activation patterns associated with high- and low-visual WM load and tested the ability of this classifier to predict verbal WM load (high low) from their associated neural activation patterns, and vice versa. We observed significant between-task prediction of load effects during WM maintenance, in posterior parietal and superior frontal regions of the dorsal attention network; in contrast, between-task prediction in sensory processing cortices was restricted to the encoding stage. Furthermore, between-task prediction of load effects was strongest in those participants presenting the highest capacity for the visual WM task. This study provides novel evidence for common, attention-based neural patterns supporting verbal and visual WM. PMID- 25146375 TI - Host lifestyle affects human microbiota on daily timescales. AB - BACKGROUND: Disturbance to human microbiota may underlie several pathologies. Yet, we lack a comprehensive understanding of how lifestyle affects the dynamics of human-associated microbial communities. RESULTS: Here, we link over 10,000 longitudinal measurements of human wellness and action to the daily gut and salivary microbiota dynamics of two individuals over the course of one year. These time series show overall microbial communities to be stable for months. However, rare events in each subjects' life rapidly and broadly impacted microbiota dynamics. Travel from the developed to the developing world in one subject led to a nearly two-fold increase in the Bacteroidetes to Firmicutes ratio, which reversed upon return. Enteric infection in the other subject resulted in the permanent decline of most gut bacterial taxa, which were replaced by genetically similar species. Still, even during periods of overall community stability, the dynamics of select microbial taxa could be associated with specific host behaviors. Most prominently, changes in host fiber intake positively correlated with next-day abundance changes among 15% of gut microbiota members. CONCLUSIONS: Our findings suggest that although human-associated microbial communities are generally stable, they can be quickly and profoundly altered by common human actions and experiences. PMID- 25146378 TI - Thiocyanate-free ruthenium(II) sensitizers for dye-sensitized solar cells based on the cobalt redox couple. AB - Two thiocyanate-free ruthenium(II) sensitizers, TFRS-41 and TFRS-42, with distinctive dialkoxyphenyl thienyl substituents were successfully prepared and tested for potential applications in making dye-sensitized solar cells (DSCs). Subsequent device fabrication was conducted by using a [Co(bpy)3 ](2+/3+) -based (bpy=2,2'-bipyridine) electrolyte, for which the best performance data, namely, JSC =13.11 mA cm(-2) , VOC =862 mV, fill factor=0.771, and eta=8.71%, were recorded for the sensitizer TFRS-42 with a 2,6-dialkoxyphenyl substituent under AM 1.5G irradiation. The markedly higher Voc value was confirmed by the longer electron lifetime revealed in transient photovoltage (TPV) measurements versus the TFRS-1 sensitizer. In addition, DFT calculation and detailed first-principles computational analysis were conducted to provide a rationale for the observed trends in their photovoltaic performances and electron lifetimes, with reference to different performances exhibited by three thiocyanate-free sensitizers, TFRS 1, TFRS-41 and TFRS-42, versus Z907 reference. Through the proper control of peripheral substituents, the thiocyanate-free ruthenium(II)-based DSC sensitizers can positively influence the performances of DSCs, with better light-harvesting capability and suppressed charge recombination, for DSC cells fabricated by using a [Co(bpy)3 ](2+/3+) -based electrolyte. PMID- 25146379 TI - Time to define a new strategy for management of hepatocellular carcinoma in thalassaemia? PMID- 25146380 TI - Wheat allergy in children - new tools for diagnostics. AB - BACKGROUND: The detection of wheat-specific IgE in children often leads to a suspicion of wheat allergy, but little information is available on the most reliable wheat allergens for predicting clinical reactivity. OBJECTIVE: To evaluate the role of allergenic components of wheat in wheat allergy diagnostics. METHODS: One hundred and eight children (median age 1.5 years; range 0.6-17.3 years) with suspected wheat allergy underwent open or double-blinded, placebo controlled oral wheat challenges. Responsiveness to different allergenic components of wheat was studied by skin prick tests and by determination of serum IgE antibodies using a semi-quantitative microarray assay. RESULTS: Thirty (28%) children reacted with immediate symptoms, and 27 (25%) with delayed symptoms to ingested wheat, whereas 51 (47%) children exhibited no reactions in oral wheat challenges. Positive IgE responses to any of the 12 allergenic components of wheat was seen in 93%, 41%, and 43% of those with immediate, delayed or no reactions to ingested wheat, respectively (P < 0.001 to P < 0.05 in every comparisons between those with immediate reactions and those with no reactions). Positive IgE responses to >=5 different allergenic components improved significantly the diagnostic accuracy (with a positive likelihood ratio (LR+) of 5.10). Alpha-amylase inhibitors (AAI), in particular dimeric AAI 0.19 (LR+ 6.12), alpha-, beta-, and gamma-gliadins (LR+ from 3.57 to 4.53), and high-molecular weight (HMW) glutenin subunits (LR+ 4.37) were the single allergenic components of wheat differentiating most effectively those with immediate symptoms from those who did not exhibit any reactions. CONCLUSIONS AND CLINICAL RELEVANCE: Wheat allergy diagnostics is difficult, even using sophisticated component methods. Our results confirm earlier findings about gliadins and identify the dimeric AAI 0.19, as a relevant allergen in clinically reactive patients when compared to non-reactive subjects. The accuracy of wheat allergy diagnosis may be improved by measuring IgE responses to several components of wheat. PMID- 25146381 TI - Liquid chromatography with mass spectrometry method based two-step precursor ion scanning for the structural elucidation of flavonoids. AB - Plant flavonoids are very important secondary metabolites for insect and virus control of their host plant and are potent nutrients for humans. To be able to understand the bioavailability and functions of plant flavonoids, it is necessary to reveal their exact chemical structures. Liquid chromatography with tandem mass spectrometry is a powerful approach for structural elucidation of metabolites. In this report, a two-step precursor ion scanning based liquid chromatography with tandem mass spectrometry method was developed for the structural elucidation of plant flavonoids. The established method consists of the two-step precursor ions scanning for possible flavonoids extraction, MS(2) fragment spectra acquisition and comparison with an online database, liquid chromatography retention rules correction, and commercial standards verification. The developed method was used for the structure elucidation of flavonoids in flowers and leaves of tobacco (Nicotiana tabacum), and 17 flavonoids were identified in the tobacco variety Yunyan 97. Nine of the 17 identified flavonoids were considered to be found in tobacco flowers or/and leaves for the first time based on the available references. This method was proved to be very effective and can be used for the identification of flavonoids in other plants. PMID- 25146382 TI - Does the pattern of amphetamine use prior to incarceration predict later psychosis?--a longitudinal study of amphetamine users in the Swedish criminal justice system. AB - OBJECTIVES: The aim of this longitudinal study was to investigate the relationship between self-reported amphetamine use prior to inclusion in the criminal justice system and hospitalization due to psychosis in the years following release. METHOD: All the information was extracted from existing databases. Amphetamine-using clients in the criminal justice system in Sweden were identified using the European version of the addiction severity index (Europ ASI) interview. Between 2001 and 2006, a total of 1709 individuals were identified. A follow-up of the subjects, using national registry data, was conducted in 2010. The outcome measure was hospitalization for primary or substance-induced psychotic episodes during the follow-up period. Data was analyzed in a multivariate logistic regression model. RESULTS: Age of onset of amphetamine use, number of years used, and use in the month prior to baseline interview were all unrelated to risk of future hospitalization due to psychosis. Prior psychiatric hospitalization and experience of hallucinations not related to drug use, as well as being born outside of a Nordic country and being homeless, were all positively linked to hospitalization due to psychosis. CONCLUSIONS: This study demonstrates that, in a cohort of amphetamine users within the criminal justice system, prior psychiatric morbidity and demographic risk factors are more important than baseline patterns of amphetamine use in predicting future risk of hospitalization due to psychosis. PMID- 25146383 TI - Risk of metabolic complications in kidney transplantation after conversion to mTOR inhibitor: a systematic review and meta-analysis. AB - Mammalian target of rapamycin (mTOR) inhibitors have been used in transplantation with the hope of minimizing calcineurin inhibitor (CNI)-induced nephrotoxicity. However, mTOR inhibitors are also associated with a range of side effects, including metabolic complications. We aimed to determine the risks of metabolic complications after the conversion from CNI to mTOR inhibitor postkidney transplant. A systematic search in PubMed up to September 2013 identified nine relevant trials (a total of 2323 patients). The primary end points were the relative risks (RRs) of new-onset diabetes after transplant (NODAT) and hypercholesterolemia. The overall RRs of NODAT and hypercholesterolemia associated with mTOR inhibitors were 1.32 (95% confidence interval [CI] 0.92 1.87) and 2.15 (95% CI 1.35-3.41), respectively, compared with CNI-based regimen. Subgroup analyses revealed no differences in the incidence of NODAT or hypercholesterolemia between sirolimus- versus everolimus-based regimen, or between early versus late conversion. Analyses of secondary outcomes revealed a higher risk of acute rejection, proteinuria and anemia, but no difference in the risk of opportunistic infections after mTOR inhibitor conversion. In conclusion, the conversion from CNI to mTOR inhibitor in low-to-moderate risk kidney transplant recipients was associated with nonsignificant trend toward increased risk of NODAT and significant increase in hypercholesterolemia, acute rejection, proteinuria and anemia. PMID- 25146385 TI - Combination of platelet count and neutrophil to lymphocyte ratio is a useful predictor of postoperative survival in patients undergoing surgery for gastric cancer. AB - OBJECTIVE: To investigate the clinical utility of the Combination of Platelet count and Neutrophil to Lymphocyte Ratio (COP-NLR) for predicting the postoperative survival of patients undergoing surgery for gastric cancer (GC). METHODS: The COP-NLR was calculated on the basis of data obtained on the day of admission as follows: patients with both an elevated platelet count (>300 * 10(3) /ul) and an elevated NLR (>3) were allocated a score of 2, and patients showing one or neither were allocated a score of 1 or 0, respectively. Five hundred forty four patients for whom data were sufficient to allow analysis of the relationship between clinicolaboratory characteristics and postoperative survival were enrolled. RESULTS: Multivariate analysis using the 12 clinical characteristics selected by univariate analyses revealed that the COP-NLR was associated with OS (hazard ratio, 1.781; 95% C.I., 1.094-2.899; P = 0.020) along with age, tumor type, lymph node metastasis and albumin level. Kaplan-Meier analysis and log rank test demonstrated significant differences in both OS and cancer-specific survival among patients with COP-NLR 0, 1, and 2 (P < 0.001). CONCLUSION: The COP-NLR is able to predict postoperative survival of patients with GC and classify such patients into three independent groups before surgery. PMID- 25146384 TI - Parietal subdural empyema as complication of acute odontogenic sinusitis: a case report. AB - INTRODUCTION: To date intracranial complication caused by tooth extractions are extremely rare. In particular parietal subdural empyema of odontogenic origin has not been described. A literature review is presented here to emphasize the extreme rarity of this clinical entity. CASE PRESENTATION: An 18-year-old Caucasian man with a history of dental extraction developed dysarthria, lethargy, purulent rhinorrhea, and fever. A computed tomography scan demonstrated extensive sinusitis involving maxillary sinus, anterior ethmoid and frontal sinus on the left side and a subdural fluid collection in the temporal-parietal site on the same side. He underwent vancomycin, metronidazole and meropenem therapy, and subsequently left maxillary antrostomy, and frontal and maxillary sinuses toilette by an open approach. The last clinical control done after 3 months showed a regression of all symptoms. CONCLUSIONS: The occurrence of subdural empyema is an uncommon but possible sequela of a complicated tooth extraction. A multidisciplinary approach involving otolaryngologist, neurosurgeons, clinical microbiologist, and neuroradiologist is essential. Antibiotic therapy with surgical approach is the gold standard treatment. PMID- 25146386 TI - Cryo-electron microscopy specimen preparation by means of a focused ion beam. AB - Here we present a protocol used to prepare cryo-TEM samples of Aspergillus niger spores, but which can easily be adapted for any number of microorganisms or solutions. We make use of a custom built cryo-transfer station and a modified cryo-SEM preparation chamber. The spores are taken from a culture, plunge-frozen in a liquid nitrogen slush and observed in the cryo-SEM to select a region of interest. A thin lamella is then extracted using the FIB, attached to a TEM grid and subsequently thinned to electron transparency. The grid is transferred to a cryo-TEM holder and into a TEM for high resolution studies. Thanks to the introduction of a cooled nanomanipulator tip and a cryo-transfer station, this protocol is a straightforward adaptation to cryogenic temperature of the routinely used FIB preparation of TEM samples. As such it has the advantages of requiring a small amount of modifications to existing instruments, setups and procedures; it is easy to implement; it has a broad range of applications, in principle the same as for cryo-TEM sample preparation. One limitation is that it requires skillful handling of the specimens at critical steps to avoid or minimize contaminations. PMID- 25146387 TI - 'Change means sacrificing a good life': perceptions about severity of type 2 diabetes and preventive lifestyles among people afflicted or at high risk of type 2 diabetes in Iganga Uganda. AB - BACKGROUND: Interventions for prevention of type 2 diabetes ought to be acceptable to target communities. We assessed perceptions about type 2 diabetes and lifestyle change among people afflicted or at high risk of this disease in a low income setting in Iganga Uganda. METHODS: Twelve focus group discussions (FGDs) of eight participants each were conducted, balancing rural and peri-urban (near the Municipality) residence and gender. The FGDs involved people with suspected type 2 diabetes (based on fasting plasma glucose (FPG), people with suspected pre-diabetes and obese people with normal FPG. Content analysis was conducted. RESULTS: Diabetes was perceived to be a very severe disease. Its severity was attributed to its incurability and its numerous health effects. Men were also concerned about reduced sexual performance. However, participants' strong concerns about the severity of diabetes were not reflected in their perceptions about the risk factors and lifestyles associated with it. While people with diabetes perceive obesity as 'sickness', those without diabetes perceive it as a sign of 'success'. Although participants are willing to change their diet, they mention numerous barriers including poverty, family size, and access to some foods. Because of their good taste, reduction of high risk foods like sugar and fried food is perceived as 'sacrificing a good life'. Increments in physical activity were said to be feasible, but only in familiar forms like domestic work. An over-arching theme emerged that 'lifestyle changes are viewed as sacrificing a good life'. CONCLUSIONS: Health promotion should target both community norms and individual awareness regarding obesity, physical activity and diet, and should address the notion that obesity and unhealthy foods represent a good life. Health educators should plan with clients on how to overcome barriers and misconceptions to lifestyle change, leveraging the pervasive perception of type 2 diabetes as a severe disease to motivate change. PMID- 25146388 TI - Integrative analysis of gene-environment interactions under a multi-response partially linear varying coefficient model. AB - Consider the integrative analysis of genetic data with multiple correlated response variables. The goal is to identify important gene-environment (G * E) interactions along with main gene and environment effects that are associated with the responses. The homogeneity and heterogeneity models can be adopted to describe the genetic basis of multiple responses. To accommodate possible nonlinear effects of some environment effects, a multi-response partially linear varying coefficient model is assumed. Penalization is adopted for marker selection. The proposed penalization method can select genetic variants with G * E interactions, no G * E interactions, and no main effects simultaneously. It adopts different penalties to accommodate the homogeneity and heterogeneity models. The proposed method can be effectively computed using a coordinate descent algorithm. Simulation study and the analysis of Health Professionals Follow-up Study, which has two correlated continuous traits, SNP measurements and multiple environment effects, show superior performance of the proposed method over its competitors. PMID- 25146389 TI - Twist1 induces endothelial differentiation of tumour cells through the Jagged1 KLF4 axis. AB - The mechanisms controlling tumour-induced angiogenesis are presently not clear. In principle, angiogenesis can be achieved through the activation of endothelial cells in existing vessels or by transdifferentiation of tumour cells into endothelial cells. However, whether tumour cells can go through a prior epithelial-mesenchymal transition and further differentiate into endothelial cells remains unknown. Here we show that overexpression of Twist1, a transcriptional regulator that induces and promotes cancer metastasis, leads to endothelial differentiation in head and neck cancer (HNC) cells. Induction of Jagged1 expression by Twist1 is essential for Twist1-induced endothelial differentiation. The Jagged1/Notch signalling subsequently activates KLF4, inducing stem-like properties in HNC cells and conferring them with drug resistance. Our results indicate that the Twist1-Jagged1/KLF4 axis is essential both for transdifferentiation of tumour cells into endothelial cells and for chemoresistance acquisition. PMID- 25146390 TI - Diagnosis and management of thyrotoxicosis. PMID- 25146391 TI - AIMP1 negatively regulates adipogenesis by inhibiting PPARgamma. AB - Adipogenesis is known to be controlled by the concerted actions of transcription factors and co-regulators. However, little is known about the mechanism of regulation of the transcription factors that control adipogenesis. In addition, the adipogenic roles of translational factors remain unclear. Here, we show that aminoacyl tRNA synthetase-interacting multifunctional protein 1 (AIMP1, also known as p43), an auxiliary factor that is associated with a macromolecular tRNA synthetase complex, negatively regulates adipogenesis through a direct interaction with the DNA-binding domain of peroxisome proliferator-activated receptor gamma (PPARgamma). We found that AIMP1 expression increases during adipocyte differentiation. Adipogenesis is augmented in AIMP1-deficient cells, as compared with control cells. AIMP1 exhibits high affinity for active PPARgamma and interacts with the DNA-binding domain of PPARgamma, thereby inhibiting its transcriptional activity. Thus, AIMP1 appears to function as a novel inhibitor of PPARgamma that regulates adipocyte differentiation by preventing the transcriptional activation of PPARgamma. PMID- 25146392 TI - Fibronectin matrix assembly is essential for cell condensation during chondrogenesis. AB - Mesenchymal cell condensation is the initiating event in endochondral bone formation. Cell condensation is followed by differentiation into chondrocytes, which is accompanied by induction of chondrogenic gene expression. Gene mutations involved in chondrogenesis cause chondrodysplasias and other skeletal defects. Using mesenchymal stem cells (MSCs) in an in vitro chondrogenesis assay, we found that knockdown of the diastrophic dysplasia (DTD) sulfate transporter (DTDST, also known as SLC26A2), which is required for normal cartilage development, blocked cell condensation and caused a significant reduction in fibronectin matrix. Knockdown of fibronectin with small interfering RNAs (siRNAs) also blocked condensation. Fibrillar fibronectin matrix was detected prior to cell condensation, and its levels increased during and after condensation. Inhibition of fibronectin matrix assembly by use of the functional upstream domain (FUD) of adhesin F1 from Streptococcus pyogenes prevented cell condensation by MSCs and also by the chondrogenic cell line ATDC5. Our data show that cell condensation and induction of chondrogenesis depend on fibronectin matrix assembly and DTDST, and indicate that this transporter is required earlier in chondrogenesis than previously appreciated. They also raise the possibility that certain of the skeletal defects in DTD patients might derive from the link between DTDST, fibronectin matrix and condensation. PMID- 25146394 TI - The meiosis-specific nuclear passenger protein is required for proper assembly of forespore membrane in fission yeast. AB - Sporulation, gametogenesis in yeast, consists of meiotic nuclear division and spore morphogenesis. In the fission yeast Schizosaccharomyces pombe, the four haploid nuclei produced after meiosis II are encapsulated by the forespore membrane (FSM), which is newly synthesized from spindle pole bodies (SPBs) in the cytoplasm of the mother cell as spore precursors. Although the coordination between meiosis and FSM assembly is vital for proper sporulation, the underlying mechanism remains unclear. In the present study, we identified a new meiosis specific protein Npg1, and found that it was involved in the efficient formation of spores and spore viability. The accumulation and organization of the FSM was compromised in npg1-null cells, leading to the error-prone envelopment of nuclei. Npg1 was first seen as internuclear dots and translocated to the SPBs before the FSM assembled. Genetic analysis revealed that Npg1 worked in conjunction with the FSM proteins Spo3 and Meu14. These results suggest a possible signaling link from the nucleus to the meiotic SPBs in order to associate the onset of FSM assembly with meiosis II, which ensures the successful partitioning of gametic nuclei. PMID- 25146393 TI - Cardiac ryanodine receptor activation by a high Ca2+ store load is reversed in a reducing cytoplasmic redox environment. AB - Here, we report the impact of redox potential on isolated cardiac ryanodine receptor (RyR2) channel activity and its response to physiological changes in luminal [Ca(2+)]. Basal leak from the sarcoplasmic reticulum is required for normal Ca(2+) handling, but excess diastolic Ca(2+) leak attributed to oxidative stress is thought to lower the threshold of RyR2 for spontaneous sarcoplasmic reticulum Ca(2+) release, thus inducing arrhythmia in pathological situations. Therefore, we examined the RyR2 response to luminal [Ca(2+)] under reducing or oxidising cytoplasmic redox conditions. Unexpectedly, as luminal [Ca(2+)] increased from 0.1 to 1.5 mM, RyR2 activity declined when pretreated with cytoplasmic 1 mM DTT or buffered with GSH?GSSG to a normal reduced cytoplasmic redox potential (-220 mV). Conversely, with 20 uM cytoplasmic 4,4'-DTDP or buffering of the redox potential to an oxidising value (-180 mV), RyR2 activity increased with increasing luminal [Ca(2+)]. The luminal redox potential was constant at -180 mV in each case. These responses to luminal [Ca(2+)] were maintained with cytoplasmic 2 mM Na2ATP or 5 mM MgATP (1 mM free Mg(2+)). Overall, the results suggest that the redox potential in the RyR2 junctional microdomain is normally more oxidised than that of the bulk cytoplasm. PMID- 25146395 TI - Arfs at a glance. AB - The Arf small G proteins regulate protein and lipid trafficking in eukaryotic cells through a regulated cycle of GTP binding and hydrolysis. In their GTP-bound form, Arf proteins recruit a specific set of protein effectors to the membrane surface. These effectors function in vesicle formation and tethering, non vesicular lipid transport and cytoskeletal regulation. Beyond fundamental membrane trafficking roles, Arf proteins also regulate mitosis, plasma membrane signaling, cilary trafficking and lipid droplet function. Tight spatial and temporal regulation of the relatively small number of Arf proteins is achieved by their guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs), which catalyze GTP binding and hydrolysis, respectively. A unifying function of Arf proteins, performed in conjunction with their regulators and effectors, is sensing, modulating and transporting the lipids that make up cellular membranes. In this Cell Science at a Glance article and the accompanying poster, we discuss the unique features of Arf small G proteins, their functions in vesicular and lipid trafficking in cells, and how these functions are modulated by their regulators, the GEFs and GAPs. We also discuss how these Arf functions are subverted by human pathogens and disease states. PMID- 25146397 TI - Correlative super-resolution fluorescence and electron microscopy of the nuclear pore complex with molecular resolution. AB - Here, we combine super-resolution fluorescence localization microscopy with scanning electron microscopy to map the position of proteins of nuclear pore complexes in isolated Xenopus laevis oocyte nuclear envelopes with molecular resolution in both imaging modes. We use the periodic molecular structure of the nuclear pore complex to superimpose direct stochastic optical reconstruction microscopy images with a precision of <20 nm on electron micrographs. The correlative images demonstrate quantitative molecular labeling and localization of nuclear pore complex proteins by standard immunocytochemistry with primary and secondary antibodies and reveal that the nuclear pore complex is composed of eight gp210 (also known as NUP210) protein homodimers. In addition, we find subpopulations of nuclear pore complexes with ninefold symmetry, which are found occasionally among the more typical eightfold symmetrical structures. PMID- 25146398 TI - [Reinforce the research on the role of inflammation during tumor development]. PMID- 25146396 TI - The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis. AB - The ATPase valosin-containing protein (VCP)/p97 has emerged as a central and important element of the ubiquitin system. Together with a network of cofactors, it regulates an ever-expanding range of processes that stretch into almost every aspect of cellular physiology. Its main role in proteostasis and key functions in signaling pathways are of relevance to degenerative diseases and genomic stability. In this Cell Science at a Glance and the accompanying poster, we give a brief overview of this complex system. In addition, we discuss the pathogenic basis for VCP/p97-associated diseases and then highlight in more detail new exciting links to the translational stress response and RNA biology that further underscore the significance of the VCP/p97 system. PMID- 25146400 TI - [The role of end-tidal carbon dioxide partial pressure in fluid responsiveness assessment in septic shock patient]. AB - OBJECTIVE: To assess whether end-tidal carbon dioxide partial pressure (PETCO2) can predict the fluid responsiveness in septic shock patients. METHODS: Septic shock patients under mechanical ventilation without spontaneous breathing and with the need of a fluid challenge test were included in this study.Heart rate, central venous pressure, pulse pressure, PETCO2, and CI before and after the fluid challenge test were conducted in all the patients. RESULTS: Of the 48 septic shock patients included, 34 had preload responsiveness, 14 had no responsiveness. DeltaCI and DeltaPETCO2 after the fluid challenge test in "volume responders" were (0.85 +/- 0.47) L*min(-1)*m(-2) and (3.5 +/- 2.5) mmHg respectively, which were higher than those in "no volume responders"(P < 0.05). The fluid-induced changes in PETCO2 and CI were correlated (r = 0.072, P < 0.05). The AUCROC of fluid challenge-induced DeltaPETCO2 as the predictor for volume responsiveness was 0.943, and its sensitivity was 87.9% and specificity was 93.4% with a critical value of 5%. The AUCROC of DeltaPP as the predictor for volume responsiveness was 0.801, and its sensitivity was 68.1% and specificity was 73.2% with a critical value of 10%. CONCLUSION: The changes of PETCO2 induced by a fluid challenge test can predict fluid responsiveness with reliability, and have a better sensitivity and specificity than the changes of PP. PMID- 25146399 TI - [A cross-sectional survey of familial aggregation of chronic obstructive pulmonary disease: in seven provinces/cities in China]. AB - OBJECTIVE: To investigate the familial aggregation in chronic obstructive pulmonary disease (COPD). METHODS: Based on a cross-sectional survey in seven provinces/cities in China (Beijing, Shanghai, Guangdong, Liaoning, Tianjin, Chongqing and Shaanxi) from 2002 to 2004, the familial aggregation of COPD was investigated with multi-stage cluster random sampling method.One urban and one rural area were selected as samples from each of seven provinces/cities. All residents equal or older than 40 years old received questionnaires and pulmonary function tests. Questionnaires included risk factors of COPD, respiratory symptoms, quality of life, diagnosis and prevention conditions of COPD. Bronchodilator tests, physical examination, X-ray and electrocardiograph (ECG) were conducted in those subjects.In pulmonary function tests, the ratio of the first second forced expiratory volume (FEV1) /forced vital capacity (FVC) less than 70% fulfill the diagnostic criteria of COPD.If any of siblings and parents had chronic bronchitis, emphysema, asthma or COPD, it should be considered as a positive family history of COPD-related disease.Otherwise, it was negative. RESULTS: FEV1 was lower in the subjects with a family history of COPD-related diseases than in those without [(2.24 +/- 0.70) L vs (2.28 +/- 0.73) L]. The prevalence of COPD in the population with history of COPD-related diseases was 12.1% (540/4 481), which was significantly higher than that without [7.2% (1 128/15 764), chi(2) = 110.599, P < 0.001]. After adjusted for potential confounder, the population with a family history of COPD-related diseases still had much higher incidence of COPD [OR = 2.18 (95%CI 1.94-2.46)]. Furthermore, the population having two or more first-degree relatives with COPD-related diseases, exhibited the highest likelihood of COPD [OR = 2.48 (95%CI 2.00-3.08)]. The population having only one first-degree relative with COPD-related diseases showed an increased risk of COPD with an OR = 2.10 (95%CI 1.84-2.40) compared with those without any one. Those whose father, mother or siblings had COPD related diseases were similarly likely to have COPD, with an OR of 1.54 (95%CI 1.32-1.80), 1.83 (95%CI 1.56-2.15) and 1.81 (95%CI 1.48-2.23), respectively. CONCLUSIONS: There is a familial aggregation in COPD. The more relatives have COPD-related diseases in the family, the greater risk of COPD the subject will have. PMID- 25146401 TI - [An analysis of clinical characteristics, etiologies and prognosis of 218 patients with infective endocarditis]. AB - OBJECTIVE: To describe the profile of patients with infective endocarditis (IE) and assess prognostic factors of IE. METHODS: Clinical and etiology data of 218 patients with IE were collected retrospectively from January 2011 to January 2013. The distribution and antimicrobial susceptibilities of pathogens causing IE were evaluated. Prognostic factors associated with IE were determined by univariate and multivariate regression analysis. RESULTS: There were 148 men and 70 women with age of (46.0 +/- 14.6) years. Ninety-five (43.6%) of them had heart diseases, including 72 cases (33.0%) of congenital heart disease and 23 cases (10.6%) of chronic rheumatic heart disease. Vegetations were detected by echocardiography in 171 (78.4%) patients. Microorganisms causing IE were identified in 84 cases (38.5%) cases. Streptococcus viridans was the dominant pathogen, accounted for 63.1% of all the pathogens, followed by Staphylococcus (13.1%) and Enterococcus (4.8%). Totally 7/11 Streptococcus viridans was susceptible to penicillin, while 100% susceptible to the third and fourth generation cephalosporins, vancomycin and linezolid. One hundred and eighty cases underwent operations. The in-hospital mortality rate of IE was 3.2%. In univariate regression, health care-associated infection, prosthetic valve, anemia and chest symptoms (distress or pain) were related to the increased risk of mortality in patients with IE, while surgery appeared to be a protective factor. In the logistic regression model, the variables significantly associated with IE prognosis were health care-associated infection (OR = 17.03, 95%CI 1.76-164.75, P = 0.014) and anemia (Hb < 90 g/L) (OR = 13.47, 95%CI 2.46-73.60, P = 0.003) and surgery treatment (OR = 0.17, 95%CI 0.03-0.97, P = 0.047). CONCLUSIONS: Although Streptococcus viridans is the most common pathogen causing IE, the pathogens of IE become versatile. The antibacterial activity of penicillin against Streptococcus viridans is low. Health care-associated infection and anemia are risk factors of IE prognosis, while surgery treatment is a protective factor of severe IE. PMID- 25146402 TI - [An investigation of brachial-ankle pulse wave velocity among middle-aged residents in Shanghai and Inner Mongolia autonomous region]. AB - OBJECTIVE: To compare the epidemiological characteristics and differences in brachial-ankle pulse wave velocity (baPWV) among middle-aged residents between Shanghai and Inner Mongolia autonomous region(Inner Mongolia), and to observe the prevalence of arterial stiffness in the two populations. METHODS: A total of 922 volunteers aged between 45 and 59 from Shanghai and Inner Mongolia were selected by stratified cluster random sample method. BaPWV was measured and related data were collected. RESULTS: A total of 903 cases were enrolled in this study, including 441 from Shanghai and 462 from Inner Mongolia. The baPWV value of middle-aged residents in Inner Mongolia was higher than that in Shanghai [(1 548 +/- 281) cm/s and (1 476 +/- 254) cm/s, P < 0.001]. The abnormal rate of baPWV (baPWV >= 1 400 cm/s) in Inner Mongolia was also higher than that in Shanghai [67.5% (312) and 57.4% (253) , P < 0.001]. The baPWV value of middle-aged men in Inner Mongolia was (1 568 +/- 299) cm/s, while it was (1 508 +/- 260) cm/s in Shanghai, no statistical difference was found (P > 0.05). The baPWV value of middle-aged women in Inner Mongolia was (1 534 +/- 268) cm/s, which was higher than that of Shanghai [(1 468 +/- 252) cm/s, P < 0.01]. The abnormal rate of baPWV of middle-aged men in Inner Mongolia and Shanghai was 67.0% (126/188) and 60.8% (59/97), respectively (P > 0.05). The abnormal rate of baPWV of middle-aged women in Inner Mongolia and Shanghai was 67.9% (186/274) and 56.4% (194/344), respectively. CONCLUSIONS: The difference of baPWV value and abnormal rate of baPWV of middle-aged residents between Inner Mongolia and Shanghai exists. Middle aged people in Inner Mongolia should be more alert to the incidence of arteriosclerosis and cardio-cerebrovascular diseases. PMID- 25146403 TI - [The clinical analysis of atrial fibrillation of 1 310 in patients in Urumqi of China]. AB - OBJECTIVE: To investigate the clinical features and current therapy of atrial fibrillation (AF) of inpatients in Urumqi, China. METHODS: The clinical data of inpatients diagnosed with AF from January, 2008 to December, 2012, in 12 hospitals in Urumqi were retrospectively analyzed. RESULTS: Totally 1 310 AF inpatients were enrolled in this study with the age of (64.8 +/- 3.3) years old and a men to women ratio of 1.39. Most patients were in age groups of 61-70 years (26.5%) and 71-80 years (27.6%). More patients with paroxysmal AF were at cardiac function class I-II (75.2%), while more patients with persistent AF were at cardiac function class III-IV (31.0%) (both P values < 0.05). The most common co morbidities of AF were hypertension (49.2%), coronary heart disease (38.5%), diabetes mellitus (20.1%). Compared with patients of chronic AF, the patients of paroxysmal AF had higher success rates in amiodarone conversation and sinus rhythm maintenance after ablation (44.8% vs 29.9%, 87.5% vs 68.9%, P values < 0.05). Among the 1 310 inpatients, 992 patients (75.7%) received antithrombotic therapy. There were statistically significant differences in CHA2DS2 score and incidence rate of cerebral infarction among patients receiving aspirin, warfarin or rivaroxaban/other anticoagulation drugs [2(1, 3) vs 3(2, 4) vs 3(2, 5) and 6.3% vs 23.8% vs 30.2%, both P values < 0.05]. CONCLUSION: Our results of AF inpatients' age, gender, related disease distribution, AF types, incidence of stoke, therapeutic and epidemiological features are in accordance with the domestic and abroad reports. PMID- 25146404 TI - [The clinical analysis for 43 cases of acute superior mesenteric artery thrombosis confirmed by angiography and surgery]. AB - OBJECTIVE: To investigate the clinical manifestations and mortality related risk factors in patients with acute superior mesenteric artery embolism (ASMAE). METHODS: Clinical data of forty-three confirmed ASMAE patients in the PLA General Hospital from June 2002 to June 2012 were retrospectively analyzed. All patients were classified into the survival group (28 cases) and the death group (15 cases) according to the prognosis. The prognosis associated factors were further analyzed. RESULTS: The study group consisted of 31 men (72.1%) and 12 women (27.9%), with average age of (63 +/- 11) years. The majority patients with ASMAE in our study had history of atherosclerotic diseases. The main clinical manifestations included abdominal pain [100% (43/43)], nausea and vomitting [55.8% (24/43)], hematochezia [32.6% (14/43)]. Abdominal CT scan was performed in 74.4% (32/43) patients with a high positive result of 96.9% (31/32).Weight loss occurred more frequently in survival group than in death group [32.1% (9/28) vs 6.7% (1/15) , P = 0.001]. Moreover, weight loss has been shown as a protective factor for ASMAE survival (OR = 0.75, P = 0.038) by logistic analysis. Compared with the death group, the incidence of either peritoneal irritation sign or ascites was significantly lower in survival group [respectively 7.1% (2/28) vs 66.7% (10/15), 14.3% (4/28) vs 73.3% (11/15), P < 0.05], which were two independent risk factors of mortality (OR = 8.51, P = 0.014; OR = 3.07, P = 0.028) . The incidence of main artery embolism of superior mesentery artery (SMA) in death group was higher than that in survival group [93.3% (14/15) vs 60.7% (17/28), P = 0.023]. Main artery embolism of SMA was also an independent mortality risk factor of ASMAE patients (OR = 5.05, P = 0.039) . A total of 18 patients were treated with enterectomy.Intestine excision length was shorter in survival group than in death group [(82.8 +/- 25.2)cm vs (141.0 +/- 18.1) cm, P = 0.017]. The time from onset to operation in survival group was shorter than that in death group [(44.8 +/- 29.7) h vs (69.1 +/- 28.0) h, P = 0.013]. CONCLUSIONS: Patients with ASMAE based on chronic ischemia have a relative good prognosis for survival. Peritoneal irritation sign, ascites and main artery embolism of SMA were independent risk factors for death in ASMAE.Intestine excision length and the interval from onset to operation may affect the mortality of ASMAE patients. PMID- 25146405 TI - [The clinical characteristics of 32 patients with autoimmune pancreatitis]. AB - OBJECTIVE: To explore the clinical characteristics and diagnosis of autoimmune pancreatitis (AIP) with the aim to raise awareness of AIP. METHODS: Clinical data of 32 patients with AIP were retrospectively analyzed, including clinical manifestations, imaging features, laboratory examination, histopathology and treatment from November 2009 to April 2013 in the First Affiliated Hospital of Medical School, Zhejiang University. RESULTS: All 32 AIP patients including 25 males and 7 females had a median age of (62.5 +/- 12.6) years (27-84 years). The initial symptoms included obstructive jaundice in 50.0% patients (16/32), abdominal pain in 43.8% (14/32), fatigue and weight loss in 12.5% (4/32), and bloody stool in 6.3% (2/32). Laboratory findings revealed abnormal liver function in 6.3% (2/32) patients, increased immunoglobulins in 71.9% (23/32) patients and elevated IgG4 in 8/10 patients. Computerized tomography (CT) scan and ultrasonography were performed in all patients. Diffusely enlarged pancreas were found in 62.5% (20/32) patients and focally enlarged in 37.5% (12/32), additionally main pancreatic duct stenosis in 62.5% (20/32) patients. Nineteen patients obtained histopathological examination, indicating pancreatic interstitial fibrosis, and infiltration of lymphocytes and plasma cells. CONCLUSIONS: Autoimmune pancreatitis is an autoimmune disease which may be misdiagnosed as pancreatic cancer. The clinical features, laboratory findings, imaging characteristics, and typical histopathologic presentation, as well as good response to glucocorticoids provide supportive evidence for the diagnosis of AIP. PMID- 25146406 TI - [The clinical electrophysiology and pathological characteristics of 15 cases of vasculitic neuropathy]. AB - OBJECTIVE: To summarize the clinical features, electrophysiology and neuropathological characteristics of peripheral nerves in patients with vasculitic neuropathy. METHODS: We retrospectively analyzed the clinical, electrophysiology and neuropathological characteristics of 15 patients with vasculitic neuropathy who underwent electrophysiology and sural nerve biopsy in our department from January 2009 to June 2013. RESULTS: There were 8 males and 7 females, aged from 38 to 82 years old, with a peripheral neuropathy course ranged from 0.5 month to 60 months. In the total of 15 patients, 3 patients were diagnosed as nonsystemic vasculitic neuropathy, while the other 12 patients were diagnosed as systemic vasculitis neuropathy (SVN) including 5 cases of primary systemic vasculitis and 7 cases of secondary systemic vasculitis. In patients diagnosed as primary systemic vasculitis, there were 2 cases of Churg-Strass syndrome (CSS) and 3 cases of ANCA associated vasculitis. In patients diagnosed as secondary systemic vasculitis, there were 1 case of systemic lupus erythematosus (SLE), 2 cases of sicca syndrome (SS), 3 cases of rheumatoid arthritis (RA), 1 case of Behcet' s disease associated with thyroid papillary carcinoma, 1 case of hepatitis B and 1 case of RA-associated SS. For the pathological features of vasculitic neuropathy, type 1 lesion was found in 4 patients, type 2 lesion in 2 patients, and type 3 lesion in 9 patients. Axon degeneration was observed in 8 patients, while 7 patients manifested as axon degeneration associated with demyelination and local thickening of the perineurium was found in 2 patients. CONCLUSION: Multiple mononeuropathy and asymmetric polyneuropathy are the common clinical presentations of vasculitic neuropathy. Electrodiagnostic testing almost always reveals the evidence of a predominantly axonal and sensorimotor process with associated demyelination presented in some cases. Sural nerve biopsy shows changes indicative of an axonopathy. PMID- 25146407 TI - [The clinical characteristics of systemic sclerosis-related pulmonary arterial hypertension]. AB - OBJECTIVE: To study the clinical, cardiopulmonary functional and hemodynamic profiles of systemic sclerosis patients with pulmonary hypertension (SSc-PAH) compared with those of idiopathic pulmonary hypertension (IPAH). METHODS: Patients diagnosed with SSc-PAH or IPAH by right heart catheterization were consecutively enrolled into the study between 2011 and 2013 in Peking Union Medical College Hospital (PUMCH). Cases with pulmonary hypertension related to other diseases were excluded. Demographic data, laboratory parameters, 6 minutes walk distance (6MWD), pulmonary function and hemodynamic variables at the time of diagnosis were collected and compared between the two groups. RESULTS: A total of 20 SSc-PAH patients including 19 females and one male with age of (43.1 +/- 12.2) years, and 18 IPAH patients including 16 females and 2 males with age of (38.4 +/ 12.4) years were enrolled in this study. Subjects in both groups had similar mean pulmonary arterial pressure, cardiac index and pulmonary vascular resistance (PVR) when recruited. Compared with IPAH patients, SSc-PAH patients showed significantly decreased all parameters including forced vital capacity (FVC)% [(77.1 +/- 13.2)% vs (88.6 +/- 14.9)%, P = 0.026], diffusing capacity of the lung for carbon monoxide (DLCO)% [(46.2 +/- 13.1) % vs (66.6 +/- 13.3)%, P < 0.001], DLCO/alveolar ventilation (VA) [(55.1 +/- 14.3)% vs (75.1 +/- 11.5)%, P < 0.001], and 6MWD [(365.6 +/- 85.1) m vs (454.3 +/- 136.8) m, P = 0.034]. In subgroup analysis of SSc-PAH patients, elevated PVR (OR 2.122, 95%CI 1.093-4.119, P = 0.026) and decreased DLCO% (OR 0.916, 95%CI 0.842-0.996, P = 0.040) were independently associated with reduced 6MWD. CONCLUSIONS: Under the similar hemodynamic condition, SSc-PAH patients had more severe restrictive ventilation dysfunction and diffusion capacity dysfunction. Decreased 6MWD in SSc-PAH patients was probably related to the impairment of pulmonary function. PMID- 25146408 TI - [The clinical characteristics of polyserositis as main presentation of chronic graft-versus-host rejection disease after allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: To analyze the clinical characteristics of polyserositis associated with chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic transplantation(allo-HSCT). METHODS: The occurrence rate and severity of cGVHD in 323 patients who received allo-HSCT in Peking University First Hospital from June 2003 to July 2013 were observed. Their clinical characteristics and therapeutic effect on polyserositis were analyzed as well. RESULTS: Of the 294 patients who survived for more than 100 days after allo-HSCT, 90 patients (30.6%) were diagnosed with cGVHD including extensive cGVHD in 25 patients (8.5%). Among the patients with cGVHD, 4 patients (4.4%) developed moderate to large amount of polyserous effusions. All of these 4 patients had extensive cGVHD. The effusion was proved to be transudate or transudate-exudate. Immunosuppressive treatment was effective but unsustainable. CONCLUSIONS: Polyserositis with large amount of effusion might be a rare manifestation of cGVHD and is refractory. When recurrent polyserous effusion presents with cGVHD after allo-HSCT, it should be considered as a manifestation of extensive cGVHD. Appropriate treatment should be given immediately. PMID- 25146409 TI - [A pedigree study of a patient with primary pigmented nodular adrenocortical disease and familial gene mutation]. AB - OBJECTIVE: To clarify the clinical features and genetic background of a kindred of primary pigmented nodular adrenocortical disease (PPNAD). METHODS: Detailed clinical characteristics and laboratory test results from a ten-year old girl diagnosed as PPNAD were collected. Seven members of her family were screened for Cushing syndrome and Carney complex, and their blood DNA was extracted and sequenced for PRKAR1A, PDE11A, PDE8B and CTNNB1 mutations with ABI3730. RESULTS: The girl presented with symptoms and signs of hypercortisolism, while no features of Carney complex were observed. Hypercortisolemia, suppressed corticotrophin and high urinary free cortisol level were revealed. Cortisol level could not be suppressed both in high and low dose dexamethasone suppression test. The diagnosis of adrenocorticotrophic hormone (ACTH)-independent Cushing syndrome was established. Image and pathology of adrenal glands were in accordance with PPNAD. Other family members showed no evidence of Cushing syndrome or Carney complex. DNA sequencing showed that the patient harbored a missense mutation, C18G. Her father and younger sister were proved to be carriers of this mutation. CONCLUSION: A Chinese PPNAD family was identified clinically and genetically, and a novel missense mutation of PRKAR1A was found. PMID- 25146410 TI - Association of renal function with vascular stiffness in older adults: the Rotterdam study. AB - BACKGROUND: arterial stiffening is a marker of vascular ageing and an independent risk factor for cardiovascular disease. A potential mechanism linking cardiovascular disease to chronic kidney disease might be the change in arterial elasticity. We aim to determine the association between renal function and arterial stiffness in older subjects. DESIGN: cross-sectional study. SETTING: Rotterdam study, a population-based cohort study. SUBJECTS: we included 3,279 subjects from 1997 to 1999 with a mean age of 71.9 years. METHODS: estimation of glomerular filtration rate (eGFR) was used to assess renal function. Aortic pulse wave velocity (PWV) and carotid distensibility coefficient were used as measures of arterial stiffness. RESULTS: each standard deviation increase in eGFR, adjusting for age and sex, was associated with 0.14 m/s lower PWV [95% confidence interval (CI): -0.23, -0.05]. Further adjustments for socio-demographic and cardiovascular risk factors did not change the association (beta: -0.16 m/s; 95% CI: -0.26, -0.06). There was a linear association between mean values of PWV and quartiles of glomerular filtration rate (P for trend = 0.006). There was no association between decreased renal function and carotid distensibility. There was no statistical difference in the strength of the association between renal function and PWV in subgroups of participants with and without cardiovascular risk factors. CONCLUSIONS: in this large population-based study of elderly subjects, our findings suggest that renal impairment is associated with aortic stiffness. This association is independent of cardiovascular risk factors. PMID- 25146411 TI - Public and patient research priorities for orthostatic hypotension. AB - With a rapidly expanding older population and increased survival of older people with chronic disease, we can expect to see increasing numbers of people with orthostatic hypotension (OH). Unfortunately the evidence base for people with OH, with particular relevance to older people, has not kept up and has resulted in a real lack of progress and little good evidence. There are several areas of research that could potentially benefit patients but establishing which ones are priority areas requires public and patient involvement (PPI). This process includes people/patients in the research team to maximise the relevance, success and translation of the research. This brief report describes the early involvement of older people in prioritising the research question, methods to improve adherence during a trial and the preferred methods to disseminate research output. The individuals' priority was to research non-pharmacological treatment strategies and to improve the education of patients about their condition. Education was felt to be the best strategy to promote adherence during a trial, with change in symptoms and quality of life felt to be the most important outcome measures as opposed to blood pressure. This report offers guidance for academics that are undertaking OH-related research and how they can improve its relevance and increase its translation into clinical practice. PMID- 25146412 TI - Phylogeographic structure, demographic history and morph composition in a colour polymorphic lizard. AB - In polymorphic species, population divergence in morph composition and frequency has the potential to promote speciation. We assessed the relationship between geographic variation in male throat colour polymorphism and phylogeographic structure in the tawny dragon lizard, Ctenophorus decresii. We identified four genetically distinct lineages, corresponding to two polymorphic lineages in the Northern Flinders Ranges and Southern Flinders Ranges/Olary Ranges regions respectively, and a monomorphic lineage in the Mt Lofty Ranges/Kangaroo Island region. The degree of divergence between these three lineages was consistent with isolation to multiple refugia during Pleistocene glacial cycles, whereas a fourth, deeply divergent (at the interspecific level) and monomorphic lineage was restricted to western New South Wales. The same four morphs occurred in both polymorphic lineages, although populations exhibited considerable variation in the frequency of morphs. By contrast, male throat coloration in the monomorphic lineages differed from each other and from the polymorphic lineages. Our results suggest that colour polymorphism has evolved once in the C. decresii species complex, with subsequent loss of polymorphism in the Mt Lofty Ranges/Kangaroo Island lineage. However, an equally parsimonious scenario, that polymorphism arose independently twice within C. decresii, could not be ruled out. We also detected evidence of a narrow contact zone with limited genotypic admixture between the polymorphic Olary Ranges and monomorphic Mt Lofty Ranges regions, yet no individuals of intermediate colour phenotype. Such genetic divergence and evidence for barriers to gene flow between lineages suggest incipient speciation between populations that differ in morph composition. PMID- 25146414 TI - Direct synthesis of phosphorus and nitrogen co-doped monolayer graphene with air stable n-type characteristics. AB - Large-area substitutional phosphorus-nitrogen co-doped monolayer graphene is directly synthesized on a Cu surface by chemical vapor deposition using molecules of phosphonitrilic chloride trimer as the phosphorus and nitrogen sources. The doping levels of both phosphorus and nitrogen atoms decrease as a function of the growth temperature. In contrast, the doping effect is enhanced with temperature because of the formation of more stable bond configurations for dopants at higher temperatures. Moreover, the doping amount of nitrogen atoms is always higher than that of phosphorus atoms at all used temperatures. The phosphorus and nitrogen co doped graphene exhibits remarkable air-stable n-type characteristics. This work demonstrates the critical role of phosphorus atoms in achieving enhanced electron donation compared to nitrogen atom doping of graphene, and is important for various applications associated with the need for air-stable n-type graphene materials. PMID- 25146413 TI - A randomized trial comparing live and telemedicine deliveries of an imagery-based behavioral intervention for breast cancer survivors: reducing symptoms and barriers to care. AB - OBJECTIVE: This multi-site randomized trial evaluates the quality of life (QOL) benefits of an imagery-based group intervention titled 'Envision the Rhythms of Life'(ERL). METHODS: Breast cancer survivors >6 weeks post-treatment were randomized to attend five weekly 4-h group sessions at a community center with therapist present (live delivery (LD), n = 48), therapist streamed via telemedicine (telemedicine delivery (TD), n = 23), or to a waitlist control (WL) group (n = 47). Weekly individual phone calls to encourage at-home practice began at session one and continued until the 3-month follow-up. Seven self-report measures of QOL were examined at baseline, 1-month and 3-month post-treatments including health-related and breast cancer-specific QOL, fatigue, cognitive function, spirituality, distress, and sleep. RESULTS: The Bonferroni method was used to correct for multiple comparisons, and alpha was adjusted to 0.01. Linear multilevel modeling analyses revealed less fatigue, cognitive dysfunction, and sleep disturbance for LD and TD compared with WL across the follow-up (p's < 0.01). Changes in fatigue, cognitive dysfunction, sleep disturbance, and health related and breast cancer-related QOL were clinically significant. There were no differences between LD and TD. CONCLUSIONS: Both the live and telemedicine delivered ERL intervention resulted in improvements in multiple QOL domains for breast cancer survivors compared with WL. Further, there were no significant differences between LD and TD, suggesting telemedicine delivered ERL intervention may represent an effective and viable option for cancer survivors in remote areas. PMID- 25146416 TI - Externalization of consciousness. Scientific possibilities and clinical implications. AB - The paper starts by analyzing recent advancements in neurotechnological assessment of residual consciousness in patients with disorders of consciousness and in neurotechnology-mediated communication with them. Ethical issues arising from these developments are described, with particular focus on informed consent. Against this background, we argue for the necessity of further scientific efforts and ethical reflection in neurotechnological assessment of consciousness and 'cerebral communication' with verbally non-communicative patients. PMID- 25146415 TI - Cobalt-catalyzed direct carbonylation of aminoquinoline benzamides. AB - A method for direct carbonylation of aminoquinoline benzamides has been developed. Reactions proceed at room temperature in trifluoroethanol solvent, use oxygen from air as an oxidant, and require Mn(OAc)3 as a cocatalyst. Benzoic and acrylic acid derivatives can be carbonylated by carbon monoxide affording imides in good yields. Halogen, nitro, ether, cyano, and ester functional groups are tolerated. The directing group can be removed under mild conditions affording phthalimides. PMID- 25146417 TI - Measuring respiratory function in mice using unrestrained whole-body plethysmography. AB - Respiratory dysfunction is one of the leading causes of morbidity and mortality in the world and the rates of mortality continue to rise. Quantitative assessment of lung function in rodent models is an important tool in the development of future therapies. Commonly used techniques for assessing respiratory function including invasive plethysmography and forced oscillation. While these techniques provide valuable information, data collection can be fraught with artefacts and experimental variability due to the need for anesthesia and/or invasive instrumentation of the animal. In contrast, unrestrained whole-body plethysmography (UWBP) offers a precise, non-invasive, quantitative way by which to analyze respiratory parameters. This technique avoids the use of anesthesia and restraints, which is common to traditional plethysmography techniques. This video will demonstrate the UWBP procedure including the equipment set up, calibration and lung function recording. It will explain how to analyze the collected data, as well as identify experimental outliers and artefacts that results from animal movement. The respiratory parameters obtained using this technique include tidal volume, minute volume, inspiratory duty cycle, inspiratory flow rate and the ratio of inspiration time to expiration time. UWBP does not rely on specialized skills and is inexpensive to perform. A key feature of UWBP, and most appealing to potential users, is the ability to perform repeated measures of lung function on the same animal. PMID- 25146419 TI - Unilateral atelectasis in a preterm infant monitored with electrical impedance tomography: a case report. AB - Electrical impedance tomography (EIT) is a non-invasive, radiation-free tool to monitor regional changes in ventilation. This report describes, for the first time, that unilateral atelectasis in an extremely low birth weight infant results in a loss of regional ventilation measured by EIT in the affected lung. CONCLUSION: EIT is currently the most promising technique to monitor regional lung aeration continuously at the bedside in this vulnerable population. PMID- 25146418 TI - Use of the Japanese health insurance claims database to assess the risk of acute pancreatitis in patients with diabetes: comparison of DPP-4 inhibitors with other oral antidiabetic drugs. AB - This study was initiated to evaluate the association of acute pancreatitis (AP) with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with diabetes in Japan. A retrospective cohort study of a large medical and pharmacy claims database was performed to compare the incidence of AP among those receiving DPP-4 inhibitors and those receiving other oral antidiabetic drugs. The incidence of all AP and hospitalizations for AP was similar between the two groups. Previous exposure to DPP-4 inhibitors did not affect occurrence of AP in patients on other oral antidiabetic drugs. The Kaplan-Meier curve for time to AP was similar between the two groups, and was not affected by previous exposure to DPP-4 inhibitors. The Cox proportional hazard models showed the incidence of AP was not significantly higher in those receiving DPP-4 inhibitors. Despite numerous, important limitations related to claims database-based analyses, our results indicate that there is no increased risk of AP with use of DPP-4 inhibitors among patients with diabetes in Japan. PMID- 25146420 TI - Design and construction of an urban runoff research facility. AB - As the urban population increases, so does the area of irrigated urban landscape. Summer water use in urban areas can be 2-3x winter base line water use due to increased demand for landscape irrigation. Improper irrigation practices and large rainfall events can result in runoff from urban landscapes which has potential to carry nutrients and sediments into local streams and lakes where they may contribute to eutrophication. A 1,000 m(2) facility was constructed which consists of 24 individual 33.6 m(2) field plots, each equipped for measuring total runoff volumes with time and collection of runoff subsamples at selected intervals for quantification of chemical constituents in the runoff water from simulated urban landscapes. Runoff volumes from the first and second trials had coefficient of variability (CV) values of 38.2 and 28.7%, respectively. CV values for runoff pH, EC, and Na concentration for both trials were all under 10%. Concentrations of DOC, TDN, DON, PO4-P, K(+), Mg(2+), and Ca(2+) had CV values less than 50% in both trials. Overall, the results of testing performed after sod installation at the facility indicated good uniformity between plots for runoff volumes and chemical constituents. The large plot size is sufficient to include much of the natural variability and therefore provides better simulation of urban landscape ecosystems. PMID- 25146421 TI - Invited commentary. PMID- 25146422 TI - Y2O3:Tm,Yb nanophosphors for correlative upconversion luminescence and cathodoluminescence imaging. AB - We present a phosphor nanoparticle that shows both upconversion luminescence (UCL) and cathodoluminescence (CL). With this particle, low-autofluorescence, deep-tissue and wide-field fluorescence imaging can be achieved with nanometer order high-spatial-resolution imaging. We synthesized Y2O3:Tm,Yb nanophosphors that emit visible and near-infrared UCL under 980 nm irradiation and blue CL via electron beam excitation. The phosphors were applied to fluorescent imaging of HeLa cells. The photostability of the phosphors was superior to that of a conventional organic dye. We show that after uptake by HeLa cells, the particles can be imaged with SEM and CL contrast in a cellular section. This indicates that correlative UCL and CL imaging of biological samples could be realized. PMID- 25146423 TI - The effect of tetrabromobisphenol A on protamine content and DNA integrity in mouse spermatozoa. AB - Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant of increasing concern to human health because of its action as an endocrine disruptor. We have previously demonstrated that TBBPA is able to increase apoptosis of testicular cells and other changes in the first and second generations of mice exposed to TBBPA. However, the potential effects of TBBPA on mouse epididymal spermatozoa have not yet been investigated. Therefore, we initiated this study to determine whether TBBPA exposure could also result in increased DNA fragmentation in epididymal spermatozoa and whether it had an effect on the protamines as the major nuclear proteins. C57Bl/6J mouse pups (n = 10) were exposed to TBBPA (experimental group) during the gestation, lactation, pre-pubertal and pubertal periods up to the age of 70 days as previously described and compared to control mouse pups (n = 10) that were not exposed. The results demonstrate that TBBPA treatment results in a significantly decreased protamine 1/protamine 2 ratio (0.362 vs. 0.494; p < 0.001), increased total protamine/DNA ratio (0.517 vs. 0.324; p < 0.001) and increased number of terminal deoxynucleotidyl transferase dUTP nick end labelling positive spermatozoa (39.5% vs. 21.2%; p < 0.05) observed between TBBPA and control mice respectively. These findings indicate that TBBPA exposure, in addition to the resulting increased sperm DNA damage, also has the potential to alter the epigenetic marking of sperm chromatin through generation of an anomalous content and distribution of protamines. The possibility is now open to study whether the detected altered protamine content and DNA integrity are related to the previously observed second generation effects upon TBBPA exposure. PMID- 25146424 TI - Nanostructuring of self-assembled porphyrin networks at a solid/liquid interface: local manipulation under global control. AB - Molecules of (5,10,15,20-tetraundecylporphyrinato)-copper(II) [(TUP)Cu] can self assemble into four different polymorphs at the interface between highly oriented pyrolytic graphite and 1-octanoic acid. Scanning tunneling microscopy (STM) reveals that it is possible to combine the global control over monolayer structure, provided by the composition and concentration of the supernatant solution, with local control, from nanomanipulation by the STM tip. In the initially formed monolayer, with a polymorph composition governed by the concentration of (TUP)Cu in the supernatant solution, the exchange of molecules physisorbed at the solid/liquid interface with those in the liquid is very limited. By using a nanoshaving procedure at the tip, defects are created in the monolayer, and these serve as local manipulation sites to create domains of higher or lower molecular density, and to incorporate a second molecular species, (TUP)Co into the monolayer of (TUP)Cu. PMID- 25146425 TI - A multivariate approach to the determination of an indicator species pool for community-based bioassessment of marine water quality. AB - Previous studies in Chinese coastal waters of the Yellow Sea have shown that periphytic ciliates are reliable indicators of marine water quality. However, traditional community-based bioassessments are time-consuming because they rely on the identification and enumeration of all species within the community. In order to improve bioassessment efficiency, step-best-matching analysis was used to identify which are the most reliable indicator species among periphytic marine ciliate communities. Based on indices of species richness, diversity and evenness, a subset of 48 species (out of a total of 141) was found to retain sufficient information for accurately predicting water quality, and was more strongly related to changes of environmental variables than the full species set. These results demonstrate that the step-best-matching analysis is a powerful approach for identifying an indicator species pool from a full species dataset of a community, and allows the development of time-efficient sampling protocols for community-based marine bioassessment. PMID- 25146426 TI - Measurement of greenhouse gas flux from agricultural soils using static chambers. AB - Measurement of greenhouse gas (GHG) fluxes between the soil and the atmosphere, in both managed and unmanaged ecosystems, is critical to understanding the biogeochemical drivers of climate change and to the development and evaluation of GHG mitigation strategies based on modulation of landscape management practices. The static chamber-based method described here is based on trapping gases emitted from the soil surface within a chamber and collecting samples from the chamber headspace at regular intervals for analysis by gas chromatography. Change in gas concentration over time is used to calculate flux. This method can be utilized to measure landscape-based flux of carbon dioxide, nitrous oxide, and methane, and to estimate differences between treatments or explore system dynamics over seasons or years. Infrastructure requirements are modest, but a comprehensive experimental design is essential. This method is easily deployed in the field, conforms to established guidelines, and produces data suitable to large-scale GHG emissions studies. PMID- 25146427 TI - Glucocorticoid-induced leucine zipper (GILZ) controls inflammation and tissue damage after spinal cord injury. AB - AIMS: Spinal cord injury (SCI) occurs following damage to the spinal column. Following trauma, tissue damage is further exacerbated by a secondary damage due to a SCI-activated inflammatory process. Control of leukocytes activity is essential to therapeutic inhibition of the spinal cord damage to ameliorate the patient's conditions. The mechanisms that regulate neuroinflammation following SCI, including T-cell infiltration, have not been completely clarified. Glucocorticoids (GC) are antiinflammatory drugs widely used in therapy, including treatment of SCI. GC efficacy may be linked to many molecular mechanisms that are involved in regulation of leukocytes migration, activation, and differentiation. We have previously shown that the antiinflammatory activity of GC is in part mediated by glucocorticoid-induced leucine zipper (GILZ). Here, we investigated the role of GILZ in inflammation and spinal cord tissue damage following a spinal trauma. METHODS: We address the role of GILZ in SCI-induced inflammation and tissue damage using a model of SCI in gilz knockout (gilz KO) and wild-type (WT) mice. RESULTS: We found that GILZ deficiency is associated with a strong reduction of SCI-induced inflammation and a significantly reduced lesion area following SCI. CONCLUSION: These results demonstrate that GILZ is involved in induction of neuroinflammation and functional outcomes of spinal cord trauma. PMID- 25146428 TI - Theoretical study of the hydrogen bonding and infrared spectroscopy in the cis vacant polymorph of dioctahedral 2:1 phyllosilicates. AB - The spatial geometry and local environment of hydroxyl groups of the cis-vacant (cv) crystal polymorph of dioctahedral 2:1 phyllosilicates are studied by computational methods, doing especial emphasis on the hydrogen bonds and electrostatic interactions of the hydroxyl groups with the neighbor atoms. Different types of phyllosilicates are explored: with only tetrahedral charge, with only octahedral charge, with simultaneous octahedral and tetrahedral substitution, and with different interlayer cation (IC). The effect of these interactions on the spectroscopic properties of these hydroxyl groups is also studied. All results are compared with the trans-vacant (tv) crystal forms of these minerals. Frequency differences between cv and tv polymorphs are smaller than those due to the local environments of these OH groups. This means that the changes in the interactions of the different local environments of each OH group are greater than the cv/tv differences. PMID- 25146429 TI - Effect of electric field on the microcosmic properties of cation compound containing 2,2,6,6-tetramethyl-1-piperidinyloxy and imidazole unit. AB - A theoretical study of the electric-field effect on the electronic structures and related properties of the cation compound containing 2,2,6,6-tetramethyl-1 piperidinyloxy (TEMPO) and imidazole unit has been carried out, using the density functional theory (DFT) at the (U) B3LYP/6-31+G(d,p) level. The changes and regularities of geometric and electronic properties of the researched compound under electric field were revealed in detail. The results show the following: (1) Electric field has a very important effect on the orbital energy, dipole moment, natural population, and structure of the cation compound. Most of these properties are changed orderly with the increase of the electric-field intensity. (2) It is very interesting to find that in the present different electric-field intensities, the structure of cation compound after getting an electron becomes bis-radical form, that is, no mater in or out of electric-field, the cation compound will exist in a triplet state after getting an electron. (3) When getting an electron, the change of the cation structure mainly appears on the imizadole head, and when losing an electron, the change mainly appears on the TEMPO head. These theoretical results considering the electric-field effect for the cation compound help to explain the related experimental phenomena and further to direct the functional molecular design of this kind of compound. PMID- 25146430 TI - Accuracy of density functionals in the description of dispersion interactions and IR spectra of phosphates and phosphorylated compounds. AB - The performances of quantum chemistry methods (i.e., DFT and ab initio) in calculating the structural and vibrational properties of phosphates and phosphorylated compounds have been evaluated. Diethyl-phosphate, phosphonic acid, dihydrogen phosphate anion, phosphoric acid dimer and protonated glycylphosphotyrosine dipeptide were selected for our study. Geometry and harmonic frequency deviations were investigated, pointing out the contribution of dispersion interactions on diethyl-phosphate, [Gly-pTyr+H](+) and the phosphoric acid dimer. The B3LYP-D functional, followed by CC2 and MP2 methods, revealed significant accuracy for frequency calculations of the majority of the phosphorylated compounds in comparison with available experimental data. These investigations provide a guide to the accurate computation of phosphorylated biological compounds. PMID- 25146431 TI - How to Promote Bedside Placement of the Postpyloric Feeding Tube: A Network Meta Analysis of Randomized Controlled Trials. AB - BACKGROUND: The optimal method of achieving fast, safe, and accurate postpyloric tube placement at the bedside remains controversial. This study investigated whether facilitating techniques of bedside placement would improve the rate of successful placement of postpyloric tubes when compared with the standard technique and whether strategies should be confined to adult or pediatric patients. METHODS: We searched electronic databases for eligible literatures that compared different methods of postpyloric tube placement, evaluating the successful rate of postpyloric tube placement. Two reviewers reviewed the quality of the studies and performed data extraction independently. Pairwise and network meta-analyses were performed to integrate the efficacy. RESULTS: Fourteen clinical trials involving 753 patients were included. Pairwise meta-analyses demonstrated that prokinetic agents (odds ratio [OR], 2.263; 95% confidence interval [CI]: 1.140-4.490; P = .02) were associated with a higher success rate as compared with the standard technique, and gastric air insufflation was associated with a higher success rate as compared with prokinetic agents (OR, 3.462; 95% CI, 1.63-7.346; P = .001) in adult patients. In network analyses, prokinetic agents and gastric air insufflation were also consistently associated with a higher success rate in adult patients. Trend analyses of rank probabilities revealed gastric air insufflation had the cumulative probability of being the most efficacious strategy (78%), especially in adult patients (88%). CONCLUSIONS: Gastric air insufflation seems to be clinically better for promoting bedside placement of postpyloric feeding tubes in adults. Clinicians should no longer use prokinetic agents in pediatric patients or patients without impaired motility. PMID- 25146432 TI - Heterogeneous expression pattern of interleukin 17A (IL-17A), IL-17F and their receptors in synovium of rheumatoid arthritis, psoriatic arthritis and osteoarthritis: possible explanation for nonresponse to anti-IL-17 therapy? AB - INTRODUCTION: Accumulating evidence suggests an important role for interleukin 17 (IL-17) in the pathogenesis of several inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Accordingly, clinical trials aimed at blocking IL-17 have been initiated, but clinical results between patients and across different diseases have been highly variable. The objective was to determine the variability in expression of IL-17A, IL-17F and their receptors IL-17RA and IL-17RC in the synovia of patients with arthritis. METHODS: Synovial biopsies were obtained from patients with RA (n = 11), PsA (n = 15) and inflammatory osteoarthritis (OA, n = 14). For comparison, synovia from noninflamed knee joints (n = 7) obtained from controls were included. Frozen sections were stained for IL-17A, IL-17F, IL-17RA and IL-17RC and evaluated by digital image analysis. We used confocal microscopy to determine which cells in the synovium express IL-17A and IL-17F, double-staining with CD4, CD8, CD15, CD68, CD163, CD31, von Willebrand factor, peripheral lymph node address in, lymphatic vessel endothelial hyaluronan receptor 1, mast cell tryptase and retinoic acid receptor-related orphan receptor gammat (RORgammat). RESULTS: IL 17A, IL-17F, IL-17RA and IL-17RC were abundantly expressed in synovial tissues of all patient groups. Whereas IL-17RA was present mostly in the synovial sublining, IL-17RC was abundantly expressed in the intimal lining layer. Digital image analysis showed a significant (P < 0.05) increase of only IL-17A in arthritis patients compared to noninflamed control tissues. The expression of IL-17A, IL 17F and their receptors was similar in the different patient groups, but highly variable between individual patients. CD4+ and CD8+ cells coexpressed IL-17A, and few cells coexpressed IL-17F. IL-17A and IL-17F were not expressed by CD15+ neutrophils. Mast cells were only occasionally positive for IL-17A or IL-17F. Interestingly, IL-17A and IL-17F staining was also observed in macrophages, as well as in blood vessels and lymphatics. This staining probably reflects receptor bound cytokine staining. Many infiltrated cells were positive for the transcription factor RORgammat. Colocalisation between RORgammat and IL-17A and IL-17F indicates local IL-17 production. CONCLUSIONS: Increased expression of IL 17A is not restricted to synovial tissues of RA and PsA patients; it is also observed in inflammatory OA. The heterogeneous expression levels may explain nonresponse to anti-IL-17 therapy in subsets of patients. PMID- 25146433 TI - Kinesin spindle protein inhibitor SB743921 induces mitotic arrest and apoptosis and overcomes imatinib resistance of chronic myeloid leukemia cells. AB - Inhibition of the cell mitotic pathway may provide a novel means for therapeutic intervention in chronic myeloid leukemia (CML). Kinesin spindle protein (KSP), a microtubule-associated motor protein which is essential for cell cycle progression, is overexpressed in bcr-abl+ CML cells. Retrovirus mediated bcr-abl transduction increases KSP expression in cord blood CD34 + cells. SB743921 is a selective KSP inhibitor which is being investigated in ongoing clinical trials for treatment of myeloma, leukemia and solid tumors. Treatment of CML cells with SB743921 resulted in reduced proliferation and colony forming cell (CFC) formation ability. SB743921 also actively blocked cell cycle progression, leading to apoptosis in both primary CML cells and cell lines. KSP inhibition sensitized CML cells to imatinib-induced apoptosis. Importantly, SB743921 inhibited the proliferation of various CML cells including T315I mutation-harboring cells. Furthermore, we demonstrated that SB743921 treatment suppressed ERK and AKT activity in CML cells. These data indicate that SB743921 may become a novel treatment agent for patients with CML. PMID- 25146434 TI - Identification of mutant alleles of JAK3 in pediatric patients with acute lymphoblastic leukemia. AB - Children with acute lymphoblastic leukemia (ALL) have an 80% chance of long-term survival. Despite the high rate of cure, children relapse, and recurrent ALL is difficult to cure with chemotherapeutic regimens. Therefore, improved biological understanding of ALL and the development of rationally designed therapeutics targeting molecules associated with the pathogenesis of ALL are essential. We identified missense and synonymous JAK3 mutations in 16 of 91 pediatric patients with ALL. The expression of JAK3(V722I) mutant caused the cytokine-independent activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling and conferred the factor-independent growth of murine interleukin-3 (IL-3)-dependent pro-B Ba/F3 cells. Importantly, inhibition of JAK3 by the known JAK3 inhibitor CP-690 550 converted the Ba/F3-JAK3(V722I) cells back to factor-dependent growth. These observations suggest that JAK3 may contribute to the pathogenesis of pediatric ALL and serve as an important therapeutic target which can be leveraged to improve outcomes for pediatric patients with ALL. PMID- 25146435 TI - Alcohol intake, alcoholic beverage type and multiple myeloma risk: a meta analysis of 26 observational studies. AB - This meta-analysis aimed to examine the association between alcohol consumption and multiple myeloma (MM) risk. Eligible publications were sought in PubMed to 31 December 2013. Separate analyses were performed by study design, gender, alcoholic beverages and levels of consumption. Sixteen case-control studies (3921 cases and 19,594 controls) and 10 cohort studies (3167 incident cases in total cohort of 2,557,649 subjects) were eligible. Ever consumption of alcohol was associated with reduced MM risk (pooled relative risk [RR] = 0.88, 95% confidence interval [CI]: 0.79-0.99) and especially consumption of wine correlated with reduced MM risk (pooled RR = 0.77, 95% CI: 0.67-0.89 for ever drinkers). MM risk was not affected by beer or liquor intake. A protective association was observed among females (pooled RR = 0.79, 95% CI: 0.69-0.89 for ever drinkers), whereas the association among males seemed null. In conclusion, contrary to most solid tumors, alcohol intake may confer protection in terms of MM risk among females, with wine being particularly beneficial. PMID- 25146436 TI - Xcc-facilitated agroinfiltration of citrus leaves: a tool for rapid functional analysis of transgenes in citrus leaves. AB - KEY MESSAGE: Xanthomonas citri subsp. citri pretreatment before agroinfiltration could significantly promote transient expression in citrus leaves which were previously recalcitrant to agroinfiltration. Transient expression via agroinfiltration is widely used in biotechnology but remains problematic in many economically important plants. Xanthomonas citri subsp. citri (Xcc)-facilitated agroinfiltration was employed to promote transient protein expression in Valencia sweet orange leaves, which are recalcitrant to agroinfiltration. However, it is unclear whether Xcc-facilitated agroinfiltration has broad application, i.e., whether Xcc-facilitated agroinfiltration could be used on other citrus varieties. In addition, we intended to investigate whether Xcc-facilitated agroinfiltration could be used to hasten transgene function assays, e.g., Cre/lox system and Cas9/sgRNA system. In this report, Xcc-facilitated agroinfiltration was further exploited to enhance beta-glucuronidase (GUS) expression in five citrus varieties. Xcc-facilitated agroinfiltration also significantly increased GFP expression in six citrus varieties tested. Both GUS and GFP assays indicated that Xcc-facilitated agroinfiltration had the best performance in grapefruit. After Xcc-facilitated agroinfiltration was carried out in grapefruit, protoplast analysis of the transformed cells indicated that there were more than 20 % leaf cells expressing GFP. In grapefruit, usefulness of Xcc-facilitated agroinfiltration was assayed in three case studies: (1) fast functional analysis of Cre/lox system, (2) the heat shock regulation of HSP70B promoter derived from Arabidopsis, and (3) Cas9/sgRNA-mediated genome modification. PMID- 25146437 TI - Litoreibacter ponti sp. nov., isolated from seawater. AB - A Gram-stain-negative, aerobic, non-motile and coccoid, ovoid or rod-shaped bacterial strain, designated GJSW-31(T), was isolated from seawater from the South Sea, South Korea. The novel strain grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of 2.0% (w/v) NaCl. Phylogenetic trees, based on 16S rRNA gene sequences, revealed that strain GJSW-31(T) clustered with the type strains of species of the genus Litoreibacter. Strain GJSW-31(T) exhibited 16S rRNA gene sequence similarity values of 95.2-98.5% to the type strains of species of the genus Litoreibacter and sequence similarities of less than 96.18% to type strains of the other species with validly published names. Strain GJSW-31(T) contained Q-10 as the predominant ubiquinone and C(18:1)omega7c as the major fatty acid. The major polar lipids of strain GJSW-31(T) were phosphatidylcholine, phosphatidylglycerol, one unidentified lipid and one unidentified aminolipid. The DNA G+C content of strain GJSW-31(T) was 62.5 mol% and its DNA-DNA relatedness values with the type strains of Litoreibacter albidus, Litoreibacter janthinus, Litoreibacter meonggei and Litoreibacter ascidiaceicola were 13-23%. The differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain GJSW-31(T) is separate from other species of the genus Litoreibacter. On the basis of the data presented, strain GJSW-31(T) is considered to represent a novel species of the genus Litoreibacter, for which the name Litoreibacter ponti sp. nov. is proposed. The type strain is GJSW-31(T) ( =KCTC 42114(T) =NBRC 110379(T)). PMID- 25146438 TI - The effects of loaded carrier mass and formulation mass on aerosolization efficiency in dry powder inhaler devices. AB - Previous studies have suggested that particle-particle impaction may influence aerosolization properties in carrier-based dry powder inhalers, through transfer of kinetic energy from large carriers to surface-deposited active drug. The importance of particle-particle collision has yet to be compared against other mechanisms that could lead to drug liberation, such as particle-wall impaction and turbulence. In particular, particle-particle collisions are difficult to model in silico due to computational restrictions. This study investigated the effects of dry powder inhaler particle-particle collisions in vitro using an established carrier-drug model dry powder inhalation formulation. Spherical polystyrene beads of median size 82.80 MUm were chosen as a model carrier as they were of uniform size, shape, surface area, density, porosity and hardness and thus eliminated potential variables that would have conflicted with the study. This model carrier was geometrically blended with micronized salbutamol sulphate (loaded blend). The correlation between the mass of loaded blend (5-40 mg) in the Rotahaler(r) DPI device and resulting fine particle fraction (FPF) was examined at a constant flow rate of 60 L.min(-1). In a second experiment, the mass of loaded blend was kept constant and a variable amount of blank carrier particles were added to the Rotahaler(r) device to ascertain if additional "blank" carrier particles affected the final FPF. The efficiency of aerosolization remained constant with varying amounts of blank carrier particles as determined by the fine particle fraction of the emitted dose (FPFED) and fine particle fraction of the loaded dose (FPFLD). No statistical difference in FPFED and FPFLD values were observed for increasing masses of blank carrier. In addition, no statistical difference in FPFED and FPFLD between the two experiments was obtained. These observations suggest that particle-particle collisions are not a driving mechanism responsible for deaggregation of drug from carrier-based systems. PMID- 25146439 TI - Nanomedicines based drug delivery systems for anti-cancer targeting and treatment. AB - Cancer is defined as an uncontrolled growth of abnormal cells. Current treatment strategies for cancer include combination of radiation, chemotherapy and surgery. The long-term use of conventional drug delivery systems for cancer chemotherapy leads to fatal damage of normal proliferate cells and this is particularly used for the management of solid tumors, where utmost tumor cells are not invaded quickly. A targeted drug delivery system (TDDS) is a system, which releases the drug at a preselected biosite in a controlled manner. Nanotechnology based delivery systems are making a significant impact on cancer treatment and the polymers play key role in the development of nanopraticlulate carriers for cancer therapy. Some important technological advantages of nanotherapeutic drug delivery systems (NDDS) include prolonged half-life, improved bio-distribution, increased circulation time of the drug, controlled and sustained release of the drug, versatility of route of administration, increased intercellular concentration of drug and many more. This review covers the current research on polymer based anticancer agents, the rationale for development of these polymer therapeutical systems and discusses the benefits and challenges of cancer nanomedicines including polymer-drug conjugates, micelles, dendrimers, immunoconjugates, liposomes, nanoparticles. PMID- 25146440 TI - Confectionery-based dose forms. AB - Conventional dosage forms such as tablets, capsules and syrups are prescribed in the normal course of practice. However, concerns about patient preferences and market demands have given rise to the exploration of novel unconventional dosage forms. Among these, confectionery-based dose forms have strong potential to overcome compliance problems. This report will review the availability of these unconventional dose forms used in treating the oral cavity and for systemic drug delivery, with a focus on medicated chewing gums, medicated lollipops, and oral bioadhesive devices. The aim is to stimulate increased interest in the opportunities for innovative new products that are available to formulators in this field, particularly for atypical patient populations. PMID- 25146441 TI - Insights into cellular uptake of nanoparticles. AB - Nanomaterials promise to improve disease diagnosis and treatment by enhancing the delivery of drugs, genes, biomolecules and imaging agents to specific subcellular targets. In order to optimize nanomaterial design for this purpose, a comprehensive understanding of how these materials are taken up and transported within the cell is required. In this review, we discuss the endocytic pathways employed by different types of nanoparticles with emphasis on the influence of nanoparticle surface modification. The use of pharmacological inhibition to probe internalization and intracellular trafficking pathways of nanoparticles is critically evaluated. Finally, approaches to target-specific delivery of therapeutics via nanoparticles into the cytoplasm and nucleus are addressed. PMID- 25146443 TI - Italianity is associated with lower risk of prostate cancer mortality in Switzerland. AB - PURPOSE: Different prostate cancer mortality rates observed in European countries may depend on cultural background. We aimed at exploring variation in prostate cancer mortality in the language regions of Switzerland as a function of "Italianity", a proxy for adherence to an Italian lifestyle. METHODS: We used data of the Swiss National Cohort, a census-based record linkage study, consisting of census (1990 and 2000) and mortality (until 2008) data. 1,163,271 Swiss and Italian nationals 40+-year old were included. Multivariate age standardized prostate cancer mortality rates and hazard ratios (HR) from Cox proportional hazards regression analysis were performed. Italianity was defined by an individual's nationality, place of birth and principal language, resulting in a score of 0-3 points. RESULTS: Age-standardized prostate cancer mortality rates (per 100,000 person-years) were lowest in the Italian-speaking region of Switzerland (66.7 vs. 87.3 in the German-speaking region). Both Italian nationality and/or place of birth were significantly associated with lower mortality. There was a graded inverse association between mortality rates and increasing Italianity score. Individuals with the highest level of Italianity had a HR of 0.67 (95 % CI 0.59-0.76) compared to those with an Italianity score of zero. Results were similar when looking at language regions separately. CONCLUSIONS: The strong and consistent association between Italianity and prostate cancer mortality suggests protective properties of an Italian lifestyle. Further research is required in order to determine which factors specific for Italian culture are responsible for the lower prostate cancer mortality. PMID- 25146444 TI - Cholelithiasis and risk of pancreatic cancer: systematic review and meta-analysis of 21 observational studies. AB - PURPOSE: To investigate the association between cholelithiasis and risk of pancreatic cancer (PaC). METHODS: We identified eligible studies in MEDLINE and EMBASE up to August 1, 2013 and the reference lists of original studies and review articles on this topic. Summary relative risks (SRRs) with their 95 % confidence intervals (CIs) were calculated with a random-effects model. RESULTS: Twenty-one studies (15 case-control studies, 6 cohort studies) met eligibility criteria. The current data suggest that cholelithiasis is associated with a 25 % excess risk of PaC (SRRs = 1.25, 95 % CI 1.10-1.41; test for heterogeneity p = 0.006, I (2) = 47.6 %). In subgroup analysis of timing of exposure, seven of eight studies in patients whose diagnosis of cholelithiasis made more than specified year (5, 3, 2, or 1 year) prior to cancer diagnosis showed no association for PaC, while all three studies in patients diagnosed less than specified year before cancer diagnosis showed a positive association. There was no publication bias in the present meta-analysis. CONCLUSION: This meta-analysis supports the hypothesis that a history of cholelithiasis may significantly increase PaC risk, particularly in Asian countries. However, the positive association disappeared over time, suggesting that cholelithiasis may be the early symptoms of PaC. PMID- 25146445 TI - Cognitive impairment and cancer mortality: a biological or health care explanation? AB - PURPOSE: To examine whether the documented association of suboptimal cognitive function with total and cardiovascular (CVD) mortality also applies to cancer mortality and probe whether the explanation for this association is biomedical or health care related. METHODS: In a subsample of 733 participants of the EPIC Greece cohort from Athens and surrounding area, we assessed cognitive function at age 65 or older in the period 2004-2006, using the Mini-Mental State Examination (MMSE). Incidence of cancer, mortality from cancer and CVD, and overall mortality were ascertained through active follow-up for a median of 4 years after MMSE assessment using Cox proportional hazards models. RESULTS: A total of 86 participants died during follow-up. A 2-point decrease in MMSE score was associated with increase in overall (hazard ratio (HR) 1.26, 95 % confidence interval (CI) 1.11-1.43), CVD (HR 1.26, 95 % CI 1.02-1.56), and cancer (HR 1.32, 95 % CI 1.02-1.70) mortality. In contrast, there was no noticeable difference in cancer incidence associated with a 2-point decrease in MMSE score (HR 1.07, 95 % CI 0.79-1.45). CONCLUSIONS: Cognitive function appears to be inversely associated not only with CVD and overall, but also with cancer mortality. Although for CVD mortality there is a biomedical explanation invoking vascular mechanisms, for cancer mortality we may need to focus on socially conditioned factors, such as compromised ability to identify early signs and suboptimal compliance to treatment. Our hypothesis-generating results need to be confirmed in larger studies, as the issue is of major importance, since cognitive decline is not uncommon among the elderly. PMID- 25146442 TI - Stem cell therapy in autoimmune rheumatic diseases: a comprehensive review. AB - The clinical management of autoimmune rheumatic diseases (ARD) has undergone significant changes in the last few decades, leading to remarkable improvements in clinical outcomes of many patients with mild to moderate ARD. On the other hand, severe refractory ARD patients often have high morbidity and mortality. Extensive basic research and clinical evidence has opened the door to new encouraging perspectives, such as the establishment of a role of stem cell transplantation (SCT) in the strategic management of ARD. Given the great heterogeneity of ARD, it is difficult to assign an optimal SCT regimen to all ARD patients. SCT remains a challenging mode of therapy in ARD patients from the standpoints of both efficacy and safety. As the clinical data of SCT in ARD increases and as we improve our understanding of stem cell biology and the downstream effects on the immune system, the future is promising for the development of optimal personalized SCT regimens in ARD. PMID- 25146446 TI - Dose heterogeneity correction for low-energy brachytherapy sources using dual energy CT images. AB - Permanent seed implant brachytherapy is currently used for adjuvant radiotherapy of early stage prostate and breast cancer patients. The current standard for calculation of dose around brachytherapy sources is based on the AAPM TG-43 formalism, which generates the dose in a homogeneous water medium. Recently, AAPM TG-186 emphasized the importance of accounting for tissue heterogeneities. We have previously reported on a methodology where the absorbed dose in tissue can be obtained by multiplying the dose, calculated by the TG-43 formalism, by an inhomogeneity correction factor (ICF). In this work we make use of dual energy CT (DECT) images to extract ICF parameters. The advantage of DECT over conventional CT is that it eliminates the need for tissue segmentation as well as assignment of population based atomic compositions. DECT images of a heterogeneous phantom were acquired and the dose was calculated using both TG-43 and TG-43 [Formula: see text] formalisms. The results were compared to experimental measurements using Gafchromic films in the mid-plane of the phantom. For a seed implant configuration of 8 seeds spaced 1.5 cm apart in a cubic structure, the gamma passing score for 2%/2 mm criteria improved from 40.8% to 90.5% when ICF was applied to TG-43 dose distributions. PMID- 25146447 TI - Propylthiouracil quantification in human plasma by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry: application in a bioequivalence study. AB - A rapid, sensitive and specific method for quantifying propylthiouracil in human plasma using methylthiouracil as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by liquid-liquid extraction using an organic solvent (ethyl acetate). The extracts were analyzed by high performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/MS) in negative mode (ES-). Chromatography was performed using a Phenomenex Gemini C18 5MUm analytical column (4.6mm*150mm i.d.) and a mobile phase consisting of methanol/water/acetonitrile (40/40/20, v/v/v)+0.1% of formic acid. For propylthiouracil and I.S., the optimized parameters of the declustering potential, collision energy and collision exit potential were -60 (V), -26 (eV) and -5 (V), respectively. The method had a chromatographic run time of 2.5min and a linear calibration curve over the range 20-5000ng/mL. The limit of quantification was 20ng/mL. The stability tests indicated no significant degradation. This HPLC-MS/MS procedure was used to assess the bioequivalence of two propylthiouracil 100mg tablet formulations in healthy volunteers of both sexes in fasted and fed state. The geometric mean and 90% confidence interval CI of Test/Reference percent ratios were, without and with food, respectively: 109.28% (103.63-115.25%) and 115.60% (109.03-122.58%) for Cmax, 103.31% (100.74 105.96%) and 103.40% (101.03-105.84) for AUClast. CONCLUSION: This method offers advantages over those previously reported, in terms of both a simple liquid liquid extraction without clean-up procedures, as well as a faster run time (2.5min). The LOQ of 20ng/mL is well suited for pharmacokinetic studies. The assay performance results indicate that the method is precise and accurate enough for the routine determination of the propylthiouracil in human plasma. The test formulation with and without food was bioequivalent to reference formulation. Food administration increased the Tmax and decreased the bioavailability (Cmax and AUC). PMID- 25146449 TI - Primary idiopathic chylopericardium presenting with cardiac tamponade. AB - Primary idiopathic chylopericardium is an extremely rare condition especially in children and young adults. Although the exact pathophysiology of primary chylopericardium has not been established, the reflux of chylous fluid into the pericardial space was suggested as the etiology. Damage to the thoracic duct valves and the communication of the thoracic duct to the pericardial lymphatics or abnormally elevated pressure in the thoracic duct could cause chylous fluid reflux. In this report, we described the case of a 4-year-old boy with primary idiopathic chylopericardium presenting as cardiac tamponade who was treated with video-assisted thoracoscopic window and then surgical duct ligation. PMID- 25146448 TI - Relationship between melatonin receptor 1B and insulin receptor substrate 1 polymorphisms with gestational diabetes mellitus: a systematic review and meta analysis. AB - Studies have investigated the relationship between genetic variants and risk of gestational diabetes mellitus (GDM). However, the results remain inconclusive. The aim of this study was to investigate the association of rs10830963 and rs1387153 variants in melatonin receptor 1B (MTNR1B) and rs1801278 variant in insulin receptor substrate 1 (IRS1) with GDM susceptibility. Electronic database of PubMed, Medline, Embase, and CNKI (China National Knowledge Infrastructure) were searched for relevant studies between 2005 and 2014. The odds ratio (OR) with its 95% confidence interval (CI) were employed to estimate the association. Total ten case-control studies, including 3428 GDM cases and 4637 healthy controls, met the inclusion criteria. Our results showed a significant association between the three genetic variants and GDM risk, rs10830963 with a P value less than 0.0001, rs1387153 with a P-value of 0.0002, and rs1801278 with a P-value of 0.001. Furthermore, all the genetic models in these three polymorphisms were associated with increased risks of GDM as well (P< = 0.009). In conclusion, our study found that the genetic polymorphisms rs10830963 and rs1387153 in MTNR1B and rs1801278 in IRS1 were associated with an increased risk of developing GDM. However, further studies with gene-gene and gene-environmental interactions should be considered. PMID- 25146450 TI - The protective effects of Rhodiola crenulata extracts on Drosophila melanogaster gut immunity induced by bacteria and SDS toxicity. AB - The aim of this study was to observe the effect of the Rhodiola crenulata extracts on gut immunity of Drosophila melanogaster. Wild-type flies fed standard cornmeal-yeast medium were used as controls. Experimental groups were supplemented with 2.5% R. crenulata aqueous extracts in standard medium. Survival rate was determined by feeding pathogenic microorganisms and toxic compounds. The levels of reactive oxygen species and dead cells were detected by dihydroethidium and 7-amino-actinomycin D staining, respectively. The expression of antimicrobial peptides was evaluated by quantitative polymerase chain reaction, and morphological change of the intestine was imaged by an Axioskop 2 plus microscope. The results demonstrate that R. crenulata increased the survival rates of adult flies and expression of antimicrobial peptide genes after pathogen or toxic compound ingestion. Moreover, decreased levels of reactive oxygen species and epithelial cell death were associated with results in improved intestinal morphology. The pharmacological action of R. crenulata from Tibet was greater than that from Sichuan. These results indicate that the R. crenulata extracts from Tibet had better pharmacological effect on D. melanogaster gut immunity after ingestion of pathogens and toxic compounds. These results may provide the pharmacological basis for prevention of inflammatory diseases of the intestine. PMID- 25146452 TI - Biosilica-loaded poly(epsilon-caprolactone) nanofibers: a step closer to bioprinted materials with tunable properties. PMID- 25146451 TI - Bmi1 expression in long-term germ stem cells. AB - Asingle cells in undifferentiated spermatogonia are considered to be the most primitive forms of germ stem cells (GSCs). Although GFRalpha1 is thought to be a marker of Asingle cells, we found that Bmi1(High) is more specific than GFRalpha1 for Asingle cells. Bmi1(High) expression in Asingle cells is correlated with seminiferous stages, and its expression was followed by the proliferative stage of Asingle GSCs. In contrast, GFRalpha1 expression was seminiferous stage independent. Fate analyses of EdU-positive Bmi1(High)-positive cell-derived Asingle cells revealed that these cells self-renewed or generated transient amplifying Apaired cells. Bmi1(High)-positive cells were resistant to irradiation induced injury, after which they regenerated. Elimination of Bmi1(High)-positive cells from seminiferous tubules resulted in the appearance of tubules with seminiferous stage mismatches. Thus, in this study, we found that Bmi1(High) is a seminiferous stage-dependent marker for long-term GSCs and that Bmi1(High) positive cells play important roles in maintaining GSCs and in regenerating spermatogenic progenitors after injury. PMID- 25146453 TI - Morphological spectrum of renal pathology and its correlation to clinical features in patients with disseminated intravascular coagulation: a study involving a series of 21 autopsy cases. AB - Disseminated intravascular coagulation (DIC), a thrombohemorrhagic disorder, occurs as a secondary complication in many diseases, but the histopathological features of kidneys in DIC have not been extensively characterized thus far. We reviewed 21 autopsy cases of patients with a clinical diagnosis of DIC and studied the repertoire of renal pathology. Eighteen patients had elevated serum creatinine levels and 15 patients had a variable degree of proteinuria. Underlying disorders included malignant neoplasms in 12 patients, and abdominal aortic aneurysm, acute myocardial infarction, and systemic infections in other patients. Coexistent glomerular pathology, such as focal segmental glomerulosclerosis (FSGS) with different morphological variants, and microthrombi formation, was present in many patients. The microthrombi were histologically similar to that seen in thrombotic microangiopathy, but characteristics associated with DIC were detected by special staining. The presence of FSGS correlated with the degree of urinary protein (P = 0.0044), and the presence of acute tubular injury (ATI) and the extent of global glomerulosclerosis both correlated with serum creatinine levels (P = 0.019 and 0.0003, respectively). FSGS was probably due to endothelial cell damage, another potential etiology for FSGS. Global glomerulosclerosis, a result of previous renal injury, can be a determinant of renal function during the acute phase of DIC. PMID- 25146454 TI - Altered cerebrovascular reactivity velocity in mild cognitive impairment and Alzheimer's disease. AB - Interindividual variation in neurovascular reserve and its relationship with cognitive performance is not well understood in imaging in neurodegeneration. We assessed the neurovascular reserve in amnestic mild cognitive impairment (aMCI) and Alzheimer's dementia (AD). Twenty-eight healthy controls (HC), 15 aMCI, and 20 AD patients underwent blood oxygen level-dependent imaging for 9 minutes, breathing alternatively air and 7% carbon dioxide mixture. The data were parcellated into 88 anatomic regions, and carbon dioxide regressors accounting for different washin and washout velocities were fitted to regional average blood oxygen level-dependent signals. Velocity of cerebrovascular reactivity (CVR) was analyzed and correlated with cognitive scores. aMCI and AD patients had significantly slower response than HC (mean time to reach 90% of peak: HC 33 seconds, aMCI and AD 59 seconds). CVR velocity correlated with Mini Mental State Examination in 35 of 88 brain regions (p = 0.019, corrected for multiple comparisons), including 10 regions of the default-mode network, an effect modulated by age. This easily applicable protocol yielded a practical assessment of CVR in cognitive decline. PMID- 25146455 TI - Specific multi-nutrient enriched diet enhances hippocampal cholinergic transmission in aged rats. AB - Fortasyn Connect (FC) is a specific nutrient combination designed to target synaptic dysfunction in Alzheimer's disease by providing neuronal membrane precursors and other supportive nutrients. The aim of the present study was to investigate the effects of FC on hippocampal cholinergic neurotransmission in association with its effects on synaptic membrane formation in aged rats. Eighteen-month-old male Wistar rats were randomized to receive a control diet for 4 weeks or an FC-enriched diet for 4 or 6 weeks. At the end of the dietary treatments, acetylcholine (ACh) release was investigated by in vivo microdialysis in the right hippocampi. On completion of microdialysis studies, the rats were sacrificed, and the left hippocampi were obtained to determine the levels of choline, ACh, membrane phospholipids, synaptic proteins, and choline acetyltransferase. Our results revealed that supplementation with FC diet for 4 or 6 weeks, significantly enhanced basal and stimulated hippocampal ACh release and ACh tissue levels, along with levels of phospholipids. Feeding rats the FC diet for 6 weeks significantly increased the levels of choline acetyltransferase, the presynaptic marker Synapsin-1, and the postsynaptic marker PSD-95, but decreased levels of Nogo-A, a neurite outgrowth inhibitor. These data show that the FC diet enhances hippocampal cholinergic neurotransmission in aged rats and suggest that this effect is mediated by enhanced synaptic membrane formation. These data provide further insight into cellular and molecular mechanisms by which FC may support memory processes in Alzheimer's disease. PMID- 25146456 TI - RIT2, a susceptibility gene for Parkinson's disease in Iranian population. PMID- 25146457 TI - A tetrameric cage with D2h symmetry through alkyne metathesis. AB - Shape-persistent covalent organic polyhedrons (COPs) with ethynylene linkers are usually prepared through kinetically controlled cross-coupling reactions. The high-yielding synthesis of ethynylene-linked rigid tetrameric cages via one-step alkyne metathesis from readily accessible triyne precursors is presented. The tetrameric cage contains two macrocyclic panels and exhibits D2h symmetry. The assembly of such a COP is a thermodynamically controlled process, which involves the initial formation of macrocycles as key intermediates followed by the connection of two macrocycles with ethynylene linkages. With a large internal cavity, the cage exhibits a high binding selectivity toward C70 (K = 3.9*10(3) L mol(-1)) over C60 (no noticeable binding). PMID- 25146460 TI - Isotope dilution challenge. PMID- 25146461 TI - Solution to Ostwald's dilution law challenge. PMID- 25146458 TI - The impact of multimorbidity on sexual function in middle-aged and older women: beyond the single disease perspective. AB - INTRODUCTION: Little is known about sexual activity and function in women with multiple chronic health conditions. AIM: To examine the impact of multimorbidity on sexual activity and function in middle-aged and older women. METHODS: Multiethnic cross-sectional cohort of 1,997 community-dwelling women (mean age of 60.2 [+/-9.5] years) in California. Structured questionnaires assessed prior diagnoses of common cardiometabolic, colorectal, neuropsychiatric, respiratory, musculoskeletal, and genitourinary conditions. MAIN OUTCOME MEASURES: Sexual desire, frequency of sexual activity, overall sexual satisfaction, and specific sexual problems (i.e., difficulty with arousal, lubrication, orgasm, and pain) were assessed by structured questionnaires. RESULTS: Seventy-one percent of women had two or more diagnosed chronic conditions. Fifty-nine percent reported low sexual desire, 53% reported less than monthly sexual activity, and 47% reported low overall sexual satisfaction. Multimorbidity was associated with increased odds of reporting low sexual desire (OR = 1.11, 95% CI = 1.06-1.17, per each additional chronic condition), less than monthly sexual activity (OR = 1.11, 95% CI = 1.05-1.17 per each additional condition), and low sexual satisfaction (OR = 1.10, 95% CI = 1.04-1.16 per each additional condition), adjusting for age, race/ethnicity, and partner status. Depression and urinary incontinence were each independently associated with low desire (OR = 1.53, 95% CI = 1.19-1.97, and OR = 1.23, 95% CI = 1.00-1.52, respectively), less than monthly sexual activity (OR = 1.39, 95% CI = 1.06-1.83, and OR = 1.29, 95% CI = 1.02-1.62, respectively), and low sexual satisfaction (OR = 1.49, 95% CI = 1.14-1.93, and OR = 1.38, 95% CI = 1.11-1.73, respectively), adjusting for other types of conditions. After adjustment for total number of chronic conditions, age remained a significant predictor of low desire and less than monthly sexual activity, but not sexual satisfaction. CONCLUSIONS: Women with multiple chronic health conditions are at increased risk for decreased sexual function. Depression and incontinence may have particularly strong effects on sexual desire, frequency of activity, and satisfaction in women, independent of other comorbid conditions. Women's overall sexual satisfaction may be more strongly influenced by multimorbidity than age. PMID- 25146459 TI - Current and emerging drugs for acute bacterial skin and skin structure infections: an update. AB - INTRODUCTION: Antibiotic resistance, the emergence of multidrug-resistant bacteria and the exponential rise of methicillin-resistant Staphylococcus aureus (MRSA) acute bacterial skin and skin structure infections (ABSSSI) pose a great threat to the public health. In order to combat these threats, development of new antibiotics is vital and measures to decrease antibiotic resistance should be prioritized. AREAS COVERED: This manuscript provides an overview of the current FDA-approved antibiotics and the antibiotics in development for MRSA ABSSSI. EXPERT OPINION: A great need exists currently for novel antibiotics to combat multidrug-resistant MRSA. As clinicians, it is imperative to implement proper management in order to reduce antibiotic resistance. PMID- 25146462 TI - Reduction of an E. coli O157:H7 and Salmonella composite on fresh strawberries by varying antimicrobial washes and vacuum perfusion. AB - A 2011 outbreak of hemorrhagic colitis, which resulted in the death of two individuals, was associated with contaminated strawberries. A study was conducted to identify antimicrobial washes effective at reducing E. coli O157:H7 and Salmonella enterica from the surface of fresh whole strawberries during two minute immersion washes. Twenty-seven antimicrobial treatments were tested. Vacuum perfusion was applied to strawberries during chlorine and peracetic acid treatments to promote infiltration of sanitizer into porous strawberry tissue. Strawberries were inoculated to 7.1logCFU/strawberry with a seven-strain bacterial composite, consisting of three strains of E. coli O157:H7 and four serovars of Salmonella enterica. Berries were air-dried for 2h and immersed in circulating antimicrobial solutions for 120s at 22 degrees C. Four treatments reduced >=3.0logCFU/strawberry, including (a) 1% acetic acid+1% H2O2, (b) 30% ethanol+1% H2O2, (c) 90ppm peracetic acid, and (d) 1% lactic acid+1% H2O2. Two additional treatments that reduced 2.8logCFU/strawberry were (a) 40% ethanol, and (b) 1% each of phosphoric+fumaric acids. Eight treatments reduced 2.0 2.6logCFU/strawberry. Five treatments reduced <1.45CFU/strawberry, including (a) 1% citric acid, (b) 1% lactic acid, (c) 1% acetic acid, (d) 0.5% each of acetic+citric acids and (e) 0.5% each of acetic+lactic acids. The use of vacuum perfusion with 200ppm chlorine or 90ppm peracetic acid did not reduce greater populations of pathogens than did the same treatments without vacuum perfusion. Fourteen treatments reduced no more pathogens (p<0.05) than did sterile deionized water. Results from this study provide some options for end-point decontamination of strawberries for retail operations just prior to serving to customers. PMID- 25146463 TI - Combination of pulsed electric fields, mild heat and essential oils as an alternative to the ultrapasteurization of liquid whole egg. AB - The production of microbiologically safe liquid whole egg (LWE) by industrial ultrapasteurization is restricted by the high thermal sensitivity of LWE components. This research proposes an alternative treatment based on the application of pulsed electric fields (PEF) and mild heat, in the presence of natural essential oils (EOs) or their individual components (ICs). The obtained results indicate that the successive application of PEF (25kV/ and 100kJ/kg) followed by heat (60 degrees C during 3.5') to LWE added with 200MUL/L of lemon EO would reach 4log10cycles of inactivation of Salmonella Senftenberg 775W and Listeria monocytogenes, when any of these barriers acting alone inactivated less than 1.5log10cycles of either bacteria. Therefore, the synergism between lemon EO and the successive application of PEF and heat would provide a safety level similar to that of ultrapasteurization treatment for Salmonella Senftenberg 775W and L. monocytogenes, but at a lower temperature. To a lesser extent, synergism with the successive application of PEF and heat was also observed in the presence of 200MUL/L of carvacrol, citral, (+)-limonene, or mandarin EO, reaching about 3.5log10cycles of inactivation in Salmonella Senftenberg and 3.0log10cycles in L. monocytogenes, respectively. A sensory test on LWE containing 200MUL/L of each additive in the form of omelets and sponge cakes revealed that this concentration of mandarin EO, lemon EO, or (+)-limonene did not decrease the sensory acceptability of the LWE-containing products, and lemon EO and mandarin EO even increased the hedonic acceptability of sponge cakes. In conclusion, this process could be applied in the food industry to obtain microbiologically safe LWE, which could be used to produce egg-based products without decreasing (and even increasing) their sensory appeal. PMID- 25146464 TI - Oxygenated monoterpenes citral and carvacrol cause oxidative damage in Escherichia coli without the involvement of tricarboxylic acid cycle and Fenton reaction. AB - Oxygenated monoterpenes citral and carvacrol are common constituents of many essential oils (EOs) that have been extensively studied as antimicrobial agents but whose mechanisms of microbial inactivation have not been totally elucidated. A recent study described a mechanism of Escherichia coli death for (+)-limonene, a hydrocarbon monoterpene also frequently present in EOs, similar to the common mechanism proposed for bactericidal antibiotics. This mechanism involves the formation of Fenton-mediated hydroxyl radical, a reactive oxygen species (ROS), via tricarboxylic acid (TCA) cycle, which would ultimately inactivate cells. Our objective was to determine whether E. coli MG1655 inactivation by citral and carvacrol follows a similar mechanism of cell death. Challenging experiments with 300MUL/L citral and 100MUL/L carvacrol inactivated at least 2.5log10cycles of exponentially growing cells in 3h under aerobic conditions. The presence of thiourea (an ROS scavenger) reduced cell inactivation in 2log10cycles, demonstrating the role of ROS in cell death. Decreased resistance of a DeltarecA mutant (deficient in an enzyme involved in SOS response to DNA damage) indicated that citral and carvacrol caused oxidative damage to DNA. Although the mechanism of E. coli inactivation by carvacrol and citral was similarly mediated by ROS, their formation did not follow the same pathways described for (+)-limonene and bactericidal drugs because neither Fenton reaction nor NADH production via the TCA cycle was involved in cell death. Moreover, further experiments demonstrated antimicrobial activity of citral and carvacrol in anaerobic environments without the involvement of ROS. As a consequence, cell death by carvacrol and citral in anaerobiosis follows a different mechanism than that observed under aerobic conditions. These results demonstrated a different mechanism of inactivation by citral and carvacrol with regard to (+)-limonene and bactericidal antibiotics, indicating the complexity of the mechanisms of bacterial inactivation among EO constituents. Advancements in the description of these mechanisms will help in extending and improving the use of these compounds as natural antimicrobials. PMID- 25146465 TI - Moral Identity and Adolescent Prosocial and Antisocial Behaviors: Interactions with Moral Disengagement and Self-regulation. AB - Moral identity has been positively linked to prosocial behaviors and negatively linked to antisocial behaviors; but, the processes by which it is linked to such outcomes are unclear. The purpose of the present study was to examine moral identity not only as a predictor, but also as a moderator of relationships between other predictors (moral disengagement and self-regulation) and youth outcomes (prosocial and antisocial behaviors). The sample consisted of 384 adolescents (42 % female), ages 15-18 recruited from across the US using an online survey panel. Latent variables were created for moral identity, moral disengagement, and self-regulation. Structural equation models assessed these latent variables, and interactions of moral identity with moral disengagement and self-regulation, as predictors of prosocial (charity and civic engagement) and antisocial (aggression and rule breaking) behaviors. None of the interactions were significant predicting prosocial behaviors. For antisocial behaviors, the interaction between moral identity and moral disengagement predicted aggression, while the interaction between moral identity and self-regulation was significant in predicting aggression and rule breaking. Specifically, at higher levels of moral identity, the positive link between moral disengagement and aggression was weaker, and the negative link between self-regulation and both antisocial behaviors was weaker. Thus, moral identity may buffer against the maladaptive effects of high moral disengagement and low self-regulation. PMID- 25146467 TI - Engineering the donor selectivity of D-fructose-6-phosphate aldolase for biocatalytic asymmetric cross-aldol additions of glycolaldehyde. AB - D-Fructose-6-phosphate aldolase (FSA) is a unique catalyst for asymmetric cross aldol additions of glycolaldehyde. A combination of a structure-guided approach of saturation mutagenesis, site-directed mutagenesis, and computational modeling was applied to construct a set of FSA variants that improved the catalytic efficiency towards glycolaldehyde dimerization up to 1800-fold. A combination of mutations in positions L107, A129, and A165 provided a toolbox of FSA variants that expand the synthetic possibilities towards the preparation of aldose-like carbohydrate compounds. The new FSA variants were applied as highly efficient catalysts for cross-aldol additions of glycolaldehyde to N carbobenzyloxyaminoaldehydes to furnish between 80-98 % aldol adduct under optimized reaction conditions. Donor competition experiments showed high selectivity for glycolaldehyde relative to dihydroxyacetone or hydroxyacetone. These results demonstrate the exceptional malleability of the active site in FSA, which can be remodeled to accept a wide spectrum of donor and acceptor substrates with high efficiency and selectivity. PMID- 25146468 TI - Unexpected synergy between magnetic iron chains and stacked B6 rings in Nb6Fe(1 x)Ir(6+x)B8. AB - The synergistic combination of experiment and density functional theory has led to the discovery of the first ferromagnetic material, Nb6Fe(1-x)Ir(6+x)B8, containing in its crystal structure iron chains embedded in stacked B6 rings. The strong ferromagnetic Fe-Fe interactions found in the iron chains induce an unexpected strengthening of the B-B interactions in the B6 rings. Beside these strong B-B interactions, strong interlayer metal-boron bonds (Ir-B and Nb-B) ensure the overall structural stability of this phase, while the magnetic Fe-Fe interactions are mainly responsible for the observed ferromagnetic ordering below T(C)=350 K. PMID- 25146466 TI - Ecological context, concentrated disadvantage, and youth reoffending: identifying the social mechanisms in a sample of serious adolescent offenders. AB - Serious youthful offenders are presented with a number of significant challenges when trying to make a successful transition from adolescence to adulthood. One of the biggest obstacles for these youth to overcome concerns their ability to desist from further antisocial behavior, and although an emerging body of research has documented important risk and protective factors associated with desistance, the importance of the neighborhoods within which these youth reside has been understudied. Guided by the larger neighborhood effects on crime literature, the current study examines the direct and indirect effects of concentrated disadvantage on youth reoffending among a sample of highly mobile, serious youthful offenders. We use data from Pathways to Desistance, a longitudinal study of serious youthful offenders (N = 1,354; 13.6% female; 41.4% African American, 33.5% Hispanic, 20.2% White), matched up with 2000 Census data on neighborhood conditions for youth's main residence location during waves 7 and 8 of the study. These waves represent the time period in which youth are navigating the transition to adulthood (aged 18-22; average age = 20). We estimate structural equation models to determine direct effects of concentrated disadvantage on youth reoffending and also to examine the possible indirect effects working through individual-level mechanisms as specified by theoretical perspectives including social control (e.g., unsupervised peer activities), strain (e.g., exposure to violence), and learning (e.g., exposure to antisocial peers). Additionally, we estimate models that take into account the impact that a change in neighborhood conditions may have on the behavior of youth who move to new residences during the study period. Our results show that concentrated disadvantage is indirectly associated with youth reoffending primarily through its association with exposure to deviant peers. Taking into account youth mobility during the study period produced an additional indirect pathway by which concentrated disadvantage is associated with goal blockage (i.e., the gap between belief in conventional goals and perceived potential to reach those goals), which was then associated with exposure to deviant peers and indirectly, reoffending behavior. We conclude that the neighborhood effects literature offers a promising framework for continued research on understanding the successful transition to adulthood by serious youthful offenders. PMID- 25146470 TI - Integrating transcriptome and epigenome: putting together the pieces of the type 2 diabetes pathogenesis puzzle. PMID- 25146471 TI - Is there a sweet spot for Nrf2 activation in the treatment of diabetic kidney disease? PMID- 25146472 TI - Role for tet in hyperglycemia-induced demethylation: a novel mechanism of diabetic metabolic memory. PMID- 25146473 TI - Visual fields refine understanding of diabetic retinopathy progression. PMID- 25146477 TI - Comment on Wu and Spiegelman. Irisin ERKs the fat. Diabetes 2014;63:381-383. PMID- 25146474 TI - Combined therapy with GABA and proinsulin/alum acts synergistically to restore long-term normoglycemia by modulating T-cell autoimmunity and promoting beta-cell replication in newly diabetic NOD mice. AB - Antigen-based therapies (ABTs) fail to restore normoglycemia in newly diabetic NOD mice, perhaps because too few beta-cells remain by the time that ABT-induced regulatory responses arise and spread. We hypothesized that combining a fast acting anti-inflammatory agent with an ABT could limit pathogenic responses while ABT-induced regulatory responses arose and spread. gamma-Aminobutyric acid (GABA) administration can inhibit inflammation, enhance regulatory T-cell (Treg) responses, and promote beta-cell replication in mice. We examined the effect of combining a prototypic ABT, proinsulin/alum, with GABA treatment in newly diabetic NOD mice. Proinsulin/alum monotherapy failed to correct hyperglycemia, while GABA monotherapy restored normoglycemia for a short period. Combined treatment restored normoglycemia in the long term with apparent permanent remission in some mice. Proinsulin/alum monotherapy induced interleukin (IL)-4- and IL-10-secreting T-cell responses that spread to other beta-cell autoantigens. GABA monotherapy induced moderate IL-10 (but not IL-4) responses to beta-cell autoantigens. Combined treatment synergistically reduced spontaneous type 1 T helper cell responses to autoantigens, ABT-induced IL-4 and humoral responses, and insulitis, but enhanced IL-10 and Treg responses and promoted beta-cell replication in the islets. Thus, combining ABT with GABA can inhibit pathogenic T cell responses, induce Treg responses, promote beta-cell replication, and effectively restore normoglycemia in newly diabetic NOD mice. Since these treatments appear safe for humans, they hold promise for type 1 diabetes intervention. PMID- 25146478 TI - Response to Comment on Wu and Spiegelman. Irisin ERKs the fat. Diabetes 2014;63:381-383. PMID- 25146479 TI - Comment on Fabbrini et al. Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects. Diabetes 2014;63:976 981. PMID- 25146480 TI - Response to Comment on Fabbrini et al. Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects. Diabetes 2014;63:976-981. PMID- 25146481 TI - Assessment of cell viability after manipulation with insulator-based dielectrophoresis. AB - The effects of insulator-based DEP (iDEP) manipulation on cell viability were investigated by varying operating conditions and the shape of the insulating structures. Experiments were conducted with Escherichia coli, Bacillus subtilis, and Saccharomyces cerevisiae cells by varying the applied potential (300-1000 V), exposure time (1-4 min), and composition of the suspending medium (0-10% glucose); using devices made from polydimethylsiloxane. Cell viability was quantified employing Trypan blue staining protocols. The results illustrated a strong decrease in cell survival at higher applied electric potentials and exposure times; and an increase in cell viability obtained by increasing suspending medium osmolality. The composition and structure of the cell wall also played a major role on cell survival, where prokaryotic Gram-positive B. subtilis was the most resilient cell strain, while eukaryotic S. cerevisiae had the lowest survival rate. Due to the popularity of iDEP in applications with biological cells, characterizing how iDEP operating conditions affect cell viability is essential. PMID- 25146482 TI - Coupling between side chain interactions and binding pocket flexibility in HLA B*44:02 molecules investigated by molecular dynamics simulations. AB - MHC class I molecules present antigenic peptides to cytotoxic T-cells at the cell surface. Peptide loading of class I molecules in the endoplasmatic reticulum can involve interaction with the tapasin chaperone protein. The human class I allotype HLA-B*44:02 with an Asp at position 116 at the floor of the F pocket (which binds the peptide C-terminal residues) depends on tapasin for efficient peptide loading. However, HLA-B*44:05 (identical to B*44:02 except for tyrosine 116) can efficiently load peptides in the absence of tapasin. Both allotypes adopt very similar structures in the presence of the same peptide. Molecular dynamics simulations indicate a significantly higher conformational flexibility of the F pocket in the absence of a peptide for B*44:02 compared to B*44:05. Free energy simulations to open the F pocket indicate a molecular side chain switch mechanism that underlies the global opening motion. This side chain switch involves the rearrangement of salt bridges and hydrogen bonding of the basic arginine 97 with three acidic aspartate residues 114, 116 and 156 near the F pocket. A replica exchange simulation to specifically accelerate side chain motions demonstrates that the same side chain rearrangements induce global opening motions of the F pocket. In case of B*44:05 the free energy barrier for F pocket opening was significantly higher compared to B*44:02 and no associated side chain rearrangement was observed. Such coupling of local side chain rearrangements with global conformational changes might be the basis for allosteric changes in other class I allotypes as well as for allosteric changes in other proteins. PMID- 25146483 TI - Structural studies of virus-antibody immune complexes (poliovirus type I): Characterization of the epitopes in 3D. AB - The inactivated polio vaccine (IPV) contains poliovirus (PVs) samples that belong to serotypes 1, 2 and 3. All three serotypes contain the D-antigen, which induces protective antibodies. The antigenic structure of PVs consists of at least four different antigenic sites and the D-antigen content represents the combined activity of multiple epitopes (Ferguson et al., 1993; Minor, 1990; Minor et al., 1986). The potency of IPV vaccines is determined by measuring the D-antigen content. Several ELISA methods have been developed using polyclonal or monoclonal antibodies (Mabs) in order to quantify the D-antigen content. Characterization of the epitopes recognized by the different Mabs is crucial to map the entire virus surface and ensure the presence of epitopes able to induce neutralizing antibodies. In a new approach, combining cryo-electron microscopy and image analysis with X-ray crystallography data available along with identification of exposed amino acids we have mapped in 3D the epitope sites recognized by five specific Fabs and one Mab and characterized precisely the antigenic sites for these Mabs. We propose this method to be used to map the entire "epitopic" surface of virus. PMID- 25146484 TI - Cell-mediated immune response: a clinical review of the therapeutic potential of human papillomavirus vaccination. AB - OBJECTIVE: This clinical review aims to assess the efficacy of human papillomavirus 16/18 (HPV16/18) vaccination on the cell-mediated immune response in women with existing cervical intraepithelial neoplasia or cervical cancer induced by HPV16 or HPV18. DATA SOURCES AND STUDY SELECTION: A focused and thorough literature search conducted in five different databases found 996 publications. Six relevant articles were chosen for further review. In total, 154 patients (>18 years of age) were enrolled in prospective study trials with 3-15 months of follow up. The vaccine applications were administered two to four times. The vaccines contained different combinations of HPV16 and HPV18 and early proteins, E6 and E7. The primary outcome was the cell-mediated immune response. Correlation to clinical outcome (histopathology) and human leukocyte antigen genes were secondary endpoints. RESULTS: All vaccines triggered a detectable cell mediated immune response, some of which were statistically significant. Correlations between immunological response and clinical outcome (histopathology) were not significant, so neoplasms may not be susceptible to vaccine-generated cytotoxic T cells (CD8(+)). CONCLUSIONS: Prophylactic HPV vaccines have been introduced to reduce the incidence of cervical cancer in young women. Women already infected with HPV could benefit from a therapeutic HPV vaccination. Hence, it is important to continue the development of therapeutic HPV vaccines to lower the rate of HPV-associated malignancies and crucial to evaluate vaccine efficacy clinically. This clinical review represents an attempt to elucidate the theories supporting the development of an HPV vaccine with a therapeutic effect on human papillomavirus-induced malignancies of the cervix. PMID- 25146485 TI - The N-terminal cleavable pre-sequence encoded in the first exon of cystathionine gamma-synthase contains two different functional domains for chloroplast targeting and regulation of gene expression. AB - Chloroplast transit peptide sequences (cTPs) located in the N-terminal region of nuclear-encoded chloroplast proteins are essential for their sorting, and are generally cleaved from the proteins after their import into the chloroplasts. The Arabidopsis thaliana cystathionine gamma-synthase (CGS), the first committed enzyme of methionine biosynthesis, is a nuclear-encoded chloroplast protein. Arabidopsis CGS possesses an N-terminal extension region that is dispensable for enzymatic activity. This N-terminal extension contains the cTP and several functional domains including an MTO1 region, the cis-element for post transcriptional feedback regulation of CGS1 that codes for CGS. A previous report suggested that the cTP cleavage site of CGS is located upstream of the MTO1 region. However, the region required for protein sorting has not been analyzed. In this study, we carried out functional analyses to elucidate the region required for chloroplast targeting by using a chimeric protein, Ex1:GFP, in which the CGS1 exon 1 coding region containing the N-terminal extension was tagged with green fluorescent protein. The sequence upstream of the MTO1 region was responsible for efficient chloroplast targeting and for avoidance of missorting to the mitochondria. Our data also showed that the major N-terminus of Ex1:GFP is Ala91, which is located immediately downstream of the MTO1 region, and the MTO1 region is not retained in the mature Ex1:GFP accumulated in the chloroplast. These findings suggest that the N-terminal cleavable pre-sequence harbors dual functions in protein sorting and in regulating gene expression. Our study highlights the unique properties of Arabidopsis CGS cTP among chloroplast targeted proteins. PMID- 25146486 TI - Characterization of a wheat R2R3-MYB transcription factor gene, TaMYB19, involved in enhanced abiotic stresses in Arabidopsis. AB - MYB-type proteins have been shown to participate in multiple stress responses. In the present study, we identified a gene in wheat induced by multiple abiotic stresses, TaMYB19, which encodes a R2R3-type MYB protein. Three highly homologous sequences of TaMYB19 were isolated from hexaploid wheat. Using the nulli tetrasomic (NT) lines of Chinese Spring wheat, the three sequences were localized to chromosomes 1A, 1B and 1D and designated as TaMYB19-A, TaMYB19-B and TaMYB19 D, respectively. The expression patterns of these three genes were similar under different stress conditions. The TaMYB19-B sequence was selected for further analysis. The TaMYB19-B protein localized to the nucleus. A detailed characterization of Arabidopsis transgenic plants overexpressing the TaMYB19-B gene revealed that the TaMYB19-B protein could improve tolerance to multiple stresses during the seedling stage. We also found that the overexpression of TaMYB19-B resulted in changes in several physiological indices and altered the expression levels of a number of abiotic stress-related genes, allowing the plants to overcome adverse conditions. These results indicate that the TaMYB19 protein plays an important role in plant stress tolerance and that modification of the expression of this protein may improve abiotic stress tolerance in crop plants. PMID- 25146487 TI - The gap between scientific evidence and clinical practice: 5-aminosalicylates are frequently used for the treatment of Crohn's disease. AB - BACKGROUND: There is uncertain evidence of effectiveness of 5-aminosalicylates (5 ASA) to induce and maintain response and remission of active Crohn's disease (CD), and weak evidence to support their use in post-operative CD. AIM: To assess the frequency and determinants of 5-ASA use in CD patients and to evaluate the physicians' perception of clinical response and side effects to 5-ASA. METHODS: Data from the Swiss Inflammatory Bowel Disease Cohort, which collects data since 2006 on a large sample of IBD patients, were analysed. Information from questionnaires regarding utilisation of treatments and perception of response to 5-ASA were evaluated. Logistic regression modelling was performed to identify factors associated with 5-ASA use. RESULTS: Of 1420 CD patients, 835 (59%) were ever treated with 5-ASA from diagnosis to latest follow-up. Disease duration >10 years and colonic location were both significantly associated with 5-ASA use. 5 ASA treatment was judged to be successful in 46% (378/825) of treatment episodes (physician global assessment). Side effects prompting stop of therapy were found in 12% (98/825) episodes in which 5-ASA had been stopped. CONCLUSIONS: 5 Aminosalicylates were frequently prescribed in patients with Crohn's disease in the Swiss IBD cohort. This observation stands in contrast to the scientific evidence demonstrating a very limited role of 5-ASA compounds in the treatment of Crohn's disease. PMID- 25146488 TI - Pathways towards risk: syndemic conditions mediate the effect of adversity on HIV risk behaviors among young men who have sex with men (YMSM). AB - Research shows that young men who have sex with men (YMSM) engage in higher rates of health risk behaviors and experience higher rates of negative health outcomes than their peers. The purpose of this study is to determine if the effects of adversity on HIV risk are mediated by syndemics (co-occurring health problems). Participants were 470 ethnically diverse YMSM ages 18 to 24 recruited between 2005 and 2006 and surveyed every 6 months for 24 months. Regression analyses examined the impact of adversity on syndemics (emotional distress, substance use, and problematic alcohol use) and the effects of both adversity and syndemics on HIV risk behaviors over time. Gay-related discrimination and victimization-among other adversity variables-were significantly associated with syndemics and condomless sex (CS). Syndemics mediated the effects of adversity on CS in all models. Adverse events impact HIV risk taking among YMSM through syndemics. These findings suggest that prevention programs aimed at reducing adversity may reduce both the synergistic effect of multiple psychosocial health problems and HIV risk taking. PMID- 25146489 TI - Engineering the electrochemical capacitive properties of graphene sheets in ionic liquid electrolytes by correct selection of anions. AB - Graphene sheet (GS)-ionic liquid (IL) supercapacitors are receiving intense interest because their specific energy density far exceeds that of GS-aqueous electrolytes supercapacitors. The electrochemical properties of ILs mainly depend on their diverse ions, especially anions. Therefore, identifying suitable IL electrolytes for GSs is currently one of the most important tasks. The electrochemical behavior of GSs in a series of ILs composed of 1-ethyl-3 methylimidazolium cation (EMIM(+)) with different anions is systematically studied. Combined with the formula derivation and building models, it is shown that the viscosity, ion size, and molecular weight of ILs affect the electrical conductivity of ILs, and thus, determine the electrochemical performances of GSs. Because the EMIM-dicyanamide IL has the lowest viscosity, ion size, and molecular weight, GSs in it exhibit the highest specific capacitance, smallest resistance, and best rate capability. In addition, because the tetrafluoroborate anion (BF4( )) has the best electrochemical stability, the GS-[EMIM][BF4] supercapacitor has the widest potential window, and thus, displays the largest energy density. These results may provide valuable information for selecting appropriate ILs and designing high-performance GS-IL supercapacitors to meet different needs. PMID- 25146490 TI - Otlertuzumab (TRU-016), an anti-CD37 monospecific ADAPTIR(TM) therapeutic protein, for relapsed or refractory NHL patients. AB - CD37 is cell surface tetraspanin present on normal and malignant B cells. Otlertuzumab (TRU-016) is a novel humanized anti-CD37 protein therapeutic. Patients with relapsed or refractory follicular non-Hodgkin lymphoma (FL), mantle cell lymphoma (MCL), or Waldenstrom's macroglobulinaemia (WM) received otlertuzumab at 20 mg/kg administered intravenously once a week for up to 8 weeks followed by 4 monthly doses. Sixteen patients were treated; median age was 62.5 years (range, 41-81), and median number of prior regimens was 4 (range, 1-7). Twelve patients were refractory to prior treatment, 5 were refractory to rituximab. The mean terminal half-life was 9.5 days. Lymph node reduction of >=50% by computerized tomography scan measurements was seen in 3 of 12 patients, including one FL patient who had a partial response. One WM patient had a minor response. The most frequent adverse events were neutropenia, fatigue, nausea, thrombocytopenia, diarrhoea, and peripheral oedema; most were grade 1/2. Otlertuzumab treatment appears to have been well tolerated by the patients in this study. Clinical activity was observed in this small heterogeneous cohort of highly refractory, heavily pretreated B-cell non-Hodgkin lymphoma patients. These data suggest that further clinical investigation in non-Hodgkin lymphoma is warranted. PMID- 25146491 TI - Differential modification of genetic susceptibility to childhood eczema by two probiotics. AB - BACKGROUND: In a double-blind, randomized, placebo-controlled birth cohort, we have recently shown a beneficial effect of Lactobacillus rhamnosus HN001 (HN001) for the prevention of eczema in children through to 6 years of age but no effect of Bifidobacterium animalis subsp lactis HN019 (HN019). OBJECTIVE: Among this cohort of children, we aim to investigate whether these probiotics could modify the expression of genetic predisposition to eczema conferred by genetic variation in susceptibility genes. METHODS: Thirty-three eczema susceptibility SNPs (in eleven genes) were genotyped in 331 children of European ancestry. RESULTS: Children who carried a genetic variant that put them at a high risk of developing eczema were less likely to develop eczema if they had been randomized to the HN001 intervention group compared to those in the placebo group. HN019 was also able to protect against the effects of some SNPs. As well as modifying genetic susceptibility to childhood eczema, HN001 was also found to modify genetic susceptibility to eczema severity and atopy risk. CONCLUSION AND CLINICAL RELEVANCE: This is the first study to show an effect of a probiotic on reducing eczema risk amongst those with particular eczema-associated genotypes. Our findings suggest that Lactobacillus rhamnosus HN001 may be particularly effective in preventing eczema in children with specific high-risk genotypes. PMID- 25146492 TI - Reduction in behavior problems with omega-3 supplementation in children aged 8-16 years: a randomized, double-blind, placebo-controlled, stratified, parallel-group trial. AB - BACKGROUND: While limited evidence suggests that omega-3 supplementation may reduce antisocial behavior in children, studies have not reported on posttreatment follow-up and most treatment periods have been of short duration. This study tests the hypothesis that omega-3 supplementation over 6 months will reduce behavior problems in children both at the end of treatment and at 6 months post treatment. METHODS: In this randomized, double-blind, placebo-controlled, stratified, parallel-group trial, a community sample of 8-16 year old children were randomized into a treatment group (N = 100) and a placebo-control group (N = 100). The supplementation consisted of a fruit drink containing 1 g/day of omega 3 or a placebo consisting of the same fruit drink without omega-3. Participants, caregivers, and research assistants were blinded to group assignment. The primary outcome measures of externalizing and internalizing behavior problems were reported by both caregivers and their children in a laboratory setting at 0 months (baseline), 6 months (end of treatment) and 12 months (6 months post treatment), together with the secondary outcome measures of parental antisocial behavior. Data were analyzed on an intention-to-treat basis including all participants. TRIAL REGISTRATION: ClinicalTrials.gov: http://clinicaltrials.gov/ct2/show/NCT02016079?term=mauritius&rank=2 RESULTS: Significant group * time interactions were observed with the treatment group showing long-term improvements in child behavior problems. The average posttreatment effect size was d = -.59. Effects were documented for parent reports, but with the exception of proactive and reactive aggression, child report data were nonsignificant. Parents whose children took omega-3 showed significant posttreatment reductions in their own antisocial and aggressive behavior. This improvement in caregiver behavior partly mediated the improvements observed in child behavior. CONCLUSIONS: Findings provide initial evidence that omega-3 supplementation can produce sustained reductions in externalizing and internalizing behavior problems. Results are the first to report improvements in caregiver behavior, and to establish this improvement as a part-mechanism for the efficacy of omega-3. PMID- 25146493 TI - Application of isoabsorption plots generated by high-performance liquid chromatography with diode array detection to the development of multicomponent quantitative analysis of traditional herbal medicines. AB - Multicomponent quantitative analysis is one of the mainstream quality control methods of traditional herbal medicines. Since the constituents of traditional herbal medicines samples are complex, the development of high-performance liquid chromatography methods is laborious. In this study, an isoabsorption plot, a chromatographic/spectrometric data image plotted by diode array detection was utilized to facilitate the establishment of a high-performance liquid chromatography method by optimizing and validating the detection conditions off line. Consequently a simple, reliable and accurate method for simultaneous determination of seven active polyphenolic components (protocatechuic acid, chlorogenic acid, caffeic acid, p-coumaric acid, rosmarinic acid, scutellarin, and apigenin) in Qingfei mixture, a long-used Chinese prescription, was developed. The chromatographic separation was performed on a C18 column with gradient elution of phosphoric acid aqueous solution (0.05%, v/v) and acetonitrile, and a wavelength switch program optimized with isoplot was adopted for detection. The method was validated in terms of linearity, sensitivity, precision, repeatability, and accuracy and was successfully applied to the simultaneous determination of the seven polyphenolic components in different production batches of Qingfei Mixture. These results indicated that isoplot is an effective tool to improve the establishment of multicomponent quantitative analysis methods. PMID- 25146494 TI - Effect of different breath alcohol concentrations on driving performance in horizontal curves. AB - Driving under the influence of alcohol on curved roadway segments has a higher risk than driving on straight segments. To explore the effect of different breath alcohol concentration (BrAC) levels on driving performance in roadway curves, a driving simulation experiment was designed to collect 25 participants' driving performance parameters (i.e., speed and lane position) under the influence of 4 BrAC levels (0.00%, 0.03%, 0.06% and 0.09%) on 6 types of roadway curves (3 radii*2 turning directions). Driving performance data for 22 participants were collected successfully. Then the average and standard deviation of the two parameters were analyzed, considering the entire curve and different sections of the curve, respectively. The results show that the speed throughout curves is higher when drinking and driving than during sober driving. The significant interaction between alcohol and radius exists in the middle and tangent segments after a curve exit, indicating that a small radius can reduce speed at high BrAC levels. The significant impairment of alcohol on the stability of speed occurs mainly in the curve section between the point of curve (PC) and point of tangent (PT), with no impairment noted in tangent sections. The stability of speed is significantly worsened at higher BrAC levels. Alcohol and radius have interactive effects on the standard deviation of speed in the entry segment of curves, indicating that the small radius amplifies the instability of speed at high BrAC levels. For lateral movement, drivers tend to travel on the right side of the lane when drinking and driving, mainly in the approach and middle segments of curves. Higher BrAC levels worsen the stability of lateral movement in every segment of the curve, regardless of its radius and turning direction. The results are expected to provide reference for detecting the drinking and driving state. PMID- 25146495 TI - The effects of cycle lanes, vehicle to kerb distance and vehicle type on cyclists' attention allocation during junction negotiation. AB - Increased frequency of cycle journeys has led to an escalation in collisions between cyclists and vehicles, particularly at shared junctions. Risks associated with passing decisions have been shown to influence cyclists' behavioural intentions. The current study extended this research by linking not only risk perception but also attention allocation (via tracking the eye movements of twenty cyclists viewing junction approaches presented on video) to behavioural intentions. These constructs were measured in a variety of contexts: junctions featuring cycle lanes, large vs. small vehicles and differing kerb to vehicle distances). Overall, cyclists devoted the majority of their attention to the nearside (side closest to kerb) of vehicles, and perceived near and offside (side furthest from kerb) passing as most risky. Waiting behind was the most frequent behavioural intention, followed by nearside and then offside passing. While cycle lane presence did not affect behaviour, it did lead to nearside passing being perceived as less risky, and to less attention being devoted to the offside. Large vehicles led to increased risk perceived with passing, and more attention directed towards the rear of vehicles, with reduced offside passing and increased intentions to remain behind the vehicle. Whether the vehicle was large or small, nearside passing was preferred around 30% of the time. Wide kerb distances increased nearside passing intentions and lower associated perceptions of risk. Additionally, relationships between attention and both risk evaluations and behaviours were observed. These results are discussed in relation to the cyclists' situational awareness and biases that various contextual factors can introduce. From these, recommendations for road safety and training are suggested. PMID- 25146496 TI - A few seconds to have an accident, a long time to recover: consequences for road accident victims from the ESPARR cohort 2 years after the accident. AB - OBJECTIVE: The aim of the present study was to describe the consequences of a road accident in adults, taking account of the type of road user, and to determine predictive factors for consequences at 2 years. DESIGN: Prospective follow-up study. METHODS: The cohort was composed of 1168 victims of road traffic accidents, aged >=16 years. Two years after the accident, 912 victims completed a self-administered questionnaire. Weighted logistic regression models were implemented to compare casualties still reporting impact related to the accident versus those reporting no residual impact. Five outcomes were analysed: unrecovered health status, impact on occupation or studies, on familial or affective life, on leisure or sport activities and but also the financial difficulties related to the accident. RESULTS: 46.1% of respondents were motorised four-wheel users, 29.6% motorised two-wheel (including quad) users, 13.3% pedestrians (including inline skate and push scooter users) and 11.1% cyclists. 53.3% reported unrecovered health status, 32.0% persisting impact on occupation or studies, 25.2% on familial or affective life, 46.9% on leisure or sport activities and 20.2% still had accident-related financial difficulties. Type of user, adjusted on age and gender, was linked to unrecovered health status and to impact on leisure or sport activities. When global severity (as measured by NISS) was integrated in the previous model, type of user was also associated with impact on occupation or studies. Type of user was further associated with impact on occupation or studies and on leisure or sport activities when global severity and the sociodemographic data obtained at inclusion were taken into account. It was not, however, related to any of the outcomes studied here, when the models focused on the injured body region. Finally, type of road user did not seem, on the various predictive models, to be related to financial difficulties due to the accident or to impact on familial or affective life. CONCLUSIONS: Overall, victims were affected by their accident even 2 years after it occurred. The severity of lesions induced by the accident was the main predictive factor. However, considering lesion as intermediary factors between the accident and the recovery status at 2 year post-accident, impact on health status was lower for cyclists than M4W users or M2W users. PMID- 25146498 TI - High-performance thin-layer chromatography for quantification of 1-octacosanol in Antarctic krill (Euphausia superba Dana). AB - 1-Octacosanol is a straight-chain aliphatic 28-carbon fatty alcohol with well known anti-fatigue function. In this study, 1-octacosanol was extracted from Antarctic krill for the first time. Separation of 1-octacosanol was achieved using high-performance thin-layer chromatography (TLC) with a mobile phase consisting of petroleum ether/ethyl acetate/toluene (4 : 1 : 0.05, v/v/v) on precoated silica gel GF254 high-performance TLC plates. The separated 1 octacosanol was quantified using spectrodensitometry with distilled water/bromothymol blue/sodium hydroxide (100 : 0.1 : 0.7, v/w/w) as a chromogenic system. The high-performance TLC method was validated with respect to specificity, linearity, intra- and interplate variation. The stability of the 1 octacosanol-chromogen complex and recovery of 1-octacosanol were also evaluated. Containing ~10.6 ug/mg 1-octacosanol, Antarctic krill is potentially a rich and renewable source of 1-octacosanol. PMID- 25146497 TI - Donor smoking is associated with pulmonary edema, inflammation and epithelial dysfunction in ex vivo human donor lungs. AB - Although recipients of donor lungs from smokers have worse clinical outcomes, the underlying mechanisms are unknown. We tested the association between donor smoking and the degree of pulmonary edema (as estimated by lung weight), the rate of alveolar fluid clearance (AFC; measured by airspace instillation of 5% albumin) and biomarkers of lung epithelial injury and inflammation (bronchoalveolar lavage [BAL] surfactant protein-D (SP-D) and IL-8) in ex vivo lungs recovered from 298 organ donors. The extent of pulmonary edema was higher in current smokers (n = 127) compared to nonsmokers (median 408 g, interquartile range [IQR] 364-500 vs. 385 g, IQR 340-460, p = 0.009). Oxygenation at study enrollment was worse in current smokers versus nonsmokers (median PaO2 /FiO2 214 mm Hg, IQR 126-323 vs. 266 mm Hg, IQR 154-370, p = 0.02). Current smokers with the highest exposure (>=20 pack years) had significantly lower rates of AFC, suggesting that the effects of cigarette smoke on alveolar epithelial fluid transport function may be dose related. BAL IL-8 was significantly higher in smokers while SP-D was lower. These findings indicate that chronic exposure to cigarette smoke has important effects on inflammation, gas exchange, lung epithelial function and lung fluid balance in the organ donor that could influence lung function in the lung transplant recipient. PMID- 25146499 TI - The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits, biochemical changes, and hippocampal synaptic plasticity in an animal model of depression. AB - Depression is a major psychiatric illness that is associated with cognitive dysfunctions. The underlying mechanism of depression-associated memory impairment is unclear. Previously, we showed altered hippocampal synaptic plasticity in an animal model of depression. Although several antidepressants are beneficial in the treatment of depression, very little is known about the effects of these drugs on depression-associated learning and memory deficits. Prolonged antidepressant treatment might contribute to neuroplastic changes required for clinical outcomes. Accordingly, we evaluated the effect of chronic reboxetine (a selective noradrenergic reuptake inhibitor) treatment on depression-induced reduced hippocampal synaptic plasticity, neurotransmitter levels, and spatial learning and memory impairments. Depression was induced in male Wistar rats by the administration of clomipramine from postnatal days 8 to 21, and these rats were treated with reboxetine in adulthood. The neonatal clomipramine administration resulted in impaired hippocampal long-term potentiation (LTP), decreased hippocampal cholinergic activity and monoamine levels, and poor performance in a partially baited eight-arm radial maze task. Chronic reboxetine treatment restored the hippocampal LTP, acetylcholinesterase activity, and levels of biogenic amines and ameliorated spatial learning and memory deficits in the depressed state. Thus, restoration of hippocampal synaptic plasticity might be a cellular mechanism underlying the beneficial effect of reboxetine in depression associated cognitive deficits. This study furthers the existing understanding of the effects of antidepressants on learning, memory, and synaptic plasticity and could ultimately assist in the development of better therapeutic strategies to treat depression and associated cognitive impairments. PMID- 25146500 TI - Overall survival by pattern of recurrence following curative intent surgery for colorectal liver metastasis. AB - BACKGROUND: Following curative intent surgery (CIS) for colorectal liver metastasis (CRLM), patterns of recurrence and subsequent survival outcomes are not widely reported. METHODS: An institutional database (January 2002-December 2012) was reviewed to evaluate patterns of recurrence following CIS for CRLM. RESULTS: 163 patients with CRLM underwent successful CIS. Median follow-up and disease-free interval were 33 and 16 months, respectively. 5-year overall survival (OS) was 55%. After initial CIS, 102 (63%) patients recurred: liver-44% (5-year OS 55%), lung-15% (5-year OS 45%), and other/multifocal-41% (5-year OS 24%). OS for isolated liver and lung recurrences were not significantly different. Liver only recurrence was associated with 1-5 mm liver resection margins (P = 0.048). Lung only recurrence was associated with extrahepatic metastasis (at the time of initial CRLM) (P = 0.025). Other/multifocal recurrence was associated with bilobar CRLM (P = 0.026), and extrahepatic metastasis (P = 0.028). CONCLUSIONS: Patterns of recurrence following CIS for CRLM have important implications for OS. 5-year OS was similar between isolated lung and liver recurrences. During CIS, decreased liver resection margin may be associated with increased risk of liver only recurrence. Patients with aggressive primary or metastatic liver disease are at higher risk for pulmonary or other/multifocal recurrence. PMID- 25146501 TI - High throughput quantitative expression screening and purification applied to recombinant disulfide-rich venom proteins produced in E. coli. AB - Escherichia coli (E. coli) is the most widely used expression system for the production of recombinant proteins for structural and functional studies. However, purifying proteins is sometimes challenging since many proteins are expressed in an insoluble form. When working with difficult or multiple targets it is therefore recommended to use high throughput (HTP) protein expression screening on a small scale (1-4 ml cultures) to quickly identify conditions for soluble expression. To cope with the various structural genomics programs of the lab, a quantitative (within a range of 0.1-100 mg/L culture of recombinant protein) and HTP protein expression screening protocol was implemented and validated on thousands of proteins. The protocols were automated with the use of a liquid handling robot but can also be performed manually without specialized equipment. Disulfide-rich venom proteins are gaining increasing recognition for their potential as therapeutic drug leads. They can be highly potent and selective, but their complex disulfide bond networks make them challenging to produce. As a member of the FP7 European Venomics project (www.venomics.eu), our challenge is to develop successful production strategies with the aim of producing thousands of novel venom proteins for functional characterization. Aided by the redox properties of disulfide bond isomerase DsbC, we adapted our HTP production pipeline for the expression of oxidized, functional venom peptides in the E. coli cytoplasm. The protocols are also applicable to the production of diverse disulfide-rich proteins. Here we demonstrate our pipeline applied to the production of animal venom proteins. With the protocols described herein it is likely that soluble disulfide-rich proteins will be obtained in as little as a week. Even from a small scale, there is the potential to use the purified proteins for validating the oxidation state by mass spectrometry, for characterization in pilot studies, or for sensitive micro-assays. PMID- 25146502 TI - Immunization coverage of 12-23 months old children and associated factors in Jigjiga District, Somali National Regional State, Ethiopia. AB - BACKGROUND: Immunization coverage in Ethiopia is less than the herd immunity level desired to prevent the spread of eight target diseases targeted by the World Health Organization's Expanded Program of Immunization. In particular, the Somali region of the country still has by far the lowest level of immunization coverage. The objective of this study was to measure the immunization coverage of 12-23 months old children and associated factors in the urban and rural areas of Jigjiga district. METHODS: A community based cross-sectional survey was conducted in 582 households with 12-23 months old children in two urban and four rural wards. The data were collected from mothers or caregivers through interviews based on pre-tested and structured questionnaires and from the review of vaccination cards. Data were processed using SPSS version 16. To identify factors associated with the immunization status of children, bivariate and multiple logistic regression analyses were worked out and the Hoshmer and Lemeshow's goodness-of-fit was used to assess the fitness of multiple logistic regression model. RESULTS: Three-fourth (74.6%) of the children surveyed were ever vaccinated, whereas 36.6% were fully vaccinated. The immunization coverage rate from card assessment for Bacillus Calmette-Guerin was 41.8%, while for Oral Polio Vaccine Zero, Oral Polio Vaccine One /Pentavalent1, Oral Polio Vaccine Two /Pentavalent2, Oral Polio Vaccine Three /Pentavalent3, and measles were 10.4%, 41.1%, 33.9%, 27.5%, and 24.9%, respectively. Maternal literacy (AOR = 3.06, 95% CI = 1.64, 5.71), Tetanus Toxoid Vaccine (AOR = 2.43, 95% CI = 1.56, 3.77), place of delivery (AOR = 2.02, 95% CI = 1.24, 3.28), place of residence (AOR = 2.04, 95% CI = 1.33, 3.13), and household visits by health workers (AOR = 1.92, 95% CI = 1.17, 3.16), were found to be factors significantly associated with full immunization in the multivariate logistic regression analysis. CONCLUSIONS: The overall immunization coverage was found to be low. Hence, to increase the immunization coverage and reduce the incidences of missed opportunity, delivery in the health institution should be promoted, the outreach activities of the health institutions should be strengthened and greater utilization of health services by mothers should be encouraged. PMID- 25146504 TI - [Sepsis-associated immunosuppression: no one can afford to neglect]. PMID- 25146505 TI - [Permissive hypohemofiltration and blood purification to salvage acute kidney injury]. PMID- 25146506 TI - [Specification of glucocorticoids application in systemic lupus erythematosus]. PMID- 25146507 TI - [The standardized application of cephalosporin antibiotics: perspective from error in skin test]. PMID- 25146503 TI - Nuclear magnetic resonance spectroscopy with single spin sensitivity. AB - Nuclear magnetic resonance spectroscopy and magnetic resonance imaging at the ultimate sensitivity limit of single molecules or single nuclear spins requires fundamentally new detection strategies. The strong coupling regime, when interaction between sensor and sample spins dominates all other interactions, is one such strategy. In this regime, classically forbidden detection of completely unpolarized nuclei is allowed, going beyond statistical fluctuations in magnetization. Here we realize strong coupling between an atomic (nitrogen vacancy) sensor and sample nuclei to perform nuclear magnetic resonance on four (29)Si spins. We exploit the field gradient created by the diamond atomic sensor, in concert with compressed sensing, to realize imaging protocols, enabling individual nuclei to be located with Angstrom precision. The achieved signal-to noise ratio under ambient conditions allows single nuclear spin sensitivity to be achieved within seconds. PMID- 25146508 TI - [Be objective to the cephalosporins intradermal test]. PMID- 25146509 TI - [The effects of prone position ventilation combined with recruitment maneuvers on outcomes in patients with severe acute respiratory distress syndrome]. AB - OBJECTIVE: To evaluate the effects of prone position ventilation combined with recruitment maneuvers (RM) on clinical outcomes in patients with severe acute respiratory distress syndrome (ARDS). METHODS: In this prospective, randomized, controlled trial, we randomly assigned 116 sequential patients with severe ARDS to the intervention group (which undergo prone-positioning with RM sessions of at least 10 hours) or to the control group (which be left in the supine position). RESULTS: From July 2012 to July 2013, 116 severe ARDS patients sequentially admitted to the critical department of Peking Union Medical College Hospital were enrolled in the study with 60 patients assigned to the control group and 56 patients to the intervention group. No significant difference was found between the two groups in the demographics including the median patient age, sex ratio, initial Acute Physiology and Chronic Health Evaluation II scores, initial pulmonary function and the sources of ARDS. The oxygenation index recorded in the supine position was significantly higher in the intervention group than in the control group since day 3, whereas the positive end-expiratory pressure and fraction of inspired O2 were significantly lower in the intervention group. The plateau pressure and static compliance of the respiratory system were similar in the two groups. The intervention group had shorter length of ICU stay, fewer ventilation days and decreased 28-day mortality than the control group. The tracheotomy ratio and the time to successful extubation were similar in the two groups. No significant difference between the two groups was shown in the incidence of complications, except for the grade 1 pressure sore, which was higher in the intervention group. CONCLUSIONS: In patients with severe ARDS, application of prolonged prone-positioning with RM sessions significantly improves the clinical outcomes. PMID- 25146510 TI - [An association between NF-E2-related factor 2-617 C/A gene polymorphisms and sepsis in Chinese Han population]. AB - OBJECTIVE: To investigate the association between the single nucleotide polymorphisms (SNPs) in NF-E2-related factor 2-617 (NRF2-617) promoter region with the susceptibility to the risk of sepsis. METHODS: In this case-control association study, 203 healthy controls and 174 patients with sepsis in Wenzhou Han population were enrolled and genotyped by DNA direct sequencing. RESULTS: (1) The (CA+AA) genotype frequency was significantly higher in the sepsis group than in the control group (59.2% vs 46.3%, P = 0.012). (2) Compared with the general sepsis group, higher (CA+AA) genotype frequency was found in the severe sepsis group (47.5% vs 65.5%, P = 0.033) . However, no significant difference was shown in the (CA+AA) genotype frequency between the shock group and the non-shock group as well as between the death group and the non-death group (61.8% vs 57.1%, P = 0.221; 56.8% vs 66.7%, P = 0.258) . (3) The unconditional logistic regression analysis showed that the mutation of C to A at the gene promoter locus of Nrf2 617 was associated with the increased onset risk of sepsis (OR = 1.584, 95%CI 1.025-2.447, P = 0.038) and the severity of sepsis (OR = 0.453, 95%CI 0.233 0.878, P = 0.019). CONCLUSION: The mutation of C to A at the gene promoter locus of Nrf2-617 may increase the onset risk of sepsis and organ failure in sepsis patients, while not associated with the incidence of shock and the prognosis of sepsis. PMID- 25146511 TI - [The prevalence and relevant factors of hyperglycemia in AIDS patients receiving antiretroviral therapy in a single center]. AB - OBJECTIVE: To investigate the prevalence of hyperglycemia and its associated factors in AIDS patients receiving antiretroviral therapy (ART). METHODS: A cross sectional survey was conducted to obtain the prevalence of hyperglycemia among AIDS patients in a single center. Univariate and multivariate non-conditional logistic regression analysis were used to determine influencing factors of hyperglycemia. RESULTS: A total of 504 AIDS patients participated in the survey, who have received ART for at least three months. The prevalence of hyperglycemia was 15.7%. Multivariate analysis showed that age (OR = 1.03, 95%CI 1.00-1.05), family history of diabetes (OR = 2.70, 95%CI 1.55-4.69), overweight (OR = 2.13, 95%CI 1.24-3.67), nadir CD4 cell counts 50-199 cells/ul (OR = 1.95, 95%CI 1.08 3.51) and less than 50 cells/ul (OR = 2.95, 95%CI 1.47-5.91) were relevant factors associated with hyperglycemia. CONCLUSIONS: Blood glucose should be monitored regularly in AIDS patients receiving ART , especially among patients with old age, family history of diabetes, overweight and nadir CD4 T cell counts less than 200 cells/ul. PMID- 25146512 TI - [The impact of early surgery on long-term outcome of patients with left-sided infective endocarditis]. AB - OBJECTIVE: This study aims to evaluate the impact of early surgery on long-term outcome of patients with left-sided native valve infective endocarditis (IE). METHODS: Clinical data were retrospectively reviewed in 239 consecutive patients with left-sided native valve IE from 2002 to 2012 in Peking Union Medical College Hospital (PUMCH). Propensity score was used to match patients in the early operation and conventional treatment groups. RESULTS: Early surgery was performed in 70 (29.3%) patients and the conventional treatment strategy was applied in 169 (70.7%) patients. The median follow-up period was 2 years. IE-related mortality was lower in the early operation group than in the conventional treatment group (10.0% vs 23.1%, P = 0.02). For 58 propensity score-matched pairs, the cumulative survival free from IE related death was significantly higher in the early operation group than in the conventional treatment group (P = 0.027). Regression analysis of the matched cohorts revealed that early surgery was independently associated with decreased IE-related mortality (HR 0.286; 95%CI 0.092-0.893; P = 0.031). While either cardiac function with NYHA Class III-IV (HR 4.044; 95%CI 1.318-12.407; P = 0.015) or uncontrolled infection (HR 52.064; 95%CI 10.996 247.194; P < 0.001) was associated with poor prognosis of increased mortality. CONCLUSIONS: Early surgery improved long-term outcome in patients with left-sided native valve IE compared with conventional therapy. Risk factors related to increased mortality included heart failure and uncontrollable infection. PMID- 25146513 TI - [Efficacy and safety of fluvastatin extended-release tablets in Chinese patients with hyperlipidemia: a multi-center, randomized, double-blind, double dummy, active-controlled, parallel-group study]. AB - OBJECTIVE: To assess the efficacy and safety of fluvastatin sodium extended release tablets (fluvastatin XL) 80 mg once daily compared to fluvastatin sodium immediate-release capsules (fluvastatin IR) 40 mg twice daily in Chinese hyperlipidemic patients with moderate or high cardiovascular risk. METHODS: In this multi-center, randomized, double-blind, double-dummy, active-controlled, parallel-group study, after 6-week open-label treatment with fluvastatin IR 40 mg once daily, patients who did not reach their lipid goals were randomized to 12 week double-blind treatment with fluvastatin XL 80 mg once daily or fluvastatin IR 40 mg twice daily. RESULTS: (1) There were 218 patients enrolled in each group. At the study endpoint, no statistical difference was found in the mean percent change from baseline for LDL-C with -8.69% [from (3.504 +/- 0.060) mmol/L to (3.153 +/- 0.065) mmol/L] in the fluvastatin XL group and -7.89% [from (3.491 +/- 0.050) mmol/L to (3.181 +/- 0.060) mmol/L] in the fluvastatin IR group (P > 0.05). The 95%CI for difference between the two groups in adjusted mean percent change from baseline was (-4.70%-3.09%), which was within the pre-specified non inferiority margin. In the fluvastatin XL group, the proportion of patients with moderate cardiovascular (CV) risk and high CV risk achieving their LDL-C treatment goals at endpoint was 50.0% and 31.5% respectively, while the proportion was 42.5% and 24.5% respectively in the fluvastatin IR group. No significant difference was found between the two groups in the proportion of patients who reached their lipid goals and the changes from baseline with other lipid parameters. (2) Similar safety profiles were observed in the two treatment groups, with 21.1% adverse event (AE) (8.3% study-drug related AE) in the fluvastatin XL group and 17.0% AE (6.3% study-drug related AE) in the fluvastatin IR group. CONCLUSION: The efficacy of fluvastatin XL 80 mg once daily is comparable to fluvastatin IR 40 mg twice daily in Chinese hyperlipidemic patients with moderate or high cardiovascular risk and both treatments are safe and well tolerated. PMID- 25146514 TI - [The prevalence and clinical significance of arthritis in patients with systemic sclerosis]. AB - OBJECTIVE: To explore the prevalence and independent influencing factors of arthritis in Chinese patients with systemic sclerosis (SSc). METHODS: A total of 248 SSc patients were enrolled in this prospective cross-sectional study in Peking Union Medical College Hospital. Demographic, clinical and laboratory data were compared in arthritis group and non-arthritis group. RESULTS: Of 248 Chinese SSc patients, mean age of onset was (37.1 +/- 13.7) years old and disease duration was (7.4 +/- 5.2) years. Overall prevalence of arthritis was 41.1% (102/248). The presence of arthralgia(95.1% vs 15.1%), muscle weakness (38.2% vs 24.7%), short of breath (60.8% vs 45.2%), and intestinal lung disease (64.7% vs 49.3%) occurred more frequently in patients with arthritis than those without arthritis (P < 0.05). The elevation of C reactive protein, anti-Sm and anti cyclic citrullinated peptide were more common in arthritis group than in non arthritis group (61.4% vs 43.9%, 11.4% vs 2.5% and 28.1% vs 2/16, respectively). There were no obvious differences in the Rodnan score, digital ulcers, pulmonary arterial hypertension, and six-minute walk test between two groups (P > 0.05). CONCLUSION: This study reveals the significant prevalence of arthritis in a large cohort of SSc patients in China. Compared to non-arthritis patients, the SSc patients with arthritis have a more severe inflammation reaction and a higher rate of intestinal lung disease. PMID- 25146515 TI - [The clinical analysis for the whole-spine magnetic resonance imaging of axial spondyloarthritis]. AB - OBJECTIVE: To investigate spinemagnetic resonance imaging(MRI) findings in patients with axial spondyloarthritis (SpA) and to analyze the correlation between imaging and clinical manifestation. METHODS: The clinical data of patients with axial SpA were recorded. All patients underwent whole spine MRI scanning. The MRI findings of spinal involvement were explored. Moreover, the correlation between lesions in spinal MRI and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), nocturnal pain visual analogue scale (VAS) score, back pain VAS score, global disease activity VAS score, Ankylosing Spondylitis Disease Activity score (ASDAS), erythrocyte sedimentation rate, C-reactive protein was analyzed. RESULTS: Thirty-three patients with axial SpA were included in this study. The image abnormalities of the spine were confirmed in 29 axial SpA patients by MRI, including Romanus lesion, Andersson lesion, the inflammation of facet joints and syndesmophyte. In correlation study, BASMI was positively correlated to the numbers of acute Romanus lesions, chronic Romanus lesions, chronic Andersson lesions and whole spinal lesions(r = 0.440, P < 0.05; r = 0.483, P < 0.05; r = 0.421, P < 0.05; r = 0.589, P < 0.05 respectively). There was a statistically significant correlation between chronic Andersson lesions and BASFI(r = 0.392, P < 0.05). But no significant associations were found between MRI lesions and other clinical findings. CONCLUSIONS: MRI lesions in axial SpA were associated with findings reflecting the spinal function, which can better guide the clinical treatment. PMID- 25146516 TI - [The value of electromyography in differentiating intramedullary tumor from inflammatory demyelinating disease of cervical region]. AB - OBJECTIVE: To investigate the value of needle electromyography (EMG) in differentiating intramedullary tumor from inflammatory demyelinating disease of cervical region. METHODS: Patients hospitalized in the Chinese PLA General Hospital from March 2008 to June 2013 with abnormalities on MRI of cervical vertebra and preliminary diagnosed as intramedullary tumor or inflammatory demyelinating disease of cervical region were enrolled in the study. Electrophysiological examination was performed before any treatment. Pathological findings were analyzed and prognosis was evaluated in all the subjects. RESULTS: A total of fifty-five patients were enrolled in the study with 33 cases of inflammatory demyelinating disease and 22 cases of intramedullary tumor defined by the postoperative pathological findings. In all the 33 cases with demyelinating disease, only one case (3.03%) presented as neurogenic damage by needle EMG. While in all the 22 cases with intramedullary tumor, needle EMG revealed neurogenic damage in 15 cases (68.18%) and the spinal segments of muscles with neurogenic damage were all within the spinal lesions demonstrated by MRI. The diagnostic sensitivity of EMG for intramedullary tumor was 68.18% and the diagnostic specificity was 96.97%, while the diagnostic sensitivity and specificity for intramedullary tumor by the medical history, symptoms and signs were 59.09% and 75.76% respectively. CONCLUSION: Needle EMG might play an important role in distinguishing intramedullary tumor from inflammatory demyelinating disease of cervical spinal cord. PMID- 25146517 TI - [The outcome of thirteen patients with nonmalignant hematologic diseases treated with HLA haploidentical stem cell transplantation]. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of human leukocyte antigen (HLA) haploidentical stem cell transplantation in nonmalignant hematologic diseases. METHOD: To analyze the outcome of 13 patients with nonmalignant hematologic diseases who underwent HLA haploidentical stem cell transplantation from September 2001 to October 2013. RESULTS: Thirteen patients including 9 of severe aplastic anemia, 3 of severe beta thalassemia, 1 of congenital pure red cell aplastic anemia underwent HLA haploidentical stem cell transplantation. Three HLA loci mismatched in 4 cases, two HLA loci mismatched in 8 cases and one HLA locus mismatched in 1 case. The conditioning regime consisted of Fludarabine (30 mg*m(-2)*d(-1)*5 d ), Busulfan(0.8 mg*kg(-1)*6h(-1)*4 d), Cyclophosphamide (60 mg*kg(-1)*d(-1)*2 d ), rabbit anti-human lymphocyte globulin ( 2.5 mg*kg(-1)*d(-1)*5 d ). To prevent from graft-versus-host disease (GVHD), cyclosporin A and short term methotrexate (MTX) were used. All patients were successfully engrafted. The incidence of grade 1-2 acute graft-versus-host disease (aGVHD) was 3/13, and that of grade 3-4 was 1/13. The cumulative incidence of total chronic GVHD (cGVHD) was 3/13. Eleven patients survived free of disease at a median follow-up period of 13 months (2-145). CONCLUSION: HLA haploidentical stem cell transplantation is an effective and safe therapy for nonmalignant hematologic diseases. PMID- 25146518 TI - [The impact and mechanism of glutamate transporter 1-mediated visceral nociception and hyperalgesia following exposure to post-traumatic stress disorder like stress in spinal cord of rats]. AB - OBJECTIVE: To investigate the expression of glutamate transporter 1 (GLT-1) and determine the effect of GLT-1 overexpression on the visceromotor response ( VMR ) to colorectal distention (CRD) following exposure to post-traumatic stress disorder (PTSD)-like stress. METHODS: A beta-lactam antibiotic, ceftriaxone (CTX) was used to selectively induce transcription of the gene encoding GLT-1 and upregulate GLT-1 expression as an agonist. SD rats were divided into five groups, including control group, PTSD group, CTX-treated group, PTSD+CTX group, PTSD+CTX+ dihydrokainate (DHK) group. Seven rats in each VMR-CRD group eventually completed the study. Ten rats in each group were used to test immunofluorescence of GLT-1, however, 8, 9, 8, 10, 7 rats completed the test respectively. The animal model of PTSD was established using basal ovalbumin (OVA)-sensitization combined with single-prolonged stress model (SPS). The alteration of visceral sensitivity following exposure to PTSD-like stress was evaluated by measuring the VMR to CRD. Spinal GLT-1 expression was evaluated by immunofluorescence using confocal laser scanning microscopy. RESULTS: By immunofluorescence analysis, CTX-treated rats exhibited an increased GLT-1 expression in spinal cord compared with the control group (absorbance: 141.38 +/- 2.91 vs 106.25 +/- 3.32, P = 0.001). Absorbance of GLT-1 in spinal cord was significantly decreased in PTSD rats, compared with the control rats (86.11 +/- 2.73 vs 106.25 +/- 3.32, P = 0.001). GLT-1 expression in PTSD rats treated with CTX was significantly increased compared with PTSD group (98.70 +/- 3.19 vs 86.11 +/- 2.73, P = 0.004 ). VMR to CRD significantly elevated in PTSD group compared with the control group at 20, 40, 60 and 80 mmHg (all P < 0.05, 1 mmHg = 0.133 kPa). VMR significantly declined in PTSD rats treated with CTX when compared with the vehicle at graded CRD pressure (all P < 0.01), however, one-hour pretreatment with selective GLT-1 antagonist dihydrokainate reversed the blunted VMR to CRD produced by CTX (P = 0.002). VMR significantly decreased in CTX group compared with the control group at 40, 60 and 80 mmHg (all P < 0.05). CONCLUSIONS: The study suggests that the PTSD alters visceral sensitivity and GLT-1 overexpression mediated the analgesic effect of CTX following exposure to PTSD-like stress, identifying a specific molecular mechanism for visceral hypersensitivity which may pave the way for novel therapeutic strategies for PTSD-like conditions. PMID- 25146519 TI - [The effect of NALP3 inflammasome pathway in visceral adipose tissue on the development of insulin resistance in catch-up growth after food restriction in rats]. AB - OBJECTIVE: To investigate the effects of catch-up growth (CUG) on the natch domain, leucine-rich repeat and PVD-containing protein 3 (NALP3) inflammasome pathway in visceral adipose tissue (VAT) and the mechanism of insulin resistance (IR) in CUG. METHODS: Sprague-Dawley rats were randomly divided into the normal chow (NC) and the catch-up growth group (CUG). General characteristics, glucose infusion rate60-120 (GIR60-120) in hyperinsulinemic-euglycemic clamp and expression of NALP3 inflammasome, caspase1(p10) and IL-1beta (p17) cleavage in VAT were respectively examined on week 4, 6 and 8 of the experiment. RESULTS: After 4-week food restriction, lower percentage of abdominal fat mass (AFM%) was presented in the CUG group than the NC group [(11.54 +/- 1.81)% vs (7.72 +/- 1.47)%, P < 0.05]. In the CUG group, decreased expression of NALP3 inflammasome, caspase1 (p10) and IL-1beta (p17) cleavage in VAT were found (0.47 +/- 0.03 vs 0.28 +/- 0.04, P < 0.01; 0.30 +/- 0.02 vs 0.20 +/- 0.03, P < 0.01; 0.52 +/- 0.04 vs 0.37 +/- 0.04, P < 0.05; respectively), whereas GIR60-120 was slightly improved [(23.47 +/- 0.89) mg*min(-1)*kg(-1) vs (25.34 +/- 1.16) mg*min(-1)*kg( 1), P > 0.05]. After refeeding, AFM% and the expression of NALP3 inflammasome, caspase1 (p10) and IL-1beta (p17) cleavage in VAT in CUG group were shown to be increased with the time. Concomitant with those changes, GIR60-120 was gradually impaired. On week 4 of refeeding, AFM% and the expression of NALP3 inflammasome, caspase1 (p10) and IL-1beta (p17) cleavage in VAT were significantly increased in the CUG group compared with the NC group [(12.52 +/- 0.64)% vs (15.16 +/- 1.10)%, P < 0.01; 0.52 +/- 0.02 vs 0.65 +/- 0.05, P < 0.05; 0.33 +/- 0.03 vs 0.54 +/- 0.02, P < 0.01; 0.55 +/- 0.04 vs 0.65 +/- 0.05, P < 0.05; respectively], while GIR60-120 was significantly attenuated [(21.45 +/- 1.20) mg*min(-1)*kg(-1) vs (14.27 +/- 1.06) mg*min(-1)*kg(-1), P < 0.05]. Correlation analysis showed that the expression of NALP3 and caspase1 (p10) in VAT were positively correlated with AFM% (r = 0.946, P < 0.01; r = 0.922, P < 0.01), while negatively correlated with GIR60-120 (r = -0.902, P < 0.01; r = -0.944, P < 0.01). CONCLUSION: NALP3 inflammasome pathway in VAT is notably activated during CUG, which may contribute to the etiology of IR in CUG. PMID- 25146520 TI - Adaptive cyanogenesis clines evolve recurrently through geographical sorting of existing gene deletions. AB - Identifying the genetic basis of parallel phenotypic evolution provides insight into the process of adaptation and evolutionary constraint. White clover (Trifolium repens) has evolved climate-associated adaptive clines in cyanogenesis (the ability to produce hydrogen cyanide upon tissue damage) in several world regions where it has been introduced. Gene-deletion polymorphisms at the CYP79D15 and Li loci underlie the presence/absence of the cyanogenic phenotype. Both loci have undergone multiple independent gene-deletion events, which are identifiable through molecular signatures in flanking regions. To investigate whether cyanogenesis clines in introduced populations have evolved through the sorting of standing genetic variation or de novo gene deletions, we examined cyanogenesis gene-flanking regions in three world regions. In comparison with native Eurasian populations, we find no evidence for novel gene deletion events in any introduced region, which suggests that these adaptive clines have evolved through the geographical sorting of pre-existing genetic variation. PMID- 25146521 TI - Structural roles of amphiphilic peptide tails on silica biomineralization. AB - De novo synthesized amphiphilic peptides can be easily designed to form various nanostructures. Natural biomineralization creates the most intricately stunning inorganic structures, such as diatoms and shells, in which peptides play an important role. Here, we present the biomineralization of three designed amphiphilic peptides, which have different types of hydrophobic tails. By changing the hydrophobic tails from a phenylalanine-serine tail to an alkyl serine tail or a serine-only tail, the conformations of peptides varied from type II beta-turn to alpha-helix or random coil, which gave rise to the silica biomineralization nanostructures with nanoribbons, nanofibers and hollow nanospheres, respectively. Figuring out the structural roles of hydrophobic tails of amphiphilic peptides can improve strategies toward the bottom-up synthesis of nanomaterials as well as peptide scaffold engineering. PMID- 25146523 TI - Mount Isa statement on quad bike safety. AB - CONTEXT: Quad bikes are the leading cause of death in Australian agriculture, with half of these deaths resulting from rollovers. Between 2001 and 2012, there were more than 160 such deaths in Australia, representing a significant burden. ISSUES: There is a diversity of public opinions offered about quad bike safety. The Are You Remotely Interested ... in Prevention; Building a Culture of Safety conference held in Mount Isa, Queensland, in August 2012 brought together subject matter experts from across Australia to discuss a range of issues relevant to rural Australia (including quad bikes). During this conference, the Mount Isa Statement for Quad Bike Safety was produced. The intent of the Statement was to draw on existing evidence to highlight solutions and provide a direction for future efforts to reduce the burden of death and injury related to quad bike use. The conference provided an opportunity for those with an interest in quad bike safety to come together in one location, discuss the issues and develop a common direction (the Statement). The Statement is presented in three sections: a statement of the facts that were available at the time of development; a set of recommendations; and what needs to happen next. LESSONS LEARNED: We believe to the best of our knowledge this is the first time where many potential solutions for keeping people safe while operating quad bikes in agriculture have been explored in a public forum. There are some immediate solutions that people can undertake to keep themselves and those in their care safe when using a quad bike: initially selecting safer vehicles to use; fitting quad bikes with crush protection devices; not carrying passengers or overloading the quads; and wearing helmets. PMID- 25146522 TI - Assessment of IgG antibodies to Pseudomonas aeruginosa in patients with cystic fibrosis by an enzyme-linked immunosorbent assay (ELISA). AB - BACKGROUND: The usefulness of serological tests for detection of P. aeruginosa pulmonary infection in cystic fibrosis (CF) is controversial. Here, we assessed the value of detecting anti-P. aeruginosa IgG by a quantitative enzyme-linked immunosorbent assay (ELISA) for identification of P. aeruginosa infection in patients with cystic fibrosis. METHODS: Serum concentrations of anti-P. aeruginosa IgG were assessed in 117 CF patients classified according to their P. aeruginosa colonization/infection status (never colonized; free of infection; intermittently colonized and chronically infected) and in 53 healthy subjects by the ELISA test standardized with the St-Ag:1-17 antigen. RESULTS: The rate of IgG seropositivity and the median of IgG concentrations of this antibody in patients chronically infected were significantly higher than those found in the other CF groups and in the healthy control group. CONCLUSION: Detection of anti-P. aeruginosa IgG can be an useful tool for identification of P. aeruginosa chronic infection in patients with CF. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_158. PMID- 25146524 TI - Advanced trauma life support training for hospital staff. AB - BACKGROUND: Injury is responsible for an increasing global burden of death and disability. As a result, new models of trauma care have been developed. Many of these, though initially developed in high-income countries (HICs), are now being adopted in low and middle-income countries (LMICs). One such trauma care model is advanced trauma life support (ATLS) training in hospitals, which is being promoted in LMICs as a strategy for improving outcomes for victims of trauma. The impact of this health service intervention, however, has not been rigorously tested by means of a systematic review in either HIC or LMIC settings. OBJECTIVES: To quantify the impact of ATLS training for hospital staff on injury mortality and morbidity in hospitals with and without such a training program. SEARCH METHODS: The search for studies was run on the 16th May 2014. We searched the Cochrane Injuries Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (Ovid), ISI WOS (SCI-EXPANDED, SSCI, CPCI-S & CPSI-SSH), CINAHL Plus (EBSCO), PubMed and screened reference lists. SELECTION CRITERIA: Randomised controlled trials, controlled trials and controlled before-and-after studies comparing the impact of ATLS-trained hospital staff versus non-ATLS trained hospital staff on injury mortality and morbidity. DATA COLLECTION AND ANALYSIS: Three authors applied the eligibility criteria to trial reports for inclusion, and extracted data. MAIN RESULTS: None of the studies identified by the search met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: There is no evidence from controlled trials that ATLS or similar programs impact the outcome for victims of injury, although there is some evidence that educational initiatives improve knowledge of hospital staff of available emergency interventions. Furthermore, there is no evidence that trauma management systems that incorporate ATLS training impact positively on outcome. Future research should concentrate on the evaluation of trauma systems incorporating ATLS, both within hospitals and at the health system level, by using more rigorous research designs. PMID- 25146525 TI - Parents who refuse vitamin K for newborns are also likely to refuse vaccinations, Canadian study finds. PMID- 25146527 TI - Novel commercially available genomic tests for prostate cancer: a roadmap to understanding their clinical impact. PMID- 25146526 TI - High-throughput assay to phenotype Salmonella enterica Typhimurium association, invasion, and replication in macrophages. AB - Salmonella species are zoonotic pathogens and leading causes of food borne illnesses in humans and livestock. Understanding the mechanisms underlying Salmonella-host interactions are important to elucidate the molecular pathogenesis of Salmonella infection. The Gentamicin protection assay to phenotype Salmonella association, invasion and replication in phagocytic cells was adapted to allow high-throughput screening to define the roles of deletion mutants of Salmonella enterica serotype Typhimurium in host interactions using RAW 264.7 murine macrophages. Under this protocol, the variance in measurements is significantly reduced compared to the standard protocol, because wild-type and multiple mutant strains can be tested in the same culture dish and at the same time. The use of multichannel pipettes increases the throughput and enhances precision. Furthermore, concerns related to using less host cells per well in 96 well culture dish were addressed. Here, the protocol of the modified in vitro Salmonella invasion assay using phagocytic cells was successfully employed to phenotype 38 individual Salmonella deletion mutants for association, invasion and intracellular replication. The in vitro phenotypes are presented, some of which were subsequently confirmed to have in vivo phenotypes in an animal model. Thus, the modified, standardized assay to phenotype Salmonella association, invasion and replication in macrophages with high-throughput capacity could be utilized more broadly to study bacterial-host interactions. PMID- 25146528 TI - Melatonin regulates proteomic changes during leaf senescence in Malus hupehensis. AB - Despite the relationship between melatonin and aging, the overall changes and regulation of proteome profiling by long-term melatonin exposure during leaf senescence is not well understood. In this study, leaf senescence in Malus hupehensis plants was delayed when exogenous melatonin was regularly applied to the roots for 2 months compared with natural leaf senescence. Proteins of samples 0 and 50 day for both treatments were extracted and labeled with TMT regents before being examined via NanoLC-MS/MS. The proteomics data showed that 622 and 309 proteins were altered by senescence and melatonin, respectively. Our GO analysis by Blast2GO revealed that most of the altered proteins that are involved in major metabolic processes exhibited hydrolase activity and were mainly located in the plastids. These proteins were classified into several senescence-related functional categories, including degradation of macromolecules, redox and stress responses, transport, photosynthesis, development, and other regulatory proteins. We found that melatonin treatment led to the downregulation of proteins that are normally upregulated during senescence. The melatonin-related delay in senescence might have occurred due to the altering of proteins involved in processes associated with senescence. And as well, there are many unknown regulatory proteins possibly being involved in the melatonin's function. This study is the first to demonstrate changes at the proteome level in response to exogenous melatonin in plants. Our findings provide a set of informative and fundamental data about the role of melatonin in apple leaf senescence. PMID- 25146529 TI - Key components of chemotherapy for thymic malignancies: a systematic review and pooled analysis for anthracycline-, carboplatin- or cisplatin-based chemotherapy. AB - PURPOSE: Thymic malignancies, comprising thymoma and thymic carcinoma, are rare. Consequently, optimal chemotherapy for advanced thymic malignancies remains controversial. Platinum-based chemotherapy is currently the consensus treatment based on the results of single-arm phase II trials and retrospective investigations. However, comparison of cisplatin-based and carboplatin-based chemotherapy has yet to be undertaken; the effectiveness of the addition of anthracycline also remains uncertain. METHODS: In the present study, clinical trials and retrospective data regarding platinum-based chemotherapy were analyzed. The endpoint was the response rate to each chemotherapy. For advanced thymoma, we compared platinum with anthracycline-based chemotherapy and platinum with non-anthracycline-based chemotherapy. For advanced thymic carcinoma, anthracycline-based versus non-anthracycline-based chemotherapy and carboplatin based versus cisplatin-based chemotherapy were compared. This analysis included a retrospective study of response of advanced thymic carcinoma to irinotecan and cisplatin in our institution. RESULTS: The response rate for the 314 patients from 15 studies with advanced thymoma, including both prospective and retrospective data, was 69.4% [95% confidence interval (CI) 63.1-75.0%] for platinum with anthracycline-based chemotherapy and 37.8% (95% CI 28.1-48.6%; p < 0.0001) for platinum with non-anthracycline-based chemotherapy. The response rates after anthracycline-based and non-anthracycline-based chemotherapy for advanced thymic carcinoma were similar (41.8 vs. 40.9%; p < 0.91), whereas the response rates after cisplatin-based and carboplatin-based chemotherapy for advanced thymic carcinoma differed significantly (53.6 vs. 32.8%; p = 0.0029) in 206 patients from 10 studies. CONCLUSIONS: Platinum with anthracycline-based chemotherapy is an optimal combination for advanced thymoma. For advanced thymic carcinoma, cisplatin-based chemotherapy may be superior to carboplatin-based chemotherapy. PMID- 25146531 TI - Real-time imaging of single engineered RNA transcripts in living cells using ratiometric bimolecular beacons. AB - The growing realization that both the temporal and spatial regulation of gene expression can have important consequences on cell function has led to the development of diverse techniques to visualize individual RNA transcripts in single living cells. One promising technique that has recently been described utilizes an oligonucleotide-based optical probe, ratiometric bimolecular beacon (RBMB), to detect RNA transcripts that were engineered to contain at least four tandem repeats of the RBMB target sequence in the 3'-untranslated region. RBMBs are specifically designed to emit a bright fluorescent signal upon hybridization to complementary RNA, but otherwise remain quenched. The use of a synthetic probe in this approach allows photostable, red-shifted, and highly emissive organic dyes to be used for imaging. Binding of multiple RBMBs to the engineered RNA transcripts results in discrete fluorescence spots when viewed under a wide-field fluorescent microscope. Consequently, the movement of individual RNA transcripts can be readily visualized in real-time by taking a time series of fluorescent images. Here we describe the preparation and purification of RBMBs, delivery into cells by microporation and live-cell imaging of single RNA transcripts. PMID- 25146532 TI - About new targets for increasing endogenous testosterone. PMID- 25146530 TI - Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer. AB - PURPOSE: PTEN is an essential tumour suppressor gene which encodes a phosphatase protein that antagonises the PI3K/Akt/mTOR antiapoptotic pathway. Impairment of this tumour suppressor pathway potentially becomes a causal factor for development of malignancies. This review aims to assess current understanding of mechanisms of dysfunction involving the PI3K/PTEN/Akt/mTOR pathway linked to tumorigenesis and evaluate the evidence for targeted therapy directed at this signalling axis. METHODS: Relevant articles in scientific databases were identified using a combination of search terms, including "malignancies", "targeted therapy", "PTEN", and "combination therapy". These databases included Medline, Embase, Cochrane Review, Pubmed, and Scopus. RESULTS: PI3K/PTEN expression is frequently deregulated in a majority of malignancies through genetic, epigenetic, and post-transcriptional modifications. This contributes to the upregulation of the PI3K/Akt/mTOR pathway which has been the focus of intense clinical studies. Targeted agents aimed at this pathway offer a novel treatment approach in a variety of haematologic malignancies and solid tumours. Compared to single-agent use, greater response rates were obtained in combination regimens, supporting further investigation of suitable drug combinations in a broad spectrum of malignancies. CONCLUSION: Activation of the PI3K/PTEN/Akt/mTOR pathway is implicated both in the pathogenesis of malignancies and development of resistance to anticancer therapies. Therefore, PI3K/Akt/mTOR inhibitors are a promising therapeutic option, in association with systemic cytotoxic and biological therapies, to enable sustained clinical outcomes in cancer treatment. Therapeutic strategies could be tailored according to appropriate biomarkers and patient-specific mutation profiles to maximise benefit of combination therapies. PMID- 25146533 TI - Docosahexaenoic acid and L-Carnitine prevent ATP loss in SH-SY5Y neuroblastoma cells after exposure to silver nanoparticles. AB - Silver nanoparticles (AgNPs) are among the most commonly used nanomaterials, but thus far, little is known about ways to mitigate against potential toxic effects of exposure. In this study, we examined the potential effects of AgNPs on mitochondrial function and cellular ATP levels, and whether these could be prevented by treatment with docosahexaenoic acid (DHA) and L-carnitine (LC). Acute exposure of AgNPs for 1 h to SH-SY5Y cells resulted in decreased mitochondrial membrane potential, and decreased ATP and ADP levels, indicating mitochondrial damage and reduced production of ATP. Incubation of cells with DHA partially reduced, while treatment with LC and DHA completely abolished the AgNP induced decreases in ATP and ADP levels. This could be due to a LC-facilitated entry of DHA to mitochondria, for repair of damaged phospholipids. It is postulated that DHA and LC may be useful for treatment of accidental environmental exposure to AgNPs. PMID- 25146534 TI - [Mini-invasive operations in patients with vessels diseases]. AB - Hybrid operations combining open and endovascular surgeries are used in cardio vascular surgery for the last 10-15 years. It leads to decrease complications frequency and mortality in case of pronounced comorbidities and severe heart, aorta and its branches disease. Authors have experience in performing of 10 hybrid surgeries and 7 aneurysms endoprosthesis of abdominal aorta. All operated patients had severe comorbidities which significantly increase risk of open surgery. These comorbidities were contraindication for open surgery in patients with abdominal aorta aneurysm. Thanks to introduction into practice hybrid operations and aorta aneurysms endoprosthesis the authors decreased complications frequency and avoided deaths in operated patients. PMID- 25146535 TI - [Microscopic investigation of vessel wall after endovascular catheter atherectomy]. AB - Endovascular target catheter atherectomy (ETCA) - method of artery patency allowing to obtain occlusion substrate. Given the high destructive effect of atherectome's elements on tissue the objective was determination possibility of histological and electron microscopic investigation of this substrate after atherectomy. The research included 8 patients who underwent ETCA of legs arteries. It was observed substrate removal from broken stent in 1 case. 2 of 8 patients had diabetes. Obtained substrate was available for histological and electron microscopic investigation. Atherosclerosis was confirmed in all cases. It was not observed substrate significant morphological changes in patients with presence or absence of diabetes. Microscopic investigation of substrate from broken stent shows pronounced development of granulation tissue that was regarded as special form of reparative regeneration. Finding internal elastic membrane during microscopic investigation in some cases proves radical intervention. The authors consider that microscopic investigation of substrate after ETCA may be used for diagnosis verification, thorough analysis of morphological changes in lesion area and radicalism of atherectomy. PMID- 25146536 TI - [Laparoscopic treatment of perforated ulcers]. AB - It was done comparative analysis the results of different treatment options using of laparoscopic treatment of 331 patients with perforated ulcers. It was defined that postoperative complications frequency is increased to 1.6% in case of perforated ulcers suturing with diameter to 0.7 cm. This indication is increased to 7.1% in case of perforated ulcers suturing and plugging by greater omentum with holes diameter to 1.0 cm. The complications are absent in case of perforated ulcer excision with subsequent vagotomy and pyloroplasty. PMID- 25146537 TI - [Surgical treatment of duodenal injuries]. AB - In was analyzed diagnostics and treatment results of 32 victims with duodenal injuries. The authors used 3% hydrogen peroxide solution for duodenal rupture diagnosis. Suggested surgical technique includes intestine intersection where it was broken and anastomosis with a loop of small intestine by using of Roux's method. Also it was done duodenal passage temporary shutdown by using of catgut purse-string suture on pyloric part of stomach. PMID- 25146538 TI - [Results of surgical treatment of cholelithiasis by laparotomic and minimally invasive accesses]. AB - The article presents the results of surgical treatment of 1038 patients with cholelithiasis, acute and chronic calculous cholecystitis and complicated forms of the disease. Operations were performed with traditional laparotomic and minimally invasive approaches. Indications for choosing access, as well as the advantages and disadvantages of various options of surgery in patients with cholelithiasis are discussed. PMID- 25146539 TI - [One-stage retrosternal colonic esophagoplasty in treatment of patients with scar burn stricture of esophagus]. AB - Esophagoplasty was done in 23 patients an average of 10.4+/-2.3 months after chemical burn of esophagus. It was necessary to perform 29 corrective operations in 18 cases for training to one-stage plastic surgery such as gastrostomy, resection of stomach, retrocolic gastrojejunostomy on short loop. One-stage esophagoplasty was done in 21 of 23 cases. Functionally the most unusable anastomosis was cervical esophageal-intestinal anastomosis side-to-side. The number of complications after esophagocoloplasty by using of right flank was less than after using of left flank (39.92% vs. 50% respectively). PMID- 25146540 TI - [Contact lithotripsy in treatment of choledocholithiasis]. AB - It was suggested to use contact ultrasonic lithotripsy in lumen of common bile duct during laparoscopic surgery in order to preserve the sphincter apparatus of major duodenal papilla. Waveguide with original structure was used for lithotripsy performing. Waveguide's total length is 400 mm. It has a radially curved 40 degrees broken part with diameter of 6 mm cone rolling in working portion with diameter of 4 mm and length of 60 mm for introduction in common bile duct. There is concave lens on waveguide working portion end with diameter of 1 mm. A lens permits concentrating the waves beam in longitudinal direction avoiding its scattering and minimizing the impact on surrounding tissues. Lithotripsy efficiency was proved in the in vitro (n=68) and in vivo (n=20) experiments. Such structure of waveguide permits to penetrate in lumen of common bile duct through dilated cystic duct or choledochendysis for calculi fragmentation. PMID- 25146541 TI - [Risk factors for aerostasis failure in case of lung resection]. AB - The results of risk factors analysis of aerostasis failure in 141 patients are presented in the article. All patients were operated in the A.V. Vishnevskogo Institute of Surgery at the period from January 2009 to December 2010. During statistical analysis it was considered surgeries volume, presence of emphysema, respiratory function etc. Also it was defined the dependence of venting duration in patients with residual pleural cavity and long aerostasis failure. PMID- 25146542 TI - [Surgical treatment of Hirschprung's disease total form in children]. AB - It was analyzed the treatment results of 24 patients under the age of 2 years with total aganglionosis for the period from 2000 to 2013. Each of these patients underwent several surgical interventions (on the average 7.8+/-2.1). All children were operated radically. It was performed ileojejunorectal anastomosis at transitional fold of peritoneum in patients with concomitant short bowel syndrome. Soave's operation was done in 14 patients including by using of laparoscopic technique in 3 cases. Inflammatory complications (paraproctitis) developed in 2 children on maceration background. Perirectal fistula was observed in 1 patient subsequently. In long-term period liquid stool incontinence persisted up to 6 months in 28% of children. In terms of more than 1 year stool incontinence was observed in 12.6% of patients. Increased growth of D-lactate producing gram-positive anaerobes was revealed during microbiological investigation of feces in 35% of patients in long-term period. Increased growth was accompanied by systemic acidosis and infectious enteritis clinically. Course monthly treatment with antibacterial drugs (Alpha-Normix, Trichopolum, Gentamicin) was prescribed in patients with short bowel syndrome and high frequent of enteritis recurrence. Treatment was used In terms from 6 to 12 months of longer if it was necessary. It was concluded that timely diagnosis and right tactic in neonatal period leads to decrease significantly the number of complications, vain interventions and to improve treatment outcomes. Our experience shows that the best results of surgical treatment were observed in children aged from 2.5-3 years when a child can control urination and defecation. The most mistakes are caused by wrong or failed morphological investigation of large bowel. PMID- 25146543 TI - [High-tech medical care in surgical endocrinology]. AB - The number of patients with endocrine system diseases increases annually. Widespread introduction of screening programs and improvement of laboratory and instrumental diagnostic is one of the most important causes for this. Treatment of patients with endocrine system diseases within the high-tech medical care leads to perform the unique surgical interventions. It increases survival and patients' life quality. PMID- 25146544 TI - [Clinical effects of packed red blood cells transfusion according to storage life and time of transfusion]. AB - It was studied 66 males aged 39.5+/-5.3 years with hemorrhagic shock II degree. Gas composition of arterial and venous blood was studied twice (before and after transfusion). It was revealed that succinct transfusion of packed red blood cells (to 2 doses) with storage life to 3 days after bleeding stop and hypovolemia filling is the most effective correction of hemorrhagic shock II degree. Replacement therapy in operating room in condition of stopped bleeding and unrepaired hypovolemia is burdening factor because it does not conducive to transfer of oxygen at the tissue level and inhibits stimulation of bone marrow in response to hypoxia. PMID- 25146545 TI - [The impact of thromboprophylaxis with enoxaparin on bleeding rate in rejuvenating facelift procedures]. AB - A retrospective study on safety of prophylactic use of Enoxaparin in rejuvenating face lift procedures. The prophylactic use of Enoxaparin was not found to be associated with increased perioperative bleeding or higher incidence of postoperative hematomas requiring reoperation. PMID- 25146546 TI - [Endovascular hemostasis in case of voluminous intestinal bleeding in patient operated for intestinal fistula]. PMID- 25146547 TI - [Giant-cell tumor of sternum]. PMID- 25146548 TI - MU-Opioid receptor attenuates Abeta oligomers-induced neurotoxicity through mTOR signaling. AB - AIMS: MU-opioid receptor (OPRM1) exerts many functions such as antinociception, neuroprotection, and hippocampal plasticity. A body of evidence has shown that OPRM1 activation could stimulate downstream effectors of mechanistic/mammalian target of rapamycin (mTOR). However, it is not clear whether OPRM1 protects neurons against beta-amyloid peptide (Abeta) neurotoxicity through mTOR signaling. METHODS: The effects of OPRM1 activation on Abeta oligomers-induced neurotoxicity were assessed by cell viability and neurite outgrowth assay in primary cultured cortical neurons. The activities of mTOR, protein kinase B (Akt) and p70 ribosomal S6 kinase (p70 S6k) upon OPRM1 activation by morphine were measured by immunoblotting their phosphorylation status. RESULTS: Morphine dose dependently attenuated Abeta oligomers-induced neurotoxicity. Abeta oligomers downregulated mTOR signaling. Morphine significantly rescued mTOR signaling by reversal of Abeta oligomers' effect on mTOR and its upstream signaling molecule Akt, as well as its downstream molecule p70 S6k. Moreover, the neuroprotective effect of morphine could be reversed by OPRM1 selective antagonist and phosphatidylinositol 3-kinases (PI3K), Akt and mTOR inhibitors. Furthermore, endogenous opioids-enkaphalins also attenuated Abeta oligomers-induced neurotoxicity. CONCLUSIONS: Our findings demonstrated OPRM1 activation attenuated Abeta oligomers-induced neurotoxicity through mTOR signaling. It may provide new insight into the pathological process and useful strategy for therapeutic interventions against Abeta neurotoxicity. PMID- 25146549 TI - Multinodular and vacuolating neuronal tumor of the cerebrum. AB - Multinodular and vacuolating neuronal tumors of the cerebrum (MVNT) are superficial neuronal tumors in adults that were first documented in 2013. Herein, we report a case of MNVT involving a 37-year-old man who presented with an epileptogenic, superficial solid lesion in the left parietal lobe. Histomorphology of the resected specimen was characterized by nodular lesions with vacuolation. Nodules comprised irregular proliferation of neuronal cells, which ranged from ganglion-like forms to those with indistinct lineage. Immunohistochemical analysis showed that the lesional cells stained positively for HuC/HuD, synaptophysin, and Olig2, and negatively for NeuN, neurofilament, chromogranin A, GFAP, CD34, IDH1(R132H), and BRAF(V600E). Eighteen months following surgery, the patient is well and without neurological deficits. MVNTs are distinctive tumors that should be differentiated from ganglion cell tumors, dysembryoplastic neuroepithelial tumors, and malformation of cortical development. PMID- 25146551 TI - Clinical features and pregnancy outcome in antiphospholipid syndrome patients with history of severe pregnancy complications. AB - Abstract Objective. To clarify the clinical significance of antiphospholipid antibody (aPL) profile in patients with obstetric antiphospholipid syndrome (APS). Methods. Clinical records of 13 pregnant patients (15 pregnancies) with obstetrical APS were reviewed over 10 years. Patients who met the Sapporo Criteria fully were studied, whereas those with only early pregnancy loss were excluded. In addition to classical aPL: lupus anticoagulant (LA), anticardiolipin antibody (aCL), and anti-beta2-glycoprotein I (abeta2GPI); phosphatidylserine dependent anti-prothrombin antibody (aPS/PT) and kininogen-dependent anti phosphatidylethanolamine antibody (aPE) were also examined in each case. Results. Cases were divided into two groups according to patient response to standard treatment: good and poor outcome groups. All cases with poor outcome presented LA, with IgG abeta2GPI and IgG aPS/PT were also frequently observed. IgG aPE did not correlate with pregnancy outcome. Conclusion. aPL profile may predict pregnancy outcome in patients with this subset of obstetric APS. PMID- 25146550 TI - The control of insulin secretion by adipokines: current evidence for adipocyte beta cell endocrine signalling in metabolic homeostasis. AB - Metabolic homeostasis is maintained by the coordinated action of multiple organ systems. Insulin secretion is often enhanced during obesity or insulin resistance to maintain glucose and lipid homeostasis, whereas a loss of insulin secretion is associated with type 2 diabetes. Adipocytes secrete hormones known as adipokines which act on multiple cell types to regulate metabolism. Many adipokines have been shown to influence beta cell function by enhancing or inhibiting insulin release or by influencing beta cell survival. Insulin, in turn, regulates lipolysis and promotes glucose uptake and lipid storage in adipocytes. As adipokine secretion and action is strongly influenced by obesity, this provides a potential route by which beta cell function is coordinated with adiposity, independently of alterations in blood glucose or lipid levels. In this review, I assess the evidence for the direct regulation of beta cell function by the adipokines leptin, adiponectin, extracellular nicotinamide phosphoribosyltransferase, apelin, resistin, retinol binding protein 4, fibroblast growth factor 21, nesfatin-1 and fatty acid binding protein 4. I summarise in vitro and in vivo data and discuss the influence of obesity and diabetes on circulating adipokine concentrations, along with the potential for influencing beta cell function in human physiology. Finally, I highlight future research questions that are likely to yield new insights into the exciting field of insulinotropic adipokines. PMID- 25146552 TI - Incretin-based therapies and acute pancreatitis risk: a systematic review and meta-analysis of observational studies. AB - Concerns raised by several animal studies, case reports, and pharmacovigilance warnings over incretin-based therapy potentially exposing type two diabetes patients to an elevated risk of pancreatitis have cast a shadow on the overall safety of this class of drugs. This systematic review evaluates the data from observational studies that compared treatment with or without incretins and the risk of pancreatitis. We searched PubMed for publications with the key terms incretins or GLP-1 receptor agonists or DPP-4 inhibitors or sitagliptin or vildagliptin or saxagliptin or linagliptin or alogliptin or exenatide or liraglutide AND pancreatitis in the title or abstract. Studies were evaluated against the following criteria: design (either cohort or case-control); outcome definition (incidence of pancreatitis); exposure definition (new or current or past incretins users); and comparison between patients receiving incretins or not for type 2 diabetes. Two authors independently selected the studies and extracted the data. Six studies meeting the inclusion criteria were reviewed. No difference was found in the overall risk of pancreatitis between incretin users and non users (odds ratio 1.08; 95 % CI [0.84-1.40]). A risk increase lower than 35 % cannot be excluded according to the power calculation. This systematic review and meta-analysis suggests that type 2 diabetes patients receiving incretin-based therapy are not exposed to an elevated risk of pancreatitis. Limitations of this analysis are the low prevalence of incretin users and the lack of a clear distinction by the studies between therapy with DPP-4 inhibitors or with GLP-1 receptor agonists. PMID- 25146553 TI - DHEAS for the prediction of subclinical Cushing's syndrome: perplexing or advantageous? AB - The diagnostic accuracy of dehydroepiandrosterone sulfate (DHEAS) to predict subclinical Cushing's syndrome (sCS) has been a matter of debate. The primary objective of this study was to assess the diagnostic power of DHEAS in predicting sCS. This retrospective study was conducted in a tertiary referral center and based on subjects referred between 2004 and 2014. Data of 249 subjects with adrenal incidentalomas were evaluated. We also reviewed 604 DHEAS measurements from adults, which were performed during the same period in our laboratory (LB group). Adrenocortical function, tumor size, and clinical characteristics were assessed. We diagnosed sCS in 15.2 % of the participants in the presence of >=2 of the following; 1 mg dexamethasone suppression test >3.0 MUg/dl, urinary free cortisol >70 MUg/24 h, and corticotrophin (ACTH) <10 pg/ml. DHEAS levels were significantly reduced in patients with sCS (n = 38) compared to sCS (-) (n = 141) and LB groups (n = 604) (27.95, 65.90, and 66.80 ug/dl, respectively, p < 0.001) while age was comparable. The ROC curve analysis showed that the cut-off of the DHEAS with the best diagnostic accuracy for detecting sCS was 40.0 MUg/dl (SN, 68 %; SP, 75; PPV, 43 %; NPV, 90 %, AUC: 0.788, p < 0.001). Logistic regression assessed the impact of age, BMI, low DHEAS (<40 MUg/dl), bilateral tumors, and tumor size on the likelihood of having sCS. The strongest predictor was low DHEAS, recording an OR of 9.41. DHEAS levels are inversely associated with the extent of cortisol excess. In subjects with intermediate laboratory findings, detection of low DHEAS could be advantageous for distinguishing sCS. PMID- 25146554 TI - Prediction of hemodynamic improvement after pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension using non-invasive imaging. AB - Pulmonary endarterectomy (PEA) is the recommended treatment in chronic thromboembolic pulmonary hypertension (CTEPH). Prediction of outcome after PEA remains challenging. In search for pre-operative predictors we evaluated non invasive parameters measured by chest CT-scan and echocardiography. Between May 2004 and January 2009, 52 consecutive patients with CTEPH who underwent PEA (59.6 % female, mean age 58.9 +/- 13.4 years) were included. Prior to surgery, pulmonary artery (PA) diameter indices were calculated by chest CT scan and different echocardiographic measurements to evaluate pulmonary hypertension were obtained. Hemodynamic improvement after PEA was defined as a pulmonary vascular resistance (PVR) <500 dyn s cm(-5) and a mean pulmonary artery pressure <35 mmHg 3 days after PEA. Mortality was evaluated at day 30. Mean pulmonary artery pressure (PAP) at baseline was 40.1 +/- 8.5 mmHg, with a PVR of 971 +/- 420 dyn s cm(-5). Persistent pulmonary hypertension was observed in 15 patients (28.8 %). Gender, pre-operative mean PAP, PA diameter indices, and tricuspid annular plane systolic excursion were all predictors for hemodynamic improvement after PEA. The indexed PA diameter on CT was the only independent predictor for hemodynamic improvement: 19.4 +/- 2.4 versus 22.9 +/- 4.9 mm/m(2) in those without improvement (OR 0.76: 95 % CI 0.58-0.99, p = 0.04). All patients who died within 30 days (9.6 %) had persistent pulmonary hypertension, with a post-operative mean PAP of 51.6 +/- 14.1 mmHg and PVR of 692 +/- 216 dyn s cm(-5). The pre-operative PA diameter indexed for body surface area is the only independent predictor for hemodynamic improvement after PEA in CTEPH patients. In all patients who died within 30 days after PEA, persistent pulmonary hypertension was present. PMID- 25146555 TI - Charge-transfer induced magnetic field effects of nano-carbon heterojunctions. AB - Room temperature magnetic field effects have not been definitively observed in either single-walled carbon nanotubes (SWCNTs) or C60 under a small magnetic field due to their weak hyperfine interaction and slight difference of g-factor between positive and negative polarons. Here, we demonstrate charge-transfer induced magnetic field effects in nano-carbon C60-SWCNT bulk heterojunctions at room temperature, where the mechanism of magnetic field effects is verified using excited state transition modeling. By controlling SWCNT concentrations and interfacial interactions, nano-carbon heterojunctions exhibit tunability of charge-transfer density and room temperature magnetoconductance of 2.8% under 100 mT external magnetic field. External stimuli, such as electric field and photoexcitation, also play an important role in controlling the magnetic field effects of nano-carbon heterojunctions, which suggests that these findings could enable the control of optoelectronic properties of nano-carbon heterojunctions. PMID- 25146556 TI - Cherenkov excited phosphorescence-based pO2 estimation during multi-beam radiation therapy: phantom and simulation studies. AB - Megavoltage radiation beams used in External Beam Radiotherapy (EBRT) generate Cherenkov light emission in tissues and equivalent phantoms. This optical emission was utilized to excite an oxygen-sensitive phosphorescent probe, PtG4, which has been developed specifically for NIR lifetime-based sensing of the partial pressure of oxygen (pO2). Phosphorescence emission, at different time points with respect to the excitation pulse, was acquired by an intensifier-gated CCD camera synchronized with radiation pulses delivered by a medical linear accelerator. The pO2 distribution was tomographically recovered in a tissue equivalent phantom during EBRT with multiple beams targeted from different angles at a tumor-like anomaly. The reconstructions were tested in two different phantoms that have fully oxygenated background, to compare a fully oxygenated and a fully deoxygenated inclusion. To simulate a realistic situation of EBRT, where the size and location of the tumor is well known, spatial information of a prescribed region was utilized in the recovery estimation. The phantom results show that region-averaged pO2 values were recovered successfully, differentiating aerated and deoxygenated inclusions. Finally, a simulation study was performed showing that pO2 in human brain tumors can be measured to within 15 mmHg for edge depths less than 10-20 mm using the Cherenkov Excited Phosphorescence Oxygen imaging (CEPhOx) method and PtG4 as a probe. This technique could allow non invasive monitoring of pO2 in tumors during the normal process of EBRT, where beams are generally delivered from multiple angles or arcs during each treatment fraction. PMID- 25146557 TI - [Kidney paired donation. Combination with extracorporeal desensitization]. AB - BACKGROUND: Live kidney donation represents the gold standard for renal replacement therapy. Due to ABO and HLA incompatibility between donor and recipient pairs, one third of possible transplantations cannot be performed. Kidney exchange programs in combination with extracorporeal desensitization have been introduced to enable successful kidney transplantation in such circumstances. OBJECTIVE: This review discusses the current indications, methods, ethical problems and results within such programs. MATERIALS AND METHODS: Relevant Medline articles were analyzed and personal experiences of the authors are included in this article. RESULTS: Kidney exchange programs in combination with extracorporeal desensitization enable successful transplantation for most patients. DISCUSSION: The best combinations of existing strategies have to be defined and newly arisen ethical questions have to be answered. PMID- 25146558 TI - Assessment of lung function in asthma and COPD using hyperpolarized 129Xe chemical shift saturation recovery spectroscopy and dissolved-phase MRI. AB - Magnetic-resonance spectroscopy and imaging using hyperpolarized xenon-129 show great potential for evaluation of the most important function of the human lung - gas exchange. In particular, chemical shift saturation recovery (CSSR) xenon-129 spectroscopy provides important physiological information for the lung as a whole by characterizing the dynamic process of gas exchange, while dissolved-phase (DP) xenon-129 imaging captures the time-averaged regional distribution of gas uptake by lung tissue and blood. Herein, we present recent advances in assessing lung function using CSSR spectroscopy and DP imaging in a total of 45 subjects (23 healthy, 13 chronic obstructive pulmonary disease (COPD) and 9 asthma). From CSSR acquisitions, the COPD subjects showed red blood cell to tissue-plasma (RBC-to TP) ratios below the average for the healthy subjects (p < 0.001), but significantly higher septal wall thicknesses as compared with the healthy subjects (p < 0.005); the RBC-to-TP ratios for the asthmatic subjects fell outside two standard deviations (either higher or lower) from the mean of the healthy subjects, although there was no statistically significant difference for the average ratio of the study group as a whole. Similarly, from the 3D DP imaging acquisitions, we found that all the ratios (TP to gas phase (GP), RBC to GP, RBC to TP) measured in the COPD subjects were lower than those from the healthy subjects (p < 0.05 for all ratios), while these ratios in the asthmatic subjects differed considerably between subjects. Despite having been performed at different lung inflation levels, the RBC-to-TP ratios measured by CSSR and 3D DP imaging were fairly consistent with each other, with a mean difference of 0.037 (ratios from 3D DP imaging larger). In ten subjects the RBC-to-GP ratios obtained from the 3D DP imaging acquisitions were also highly correlated with their diffusing capacity of the lung for carbon monoxide per unit alveolar volume ratios measured by pulmonary function testing (R = 0.91). PMID- 25146559 TI - Direct megavoltage photon calibration service in Australia. AB - The Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) maintains the Australian primary standard of absorbed dose. Until recently, the standard was used to calibrate ionisation chambers only in (60)Co gamma rays. These chambers are then used by radiotherapy clinics to determine linac output, using a correction factor (k Q) to take into account the different spectra of (60)Co and the linac. Over the period 2010-2013, ARPANSA adapted the primary standard to work in megavoltage linac beams, and has developed a calibration service at three photon beams (6, 10 and 18 MV) from an Elekta Synergy linac. We describe the details of the new calibration service, the method validation and the use of the new calibration factors with the International Atomic Energy Agency's TRS-398 dosimetry Code of Practice. The expected changes in absorbed dose measurements in the clinic when shifting from (60)Co to the direct calibration are determined. For a Farmer chamber (model 2571), the measured chamber calibration coefficient is expected to be reduced by 0.4, 1.0 and 1.1 % respectively for these three beams when compared to the factor derived from (60)Co. These results are in overall agreement with international absorbed dose standards and calculations by Muir and Rogers in 2010 of k Q factors using Monte Carlo techniques. The reasons for and against moving to the new service are discussed in the light of the requirements of clinical dosimetry. PMID- 25146560 TI - Nurses' knowledge and attitudes about pain. PMID- 25146561 TI - Nanothorn electrodes for ionic polymer-metal composite artificial muscles. AB - Ionic polymer-metal composites (IPMCs) have recently received tremendous interest as soft biomimetic actuators and sensors in various bioengineering and human affinity applications, such as artificial muscles and actuators, aquatic propulsors, robotic end-effectors, and active catheters. Main challenges in developing biomimetic actuators are the attainment of high strain and actuation force at low operating voltage. Here we first report a nanostructured electrode surface design for IPMC comprising platinum nanothorn assemblies with multiple sharp tips. The newly developed actuator with the nanostructured electrodes shows a new way to achieve highly enhanced electromechanical performance over existing flat-surfaced electrodes. We demonstrate that the formation and growth of the nanothorn assemblies at the electrode interface lead to a dramatic improvement (3 to 5-fold increase) in both actuation range and blocking force at low driving voltage (1-3 V). These advances are related to the highly capacitive properties of nanothorn assemblies, increasing significantly the charge transport during the actuation process. PMID- 25146562 TI - Coenzyme B12 can be produced by engineered Escherichia coli under both anaerobic and aerobic conditions. AB - Coenzyme B12 (Vitamin B12 ) is one of the most complex biomolecules and an essential cofactor required for the catalytic activity of many enzymes. Pseudomonas denitrificans synthesizes coenzyme B12 in an oxygen-dependent manner using a pathway encoded by more than 25 genes that are located in six different operons. Escherichia coli, a robust and suitable host for metabolic engineering was used to produce coenzyme B12 . These genes were cloned into three compatible plasmids and expressed heterologously in E. coli BL21 (DE3). Real-time PCR, SDS PAGE analysis and bioassay showed that the recombinant E. coli expressed the coenzyme B12 synthetic genes and successfully produced coenzyme B12 . However, according to the quantitative determination by inductively coupled plasma-mass spectrometry, the amount of coenzyme B12 produced by the recombinant E. coli (0.21 +/- 0.02 MUg/g cdw) was approximately 13-fold lower than that by P. denitrificans (2.75 +/- 0.22 MUg/g cdw). Optimization of the culture conditions to improve the production of coenzyme B12 by the recombinant E. coli was successful, and the highest titer (0.65 +/- 0.03 MUg/g cdw) of coenzyme B12 was obtained. Interestingly, although the synthesis of coenzyme B12 in P. denitrificans is strictly oxygen-dependent, the recombinant E. coli could produce coenzyme B12 under anaerobic conditions. PMID- 25146563 TI - Bilateral atrophic kidney-like tumors. PMID- 25146565 TI - Formation of polydopamine nanofibers with the aid of folic acid. AB - Polydopamine (PDA) generated by the oxidative self-polymerization of dopamine shows great potential for surface modification. Observed PDA nanostructures are nanoparticles and thin films. The formation mechanism of PDA is still unclear; thus, the manipulation of PDA nanostructures is a big challenge. In this study, we first demonstrated that folic acid shows a dramatic effect on the PDA nanostructure: New aggregated nanostructures of PDA, nanobelts and nanofibers, were generated in a dopamine/folic acid system. We hypothesized that folic acid may be involved in the stacking of protomolecules of PDA by pi-pi interactions and hydrogen bonding. Herein we describe the first experimental strategy to manipulate the aggregation of PDA by using small molecules. This study not only provides a new method for generating PDA nanofibers, which are proposed bioorganic electronic materials, but also a possible way to understand the formation mechanism of PDA and its analogues in nature, melanins. PMID- 25146564 TI - Record-linkage comparison of verbal autopsy and routine civil registration death certification in rural north-east South Africa: 2006-09. AB - BACKGROUND: South African civil registration (CR) provides a key data source for local health decision making, and informs the levels and causes of mortality in data-lacking sub-Saharan African countries. We linked mortality data from CR and the Agincourt Health and Socio-demographic Surveillance System (Agincourt HDSS) to examine the quality of rural CR data. METHODS: Deterministic and probabilistic techniques were used to link death data from 2006 to 2009. Causes of death were aggregated into the WHO Mortality Tabulation List 1 and a locally relevant short list of 15 causes. The matching rate was compared with informant-reported death registration. Using the VA diagnoses as reference, misclassification patterns, sensitivity, positive predictive values and cause-specific mortality fractions (CSMFs) were calculated for the short list. RESULTS: A matching rate of 61% [95% confidence interval (CI): 59.2 to 62.3] was attained, lower than the informant reported registration rate of 85% (CI: 83.4 to 85.8). For the 2264 matched cases, cause agreement was 15% (kappa 0.1083, CI: 0.0995 to 0.1171) for the WHO list, and 23% (kappa 0.1631, CI: 0.1511 to 0.1751) for the short list. CSMFs were significantly different for all but four (tuberculosis, cerebrovascular disease, other heart disease, and ill-defined natural) of the 15 causes evaluated. CONCLUSION: Despite data limitations, it is feasible to link official CR and HDSS verbal autopsy data. Data linkage proved a promising method to provide empirical evidence about the quality and utility of rural CR mortality data. Agreement of individual causes of death was low but, at the population level, careful interpretation of the CR data can assist health prioritization and planning. PMID- 25146566 TI - Rectal Lactobacillus species and their influence on the vaginal microflora: a model of male-to-female transsexual women. AB - INTRODUCTION: Based on Lactobacillus species co-colonizing the vagina and rectum, it has been hypothesized that the rectum may be an important reservoir for vaginal colonization by lactobacilli. There are no data on this issue in male-to female transsexual women. AIM: We undertook this observational study to characterize the Lactobacillus species present in the neovagina and rectum of male-to-female transsexual women and to determine the degree of neovaginal-rectal co-colonization in order to gain a better understanding of the potential role of the gut as a reservoir for genital lactobacilli. METHODS: Sixty-one male-to female transsexual women with penile skin lined neovagina without clinical signs of infection were recruited on an ongoing basis from among male-to-female transsexual outpatients. Neovaginal and rectal smears were taken for molecular Lactobacillus species profiling by denaturing gradient gel electrophoresis (PCR DGGE). MAIN OUTCOME MEASURES: Matching Lactobacillus species between neovagina and rectum. RESULTS: Forty-three of the 61 male-to-female transsexual women (70.5%) simultaneously harbored the same lactobacilli in both the neovagina and rectum. We found 276 neovaginal and 258 rectal DGGE bands representing 11 Lactobacillus species, with 201 matches of the same Lactobacillus species in neovagina and rectum. 37 of the 61 women (61%) had two or more matching Lactobacillus species. CONCLUSION: These data support the hypothesis that the rectum may play an important role as source of Lactobacillus species that colonies neovagina of male-to-female transsexual women. In view of the specific anatomical circumstances of the study population, these findings may be extended to the general population of women. PMID- 25146567 TI - ATP-dependent binding cassette transporter G family member 16 increases plant tolerance to abscisic acid and assists in basal resistance against Pseudomonas syringae DC3000. AB - Plants have been shown previously to perceive bacteria on the leaf surface and respond by closing their stomata. The virulent bacterial pathogen Pseudomonas syringae pv tomato DC3000 (PstDC3000) responds by secreting a virulence factor, coronatine, which blocks the functioning of guard cells and forces stomata to reopen. After it is inside the leaf, PstDC3000 has been shown to up-regulate abscisic acid (ABA) signaling and thereby suppress salicylic acid-dependent resistance. Some wild plants exhibit resistance to PstDC3000, but the mechanisms by which they achieve this resistance remain unknown. Here, we used genome-wide association mapping to identify an ATP-dependent binding cassette transporter gene (ATP-dependent binding cassette transporter G family member16) in Arabidopsis (Arabidopsis thaliana) that contributes to wild plant resistance to PstDC3000. Through microarray analysis and beta-glucuronidase reporter lines, we showed that the gene is up-regulated by ABA, bacterial infection, and coronatine. We also used a green fluorescent protein fusion protein and found that transporter is more likely to localize on plasma membranes than in cell walls. Transferred DNA insertion lines exhibited consistent defective tolerance of exogenous ABA and reduced resistance to infection by PstDC3000. Our conclusion is that ATP-dependent binding cassette transporter G family member16 is involved in ABA tolerance and contributes to plant resistance against PstDC3000. This is one of the first examples, to our knowledge, of ATP-dependent binding cassette transporter involvement in plant resistance to infection by a bacterial pathogen. It also suggests a possible mechanism by which plants reduce the deleterious effects of ABA hijacking during pathogen attack. Collectively, these results improve our understanding of basal resistance in Arabidopsis and offer unique ABA related targets for improving the innate resistance of plants to bacterial infection. PMID- 25146568 TI - Emerging drugs for levodopa-induced dyskinesia. AB - INTRODUCTION: Levodopa continues to be the main symptomatic therapy for clinical features of Parkinson's disease. However, prolonged use leads to motor complications, including levodopa-induced dyskinesia (LID). This has debilitating impact on the patients and is a significant challenge for the treating physician. There are currently limited pharmacological options for reducing established LID without causing side effects. Drugs to prevent or delay LID are also an increasing part of the strategy to manage LID, but have yet to show promise. Agents that allow levodopa to be used effectively, without inducing LID, are the goal of current research strategies. AREAS COVERED: LID occurs due to significant modifications in the basal ganglia circuitry, probably related to the chronic, pulsatile stimulation of striatal dopaminergic receptors by levodopa, as well as altered non-dopaminergic neurotransmitter system signaling pathways. Novel treatments that either result in continuous dopaminergic receptor stimulation, levodopa 'sparing strategies' or non-dopaminergic targets, including glutamatergic, serotonergic, adenosine, adrenergic and cholinergic neurotransmission are thus the main treatment options and the focus of this manuscript. Randomized controlled trials in progress (ClinicalTrials.org) or recently published articles are included. EXPERT OPINION: The success of future therapeutic approaches will depend on the potential success of translational research. PMID- 25146569 TI - Thermoluminescence characteristics of Nd-doped SiO2 optical fibers irradiated with the (60)Co gamma rays. AB - Thermoluminescence (TL) properties (radiation sensitivity, dose response, signal fading) of Nd-doped SiO2 optical fibers irradiated with 1.25MeV photons to 1-50Gy were studied. The peak of the glow curve is around 190 degrees C regardless of the dose. The dose response is linear up to 50Gy. The radiation sensitivity is 219nCmg(-1)Gy(-1). The fiber can be a potential candidate for photon radiotherapy dosimetry due to its high radiation sensitivity, linear dose response in a wide range, slow fading, and high spatial resolution due to the small size of the fiber. PMID- 25146570 TI - Institutional development of freshwater fish stocking in Mexico. AB - By using freshwater fish stocking information from the Mexican government, this work described the current situation of the national stocking and its associated fishery policy. There is a lack of effective freshwater stocking programmes as a result of limited fisheries management, unharmonized fisheries regulations and institutional performance. The fry production has decreased from 140 to 20 million in the past 11 years. PMID- 25146571 TI - Sensory integration during reaching: the effects of manipulating visual target availability. AB - When using visual and proprioceptive information to plan a reach, it has been proposed that the brain combines these cues to estimate the object and/or limb's location. Specifically, according to the maximum-likelihood estimation (MLE) model, sensory inputs are combined such that more reliable inputs are assigned a greater weight (Ernst and Banks in Nature 415:429-433, 2002). In this paper, we examined if the brain is able to adjust which sensory cue it weights the most. Specifically, we asked if the brain changes how it weights sensory information when the availability of a visual cue is manipulated. Twelve healthy subjects reached to visual (V), proprioceptive (P), or visual + proprioceptive (VP) targets under different visual delay conditions (e.g., on V and VP trials, the visual target was available for the entire reach; it was removed with the go signal, or it was removed 1 s before the go signal). To establish which sensory cue subjects weighted the most, we compared endpoint positions achieved on V and P reaches to VP reaches. Results indicated that subjects combined visual and proprioceptive cues in accordance with the MLE model when reaching to VP targets. Moreover, subjects' reaching errors to visual targets increased with longer visual delays (particularly in the vertical direction). However, there was no change in reach variability with longer delays, and subjects did not reweight visual information as the availability of visual information was manipulated. Thus, a change in visual environment is not sufficient to cause the brain to reweight how it processes sensory information. PMID- 25146572 TI - The influence of horizontally rotating sound on standing balance. AB - Postural control is known to be the result of the integration and processing of various sensory inputs by the central nervous system. Among the various afferent inputs, the role of auditory information in postural regulation has been addressed in relatively few studies, which led to conflicting results. The purpose of the present study was to investigate the influence of a rotating auditory stimulus, delivered by an immersive 3D sound spatialization system, on the standing posture of young subjects. The postural sway of 20 upright, blindfolded subjects was recorded using a force platform. Use of various sound source rotation velocities followed by sudden immobilization of the sound was compared with two control conditions: no sound and a stationary sound source. The experiment showed that subjects reduced their body sway amplitude and velocity in the presence of rotating sound compared with the control conditions. The faster the sound source was rotating, the greater the reduction in subject body sway. Moreover, disruption of subject postural regulation was observed as soon as the sound source was immobilized. These results suggest that auditory information cannot be neglected in postural control and that it acts as additional information influencing postural regulation. PMID- 25146573 TI - Information and control strategy to solve the degrees-of-freedom problem for nested locomotion-to-reach. AB - Locomoting-to-reach to a target is a common visuomotor approach behavior that consists of two nested component actions: locomotion and reaching. The information and control strategies that guide locomotion and reaching in isolation are well studied, but their interaction during locomoting-to-reach behavior has received little attention. We investigated the role of proportional rate control in unifying these components into one action. Individuals use this control strategy with hand-centric disparity-based tau information to guide seated reaching (Anderson and Bingham in Exp Brain Res 205:291-306. doi: 10.1007/s00221-010-2361-9 , 2010) and use it with sequential information to perform targeted locomotion to bring an outstretched arm and hand to a target; first with eye-centric tau information and then hand-centric tau information near the target (Anderson and Bingham in Exp Brain Res 214:631-644. doi: 10.1007/s00221-011-2865-y , 2011). In the current study, participants performed two tasks: locomoting to bring a rigidly outstretched arm and hand to a target (handout), and locomoting to initiate and guide a reach to a target (locomoting to-reach). Movement trajectories were analyzed. Results show that participants used proportional rate control throughout both tasks, in the sequential manner that was found by Anderson and Bingham (Exp Brain Res 214:631-644. doi: 10.1007/s00221-011-2865-y , 2011). Individual differences were found in the moment at which this information switch occurred in the locomoting-to-reach task. Some participants appeared to switch to proportional rate control with hand-tau once the hand came into view and others switched once the reaching component was complete and the arm was fully outstretched. In the locomoting-to-reach task, participants consistently initiated reaches when eye-tau specified a time-to contact of 1.0 s. Proportional rate control provides a solution to the degrees-of freedom problem in the classic manner, by making multiple things one. PMID- 25146574 TI - Distinguishing bias from sensitivity effects in multialternative detection tasks. AB - Studies investigating the neural bases of cognitive phenomena increasingly employ multialternative detection tasks that seek to measure the ability to detect a target stimulus or changes in some target feature (e.g., orientation or direction of motion) that could occur at one of many locations. In such tasks, it is essential to distinguish the behavioral and neural correlates of enhanced perceptual sensitivity from those of increased bias for a particular location or choice (choice bias). However, making such a distinction is not possible with established approaches. We present a new signal detection model that decouples the behavioral effects of choice bias from those of perceptual sensitivity in multialternative (change) detection tasks. By formulating the perceptual decision in a multidimensional decision space, our model quantifies the respective contributions of bias and sensitivity to multialternative behavioral choices. With a combination of analytical and numerical approaches, we demonstrate an optimal, one-to-one mapping between model parameters and choice probabilities even for tasks involving arbitrarily large numbers of alternatives. We validated the model with published data from two ternary choice experiments: a target detection experiment and a length-discrimination experiment. The results of this validation provided novel insights into perceptual processes (sensory noise and competitive interactions) that can accurately and parsimoniously account for observers' behavior in each task. The model will find important application in identifying and interpreting the effects of behavioral manipulations (e.g., cueing attention) or neural perturbations (e.g., stimulation or inactivation) in a variety of multialternative tasks of perception, attention, and decision making. PMID- 25146575 TI - Attention to multiple locations is limited by spatial working memory capacity. AB - What limits the ability to attend several locations simultaneously? There are two possibilities: Either attention cannot be divided without incurring a cost, or spatial memory is limited and observers forget which locations to monitor. We compared motion discrimination when attention was directed to one or multiple locations by briefly presented central cues. The cues were matched for the amount of spatial information they provided. Several random dot kinematograms (RDKs) followed the spatial cues; one of them contained task-relevant, coherent motion. When four RDKs were presented, discrimination accuracy was identical when one and two locations were indicated by equally informative cues. However, when six RDKs were presented, discrimination accuracy was higher following one rather than multiple location cues. We examined whether memory of the cued locations was diminished under these conditions. Recall of the cued locations was tested when participants attended the cued locations and when they did not attend the cued locations. Recall was inaccurate only when the cued locations were attended. Finally, visually marking the cued locations, following one and multiple location cues, equalized discrimination performance, suggesting that participants could attend multiple locations when they did not have to remember which ones to attend. We conclude that endogenously dividing attention between multiple locations is limited by inaccurate recall of the attended locations and that attention poses separate demands on the same central processes used to remember spatial information, even when the locations attended and those held in memory are the same. PMID- 25146576 TI - Spatial vision is superior in musicians when memory plays a role. AB - Musicians' perceptual advantage in the acoustic domain is well established. Recent studies show that musicians' verbal working memory is also superior. Additionally, some studies report that musicians' visuospatial skills are enhanced although others failed to find this enhancement. We now examined whether musicians' spatial vision is superior, and if so, whether this superiority reflects refined visual skills or a general superiority of working memory. We examined spatial frequency discrimination among musicians and nonmusician university students using two presentation conditions: simultaneous (spatial forced choice) and sequential (temporal forced choice). Musicians' performance was similar to that of nonmusicians in the simultaneous condition. However, their performance in the sequential condition was superior, suggesting an advantage only when stimuli need to be retained, i.e., working memory. Moreover, the two groups showed a different pattern of correlations: Musicians' visual thresholds were correlated, and neither was correlated with their verbal memory. By contrast, among nonmusicians, the visual thresholds were not correlated, but sequential thresholds were correlated with verbal memory scores, suggesting that a general working memory component limits their performance in this condition. We propose that musicians' superiority in spatial frequency discrimination reflects an advantage in a domain-general aspect of working memory rather than a general enhancement in spatial-visual skills. PMID- 25146577 TI - Evidence for participation by object-selective visual cortex in scene category judgments. AB - Scene recognition is a core function of the visual system, drawing both on scenes' intrinsic global features, prominently their spatial properties, and on the identities of the objects scenes contain. Neuroimaging and neuropsychological studies have associated spatial property-based scene categorization with parahippocampal cortex, while processing of scene-relevant object information is associated with the lateral occipital complex (LOC), wherein activity patterns distinguish between categories of standalone objects and those embedded in scenes. However, despite the importance of objects to scene categorization and the role of LOC in processing them, damage or disruption to LOC that hampers object recognition has been shown to improve scene categorization. To address this paradox, we used functional magnetic resonance imaging (fMRI) to directly assess the contributions of LOC and the parahippocampal place area (PPA) to category judgments of indoor scenes that were devoid of objective identity signals. Observers were alternately cued to base judgments on scenes' objects or spatial properties. In both LOC and PPA, multivoxel activity patterns better decoded judgments based on their typically associated features: LOC more accurately decoded object-based judgments, while PPA more accurately decoded spatial property-based judgments. The cue contingency of LOC decoding accuracy indicates that it was not an outcome of feedback from judgments and is instead consistent with dependency of judgments on the output of object processing pathways in which LOC participates. PMID- 25146578 TI - Activation of response force by self-splitting objects: where are the limits of feedforward Gestalt processing? AB - Most objects can be recognized easily even when they are partly occluded. This also holds when several overlapping objects share the same surface features (self splitting objects) which is an illustration of the grouping principle of Good Gestalt. We employed outline and filled contour stimuli in a primed flanker task to test whether the processing of self-splitting objects is in accordance with a simple feedforward model. We obtained priming effects in response time and response force for both types of stimuli, even when increasing the number of occluders up to three. The results for outline contours were in full accordance with a feedforward account. This was not the case for the results for filled contours (i.e., for self-splitting objects), especially under conditions of strong occlusion. We conclude that the implementation of the Good Gestalt principle is fast but still based on recurrent processing. PMID- 25146579 TI - Size-based cell sorting with a resistive pulse sensor and an electromagnetic pump in a microfluidic chip. AB - An electrokinetic microfluidic chip is developed to detect and sort target cells by size from human blood samples. Target-cell detection is achieved by a differential resistive pulse sensor (RPS) based on the size difference between the target cell and other cells. Once a target cell is detected, the detected RPS signal will automatically actuate an electromagnetic pump built in a microchannel to push the target cell into a collecting channel. This method was applied to automatically detect and sort A549 cells and T-lymphocytes from a peripheral fingertip blood sample. The viability of A549 cells sorted in the collecting well was verified by Hoechst33342 and propidium iodide staining. The results show that as many as 100 target cells per minute can be sorted out from the sample solution and thus is particularly suitable for sorting very rare target cells, such as circulating tumor cells. The actuation of the electromagnetic valve has no influence on RPS cell detection and the consequent cell-sorting process. The viability of the collected A549 cell is not impacted by the applied electric field when the cell passes the RPS detection area. The device described in this article is simple, automatic, and label-free and has wide applications in size based rare target cell sorting for medical diagnostics. PMID- 25146580 TI - Near-infrared croconaine rotaxanes and doped nanoparticles for enhanced aqueous photothermal heating. AB - The photothermal effect is the generation of heat by molecules or particles upon high-energy laser irradiation, and near-infrared absorbers such as gold nanoparticles and organic dyes have a range of potential photothermal applications. The favourable photothermal properties of thiophene-functionalised croconaine dyes were recently discovered. The synthesis and properties of novel croconaine rotaxane and pseudorotaxane architectures capable of efficient photothermal performance in both organic and aqueous environments are reported. The versatility of this dye-encapsulation strategy was demonstrated by the preparation of two organic croconaine rotaxanes using different synthetic methods: the formation of an aqueous pseudorotaxane association complex, and the synthesis of water-soluble, croconaine-doped silicated micelle nanoparticles. All of these near-infrared-absorbing systems exhibit excellent photothermal behaviour, with pseudorotaxane and rotaxane formation vital for effective aqueous heat generation. Dye encapsulation provides steric protection to enhance the stability of a water-sensitive croconaine dye, while rotaxane-doped nanoparticles avoid detrimental band broadening caused by chromophore coupling. PMID- 25146581 TI - Ionic liquid foam floatation coupled with ionic liquid dispersive liquid-liquid microextraction for the separation and determination of estrogens in water samples by high-performance liquid chromatography with fluorescence detection. AB - An ionic liquid foam floatation coupled with ionic liquid dispersive liquid liquid microextraction method was proposed for the extraction and concentration of 17-alpha-estradiol, 17-beta-estradiol-benzoate, and quinestrol in environmental water samples by high-performance liquid chromatography with fluorescence detection. 1-Hexyl-3-methylimidazolium tetrafluoroborate was applied as foaming agent in the foam flotation process and dispersive solvent in microextraction. The introduction of the ion-pairing and salting-out agent NH4 PF6 was beneficial to the improvement of recoveries for the hydrophobic ionic liquid phase and analytes. Parameters of the proposed method including concentration of 1-hexyl-3-methylimidazolium tetrafluoroborate, flow rate of carrier gas, floatation time, types and concentration of ionic liquids, salt concentration in samples, extraction time, and centrifugation time were evaluated. The recoveries were between 98 and 105% with relative standard deviations lower than 7% for lake water and well water samples. The isolation of the target compounds from the water was found to be efficient, and the enrichment factors ranged from 4445 to 4632. This developing method is free of volatile organic solvents compared with regular extraction. Based on the unique properties of ionic liquids, the application of foam floatation, and dispersive liquid liquid microextraction was widened. PMID- 25146582 TI - Usefulness of the insulin-like growth factor binding protein-1 bedside test for ruptured fetal membranes. AB - OBJECTIVE: We evaluated whether phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) in blood or from other sources interferes with the vaginal IGFBP-1 dipstick test in rupture of fetal membranes (ROM). DESIGN: Cross sectional study. SETTING: Antenatal Clinic, University Hospital. POPULATION: A total of 247 pregnant women consulting the emergency obstetric unit with self reported amniotic fluid leakage. METHODS: Vaginal samples were tested with the IGFBP-1 dipstick test and the concentrations of different IGFBP-1 isoforms were measured by two immunoenzymometric assays. MAIN OUTCOME MEASURE: IGFBP-1 dipstick test result in the presence or absence of blood and different phosphoisoforms of IGFBP-1. RESULTS: The dipstick test was positive in 37.2% of women and negative in 62.8% of women. Vaginal bleeding was present in 19.4%. In women with a positive test and clinical evidence of ROM, both IGFBP-1 and phIGFBP-1 concentrations in vaginal fluid were lower in women with than in women without bleeding (p = 0.025 and p = 0.031, respectively). No difference was found in concentrations of IGFBP-1 and phIGFBP-1 in women with a positive dipstick test without ROM, with or without vaginal bleeding. In women with a negative test the concentrations of IGFBP-1 and phIGFBP-1 remained below the cut-off for the test, regardless of bleeding. IGFBP-1 concentration did not differ by cervical status, but phIGFBP-1 concentration was higher in women with a ripe cervix (p = 0.001). CONCLUSIONS: Rapid vaginal dipstick test can be used in the detection of ROM irrespective of the presence or absence of blood. Positive tests near term indicate either ROM or leakage of less phIGFBP-1 associated with onset of delivery. PMID- 25146583 TI - Sonochemistry: what potential for conversion of lignocellulosic biomass into platform chemicals? AB - This Review focuses on the use of ultrasound to produce chemicals from lignocellulosic biomass. However, the question about the potential of sonochemistry for valorization/conversion of lignocellulosic biomass into added value chemicals is rather conceptual. Until now, this technology has been mainly used for the production of low-value chemicals such as biodiesel or as simple method for pretreatment or extraction. According to preliminary studies reported in literature, access to added-value chemicals can be easily and sometimes solely obtained by the use of ultrasound. The design of sonochemical parameters offers many opportunities to develop new eco-friendly and efficient processes. The goal of this Review is to understand why the use of ultrasound is focused rather on pretreatment or extraction of lignocellulosic biomass rather than on the production of chemicals and to understand, through the reported examples, which directions need to be followed to favor strategies based on ultrasound-assisted production of chemicals from lignocellulosic biomass. We believe that ultrasound assisted processes represent an innovative approach and will create a growing interest in academia but also in the industry in the near future. Based on the examples reported in the literature, we critically discuss how sonochemistry could offer new strategies and give rise to new results in lignocellulosic biomass valorization. PMID- 25146584 TI - Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide for the treatment of patients with relapsed and refractory multiple myeloma. AB - This single institution, open label Phase I-II dose escalation trial evaluated the safety and efficacy of the combination of lenalidomide (Revlimid(r)), cyclophosphamide and prednisone (CPR) in patients with relapsed/refractory multiple myeloma. The maximal administered dose of CPR consisted of cyclophosphamide 300 mg/m(2) on day 1, 8, and 15, lenalidomide 25 mg on d 1-21 and prednisone 100 mg every other day in a 28-d cycle. Between November 2007 and June 2009, 32 patients were entered in cohorts of three at three dose levels. The median age was 64 years, 59% were male, with a median two prior regimens. Responding patients could stay on treatment until progression. The full-dose CPR regimen produced no dose-limiting toxicity and was delivered for a median of 16 months (3.5-65 months) with acceptable safety and tolerance. The overall response rate (>= partial response) was 94% at a median follow up of 28 months. The median progression-free survival was 16.1 months [95% confidence interval (CI); 10.9 22.5 months], while the median overall survival was 27.6 months (95% CI; 16.8 36.6 months). Only the beta-2 microglobulin level at protocol entry correlated with a better survival (P = 0.047). These observations compare favourably with other 2- and 3- drug combinations for relapsed/refractory myeloma, and suggest that CPR should be evaluated further in the setting of relapsed/refractory disease, or in newly diagnosed patients. PMID- 25146585 TI - gammadeltaT cells regulate chronic airway inflammation and development of airway remodelling. AB - BACKGROUND: gammadeltaT cells play a crucial immunoregulatory role in the lung, maintaining normal airway tone and preventing hyperresponsiveness to innocuous allergen. During acute inflammatory episodes, gammadeltaT cells promote resolution of acute inflammation. However, their contribution to inflammation associated airway remodelling remains unexplored. Here we investigate the effects of gammadeltaT cell blockade on established allergic airway inflammation and development of remodelling. METHODS: Sensitised mice were exposed to prolonged ovalbumin challenge or continuous house-dust mite exposure to induce chronic inflammation and remodelling. Functional blocking anti-TCRdelta antibody was administered therapeutically, and parameters of airway inflammation and remodelling were examined. RESULTS: Therapeutic blockade of gammadeltaT cells prevented the typical resolution of acute airway inflammation characterised by elevated eosinophil and Th2 cell numbers. Moreover, the lung displayed exacerbated airway remodelling, typified by excess peribronchiolar collagen deposition. CONCLUSIONS: These results demonstrate a unique role for gammadeltaT cells in constraining allergen-induced airway remodelling. Manipulating the gammadeltaT cell compartment may therefore contribute to strategies to prevent and treat remodelling. PMID- 25146586 TI - Long-term safety and efficacy of certolizumab pegol in the treatment of Crohn's disease: 7-year results from the PRECiSE 3 study. AB - BACKGROUND: The efficacy and safety of certolizumab pegol (CZP) in moderate-to severe Crohn's disease were demonstrated in two 26-week double-blind studies (PRECiSE 1 & 2). AIM: To report the safety and efficacy outcomes of long-term, CZP therapy from PRECiSE 3, in which patients received treatment up to 7 years treatment. METHODS: Patients completing PRECiSE 1 or 2 were eligible to enter PRECiSE 3 in which they received CZP 400 mg, open-label, every 4 weeks (without additional induction therapy) for up to 7 years, for up to 91 doses from study start. Safety (adverse events, including infections and malignancies) and efficacy (Harvey-Bradshaw Index, faecal calprotectin, C-reactive protein) were prospectively monitored. Remission was analysed using observed cases, last observation carried forward imputation and nonresponder imputation. RESULTS: A total of 595 patients entered the study; 117 (20%) completed 7 years. Discontinuation rates were 29.2%, 13.6%, 16.1%, 7.9%, 5.0%, 4.5% and 3.9% (years 1-7 respectively). During 1920 patient-years of exposure to CZP, no new safety signals were observed. Incidence rates (new cases/100 patient-years) for serious infections and malignant neoplasms were 4.37 and 1.06 respectively. No lymphoproliferative malignancies were reported. Clinical remission rates were >=68% at each year (observed cases); rates by last observation carried forward and nonresponder imputation were 58% and 45% at year 1, 56% and 26% at year 3 and 55% and 13% at year 7 respectively. CONCLUSION: Certolizumab pegol was well tolerated in the long-term treatment of Crohn's disease, with sustained remission in some patients continuing in the study for up to 7 years. ClinicalTrials.gov identifier NCT00552058. PMID- 25146587 TI - Primum non nocere: shared informed decision making in low back pain--a pilot cluster randomised trial. AB - BACKGROUND: Low back pain is a common and disabling condition leading to large health service and societal costs. Although there are several treatment options for back pain little is known about how to improve patient choice in treatment selection. The purpose of this study was to pilot a decision support package to help people choose between low back pain treatments. METHODS: This was a single centred pilot cluster randomised controlled trial conducted in a community physiotherapy service. We included adults with non-specific low back pain referred for physiotherapy. Intervention participants were sent an information booklet prior to their first consultation. Intervention physiotherapists were trained to enhance their skills in shared informed decision making. Those in the control arm received care as usual. The primary outcome was satisfaction with the treatment received at four months using a five-point Likert Scale dichotomised into "satisfaction" (very satisfied or somewhat satisfied) and "non-satisfaction" (neither satisfied nor dissatisfied, somewhat dissatisfied or very dissatisfied). RESULTS: We recruited 148 participants. In the control arm 67% of participants were satisfied with their treatment and in the intervention arm 53%. The adjusted relative risk of being satisfied was 1.28 (95% confidence interval 0.79 to 2.09). For most secondary outcomes the trend was towards worse outcomes in the intervention group. For one measure; the Roland Morris Disability Questionnaire, this difference was clinically important (2.27, 95% confidence interval 0.08 to 4.47). Mean healthcare costs were slightly lower (L38 saving per patient) within the intervention arm but health outcomes were also less favourable (0.02 fewer QALYs); the estimated probability that the intervention would be cost-effective at an incremental threshold of L20,000 per QALY was 16%. CONCLUSION: We did not find that this decision support package improved satisfaction with treatment; it may have had a substantial negative effect on clinical outcome, and is very unlikely to prove cost-effective. That a decision support package might have a clinically important detrimental effect is of concern. To our knowledge this has not been observed previously. Decision support packages should be formally tested for clinical and cost-effectiveness, and safety before implementation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN46035546 registered on 11/02/10. PMID- 25146588 TI - Superabsorption of light via quantum engineering. AB - Almost 60 years ago Dicke introduced the term superradiance to describe a signature quantum effect: N atoms can collectively emit light at a rate proportional to N(2). Structures that superradiate must also have enhanced absorption, but the former always dominates in natural systems. Here we show that this restriction can be overcome by combining several well-established quantum control techniques. Our analytical and numerical calculations show that superabsorption can then be achieved and sustained in certain simple nanostructures, by trapping the system in a highly excited state through transition rate engineering. This opens the prospect of a new class of quantum nanotechnology with potential applications including photon detection and light based power transmission. An array of quantum dots or a molecular ring structure could provide a suitable platform for an experimental demonstration. PMID- 25146589 TI - Converting chemical energy into electricity through a functionally cooperating device with diving-surfacing cycles. AB - A smart device that can dive or surface in aqueous medium has been developed by combining a pH-responsive surface with acid-responsive magnesium. The diving surfacing cycles can be used to convert chemical energy into electricity. During the diving-surfacing motion, the smart device cuts magnetic flux lines and produces a current, demonstrating that motional energy can be realized by consuming chemical energy of magnesium, thus producing electricity. PMID- 25146590 TI - Incidence of metallo-beta-lactamase producing clinical isolates of Escherichia coli and Klebsiella pneumoniae in central Nepal. AB - BACKGROUND: The increasing and rapid spread of metallo-beta-lactamase (MBL) producing Enterobacteriaceae, particularly Escherichia coli and Klebsiella pneumoniae represents an emerging public health threat. However, limited data is available on MBL production in clinical isolates of E. coli and K. pneumoniae from Nepal. We have therefore undertaken this study to ascertain the incidence of MBL production in clinical isolates of E. coli and K. pneumoniae at a tertiary care teaching hospital in central Nepal. METHODS: A total of 401 consecutive, non duplicate isolates of E. coli (n = 216) and K. pneumoniae (n = 185) were recovered from various clinical samples between July and December, 2012. These isolates were screened for the detection of carbapenemase production on the basis of their reduced susceptibility to meropenem or ertapenem by the disc diffusion method. The screened isolates were further phenotypically studied for carbapenemase production by modified Hodge test (MHT). MBL production was detected by performing combined disc test by using imipenem discs with and without ethylenediaminetetraacetic acid (EDTA), which chelates zinc required for MBL activity. RESULTS: Out of 216 E. coli isolates, a total of 41 isolates (18.98%) and out of 185 K. pneumoniae isolates, a total of 39 isolates (21.08%) were suspected to be carbapenemase- producers on the basis of their reduced susceptibility to meropenem or ertapenem. Interestingly, all the initially suspected isolates of E. coli and K. pneumoniae for carbapenemase production were found to be positive in both MHT and combined disc test. However, few weakly positive reactions were observed in MHT. All the MBL producing isolates were multidrug-resistant (MDR). In addition, 75.60% E. coli and 71.79% of K. pneumoniae isolates producing MBL were found to be "pandrug- resistant". CONCLUSIONS: Our findings showed MBL production in a considerable number of E. coli and K. pneumoniae isolates with MDR and pandrug-resistant phenotypes. Combined disc method can provide a sensible choice for phenotypic detection of MBL production in clinical microbiology laboratories as detection of MBL in bacterial isolates is indispensable for establishing the effective antibiotic policies and infection control strategies in the hospital setting. PMID- 25146591 TI - Disparity in perception of the working condition of dental hygienists between dentists and dental hygiene students in Japan. AB - OBJECTIVES: In Japan, there continues to be a shortage of active dental hygienists. The scope of dental hygienists' practice is also considered to be unclear. One of the reasons for this is that dental hygienists find the working conditions during dental hygiene education different from those in reality. The purpose of this study was to clarify the actual working condition of dental hygienists in dental clinics, as well as evaluate the awareness of dental hygiene students and dentists regarding the working condition of dental hygienists. METHODS: Questionnaires were sent by post to 481 dentists and were distributed to 89 dental hygiene students. The awareness about the working condition of dental hygienists was compared between dentists and dental hygiene students. RESULTS: Two hundred twenty-two dentists and 89 dental hygiene students responded to questionnaires. Dental hygiene students considered the team of 'dental hygienist, dental technician and clerk' to be more effective in providing dental care than dentists (P < 0.001). Among the dentists, 37.1% did not find any clear distinction between hygienists and assistants in their clinics. However, 97.4% of dental hygiene students answered that dental team members should clearly inform patients of the distinction between hygienists and assistants. CONCLUSIONS: This study indicated that there was disparity between dentists' and dental hygiene students' perception of dental hygienists' working conditions, and dental team work was not always effective. For training high quality dental hygienists, all educational institutions related to dentistry must educate students regarding the more realistic dental hygienists' working condition, as well as benefits. PMID- 25146592 TI - A mathematical model of sickle cell genome frequency in response to selective pressure from malaria. AB - Because of the relative prevalence of hereditary sickle cell disease and the auxiliary role of the sickle cell gene in reducing the mortality of malaria, it is believed that P. falciparum has exerted selection pressure on human populations to increase the prevalence of this otherwise detrimental gene. A model incorporating three genotypes and two age cohorts is used to test the hypothesis that higher death rates due to malaria can exert selective pressure to increase the prevalence of the sickle cell gene. The model displays selection pressure for the carrier gene in the presence of increasing malaria death rates for either adults or children, showing both higher final frequencies of the gene as well as shortened time to reach these frequencies. PMID- 25146593 TI - Outcomes in the management of esophageal cancer. AB - Esophageal cancer rates have continued to rise in the Western World. Esophageal cancer will be responsible for an estimated 15,450 deaths in the United States in 2014 alone. Esophageal resection with or without preoperative therapy remains the mainstay of treatment. Advances in surgical technique and perioperative care have improved short-term outcomes considerably by decreasing operative mortality. Despite these advances though, esophagectomy remains a procedure associated with considerable morbidity from a wide range of complications. Prompt recognition and treatment of complications can lower overall morbidity and mortality. Unfortunately, long-term outcomes remain poor as the vast majority of patients present with loco-regionally advanced or metastatic disease. Surgery by itself provides poor loco-regional control and fails to address micrometastatic disease. Neoadjuvant chemotherapy or chemoradiation provides a modest survival advantage compared to surgical resection alone. Future gains in understanding the molecular biology of esophageal cancer will hopefully lead to improved therapeutics and resultant outcomes. PMID- 25146594 TI - In memoriam: Loretta "Deliana" Fuddy (1948-2013). PMID- 25146595 TI - Long-lived trifluoromethanide anion: a key intermediate in nucleophilic trifluoromethylations. AB - The trifluoromethanide anion is the postulated key intermediate in nucleophilic trifluoromethylation reactions. However, for more than six decades, the trifluoromethanide anion was widely believed to exist only as a short-lived transient species in the condensed phase. It has now been prepared in bulk for the first time in THF solution. The trifluoromethanide anion with the [K(18-crown 6)](+) cation was unequivocally characterized by low-temperature (19)F and (13)C NMR spectroscopy. Its intermediacy in nucleophilic trifluoromethylation reactions was directly evident by its reaction chemistry with various electrophilic substrates. Variable-temperature NMR spectroscopy, along with quantum mechanical calculations, support the persistence of the trifluoromethanide anion. PMID- 25146596 TI - Characterization of G protein-coupled receptors by a fluorescence-based calcium mobilization assay. AB - For more than 20 years, reverse pharmacology has been the preeminent strategy to discover the activating ligands of orphan G protein-coupled receptors (GPCRs). The onset of a reverse pharmacology assay is the cloning and subsequent transfection of a GPCR of interest in a cellular expression system. The heterologous expressed receptor is then challenged with a compound library of candidate ligands to identify the receptor-activating ligand(s). Receptor activation can be assessed by measuring changes in concentration of second messenger reporter molecules, like calcium or cAMP. The fluorescence-based calcium mobilization assay described here is a frequently used medium-throughput reverse pharmacology assay. The orphan GPCR is transiently expressed in human embryonic kidney 293T (HEK293T) cells and a promiscuous Galpha16 construct is co transfected. Following ligand binding, activation of the Galpha16 subunit induces the release of calcium from the endoplasmic reticulum. Prior to ligand screening, the receptor-expressing cells are loaded with a fluorescent calcium indicator, Fluo-4 acetoxymethyl. The fluorescent signal of Fluo-4 is negligible in cells under resting conditions, but can be amplified more than a 100-fold upon the interaction with calcium ions that are released after receptor activation. The described technique does not require the time-consuming establishment of stably transfected cell lines in which the transfected genetic material is integrated into the host cell genome. Instead, a transient transfection, generating temporary expression of the target gene, is sufficient to perform the screening assay. The setup allows medium-throughput screening of hundreds of compounds. Co transfection of the promiscuous Galpha16, which couples to most GPCRs, allows the intracellular signaling pathway to be redirected towards the release of calcium, regardless of the native signaling pathway in endogenous settings. The HEK293T cells are easy to handle and have proven their efficacy throughout the years in receptor deorphanization assays. However, optimization of the assay for specific receptors may remain necessary. PMID- 25146597 TI - Functional morphology of the copulatory system of box crabs with long second gonopods (Calappidae, Eubrachyura, Decapoda, Crustacea). AB - Male True Crabs use two pairs of gonopods to deliver mating products during copulation. Commonly, the second pair is shorter than the first pair, and most research to date has focused on species with short second gonopods. We investigated male and female copulatory organs in Calappula saussurei and Calappa pelii, two species of box crabs (Calappidae) with second gonopods which are longer than the first pair. Scanning electron microscopy and histological cross sectioning show that the female copulatory system is unique in several aspects: the genital duct is part concave and part simple type. The seminal receptacle is divided into two chambers, a ventral chamber of ectodermal and mesodermal origin, and a dorsal chamber of ectodermal origin. This dorsal chamber is the location of spermatophore reception during copulation. A sperm plug closes the dorsal chamber off. We propose that long second gonopods deliver male mating products directly into the dorsal chamber. To date, spermatophore reception has been associated with the mesodermal tissue of the seminal receptacle. The copulatory system of box crabs with long second gonopods shows novel deviations from this general pattern. PMID- 25146598 TI - The differential contribution of executive functions to temporal generalisation, reproduction and verbal estimation. AB - Evidence from dual-task studies suggests that executive resources are recruited during timing. However, there has been little exploration of whether executive recruitment is universal across temporal tasks, or whether different temporal tasks recruit different executive resources. The current study explored this further by examining how individual differences in updating, switching, inhibition and access affected performance on temporal generalisation, reproduction and verbal estimation tasks. It was found that temporal tasks differentially loaded onto different executive resources. Temporal generalisation performance was related to updating and access ability. Reproduction performance was related to updating, access and switching. Verbal estimation performance was only related to access. The results suggest that executive resources may be recruited when monitoring and maintaining multiple durations in memory at the same time, and when retrieving duration representations from long-term memory. The findings emphasise the need to consider timing behaviour as the product of a wide range of complex, integrated, cognitive systems, rather than as the output of a clock in isolation. PMID- 25146599 TI - Increased virulence of rabbit haemorrhagic disease virus associated with genetic resistance in wild Australian rabbits (Oryctolagus cuniculus). AB - The release of myxoma virus (MYXV) and Rabbit Haemorrhagic Disease Virus (RHDV) in Australia with the aim of controlling overabundant rabbits has provided a unique opportunity to study the initial spread and establishment of emerging pathogens, as well as their co-evolution with their mammalian hosts. In contrast to MYXV, which attenuated shortly after its introduction, rapid attenuation of RHDV has not been observed. By studying the change in virulence of recent field isolates at a single field site we show, for the first time, that RHDV virulence has increased through time, likely because of selection to overcome developing genetic resistance in Australian wild rabbits. High virulence also appears to be favoured as rabbit carcasses, rather than diseased animals, are the likely source of mechanical insect transmission. These findings not only help elucidate the co evolutionary interaction between rabbits and RHDV, but reveal some of the key factors shaping virulence evolution. PMID- 25146600 TI - Terminal sialic acid linkages determine different cell infectivities of human parainfluenza virus type 1 and type 3. AB - Human parainfluenza virus type 1 (hPIV1) and type 3 (hPIV3) initiate infection by sialic acid binding. Here, we investigated sialic acid linkage specificities for binding and infection of hPIV1 and hPIV3 by using sialic acid linkage-modified cells treated with sialidases or sialyltransferases. The hPIV1 is bound to only alpha2,3-linked sialic acid residues, whereas hPIV3 is bound to alpha2,6-linked sialic acid residues in addition to alpha2,3-linked sialic acid residues in human red blood cells. alpha2,3 linkage-specific sialidase treatment of LLC-MK2 cells and A549 cells decreased the infectivity of hPIV1 but not that of hPIV3. Treatment of A549 cells with alpha2,3 linkage-specific sialyltransferase increased infectivities of both hPIV1 and hPIV3, whereas alpha2,6 linkage specific sialyltransferase treatment increased only hPIV3 infectivity. Clinical isolates also showed similar sialic acid linkage specificities. We concluded that hPIV1 utilizes only alpha2,3 sialic acid linkages and that hPIV3 makes use of alpha2,6 sialic acid linkages in addition to alpha2,3 sialic acid linkages as viral receptors. PMID- 25146601 TI - The interaction of nonstructural protein 9 with retinoblastoma protein benefits the replication of genotype 2 porcine reproductive and respiratory syndrome virus in vitro. AB - The nonstructural protein 9 (Nsp9) of porcine reproductive and respiratory syndrome virus (PRRSV) is a RNA-dependent RNA polymerase (RdRp) that plays a vital role in viral replication. This study first demonstrated that the Nsp9 of genotype 2 PRRSV interacted with cellular retinoblastoma protein (pRb), and Nsp9 co-localized with pRb in the cytoplasm of PRRSV-infected MARC-145 cells and pulmonary alveolar macrophages (PAMs). Next, the overexpression of truncated pRb was shown to inhibit the PRRSV replication and silencing the pRb gene could facilitate the PRRSV replication in MARC-145 cells. Finally, the pRb level was confirmed to be down-regulated in PRRSV-infected MARC-145 cells, and Nsp9 was shown to promote the pRb degradation by proteasome pathway. These findings indicate that the interaction of Nsp 9 with pRb benefits the replication of genotype 2 PRRSV in vitro, helping to understand the roles of Nsp9 in the replication and pathogenesis of PRRSV. PMID- 25146602 TI - Modified bibenzimidazole ligands as spectator ligands in photoactive molecular functional Ru-polypyridine units? Implications from spectroscopy. AB - The photophysical properties of Ruthenium-bipyridine complexes bearing a bibenzimidazole ligand were investigated. The nitrogens on the bibenzimidazole ligand were protected, by adding either a phenylene group or a 1,2-ethandiyl group, to remove the photophysical dependence of the complex on the protonation state of the bibenzimidazole ligand. This protection results in the bibenzimidazole ligand contributing to the MLCT transition, which is experimentally evidenced by (resonance) Raman scattering in concert with DFT calculations for a detailed mode assignment in the (resonance) Raman spectra. PMID- 25146604 TI - Presence of notched QRS on paced electrocardiographs as a predictor of poor response to cardiac resynchronization therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) on patients with advanced and refractory heart failure has made remarkable progress. Clinically, notched QRS (nQRS) is commonly seen on electrocardiographs (ECGs) with bundle branch block morphology and on paced ECGs after implantation of a CRT device, which may reflect the heterogeneity of ventricular myocardial depolarization and electrical activity. The aim of this study was to determine whether patients with more nQRS myocardial segments on paced ECGs had a worse response to CRT than patients with fewer nQRS myocardial segments. METHODS: We prospectively enrolled 56 patients of CRT with chronic heart failure from People's Hospital affiliated to Peking University from January 2007 to October 2013. Based on nQRS segments on ECGs before CRT, we allocated them to two groups: fewer nQRS (<2) myocardial segments (lateral, inferior, anterior segments) group (F-nQRS, G1, n = 23) and more nQRS (>=2) myocardial segments group (M-nQRS, G2, n = 33). Then according to nQRS segments on ECGs after CRT, we divided them into two groups similarly: fewer nQRS (<2) myocardial segments group (G3, n = 24) and more nQRS (>=2) myocardial segments group (G4, n = 32). This study was approved by the ethics committee of People's Hospital. RESULTS: At 6 months in the baseline-ECG group, there was a greater absolute increase in left ventricular ejection fraction (LVEF) in G2 than in G1 ((11.5+/-8.9)% vs. (5.5+/-10.4)%, P = 0.023), with the incidence of nonresponse lower in G2 than in G1 (9.1% vs. 39.1%, P = 0.018). In the paced-ECG group, the absolute increase in LVEF was less in G4 than in G3 ((6.4+/-8.8)% vs. (12.5+/-10.4)%, P = 0.024) and the incidence of nonresponse was higher in G4 than in G3 (31.3% vs. 8.3%, P = 0.039). Multivariate analysis showed that fewer nQRS (<2) myocardial segments on paced ECGs (odds ratio 13.920) was a predictor of positive response to CRT. CONCLUSION: nQRS >=2 myocardial segments (lateral, inferior, anterior) on paced ECGs may predict a poor response to CRT. PMID- 25146603 TI - Traditional Chinese medicine compound ShengJinRunZaoYangXue granules for treatment of primary Sjogren's syndrome: a randomized, double-blind, placebo controlled clinical trial. AB - BACKGROUND: Traditional Chinese medical treatment of primary Sjogren's syndrome has advantages over Western medicine in terms of fewer side effects and improved patient conditions. This study was a multicenter, randomized, double-blind, placebo-controlled clinical trial of the efficacy and safety of ShengJinRunZaoYangXue granules for the treatment of primary Sjogren's syndrome, including the symptoms of dry mouth and dry eye. METHODS: We undertook a 6-week, double-blind, randomized trial involving 240 patients with primary Sjogren's syndrome at five centers in East China. A computer-generated randomization schedule assigned patients at a 2:1 ratio to receive either ShengJinRunZaoYangXue granules or placebo once daily. Patients and investigators were blinded to treatment allocation. The primary endpoints were the salivary flow rate, Schirmer test results, and sugar test results. Intention-to-treat and per-protocol analyses were performed. RESULTS: All 240 patients were randomly allocated to either the treatment group (n = 160, ShengJinRunZaoYangXue granules) or placebo group (n = 80) and were included in the intention-to-treat analysis. After program violation and loss to follow-up, a total of 199 patients were included in the per-protocol analysis. At six week, intention-to-treat and per-protocol analyses of the left-eye Schirmer I test results showed an improved difference of 1.36 mm/5 min (95% CI: 0.03 to 2.69 mm/5 min) and 1.35 mm/5 min (95% CI: 0.04 to 2.73 mm/5 min), respectively, and those of the right-eye Schirmer I test results showed an improved difference of 1.12 mm/5 min (95% CI: 0.02 to 2.22 mm/5 min) and 1.12 mm/5 min (95% CI: -0.02 to 2.27 mm/5 min), respectively. There was no significant difference between the two groups before treatment. After treatment, the between-group and within-group before-and-after paired comparison results were statistically significant (P < 0.05). Intention-to-treat and per-protocol analyses showed an improved salivary flow rate by 0.04 ml/15 min (95% CI: -0.49 to 0.58 ml/15 min) and 0.04 ml/15 min (95% CI: -0.52 to 0.60 ml/15 min), respectively, but the differences were not significant. Intention-to-treat and per-protocol analyses showed that the sugar test results were improved by 1.77 minutes (95% CI: 0.11 to 3.44 minutes) and 1.84 minutes (95% CI: 0.12 to 3.55 minutes), respectively, but the differences were not significant. For the secondary endpoint, intention-to-treat and per-protocol analyses showed significant improvement in the integrated evaluation of treated patients with dry eye and dry mouth after six weeks of treatment. The incidence of adverse events was 15.6% in the treatment group and 10.0% in the placebo group. Most (94%) adverse events were mild to moderate in the two groups, and only two cases of serious adverse events occurred in the treatment group; both were caused by autoimmune liver disease. CONCLUSIONS: Six-week treatment with ShengJinRun ZaoYangXue granules for primary Sjogren's syndrome in this large-scale study improved the symptoms of dry mouth, dry eyes, and low tear flow rate with minimal adverse events. PMID- 25146605 TI - Presenting features and clinical course of 34 patients with septic pulmonary embolism caused by right-sided infective endocarditis. AB - BACKGROUND: Misdiagnosis and missed diagnosis of septic pulmonary embolism (SPE), a rare disease, occurs among the patients with right heart infective endocarditis. The purpose of this study was to analyze the characteristics of SPE and improve the early diagnosis and treatment. METHODS: We retrospectively studied 34 patients with septic pulmonary embolism caused by right-sided infective endocarditis who were seen from June 1, 2002 to June 1, 2013. We reviewed the medical records and radiological images of these cases and extracted the following information: age, gender, and symptoms, physical examination, laboratory findings, transthoracic echocardiography (TTE) results, treatment information, comorbid medical conditions, and outcomes. Microbiological samples were collected and processed according to well-established and published guidelines. RESULTS: We identified basic heart disease in 97.1% of the patients. A high proportion of the right-sided infective endocarditis patients had congenital heart defects (82.4%); predominantly, ventricular septal defects. Clinical symptoms were fever (97.1%), cardiac murmurs (94.1%) and fatigue (88.2%). Respiratory symptoms included cough (58.8%), pleuritic chest pain (47.1%) and hyoxemia (52.9%). Positive blood cultures were grown from 35.2% of patients and 50.0% were caused by staphylococcal species. Chest X-rays or CT examinations detected patchy infiltrates and/or nodules in all cases. Transthoracic echocardiography demonstrated infectious foci of the right-side heart in all cases. Parenteral antibiotics were administered for all, and cardiac surgery was carried out for 76.5% of patients with an effective rate of 82.3%. CONCLUSIONS: SPE lacks characteristic clinical manifestation. Congenital heart disease is a common risk of SPE. Most patients with SPE have a good prognosis as long as early diagnosis and proper treatment can be provided. PMID- 25146606 TI - Prevalence of osteoporosis and vertebral fractures and related factors in patients with ankylosing spondylitis. AB - BACKGROUND: Osteoporosis and vertebral factures are well recognized features in patients with ankylosing spondylitis (AS). The aim of this study was to investigate the prevalence and risk factors of osteoporosis and vertebral fractures in patients with AS. METHODS: Fifty-nine AS patients and 40 healthy controls were enrolled. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DEXA) at posterior-anterior (PA) lumbar, lateral lumbar and hip regions. Thoracic and lumbar X-rays were obtained for morphometric measurements. Clinical, biological and radiological statuses were evaluated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Radiology Index-total (BASRI-t), erythrocyte sedimentation rate (ESR) and the C-reactive protein levels. RESULTS: Osteoporosis was present in 32% of patients and 5% of controls according to lateral vertebral BMD measurements. Fracture was present in 31% of patients. The effect of some clinical and laboratory parameters on BMD status and vertebral fractures was analyzed in the patient group. Osteoporosis in lateral lumbar DEXA was associated with higher BASMI, BASFI, BASRI-t scores and ESR level. Low hip BMD was associated with low BMI and high BASFI and BASRI-t scores. Vertebral fractures were associated with advanced age, longer disease duration, longer duration since diagnosis, higher BASMI and BASRI-t scores, higher ESR level, reduced femoral and lateral lumbar BMD. Logistic regression analysis revealed that only BASRI-t score was significantly associated with low lateral spinal BMD and BMI and BASFI score were independently associated with low hip BMD. The presence of compression fractures was independently associated with BASRI-t score and low lateral lumbar BMD. CONCLUSIONS: Osteoporosis and vertebral fractures in AS seem to be related to the extent of radiological involvement. A low lateral lumbar BMD is an important risk factor for vertebral fractures. PMID- 25146607 TI - Pathogenic analysis in different types of orthopedic implant infections. AB - BACKGROUND: Diversity of orthopedic infections with various local environments affects the pattern and prevalence of pathogens. It is not well-characterized whether different pathogens have different propensity to cause different types of orthopedic infections. We aimed to investigate the frequency of different pathogens derived from orthopedic infections, and determine the relationship between the prevalence of clinical isolates and the type of orthopedic implants, especially focusing on staphylococci. METHODS: From January 2006 to December 2011, orthopedic infections were identified retrospectively from clinical microbiology laboratory and orthopedic medical records. The sources of orthopedic infections were divided into two main groups: those associated with implants and those not associated with implants. Implants-associated infections were further subdivided into five subgroups: arthroplasty, internal fixation, external fixation, internal and external fixation, and others. We analyzed microbiological spectrum in different groups and subgroups. Antibiotic susceptibility of staphylococci was analyzed. RESULTS: Only coagulase-negative staphylococci (CoNS) was significantly more likely to be associated with implants-associated infections (P = 0.029). The overall pathogens prevalence of arthroplasty was significantly different from other subgroups (P < 0.05). 65% isolates from external fixation was Gram-negative bacteria. Some percentage (55%) of S. aureus and (83%) CoNS were resistant to methicillin. No resistance to glycopeptide was seen in all of staphylococci. CONCLUSIONS: Staphylococcus aureus was the most frequent isolates in orthopedic infections but was not associated with the presence or absence of implants. Only CoNS was implants-associated, especially for arthroplasty infection. Cefazolin alone is not enough for orthopedic surgery prophylaxis in settings with a high prevalence of methicillin-resistant staphylococci. PMID- 25146608 TI - Mechanical tests on the reconstructed anterior cruciate ligament fixed with allogenetic cortical bone cross-pin on the femoral side. AB - BACKGROUND: Anterior cruciate ligament reconstruction (ACLR) has developed dramatically in the last century. Now, ACLR has become a reliable and productive procedure. Patients feel satisfied in >90% cases. The aim of this study was to evaluate the feasibility of allogenetic cortical bone cross-pin (ACBCP) used as a clinical fixation method in anterior cruciate ligament reconstruction on the femoral side based on biomechanical tests in vitro. METHODS: The specimens were provided by the bone banks of the First Affiliated Hospital of People's Liberation Army of General Hospital from September 2011 to June 2012. Fresh deep frozen human allogenetic cortical bone was machined into cross-pins which is 4.0 mm in diameter and 75.0 mm in length. Biomechanical parameters compared with Rigidfix were collected while cross-pins were tested in double-shear test. The load-to-failure test and cycling test were carried out in a goat model to reconstruct anterior cruciate ligament with Achilles tendon autograft on the femoral side fixed by human 4.0 mm ACBCP and 3.3 mm Rigidfix served as control. Maximum failure load, yield load, and stiffness of fixation in single load-to failure test were compared between the two groups. Cycle-specific stiffness and displacement at cycles 1, 30, 200, 400, and 1 000 were also compared in between. RESULTS: In double-shear test both maximum failed load and yield load of 4.0 mm human ACBCP were (1 236.998+/-201.940) N. Maximum failed load and yield load of Rigidfix were (807.929+/-110.511) N and (592.483+/-58.821) N. The differences of maximum failed load and yield load were significant between ACBCP and Rigidfix, P < 0.05. The shear strength of ACBCP and Rigidfix were (49.243+/-8.039) MPa and (34.637+/-3.439) MPa, respectively, P < 0.05. In the load-to-failure test ex vivo, yield load and maximum failed load of ACBCP fixation complexity ((867.104+/ 132.856)N, (1 032.243+/-196.281) N) were higher than those of Rigidfix ((640.935+/-42.836) N, (800.568+/-64.890) N, P < 0.05). However, stiffness did not differ significantly between ACBCP group ((247.116+/-31.897)N/mm) and Rigidfix group ((220.413+/-51.332) N/mm, P > 0.05). In the cycling test, the cycle-specific stiffness and displacement at cycles 1, 30, 200, 400, and 1 000 did not differ significantly between the ACBCP group and Rigidfix group, P > 0.05. CONCLUSIONS: Allogenetic cortical bone cross-pin possesses satisfactory biomechanical profile which is safe for ACLR and suitable for an aggressive rehabilitation program. Animal and clinical tests should be recommended before clinical use to secure the ACBCP could successfully substituted by host new bone in vivo. PMID- 25146609 TI - Chordomas of the upper cervical spine: clinical characteristics and surgical management of a series of 21 patients. AB - BACKGROUND: Chordomas of the upper cervical spine are rare and present unique surgical challenge. This study aimed to describe the clinical characteristics and surgical management of patients with chordomas of the upper cervical spine. METHODS: Twenty-one patients with chordomas of the upper cervical spine who were treated in Peking University Third Hospital from January 1999 to October 2012 were retrospectively analyzed. Survival was calculated by the Kaplan-Meier method and was compared between groups using the log-rank test. RESULTS: The postoperative diagnosis was classical chordoma in 20 cases and chondroid chordoma in one case. The mean operative time was 9.5 hours (range 6-17 hours), and the mean blood loss was 2 812 ml (range 700-4 800 ml). There were two postoperative deaths. Unilateral vertebral artery ligation was performed in six patients, cervical nerve roots were cut in six patients, and the external branch of the superior laryngeal nerve was repaired after being cut in one case. Two patients developed postoperative velopharyngeal incompetence, and loosening of the occipitocervical screws was observed in one patient. The recurrence rate was 66.7% (10/15) after a mean follow-up period of 46.8 months (range 14-150 months). The 5- and 10- year overall survival rates were (39.8+/-13.1)% and (31.9+/ 12.7)%, respectively. There was a significant difference in survival rate between patients who underwent surgery and those who did not. CONCLUSION: In spite of the high rates of recurrence and complications after surgical treatment of chordomas of the upper cervical spine, intralesional resection combined with adjuvant radiotherapy remains the optimal treatment to prolong survival. PMID- 25146610 TI - Immunophenotypic analysis of abnormal plasma cell clones in bone marrow of primary systemic light chain amyloidosis patients. AB - BACKGROUND: Primary systemic light chain amyloidosis (AL) is a rare plasma cell disease, our purpose was to analyze the immunophenotypic characteristics of the plasma cells in bone marrow in AL patients, and explore whether the detection of abnormal plasma cell clones in bone marrow by flow cytometry (FCM) could be used as an important indicator of AL diagnosis. METHODS: Fresh bone marrow samples were collected from 51 AL, 21 multiple myeloma (MM), and 5 Waldenstrom's macroglobulinemia (WM) patients. The immunophenotype of bone marrow cells were analyzed and compared by FCM using a panel of antibodies including CD45, CD38, CD138, CD117, CD56, and CD19. RESULTS: In AL, light chain restriction could be identified in 31 cases (60.9%), in which the lambda light chain restriction was found in 24 cases (77.4%). In MM, kappa light chain restriction was found in 13 cases (61.9%), and lambda light chain restriction in eight cases. CD45 on abnormal plasma cells was negative to weakly positive in both AL and MM, but was positive to strongly positive in WM. In the bone marrow plasma cells of the 51 AL, 78.4% were CD56+, 68.6% were CD117+, and 88.2% were CD19-. While in the 21 MM cases, 66.7% were CD56+, 38.1% were CD117+, and 90.4% were CD19-. The plasmacytoid lymphocytes in the five WM patients were CD19+ and CD56-, CD117-. CONCLUSION: Detection of abnormal plasma cell clones in bone marrow by FCM is valuable for the diagnosis of AL. PMID- 25146611 TI - A comparative study on the levels of serum cytokines and cortisol among post traumatic stress disorder patients of Li and Han ethnicities in Hainan. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is a mental disorder with delayed or chronic onset caused by unusual, threatening, or disastrous psychological trauma, and it is an important manifestation of post-disaster mental and behavioral disorders. Studies have shown that IL-6 is a cytokine associated with PTSD occurrence. This study aimed to explore the role of cytokine and ethnicity in the pathogenesis of PTSD by examining levels of serum cytokines IL-2, IL-6, IL-8, TNF-alpha, and cortisol in PTSD patients of Li and Han ethnic groups. METHODS: Levels of serum cytokines IL-2, IL-6, IL-8, TNF-alpha, and cortisol were examined by enzyme-linked immunoabsorbent assay (ELISA) method and assessed by PCL-C scale among 30 PTSD patients of Han ethnicity and 30 of Li ethnicity, and compared with 30 normal controls of Han and Li ethnicity, respectively. RESULTS: PTSD patients of Li ethnicity scored higher than PTSD patients of Han ethnicity, and normal controls of Li and Han ethnic groups in each of the re-experiencing, avoidance/numbing, and hyperarousal symptoms. The differences reached statistical significance (P < 0.05). In PTSD patients of Li ethnicity compared to patients of Han ethnicity and normal controls of either Li or Han ethnicity, the levels of IL-2, IL-6, IL-8, and TNF-alpha were higher, and the level of cortisol was lower. CONCLUSIONS: There are ethnic differences in re experiencing, avoidance/numbing, and hyperarousal symptoms among PTSD patients. The levels of serum cortisol and cytokines are strongly associated with the race. PMID- 25146612 TI - Association of poly(ADP-ribose) polymerase activity in circulating mononuclear cells with myocardial dysfunction in patients with septic shock. AB - BACKGROUND: Severe sepsis and septic shock are the leading causes of morbidity and mortality in hospitalized patients. This study aimed to investigate the association of poly (ADP-ribose) polymerase-1 (PARP-1) activity in circulating mononuclear cells with myocardial dysfunction in patients with septic shock. METHODS: A total of 64 patients with septic shock were divided into the survival group (n = 41) and the nonsurvival group (n = 23) according to mortality at 28 days after enrollments. PARP-1 activity in circulating mononuclear cells, brain natriuretic peptide, Acute Physiology and Chronic Health Evaluation II score, the cardiac index (CI), the cardiac function index (CFI), global ejection fraction (GEF), and the left ventricular contractility index (dp/dt max) were measured after admission to the intensive care unit. RESULTS: PARP-1 activity in circulating mononuclear cells of nonsurvival patients with septic shock was significantly higher than that in survival patients. PARP-1 activity in circulating mononuclear cells was strongly, negatively correlated with the CI, the CFI, GEF, and dp/dt max. Multiple Logistic regression analysis showed that PARP-1 activity in circulating mononuclear cells was an independent risk factor of myocardial dysfunction. The optimal cutoff point of PARP-1 activity for predicting 28-day mortality was 942 nmol/L with a sensibility of 78.2% and specificity of 65.1%. CONCLUSION: PARP-1 activity in circulating mononuclear cells is significantly associated with myocardial dysfunction and may have prognostic value in patients with septic shock. PMID- 25146613 TI - Younger age of onset and multiple primary lesions associated with esophageal squamous cell carcinoma cases with a positive family history of the cancer suggests genetic predisposition. AB - BACKGROUND: Previous epidemiological studies have consistently found a positive family history of esophageal cancer is associated with a significantly increased risk of the cancer. However, whether the elevated risk could be attributed to common household exposure or inherited susceptibility is uncertain. This study aimed to highlight the effect of genetic predisposition by noting the significant differences in onset age and multiple primary cancers between esophageal squamous cell carcinoma (ESCC) cases with or without a positive family history of the cancer. METHODS: Age at onset and the percentage of multiple primary cancers were compared between ESCCs with (n = 766) or without (n = 1 776) a positive family history of the cancer in a consecutive surgery cohort at the Department of Thoracic Surgery of Hebei Tumor Hospital and the Fourth Hospital of Hebei Medical University. RESULTS: Overall, ESCCs with a positive family history of the cancer featured both a significantly younger age of onset and significantly more multiple primary cancers than those with a negative family history (onset age 51.83 vs. 53.49 years old, P < 0.01; percent of multiple primary cancers 5.50% vs. 1.70%, chi(2) = 25.42, P < 0.01). Both the differences were evident in subgroup analyses, but did not correlate. While age at onset differed significantly by family history among the male, smoking, and drinking groups, the difference of multiple primary cancers was significant among the otherwise nonsmoking, nondrinking, and younger onset age groups. CONCLUSIONS: Younger age of onset and multiple primary cancers associated with ESCCs with a positive, as opposed to a negative family history of the cancer, suggest a genetic predisposition. The results of subgroup analyses indicate a younger age of ESCC development results from the interaction of environmental and genetic risk factors, but multiple primary cancers may be related only to genetic predisposition. PMID- 25146614 TI - Comparison of result judgment algorithm of test for interfering factors in the bacterial endotoxins test among Chinese, Japanese, European, American, and Indian pharmacopeias. AB - BACKGROUND: The bacterial endotoxins test (BET) is a method used to detect or quantify endotoxins (lipo-polysaccharide, LPS) and is widely used in the quality control of parenteral medicines/vaccines and clinical dialysis fluid. It is also used in the diagnosis of endotoxemia and in detection of environment air quality control. Although BET has been adopted by most pharmacopoeias, result judgment algorithms (RJAs) of the test for interfering factors in the BET still differ between certain pharmacopoeias. We have evaluated RJAs of the test for interfering factors for the revision of BET described in the Chinese Pharmacopoeia 2010 (CHP2010). METHODS: Original data from 1 748 samples were judged by RJAs of the Chinese Pharmacopoeia 2010, the Japanese Pharmacopoeia 2011 (JP2011), the European Pharmacopoeia 7.0 (EP7.0), the United States Pharmacopoeia 36 (USP36), and the Indian Pharmacopoeia 2010 (IP2010), respectively. A SAS software package was used in the statistical analysis. RESULTS: The results using CHP2010 and USP36, JP2011, EP7.0, and IP2010 had no significant difference (P = 0.7740). The results using CHP2010 of 1 748 samples showed that 132 samples (7.6%) required an additional step; nevertheless there was no such requirement when using the other pharmacopeias. The kappa value of two RJAs (CHP2010 and EP7.0) was 0.6900 (0.6297-0.7504) indicating that the CHP2010 and other pharmacopoeias have good consistency. CONCLUSIONS: The results using CHP2010 and USP36, JP2011, EP7.0, and IP2010 have different characteristics. CHP2010 method shows a good performance in Specificity, mistake diagnostic rate, agreement rate, predictive value for suspicious rate, and predictive value for passed rate. The CHP2010 method only had disadvantages in sensitivity compared with other pharmacopeias. We suggest that the Chinese pharmacopoeia interference test be revised in accordance with the USP36, JP2011, EP7.0, and IP2010 judgment model. PMID- 25146615 TI - Comparison of simple discectomy and instrumented posterior lumbar interbody fusion for treatment of lumbar disc herniation combined with Modic endplate changes. AB - BACKGROUND: The purpose of this retrospective study was to compare the surgical outcomes of simple discectomy and instrumented posterior lumbar interbody fusion (iPLIF) in patients with lumbar disc herniation and Modic endplate changes. Our hypothesis was that iPLIF could provide better outcome for patients with refractory lumbar disc herniation and Modic changes (LDH-MC). METHODS: Ninety-one patients with single-segment LDH-MC were recruited. All patients experienced low back pain as well as radicular leg pain, and low back pain was more severe than leg pain. Forty-seven patients were treated with discectomy and 44 were treated with iPLIF. The outcomes of both low back pain and radicular leg pain using visual analogue scale (VAS) as well as the clinical outcome related to low back pain using Japanese Orthopaedic Association (JOA) score were assessed before and 18 months after surgery, respectively. RESULTS: Both low back and leg pain were significantly improved 18 months after simple discectomy and iPLIF. Compared to patients undergoing simple discectomy, low back pain was significantly reduced in patients undergoing iPLIF, but there was no significant difference in leg pain between two groups. Solid fusion was achieved in all patients who underwent iPLIF. CONCLUSIONS: In patients with LDH-MC, iPLIF can yield significantly superior outcome on the relief of low back pain compared to simple discectomy. Simple discectomy can relieve radicular leg pain as efficient as iPLIF. Accordingly, iPLIF seems to be a reliable treatment for patients with LDH-MC and predominant low back pain. PMID- 25146616 TI - Over-expression of heme oxygenase-1 in peripheral blood predicts the progression and relapse risk of chronic myeloid leukemia. AB - BACKGROUND: There are limited eligible clinical markers at present to monitor the progress of chronic myeloid leukemia (CML). Heme oxygenase-1 (HO-1), as one of the most important oxidation-regulating enzymes in vivo, suggests the onset and progression of cancer when highly expressed. Furthermore, HO-1 level is related with the occurrence and development of hematological diseases. But the relationship between HO-1 expression and progression/relapse of CML has seldom been studied hitherto. This study aimed to investigate the relationship between them to find out a new molecular marker for prediction. METHODS: A total of 60 peripheral blood and bone marrow (BM) samples from 25 CML patients in different phases were collected respectively to detect the expressions of HO-1 and bcr/abl using real-time PCR. Routine blood test was performed to detect the changes of leukocyte and platelet counts. The proportion of primitive cells in BM was detected by flow cytometry. The relationship between high HO-1 expression and CML progression and relapse was explored by the analysis of variance by Wilcoxon test and linear regression analysis. The diagnostic accuracy and cutoff values were determined by receiver operating characteristic curve. RESULTS: Relative expression of HO-1 mRNA in CML patients peripheral blood was significantly higher than that of donors (P < 0.0001), which were 0.57+/-3.78 and (1.417+/-1.125)*10( 6), respectively. HO-1 expression level in CML patients was 0.061 5+/-0.062 4, which decreased to 0.009 4+/-0.006 7 upon CMoR, and remained remarkably higher 0.016 3+/-0.017 5 than that of normal donors (1.417+/-1.125)*10(-6), P < 0.001. When relapse occurred, HO-1 expression significantly increased from 0.020 6+/ 0.021 0 to 3.852+/-10.285 in CMoR stage and undergoing relapse. According to progression of CML, HO-1 expression level in CML patients increased from CP (0.009 5+/-0.017 6) to AP (0.028 0+/-0.055 7) and then to BP (0.276 7 +/- 0.447 0). And there was a linear correlation between HO-1 expression and proportion of primitive CML cells. The diagnostic accuracies and cutoff values of HO-1 expression for CML-CP, CML-AP, and CML-BP were 1.0, 0.748, and 0.965, respectively, as well as 0.000 070, 0.001 917, and 0.020 696, respectively. CONCLUSION: HO-1 may be a potential molecular indicator for the progression and relapse of CML. PMID- 25146617 TI - Management and outcome of pelvic fractures in elderly patients: a retrospective study of 40 cases. AB - BACKGROUND: Pelvic fractures are uncommon in elderly patients and so are infrequently addressed in the literature. The purpose of this study was to investigate the management and outcome of pelvic fractures in elderly patients. METHODS: We retrospectively reviewed the records of pelvic fractures in elderly patients (age >=55 years) who were treated in our department from September 1997 to May 2010. RESULTS: A total of 40 elderly patients with pelvic fractures were identified. Their mean age was 65.8 years (range 55-87 years). About 68% (n = 27) were men. The average Injury Severity Score (ISS) was 17.8 (range 6-45). Twelve (30%) patients required blood transfusion (mean 10 units) during the first 24 hours. The fractures were most frequently due to falling from a standing position (48%). Almost half (48%) were grade I breaks. Associated injuries were present in 70% (n = 28) of patients, and 65% (n = 26) had medical co-morbidities. Altogether, 29 patients (73%) underwent non-surgical management of their pelvic fracture. The average hospital stay was 25 days. There were five in-hospital deaths and one death 10 months after discharge. High ISSs (>25) were associated with increased in-hospital mortality (P = 0.018). At the final assessment (mean follow-up 15 months), 52% of the surviving patients had experienced decreased self-sufficiency. CONCLUSIONS: Pelvic fractures in elderly patients result in high morbidity and mortality rates. A high ISS (>25) can be used to identify a patient at high risk. We recommend aggressive resuscitation and intensive care for that patient. For patients with an unstable pelvic or displaced acetabular fracture (>=2 mm) who can endure surgery, open reduction and internal fixation can provide adequate fixation for early weight-bearing and restoration of the bone stock. PMID- 25146618 TI - Perioperative management for separation of thoraco-omphalopagus symmetrically conjoined twins. PMID- 25146619 TI - Microvascular protective role of pericytes in melatonin-treated spinal cord injury in the C57BL/6 mice. AB - BACKGROUND: Pericytes, located on microvessels, help to maintain vascular stability and blood-brain barrier integrity. The influence of pericytes on microvessels after spinal cord injury (SCI) is less clear. Therefore, the aim of this study was to investigate whether pericytes took a protective effect on microvessels in melatonin-treated SCI. METHODS: C57BL/6 mice were randomly divided into three groups: sham group, SCI group, and melatonin group (n = 27 per group). Functional recovery was evaluated using the Basso Mouse Scale. Motor neurons were observed using hematoxylin and eosin staining. Pericyte coverage was analyzed using immunofluorescence. Permeability of blood-spinal cord barrier (BSCB) was assessed by administration of Evan's Blue. Protein levels of occludin, aquaporin-4 (AQP4), angiopoietin-1 (Ang1), intercellular cell adhesion molecule-1 (ICAM-1), Bcl-2, and Bax were determined using Western blotting. Mimicking the pathological conditions of SCI, melatonin-treated primary pericytes were subjected to oxygen-glucose deprivation/reperfusion (OGD/R). Secretion of Ang1 was analyzed using an enzyme-linked immunosorbent assay, and the expression of ICAM-1 was detected by immunofluorescence. RESULTS: Melatonin treatment improved locomotor functional outcome and rescued motor neurons. Pericyte coverage was significantly reduced after SCI; melatonin treatment alleviated the loss of pericyte coverage and rescued perfused microvessels 7 days after injury. The permeability of BSCB and loss of occludin were attenuated, and edema formation and upregulation of AQP4 were inhibited, after melatonin treatment. The expression of Ang1 and Bcl-2 was improved, while the expression of ICAM-1 and Bax was inhibited, in melatonin-treated SCI mice. Furthermore, the secretion of Ang1 was increased and the expression of ICAM-1 was inhibited in melatonin-treated pericytes after OGD/R. CONCLUSIONS: Melatonin ameliorated the loss of blood vessels and disruption of BSCB to exert a protective effect on SCI, which might be mediated by increased pericyte coverage. The upregulation of Ang1 in pericytes could inhibit inflammation and apoptosis to protect the microvessels. PMID- 25146620 TI - Adverse factors increase preeclampsia-like changes in pregnant mice with abnormal lipid metabolism. AB - BACKGROUND: Preeclampsia (PE) is a multifactorial pregnancy complication. Maternal underlying condition and adverse factors both influence the pathogenesis of PE. Abnormal lipid metabolism as a maternal underlying disease may participate in the occurrence and development of PE. This study aimed to observe the effects of adverse factors on PE-like symptoms of pregnant mice with genetic abnormal lipid metabolism. METHODS: Apolipoprotein C-III (ApoC3) transgenic mice with abnormal lipid metabolism were subcutaneously injected with L-arginine methyl ester (L-NAME) or normal saline (NS) daily starting at Day 7 or 16 of pregnancy (ApoC3+L-NA and ApoC3+NS groups), and wild-type (WT) mice served as a control (WT+L-NA and WT+NS groups). All mice were subdivided into early and late subgroups by injection time. The mean arterial pressure (MAP) and urinary protein were measured. Pregnancy outcomes, including fetal weight, placental weight, live birth rate, and fetal absorption rate, were analyzed. Pathologic changes in the placenta were observed by hematoxylin-eosin staining. One-way analysis of variance, t-test, and chi(2) test were used for statistical analysis. RESULTS: MAP significantly increased for ApoC3+NS groups compared with WT+NS groups (P < 0.05), without significant difference in urine protein. Following L-NAME injection, MAP and urinary protein significantly increased for ApoC3+L-NA and WT+L-NA compared with the corresponding NS groups (P < 0.05), and the increase for ApoC3+L-NA was more obvious. Urinary protein levels in early ApoC3+L-NA and WT+L-NA significantly increased compared with the corresponding late groups (P < 0.05). Fetal absorption rate significantly increased and fetal and placental weights significantly decreased in early ApoC3+L-NA and WT+L-NA compared with the corresponding NS groups (P < 0.05), without significant difference in late ApoC3+L-NA and WT+L-NA groups. Fetal weight in early ApoC3+L-NA was significantly lower than in early WT+L-NA group (P < 0.05). Morphologic examination of placentas from early ApoC3+L-NA and WT+L-NA groups showed varying degrees of fibrinoid necrosis. CONCLUSIONS: ApoC3 transgenic mice with abnormal lipid metabolism showed gestational hypertension. Adverse factors and early effect time could aggravate the PE-like symptoms for ApoC3 transgenic mice. PMID- 25146621 TI - Giant cell interstitial pneumonia: unusual lung disorder and an update. AB - BACKGROUND: Giant cell interstitial pneumonia (GIP) was a rare form of pneumoconiosis, associated with exposure to hard metals, which had been reported mostly as isolated case reports. We described eight cases of GIP diagnosed in our hospital during the past seven years, with particular reference to new findings. METHODS: Eight patients with GIP confirmed by biopsy in the Nanjing Drum Tower Hospital affiliated to Medical School of Nanjing University from 2005 to 2011 were retrospectively analyzed. For each patient, the occupy histories and medical records were thoroughly reviewed and clinic data were extracted. Two radiologists, without knowledge of any of the clinical and functional findings, independently reviewed the HRCT scans of all patients. Follow-up data were collected. RESULTS: Among the eight patients, seven had a history of exposure to hard metal dusts, one denied an exposure history. The most common manifestations were cough and dyspnea. One patient initiated with pneumothorax and another pleural effusion, both of which were uncommon to GIP. The main pathologic appearances were the presence of macrophages and multinucleated giant cells in the alveolar space. The clinical symptoms and radiographic abnormalities were obviously improved after cessation of exposure and receiving corticosteroid treatments, recurrences were observed in two patients when they resumed work. In spite of exposure cessation and corticosteroid treatment, one patient developed pulmonary fibrosis at seven years follow-up. CONCLUSIONS: Awareness of the patients' occupational history often provided clues to the diagnosis of GIP. Histopathologic examinations were necessary to establish the right diagnosis. Exposure cessation was of benefit to most patients; however, pulmonary fibrosis was possible in spite of exposure cessation and corticosteroid treatment. Better ways should be found out to improve the outcome and quality of life. PMID- 25146622 TI - Association between plasma brain natriuretic peptide/N-terminal pro-brain natriuretic peptide levels and atrial fibrillation: evidence from a meta analysis. AB - BACKGROUND: Several small sample-size observational studies evaluated the association of plasma brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP) with atrial fibrillation (AF), but the results were contradictory. We aimed to perform a meta-analysis of relevant studies to evaluate the availability of this association. METHODS: We performed an extensive literature search on PubMed, Web of Science (WOS) and the Cochrane Library databases. Pooled standardized mean difference (SMD) and 95% confidence interval (CI) were calculated to assess the strength of association using random effects models. We performed sensitivity and subgroup analyses to explore the potential sources of heterogeneity. We also estimated publication biases. Statistical analyses were performed using the STATA 12.0 software. RESULTS: A total of 11 studies including 777 cases and 870 controls were finally analyzed. Overall, the brain natriuretic peptide/N-terminal pro-brain natriuretic peptide levels were higher in atrial fibrillation patients than controls without atrial fibrillation. RESULTS: showed that the SMD in the natriuretic peptide levels between cases and controls was 2.68 units (95% CI 1.76 to 3.60); test for overall effect z-score = 5.7 (P < 0.001). There was significant heterogeneity between individual studies (I(2) = 97.8%; P < 0.001). Further analysis revealed that differences in the assay of natriuretic peptide possibly account for this heterogeneity. CONCLUSIONS: Increased BNP/NT-proBNP levels were associated with the presence of atrial fibrillation. This finding indicates that BNP/NT-proBNP may prove to be a biomarker of an underlying predisposition to AF. PMID- 25146623 TI - Outcome of kidney transplantation between controlled cardiac death and brain death donors: a meta-analysis. AB - BACKGROUND: Our goal was to evaluate the outcomes of kidney transplants from controlled cardiac death donors compared with brain death donors by conducting a meta-analysis of cohort studies. METHODS: The PubMed database and EMBASE were searched from January 1980 to July 2013 to identify studies that met pre-stated inclusion criteria. Reference lists of retrieved articles were also reviewed. Two authors independently extracted information on the designs of the studies, the characteristics of the study participants, and outcome assessments. RESULTS: Nine cohort studies involving 84 398 participants were included in this meta-analysis; 3 014 received kidneys from controlled cardiac death donors and 80 684 from brain death donors. Warm ischemia time was significantly longer for the controlled cardiac death donor group. The incidence of delayed graft function was 2.74 times (P < 0.001) greater in the controlled cardiac death donor group. The results are in favor of the brain death donor group on short-term patient and graft survival while this difference became nonsignificant at mid-term and long term. Sensitivity analysis yielded similar results. No evidence of publication bias was observed. CONCLUSION: This meta-analysis of retrospective cohort studies suggests that the outcome after controlled cardiac death donors is comparable with that obtained using kidneys from brain death donors. PMID- 25146624 TI - Efficacy and safety of vitamin D3 in patients with diabetic nephropathy: a meta analysis of randomized controlled trials. AB - BACKGROUND: Several studies found that vitamin D3 might alter glucose metabolism, protect kidney from injury and even proposed the mechanisms. But results from previous studies have been conflicting. The aim of this study was to evaluate the efficacy and safety of vitamin D3 in patients with diabetic nephropathy. The underlying mechanism of vitamin D3 decreasing proteinuria is also discussed. METHODS: We conducted a search of English and Chinese articles using database of Pubmed, Embase, Sinomed, CNKI, Wanfang and clinical trial register centers, for randomized controlled trials of vitamin D3 in diabetic nephropathy patients. Two reviewers performed independently. Meta-analysis was used when studies were homogeneous enough. RESULTS: Twenty studies, including 1 497 patients with diabetic nephropathy, were involved in this systemic review. Vitamin D3-treated patients with diabetic nephropathy had a statistically significant reduction in 24-hour proteinuria (weighted mean difference -0.44, 95% CI -0.54 to -0.34, Z = 8.80, P < 0.000 01) and urine albumin/creatine ratio (standardized mean difference -0.29, 95% CI -0.48 to -0.10, Z = 2.96, P = 0.003). But vitamin D3 supplementation did not significantly reduce blood pressure and hemoglobin A1c compared with control group. The potential mechanisms about the renal protection of vitamin D3, including the inhibition of rennin-angiotensin system, the protection of kidney from inflammation, fibrosis and the structure change of kidney are discussed. In addition, vitamin D3 did not significantly increase the incidence of adverse effects, including total adverse effects, gastrointestinal adverse effects and fluctuation of blood pressure. CONCLUSIONS: Vitamin D3 can ameliorate proteinuria and protect kidney from injury in patients with diabetic nephropathy. This renoprotective effect is independent of blood pressure and glucose reduction. And it does not increase any adverse effects than control, even in combination therapy with angiotensin converting enzyme inhibitors/angiotensin receptor blockers. But due to the limited randomized controlled trials of high quality, more clinical researches should be taken in the future. PMID- 25146625 TI - A systematic review on food lead concentration and dietary lead exposure in China. AB - BACKGROUND: By synthesizing results from primary studies, systematic review can provide empirical information of concerned problems. This study aimed to review the available surveillance data from studies reporting the contamination surveillance of food lead in China. METHODS: Relevant studies were identified by systematically searching Chinese Biological Medicine Database and China National Knowledge Infrastructure using the key term of "lead" for surveillance data published in Chinese between 2006 and 2012. To avoid potential selection bias, all articles were evaluated by two independent reviewers, and the disagreements were resolved by discussion or the third author was asked to arbitrate. RESULTS: Among 269 identified publications on surveillance data of lead in food, 43 articles met the defined inclusion criteria. The food samples were divided into 11 groups (cereal grains and pulses, fish, eggs, vegetables, meat, edible fungi, milk and dairy products, fruits, offal, tea and preserved egg). Surveillance data of publications were reviewed to calculate the weighted mean and rate exceeding maximum levels. Our results indicated that the highest lead concentration was 1.937 mg/kg in tea. The total percentage of samples exceeding the maximum levels was 5.57%. Dietary exposure to lead was assessed by combining the weighted mean concentration of surveillance data with national consumption data in 2002. In this review, dietary intake of lead was 1.232 ug/kg b.w./day. CONCLUSION: Further control measures should be taken to reduce exposure to lead, from both dietary and non-dietary sources. PMID- 25146626 TI - Experimental drugs for treatment of autoimmune myocarditis. AB - OBJECTIVE: To review the experimental drugs for the treatment of autoimmune myocarditis. DATA SOURCES: The literatures published in English about different kinds of experimental drugs based on different therapeutic mechanisms for the treatment of autoimmune myocarditis were obtained from PubMed from 2002 to 2013. STUDY SELECTION: Original articles regarding the experimental drugs for treatment of autoimmune myocarditis were selected. RESULTS: This study summarized the effects of the experimental drugs for the treatment of autoimmune myocarditis, such as immunomodulators and immunosuppressants, antibiotics, Chinese medicinal herbs, cardiovascular diseases treatment drugs, etc. These drugs can significantly attenuate autoimmune myocarditis-induced inflammation and fibrosis, alleviate autoimmune myocarditis-triggered overt lymphocyte proliferation, and meanwhile reduce Th1 cytokines (IFN-gamma and IL-2) and increase Th2 cytokines (IL-4 and IL-10). CONCLUSION: This study summarized recent advances in autoimmune myocarditis treatment and further proposes that traditional Chinese medicine and immune regulators will play important roles in the future. PMID- 25146627 TI - Research of admission management standards and working patterns of first class medical technologies. PMID- 25146628 TI - Successful resuscitation after fatal carbon dioxide embolism during laparoscopic nephrectomy. PMID- 25146629 TI - Immune-mediated neuromuscular complications after haploidendtical hematopoietic stem cell transplantation. PMID- 25146630 TI - Primary pulmonary artery chondrosarcoma: the use of different imaging modalities. PMID- 25146631 TI - Application of customized augments fabricated by rapid prototyping for severe bone defects of the knee. PMID- 25146632 TI - Pulmonary artery injury management during pulmonary thromboendarterectomy. PMID- 25146633 TI - Predictors and outcomes of photodynamic therapy on circumscribed choroidal hemangiomas in Chinese patients. PMID- 25146634 TI - Giant juvenile fibroadenoma associated with dysplasia on the underdeveloped breast. PMID- 25146635 TI - Obstruction of ileal loop in bricker type bladder after laparoscopic radical cystectomy. PMID- 25146636 TI - An aortic arch anomaly protruding into the esophagus misdiagnosed as leiomyoma of the esophagus. PMID- 25146637 TI - Needle in kidney migrated from urethra treated with percutaneous nephroscopy. PMID- 25146638 TI - Interobserver variation in classifying lymphomas among hematopathologists. AB - BACKGROUND: Lymphomas are common malignancies that have various subtypes with many overlapping histologic, immunophenotypic and genetic features. Therefore, discordance in classifying lymphoma among pathologists may be encountered. But this issue is not well characterized. We conducted the present study to demonstrate discordances among Thai hematopathologists as well as to highlight common arguing points for classifying lymphomas. METHODS: The 117 lymphoma cases were randomly retrieved and individually reviewed by 7 hematopathologists, members of the "Thai Hematopathologist Group," without knowing the original diagnoses. The consensus diagnoses were given from a discussion by all members. In each case, the diagnosis from each participant was compared with the consensus diagnosis and classified into 4 categories as follow: 1) concordance, 2) minor discordance, 3) major discordance and 4) serious discordance. RESULTS: There were approximately 11% discordances between original and consensus diagnoses. The average discordances among all pathologists according to minor, major and serious discordances were 10%, 3.5% and 0.3%, respectively. Diffuse large B-cell lymphoma had the least discordance (7%). Small biopsies had been found to increase discordances in some lymphoma subtypes. CONCLUSIONS: The present study reveals some degrees of interobserver variation in classifying of lymphoma by using the 2008 WHO classification among hematopathologists. Some types of lymphomas on small biopsies were found to have a significant higher discordance rate. This study also described some common diagnostic discordances regarded as potential pitfalls in classifying lymphomas. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_162. PMID- 25146639 TI - Intra- and interspecific variation in macaque molar enamel thickness. AB - Enamel thickness has played an important role in studies of primate taxonomy, phylogeny, and functional morphology, although its variation among hominins is poorly understood. Macaques parallel hominins in their widespread geographic distribution, relative range of body sizes, and radiation during the last five million years. To explore enamel thickness variation, we quantified average and relative enamel thickness (AET and RET) in Macaca arctoides, Macaca fascicularis, Macaca fuscata, Macaca mulatta, Macaca nemestrina, and Macaca sylvanus. Enamel area, dentine area, and enamel-dentine junction length were measured from mesial sections of 386 molars scanned with micro-computed tomography, yielding AET and RET indices. Intraspecific sex differences were not found in AET or RET. Macaca fuscata had the highest AET and RET, M. fascicularis showed the lowest AET, and M. arctoides had the lowest RET. The latitudinal distribution of macaque species was associated with AET for these six species. Temperate macaques had thicker molar enamel than did tropical macaques, suggesting that thick enamel may be adaptive in seasonal environments. Additional research is needed to determine if thick enamel in temperate macaques is a response to intensified hard-object feeding, increased abrasion, and/or a broader diet with a greater range of food material properties. The extreme ecological flexibility of macaques may prohibit identification of consistent trends between specific diets and enamel thickness conditions. Such complications of interpretation of ecological variability, dietary diversity, and enamel thickness may similarly apply for fossil Homo species. PMID- 25146640 TI - Measurement of breast density with digital breast tomosynthesis--a systematic review. AB - Digital breast tomosynthesis (DBT) has gained acceptance as an adjunct to digital mammography in screening. Now that breast density reporting is mandated in several states in the USA, it is increasingly important that the methods of breast density measurement be robust, reliable and consistent. Breast density assessment with DBT needs some consideration since quantitative methods are modelled for two-dimensional (2D) mammography. A review of methods used for breast density assessment with DBT was performed. Existing evidence shows Cumulus has better reproducibility than that of the breast imaging reporting and data system (BI-RADS(r)) but still suffers from subjective variability; MedDensity is limited by image noise, whilst Volpara and Quantra are robust and consistent. The reported BI-RADs inter-reader breast density agreement (k) ranged from 0.65 to 0.91, with inter-reader correlation (r) ranging from 0.70 to 0.93. The correlation (r) between BI-RADS and Cumulus ranged from 0.54-0.94, whilst that of BI-RADs and MedDensity ranged from 0.48-0.78. The reported agreement (k) between BI-RADs and Volpara is 0.953. Breast density correlation between DBT and 2D mammography ranged from 0.73 to 0.97, with agreement (k) ranging from 0.56 to 0.96. To avoid variability and provide more reliable breast density information for clinicians, automated volumetric methods are preferred. PMID- 25146641 TI - Multidisciplinary urological engagement in translational renal cancer research. PMID- 25146642 TI - Branched porphyrins as functional scaffolds for multisite bioconjugation. AB - Bioconjugation is a rapidly expanding field because of the numerous potential applications of bioconjugate materials. We explored the usefulness of branched porphyrins as rigid scaffolds, bearing multiple sites for bioconjugation. To this end, we first selected the tetrakis(p-[aminomethyl] phenyl) porphyrin (TAMPP) macrocycle and developed a straightforward synthetic protocol, able to provide the desired tetraphenylporphyrin, carrying four functional amino groups. The partially protection of the amino groups by tert-butoxy-carbonyl allowed the selective and specific decoration of the porphyrin with different peptide sequences. To explore the utility of the macrocycle as molecular scaffold for bioconjugation, we selected peptide sequences able to function as thrombin inhibitors. In particular, two peptide sequences, named CS3 and ES7, able to interact, respectively, with the thrombin catalytic site and the fibrinogen recognition exosite, were joined onto the porphyrin macrocycle, providing the multisite-directed inhibitor CS3-TAMPP-ES7. This multisite inhibitor and its Mn(III) complex are able to inhibit alpha-thrombin-catalyzed hydrolysis of Tos Gly-Pro-Arg-nitroanilide with inhibition constants in the micromolar range, as well as the hydrolysis of the natural substrate fibrinogen. The inhibitor is resistant against enzymatic degradation by thrombin and is highly selective. The Mn(III) complex is capable of interacting with clot-bound thrombin and partially inhibits clot growth in the presence of fibrinogen. The results herein reported are very promising, suggesting the potential of the newly developed conjugate as new imaging agents for clot detection. PMID- 25146643 TI - Modeling astrocytoma pathogenesis in vitro and in vivo using cortical astrocytes or neural stem cells from conditional, genetically engineered mice. AB - Current astrocytoma models are limited in their ability to define the roles of oncogenic mutations in specific brain cell types during disease pathogenesis and their utility for preclinical drug development. In order to design a better model system for these applications, phenotypically wild-type cortical astrocytes and neural stem cells (NSC) from conditional, genetically engineered mice (GEM) that harbor various combinations of floxed oncogenic alleles were harvested and grown in culture. Genetic recombination was induced in vitro using adenoviral Cre mediated recombination, resulting in expression of mutated oncogenes and deletion of tumor suppressor genes. The phenotypic consequences of these mutations were defined by measuring proliferation, transformation, and drug response in vitro. Orthotopic allograft models, whereby transformed cells are stereotactically injected into the brains of immune-competent, syngeneic littermates, were developed to define the role of oncogenic mutations and cell type on tumorigenesis in vivo. Unlike most established human glioblastoma cell line xenografts, injection of transformed GEM-derived cortical astrocytes into the brains of immune-competent littermates produced astrocytomas, including the most aggressive subtype, glioblastoma, that recapitulated the histopathological hallmarks of human astrocytomas, including diffuse invasion of normal brain parenchyma. Bioluminescence imaging of orthotopic allografts from transformed astrocytes engineered to express luciferase was utilized to monitor in vivo tumor growth over time. Thus, astrocytoma models using astrocytes and NSC harvested from GEM with conditional oncogenic alleles provide an integrated system to study the genetics and cell biology of astrocytoma pathogenesis in vitro and in vivo and may be useful in preclinical drug development for these devastating diseases. PMID- 25146644 TI - A mouse model for pathogen-induced chronic inflammation at local and systemic sites. AB - Chronic inflammation is a major driver of pathological tissue damage and a unifying characteristic of many chronic diseases in humans including neoplastic, autoimmune, and chronic inflammatory diseases. Emerging evidence implicates pathogen-induced chronic inflammation in the development and progression of chronic diseases with a wide variety of clinical manifestations. Due to the complex and multifactorial etiology of chronic disease, designing experiments for proof of causality and the establishment of mechanistic links is nearly impossible in humans. An advantage of using animal models is that both genetic and environmental factors that may influence the course of a particular disease can be controlled. Thus, designing relevant animal models of infection represents a key step in identifying host and pathogen specific mechanisms that contribute to chronic inflammation. Here we describe a mouse model of pathogen-induced chronic inflammation at local and systemic sites following infection with the oral pathogen Porphyromonas gingivalis, a bacterium closely associated with human periodontal disease. Oral infection of specific-pathogen free mice induces a local inflammatory response resulting in destruction of tooth supporting alveolar bone, a hallmark of periodontal disease. In an established mouse model of atherosclerosis, infection with P. gingivalis accelerates inflammatory plaque deposition within the aortic sinus and innominate artery, accompanied by activation of the vascular endothelium, an increased immune cell infiltrate, and elevated expression of inflammatory mediators within lesions. We detail methodologies for the assessment of inflammation at local and systemic sites. The use of transgenic mice and defined bacterial mutants makes this model particularly suitable for identifying both host and microbial factors involved in the initiation, progression, and outcome of disease. Additionally, the model can be used to screen for novel therapeutic strategies, including vaccination and pharmacological intervention. PMID- 25146645 TI - Adulticidal properties of synthesized silver nanoparticles using leaf extracts of Feronia elephantum (Rutaceae) against filariasis, malaria, and dengue vector mosquitoes. AB - Mosquito-borne diseases with an economic impact create loss in commercial and labor outputs, particularly in countries with tropical and subtropical climates. Mosquito control is facing a threat because of the emergence of resistance to synthetic insecticides. Extracts from plants may be alternative sources of mosquito control agents because they constitute a rich source of bioactive compounds that are biodegradable into nontoxic products and potentially suitable for use to control mosquitoes. Insecticides of botanical origin may serve as suitable alternative biocontrol techniques in the future. In view of the recently increased interest in developing plant origin insecticides as an alternative to chemical insecticide, in the present study, the adulticidal activity of silver nanoparticles (AgNPs) synthesized using Feronia elephantum plant leaf extract against adults of Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus was determined. The range of concentrations of synthesized AgNPs (8, 16, 24, 32, and 40 MUg mL(-1)) and aqueous leaf extract (40, 80, 120, 160, and 200 MUg mL( 1)) were tested against the adults of A. stephensi, A. aegypti, and C. quinquefasciatus. Adults were exposed to varying concentrations of aqueous crude extract and synthesized AgNPs for 24 h. Considerable mortality was evident after the treatment of F. elephantum for all three important vector mosquitoes. The synthesized AgNPs from F. elephantum were highly toxic than crude leaf aqueous extract to three important vector mosquito species. The results were recorded from UV-visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) with energy-dispersive X-ray spectroscopy analysis (EDX), and transmission electron microscopy (TEM). Synthesized AgNPs against the vector mosquitoes A. stephensi, A. aegypti, and C. quinquefasciatus had the following lethal dose (LD)50 and LD90 values: A. stephensi had LD50 and LD90 values of 18.041 and 32.575 MUg mL(-1); A. aegypti had LD50 and LD90 values of 20.399 and 37.534 MUg mL(-1); and C. quinquefasciatus had LD50 and LD90 values of 21.798 and 39.596 MUg mL(-1). No mortality was observed in the control. These results suggest that the leaf aqueous extracts of F. elephantum and green synthesis of AgNPs have the potential to be used as an ideal eco-friendly approach for the control of the A. stephensi, A. aegypti, and C. quinquefasciatus. This is the first report on the adulticidal activity of the plant extracts and AgNPs. PMID- 25146646 TI - Contralateral biopsies in patients with testicular germ cell tumours: patterns of care in Germany and recent data regarding prevalence and treatment of testicular intra-epithelial neoplasia. AB - The precursor of testicular germ cell tumours (GCTs), called testicular intra epithelial neoplasia (TIN/CIS), is safely diagnosed immunohistologically. Testicular biopsy provides a valuable tool for early detection of GCTs in risk groups. Although this knowledge is undisputed, testicular biopsies are utilized poorly. The patterns of care regarding the use of biopsies remain unknown. Uncertainty exists about the prevalence and specific treatment of TIN/CIS. We asked clinical urologists in Germany whether or not they employed contralateral biopsies in GCT patients. We evaluated the prevalence of contralateral TIN/CIS in a retrospective analysis of 780 consecutive GCT patients. All had contralateral double biopsies. Discordance of TIN/CIS findings among biopsy pairs as well as age, histology of the primary tumour and clinical stage was noted. Evaluation of data comprised descriptive statistical methods. To evaluate treatment options for TIN/CIS, we performed a literature search. 52.1% of German urologists always perform the biopsy, 17% do it mostly, 27.3% in select cases, 3.5% never. Curiously, there was a geographic north-south gradient regarding biopsy use. Contralateral TIN/CIS was found in 5%. The median ages of patients with TIN/CIS and those without were 31.8 and 34.9 years respectively (p = 0.02). The discordance rate among biopsy pairs was of 33%. Two-site biopsies provide a 17% gain in diagnostic sensitivity. Local radiotherapy with 20 Gy is the safest treatment of TIN/CIS failing in 2%. Chemotherapy has significantly lower efficacy. Contralateral testicular biopsies in GCT patients are well accepted among German urologists. The prevalence of contralateral TIN/CIS found in this series is in accordance with previous reports. Double biopsies should be the diagnostic standard because of their diagnostic superiority. Local radiotherapy with 20 Gy is the safest way of eradicating TIN/CIS. Failures occur in only 2%, usually many years after irradiation. Cisplatin-based chemotherapy is dose dependent and less effective. PMID- 25146647 TI - The evolution of the four subunits of voltage-gated calcium channels: ancient roots, increasing complexity, and multiple losses. AB - The alpha subunits of voltage-gated calcium channels (Ca(v)s) are large transmembrane proteins responsible for crucial physiological processes in excitable cells. They are assisted by three auxiliary subunits that can modulate their electrical behavior. Little is known about the evolution and roles of the various subunits of Ca(v)s in nonbilaterian animals and in nonanimal lineages. For this reason, we mapped the phyletic distribution of the four channel subunits and reconstructed their phylogeny. Although alpha subunits have deep evolutionary roots as ancient as the split between plants and opistokonths, beta subunits appeared in the last common ancestor of animals and their close-relatives choanoflagellates, gamma subunits are a bilaterian novelty and alpha2/delta subunits appeared in the lineage of Placozoa, Cnidaria, and Bilateria. We note that gene losses were extremely common in the evolution of Ca(v)s, with noticeable losses in multiple clades of subfamilies and also of whole Ca(v) families. As in vertebrates, but not protostomes, Ca(v) channel genes duplicated in Cnidaria. We characterized by in situ hybridization the tissue distribution of alpha subunits in the sea anemone Nematostella vectensis, a nonbilaterian animal possessing all three Ca(v) subfamilies common to Bilateria. We find that some of the alpha subunit subtypes exhibit distinct spatiotemporal expression patterns. Further, all six sea anemone alpha subunit subtypes are conserved in stony corals, which separated from anemones 500 MA. This unexpected conservation together with the expression patterns strongly supports the notion that these subtypes carry unique functional roles. PMID- 25146648 TI - Missing genes, multiple ORFs, and C-to-U type RNA editing in Acrasis kona (Heterolobosea, Excavata) mitochondrial DNA. AB - Discoba (Excavata) is an ancient group of eukaryotes with great morphological and ecological diversity. Unlike the other major divisions of Discoba (Jakobida and Euglenozoa), little is known about the mitochondrial DNAs (mtDNAs) of Heterolobosea. We have assembled a complete mtDNA genome from the aggregating heterolobosean amoeba, Acrasis kona, which consists of a single circular highly AT-rich (83.3%) molecule of 51.5 kb. Unexpectedly, A. kona mtDNA is missing roughly 40% of the protein-coding genes and nearly half of the transfer RNAs found in the only other sequenced heterolobosean mtDNAs, those of Naegleria spp. Instead, over a quarter of A. kona mtDNA consists of novel open reading frames. Eleven of the 16 protein-coding genes missing from A. kona mtDNA were identified in its nuclear DNA and polyA RNA, and phylogenetic analyses indicate that at least 10 of these 11 putative nuclear-encoded mitochondrial (NcMt) proteins arose by direct transfer from the mitochondrion. Acrasis kona mtDNA also employs C-to-U type RNA editing, and 12 homologs of DYW-type pentatricopeptide repeat (PPR) proteins implicated in plant organellar RNA editing are found in A. kona nuclear DNA. A mapping of mitochondrial gene content onto a consensus phylogeny reveals a sporadic pattern of relative stasis and rampant gene loss in Discoba. Rampant loss occurred independently in the unique common lineage leading to Heterolobosea + Tsukubamonadida and later in the unique lineage leading to Acrasis. Meanwhile, mtDNA gene content appears to be remarkably stable in the Acrasis sister lineage leading to Naegleria and in their distant relatives Jakobida. PMID- 25146649 TI - Phylogenomic study indicates widespread lateral gene transfer in Entamoeba and suggests a past intimate relationship with parabasalids. AB - Lateral gene transfer (LGT) has impacted the evolutionary history of eukaryotes, though to a lesser extent than in bacteria and archaea. Detecting LGT and distinguishing it from single gene tree artifacts is difficult, particularly when considering very ancient events (i.e., over hundreds of millions of years). Here, we use two independent lines of evidence--a taxon-rich phylogenetic approach and an assessment of the patterns of gene presence/absence--to evaluate the extent of LGT in the parasitic amoebozoan genus Entamoeba. Previous work has suggested that a number of genes in the genome of Entamoeba spp. were acquired by LGT. Our approach, using an automated phylogenomic pipeline to build taxon-rich gene trees, suggests that LGT is more extensive than previously thought. Our analyses reveal that genes have frequently entered the Entamoeba genome via nonvertical events, including at least 116 genes acquired directly from bacteria or archaea, plus an additional 22 genes in which Entamoeba plus one other eukaryote are nested among bacteria and/or archaea. These genes may make good candidates for novel therapeutics, as drugs targeting these genes are less likely to impact the human host. Although we recognize the challenges of inferring intradomain transfers given systematic errors in gene trees, we find 109 genes supporting LGT from a eukaryote to Entamoeba spp., and 178 genes unique to Entamoeba spp. and one other eukaryotic taxon (i.e., presence/absence data). Inspection of these intradomain LGTs provide evidence of a common sister relationship between genes of Entamoeba (Amoebozoa) and parabasalids (Excavata). We speculate that this indicates a past close relationship (e.g., symbiosis) between ancestors of these extant lineages. PMID- 25146650 TI - Phytochemical genomics of the Madagascar periwinkle: Unravelling the last twists of the alkaloid engine. AB - The Madagascar periwinkle produces a large palette of Monoterpenoid Indole Alkaloids (MIAs), a class of complex alkaloids including some of the most valuable plant natural products with precious therapeutical values. Evolutionary pressure on one of the hotspots of biodiversity has obviously turned this endemic Malagasy plant into an innovative alkaloid engine. Catharanthus is a unique taxon producing vinblastine and vincristine, heterodimeric MIAs with complex stereochemistry, and also manufactures more than 100 different MIAs, some shared with the Apocynaceae, Loganiaceae and Rubiaceae members. For over 60 years, the quest for these powerful anticancer drugs has inspired biologists, chemists, and pharmacists to unravel the chemistry, biochemistry, therapeutic activity, cell and molecular biology of Catharanthus roseus. Recently, the "omics" technologies have fuelled rapid progress in deciphering the last secret of strictosidine biosynthesis, the central precursor opening biosynthetic routes to several thousand MIA compounds. Dedicated C. roseus transcriptome, proteome and metabolome databases, comprising organ-, tissue- and cell-specific libraries, and other phytogenomic resources, were developed for instance by PhytoMetaSyn, Medicinal Plant Genomic Resources and SmartCell consortium. Tissue specific library screening, orthology comparison in species with or without MIA biochemical engines, clustering of gene expression profiles together with various functional validation strategies, largely contributed to enrich the toolbox for plant synthetic biology and metabolic engineering of MIA biosynthesis. PMID- 25146651 TI - [Connexin-43 antibodies in intraoperative diagnosis of experimental poorly differentiated gliomas]. AB - Fluorescent diagnosis was first proposed in the early XX century and has been used in neurosurgery for about 15 years. The method relies on selective accumulation of strongly fluorescent protoporphyrin IX in tumor cells. Over the past years, the method of intraoperative fluorescence diagnosis has occupied its niche in many neurosurgical clinics around the world and is now used for fast intraoperative diagnosis in brain tumor surgery. However, the efficiency of fluorescent intraoperative diagnosis using 5-aminolevulinic acid is 80-90% and 58.8% for surgery of Grade III-IV and I-II gliomas, respectively. One of the methods to improve the efficiency of fluorescent diagnosis is to use vector systems for delivering fluorescent drugs into the tumor. This paper reports the results of an experimental study of systems for delivering fluorescent agents (protoporphyrin IX, Alexa 488, Alexa 660) using connexin-43 antibodies in rats with transplanted C6 glioma. PMID- 25146652 TI - [Results of using Spine Assist Mazor in surgical treatment of spine disorders]. AB - In this paper, we describe the possibility of using a bone-mounted miniature robot based on the experience of different surgeries performed in 77 patients divided into four groups according to the general pathology (degenerative stenosis of the vertebral canal, fractures of vertebral bodies, spondylolisthesis, hemangiomas, and tumors). All the patients underwent surgical intervention using Spine Assist Mazor, such as stabilization using the Go-Lif system, transpedicular systems, vertebroplasty, and vertebral body biopsy. The new method and the technology of stabilizing surgeries using Spine Assist Mazor allow one to perform preoperative virtual planning based on CT images and to identify an ideal and safe trajectory of placing screws or needles for vertebroplasty or biopsy. PMID- 25146653 TI - [Experience of using an intraoperative cone beam computed tomography scanner and the modern navigation system in surgical treatment of spine and spinal cord disorders]. AB - Spine disorders are a highly relevant problem in neurosurgical pathology. The development of diagnostic imaging methods makes it possible to perform intraoperative computed tomography. A special intraoperative cone beam computed tomography scanner "O-arm" has been designed; it combines a function of a C-arm machine and computer tomography scanner. The O-arm system can be used along with navigation system and robotic assistance device. Availability of these devices in an operating room allowed us to study the effectiveness and features of intraoperative CT imaging. OBJECTIVE: To evaluate the intraoperative use a cone beam computed tomography scanner "O-arm" and the navigation system in surgical treatment of spine disorders. MATERIAL AND METHODS: In August-November 2013, 43 patients with degenerative spine disorders, spine and spinal canal tumors underwent surgeries at the N.N. Burdenko Neurosurgical Institute using an intraoperative computed tomography scanner "O-arm" and the navigation system. RESULTS: It is reasonable to use intraoperative CT "O-arm" device with the navigation system when surgical treatment is performed under complex anatomical conditions (a thin root of the vertebral arch, scoliotic or post-traumatic spinal deformity) and the surgery zone cannot be visualized using 2D imaging methods. Intraoperative CT control and navigation system can be employed by neurosurgeons in clinics where the standard stabilizing surgeries and percutaneous methods either are employed rarely or have just started to be used. CONCLUSIONS: The use of an intraoperative CT device "O-arm" with the modern navigation system for surgical treatment of spine and spinal cord disorders allows one to perform surgical interventions under complex anatomical conditions, reduces the absorbed radiation dose, and is safe for patients. PMID- 25146654 TI - [Pericranial sinus. Definition, diagnosis, surgical treatment]. AB - Pericranial sinus (Sinus pericranii - SP) is a rare pathology of the extra intracranial cerebral venous system. However, SP is not just an additional transosseous canal that connects the extra- and intracranial venous systems. This "emissary vein" connects the intracranial sinus and the variceally extended thin walled veins localized on the outer surface of the skull where blood flows fun in opposite directions. We present a literature review and two case reports of patients with pericranial sinus who underwent surgical treatment. We discuss the problems related to etiology, clinical signs, diagnosis, and surgical treatment of the anomaly. PMID- 25146655 TI - [Placement of the Ommaya reservoir in narrow and slit-like ventricles using a neuronavigation system. Author's own experience and literature review]. AB - In modern neuro-oncology and onco-hematology, intraventricular injection of chemotherapeutic agents (most typically, methotrexate) is an inevitable part of many protocols for treating patients with malignant tumors of the CNS, neuroleukemia, CNS lymphomas and some other disorders. A ventricular catheter system (also known as the Ommaya reservoir) is used to provide repeated injection of chemotherapeutic agents to cerebral ventricles. The use of modern neuronavigation systems allows one to place Ommaya reservoir in patients with narrow and slit-like ventricles. Material and methods. During the period between March 2012 and October 2013, 27 patients underwent stereotactic placement of the Ommaya reservoir using a Cart II optical neuronavigation system (Stryker) at the Dmitry Rogachev Federal Scientific and Clinical Center of Pediatric Hematology, Oncology and Immunology. The patients for stereotactic placement of a ventricular catheter were selected on a subjective basis (small ventricular size was the criterion for selection). In one patient, the surgery for placement of the Ommaya reservoir was combined with stereotactic biopsy. Results. In all patients, a ventricular catheter was placed in the anterior horn of the lateral ventricle on the first try; no intraoperative complications were observed. Conclusions. Frameless navigation is an illustrative, mobile, and multifunctional method. The same device can be used to perform brain, transsphenoidal, ENT, and spine surgeries, as well as orthopedic interventions. Today, neuronavigation systems are used in neurosurgical operating rooms and make it possible to avoid using stereotactic frames in most cases. PMID- 25146656 TI - [Simultaneous operations in patients with kidney cancer with simultaneous brain tumor lesion]. AB - Three clinical cases of simultaneous operations upon synchronous identification of brain tumor and kidney cancer are described. A metastatic lesion of the brain was detected in two of them, and a combination of a primary CNS tumor (glioblastoma) with kidney cancer was identified in one case. PMID- 25146657 TI - [Case report of spine and spinal cord injury]. AB - We present a case report of spine and spinal cord injury caused by wound to the face by a foreign body followed by its penetration to cervical soft tissues and lateral compression of the spinal canal by the foreign body causing a neurological deficit. A significant regression of neurological disorders was observed after the dislocation of the vertebra had been eliminated. PMID- 25146658 TI - Correlation of hippocampal volume and cognitive performances in patients with either mild cognitive impairment or Alzheimer's disease. AB - OBJECTIVE: To evaluate hippocampal volume changes and neuropsychological performances in patients with either amnestic mild cognitive impairment (aMCI) or Alzheimer's disease (AD). METHODS: Thirty-eight AD dementia, 22 aMCI patients, and 20 healthy controls were enrolled. Bilateral hippocampal volume was measured concurrently with mini-mental state examination (MMSE), auditory verbal learning test (AVLT), Boston naming test (BNT), and activities of daily living (ADL) test. Baseline and two additional follow-up examinations were conducted. RESULTS: Baseline hippocampal volumes were significantly smaller in AD group than that in aMCI and control groups. MMSE, AVLT, ADL, and BNT scores for the AD group were significantly different from that of both aMCI and control groups. Baseline hippocampal volumes were positively correlated with MMSE and AVLT scores in AD and aMCI patients. At follow-up, left hippocampal volume loss was positively correlated with decreased MMSE and AVLT scores both in AD and aMCI groups, while right hippocampal volume loss was positively associated with decreased AVLT performance only in AD group. Increased ADL and decreased BNT scores were positively associated with left hippocampal volume reduction only in the AD group. CONCLUSIONS: Current findings provide evidence of a close relationship between hippocampal volume and cognitive performances in patients with AD and aMCI, both at baseline and over follow-up. PMID- 25146659 TI - Use of tissue Doppler and its comparison with other pulse Doppler echocardiography in the evaluation of diastolic functions in patients with active juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) is a systemic chronic inflammatory disease. Cardiac involvement as pericarditis, myocarditis and valvular disease is common in JIA. This study aims to assess left ventricular (LV) diastolic functions with tissue Doppler imaging (TDI) and to compare it with conventional Doppler echocardiography (pulse wave Doppler (PWD)) techniques in patients with active JIA. Forty-five patients with active JIA and 47 healthy age- and sex-matched controls were included in this study. Duration of disease ranged from 6 to 138 months (mean 49.59 +/- 31.25 months). In addition to PWD echocardiographic methods, TDI was performed to assess LV functions in all participants. On PWD echocardiography analysis, the JIA group had lower peak E velocity (p < 0.001), higher peak A velocity (p < 0.001) and more prolonged isovolumic relaxation time (IVRT) (p = 0.02). E/A ratio was found to be lower in patients with JIA than that in the control group (p < 0.001). Patients with JIA had a much higher E velocity trace integral (VTI) and A VTI when compared to controls (respectively p = 0.03, p = 0.04). Mitral annular early diastolic velocity (Em), among TDI parameters, was found to be lower in patients with JIA than that in the control group (p < 0.001). Em/Am (mitral annular late diastolic velocity) ratio was found to be lower in JIA patients compared with that in the control group (p < 0.001). There was an increase in IVRT in JIA patients compared to control group (p = 0.04). Though Em VTI was similar in the two groups, patients with JIA had a much higher Am VTI when compared to controls (respectively p = 0.48, p < 0.001). E/Em ratio was higher in patients with JIA than in the control group (p < 0.05). LV diastolic functions were impaired in patients with active JIA, in the absence of clinical evidence of cardiac disease. We have concluded that TDI solo, or jointly with PWD echocardiography, is valuable for the evaluation of diastolic functions in active JIA patients. PMID- 25146660 TI - Feline clinical trials: considerations for improving recruitment. PMID- 25146661 TI - Measurement of glomerular filtration rate in cats: methods and advantages over routine markers of renal function. AB - PRACTICAL RELEVANCE: Routinely used markers of renal function in clinical practice include urea and creatinine. However, these are insensitive markers, particularly in the early stages of kidney disease. Measurement of glomerular filtration rate (GFR) is regarded as the most sensitive index of functioning renal mass. It may be useful for feline patients in varying clinical scenarios; for example, where a more accurate measurement of renal function may aid diagnosis, to enable response to therapeutic interventions to be more closely monitored, or to evaluate renal function prior to the use of nephrotoxic or renally cleared drugs. CLINICAL CHALLENGES: Traditional methods of measuring GFR, such as renal clearance or multisample plasma clearance techniques, are generally impractical for clinical use. Limited sampling and single sample plasma clearance methods using the filtration marker iohexol have been validated in cats. These have the advantages of reduced stress to cats associated with repeated sampling and reduced costs of analysis, and therefore offer greater clinical utility. Attempts to develop an estimated GFR (eGFR) formula similar to that used in human patients have been made in cats, although currently an accurate and reliable formula is not available. AUDIENCE: This review presents the basis for the theoretical understanding and practical measurement of GFR for any veterinary practitioner wishing to obtain a more accurate and sensitive assessment of renal function than routinely used markers provide. EVIDENCE BASE: The review draws evidence from peer-reviewed publications, the author's PhD thesis and also clinical experience. PMID- 25146662 TI - Pharmacological appetite stimulation: rational choices in the inappetent cat. AB - PRACTICAL RELEVANCE: Inappetence is a commonly encountered problem in feline medicine. Primary goals in managing the inappetent or anorectic cat are to diagnose and treat the underlying disease and reinstate adequate nutrition. RATIONALE: As cats are intolerant of prolonged periods of inadequate nutritional intake, especially given their propensity to develop hepatic lipidosis, their increased requirements for amino acids, and inability to slow their rate of gluconeogenesis, symptomatic therapy and nutritional support is often required during diagnostic investigations. CLINICAL CHALLENGES: Most cats presenting with reduced food intake will be suffering from an underlying systemic disease, and so the mechanism of action, pharmacokinetics and contraindications of appetite stimulating medications will need to be considered in each case to ensure rational use of these agents. Pharmacological appetite stimulation should never replace monitoring and ensuring adequate caloric intake, and may not be appropriate in some cases, such as critically ill or severely malnourished patients. EVIDENCE BASE: While there are no medications approved specifically for the treatment of anorexia in cats, some drugs have proven efficacious in the clinical field. Although several agents have been used historically for appetite stimulation, due to potential side effects and/or lack of efficacy or predictability only cyproheptadine and mirtazapine can currently be recommended for use. PMID- 25146665 TI - Feline house-soiling: useful information for cat owners. PMID- 25146663 TI - Feline cutaneous lymphocytosis: case report and summary of the literature. AB - PRACTICAL RELEVANCE: Feline cutaneous lymphocytosis is a rare disease characterized by proliferation of T and/or B lymphocytes in the dermis. Although some of the clinical and histopathologic findings of this condition can overlap with cutaneous lymphoma, it is important to distinguish these entities since their treatment and clinical outcomes vary greatly. SCOPE: This report presents a summary of the literature on feline cutaneous lymphocytosis and describes a case of this condition which showed some unique clinical features and was successfully controlled with oral glucocorticoids. PMID- 25146667 TI - Protective effects of phillyrin on H2O 2-induced oxidative stress and apoptosis in PC12 cells. AB - Oxidative stress is a major component of harmful cascades activated in neurodegenerative disorders. We sought to elucidate possible effects of phillyrin, an active constituent isolated from the Chinese medicinal herb Forsythia suspense, on hydrogen peroxide (H2O2)-induced cell death and determine the underlying molecular mechanisms in neuron-like PC12 cells. By MTT assay and lactate dehydrogenase (LDH) leakage assay, we found that phillyrin treatment effectively protected PC12 cells against H2O2-induced cell damage. H2O2 exposure induced oxidative stress in PC12 cells, as revealed by enhanced oxidative stress and decreased activities of antioxidative enzymes, which were inhibited by phillyrin pretreatment. ROS activated mitochondria-dependent apoptosis. The anti apoptotic effects of phillyrin were also confirmed by acridine orange/ethidium bromide (AO/EB) staining. Mitochondrial membrane potential decrease, cytochrome c release, caspases activation, activation of AIF and Endo G were observed in H2O2 treated cells by rhodamine 123 or western blot. Interestingly, phillyrin effectively suppressed these changes. Moreover, phillyrin could inhibit H2O2 induced up-regulation of Bax/Bcl-2 ratio. In conclusion, phillyrin effectively inhibited H2O2-induced oxidative stress and apoptosis in PC12 cells. PMID- 25146668 TI - The relationship between genetic variants of XRCC1 gene and lung cancer susceptibility in Chinese Han population. AB - Previous evidence indicate that genetic variants of X-ray repair cross complementing group 1 gene (XRCC1) are potentially associated with the development of lung cancer. This study aimed to detect the relationship between the XRCC1 genetic variants and lung cancer susceptibility. A total of 420 lung cancer patients and 425 cancer-free healthy controls were recruited in this case control study. The genotypes of XRCC1 genetic variants were investigated by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The relationship between the XRCC1 genetic variants and lung cancer susceptibility was determined by the association analyses. We found that the distributions of allelic and genotypic in lung cancer patients were significantly different from those of cancer-free healthy controls. Our data indicated that the XRCC1 c.1161G>A and c.1779C>G genetic variants were significantly associated with the increased susceptibility to lung cancer [for c.1161G>A, AA versus (vs.) GG: odds ratio (OR) 2.59, 95 % confidence interval (95 % CI) 1.59-4.21, chi (2) = 15.17, P < 0.001; A vs. G: OR 1.39, 95 % CI 1.13-1.70, P = 0.002; for c.1779C>G, GG vs. CC: OR 2.51, 95 % CI 1.42-4.44, chi (2) = 10.60, P = 0.001; G vs. C: OR 1.24, 95 % CI 1.00-1.54, chi (2) = 3.98, P = 0.046]. The allele A and genotype AA of c.1161G>A and allele G and genotype GG of c.1779C>G genetic variants may enhance lung cancer susceptibility. Taken together, these findings show that the functional c.1161G>A and c.1779C>G genetic variants of XRCC1 are associated with lung cancer susceptibility in the Chinese Han populations and might be used as molecular markers for evaluating the risk of lung cancer. PMID- 25146669 TI - A sub-pathway based method to identify candidate drugs for glioblastomas. AB - Glioblastomas (GBM) are the most common primary malignant brain tumors with a high invasiveness and resistance to radiation and other treatments. The need for the development of new therapeutic agents for GBM is urgent. Here, we aimed to explore the metabolic mechanism of GBM and identified potential novel drugs for GBM by a sub-pathway-based method. By using the GBM microarray data from "The Cancer Genome Atlas" database, we first identified the 274 differentially expressed genes between GBM and normal samples. Then, we identified 18 significant enriched metabolic sub-pathways that may involve in the development of GBM. Finally, by an integrated analysis of GBM-involved sub-pathways and drug affected sub-pathways, we identified 66 novel small-molecular drugs capable to target the GBM-involved sub-pathways. Our method could not only identify existing drug (paclitaxel) for GBM, but also predict potentially novel agents (pergolide) that might have therapeutic effects. We also experimentally verified that pergolide could induce GBM cell death. These candidate small-molecular drugs identified by our approach may provide insights into a novel therapy approach for GBM. PMID- 25146670 TI - Assessment of health-related quality of life in Japanese patients with metastatic renal cell carcinoma during treatment with tyrosine kinase inhibitors. AB - The objective of this study was to comprehensively analyze the health-related quality of life (HRQOL) in Japanese patients with metastatic renal cell carcinoma (mRCC) during treatment with tyrosine kinase inhibitors (TKIs). This study included 240 Japanese mRCC patients treated with TKIs. We conducted a total of 305 surveys assessing the HRQOL before and 3 months after the introduction of TKIs, including 150, 95 and 60 during treatment with sorafenib, sunitinib and axitinib, respectively, using the Medical Outcomes Study 36-Item Short Form, consisting of eight multi-item scales measuring the health status. There were no significant differences in any of the eight scale scores between these 305 surveys conducted before and 3 months after TKI treatment. Two scores in the surveys during axitinib treatment were significantly superior to those during sorafenib treatment; however, no significant differences were noted in any of the remaining scale scores among the surveys during treatment with the three TKIs. Multivariate analyses, which were performed to evaluate the contribution of several factors to each scale score, revealed that the therapeutic efficacy had independent impacts on two scale scores, despite the lack of an independent association between any scores and the remaining factors, including the age, gender, introduced TKI, timing of TKI introduction and degree of adverse events. Collectively, these findings suggest that treatment with TKIs did not result in a significant impairment of the HRQOL in Japanese patients with mRCC; however, patients with unfavorable disease control appeared to fail to achieve a satisfactory HRQOL during treatment with TKIs. PMID- 25146671 TI - Increased micro-RNA 17, 21, and 192 gene expressions improve early diagnosis in non-small cell lung cancer. AB - Lung cancer is the most commonly diagnosed type of cancer worldwide. About 90 % lung cancer patients died within 5 years after diagnosis. It is reasonable to assume that early detection of lung cancer could reduce mortality. MicroRNAs (miRNAs) are a class of small noncoding, single-stranded RNAs that regulate gene expression by affecting the stability or the translation efficiency of target messenger RNAs. Altered expressions of miRNAs were associated with the development, invasion, metastasis and prognosis of cancer. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Here, we describe a blood test based on detection of serum miRNAs that distinguish early NSCLC patients from healthy volunteers. Three miRNAs, miR-17, 21 and 192 expression levels were significantly higher in the stage I NSCLC patients than the healthy volunteer groups. This suggests that miR-17, 21 and 192 could be considered as biomarkers for diagnosis of early-stage NSCLC. PMID- 25146672 TI - Tuneable complementary metamaterial structures based on graphene for single and multiple transparency windows. AB - Novel graphene-based tunable plasmonic metamaterials featuring single and multiple transparency windows are numerically studied in this paper. The designed structures consist of a graphene layer perforated with quadrupole slot structures and dolmen-like slot structures printed on a substrate. Specifically, the graphene-based quadrupole slot structure can realize a single transparency window, which is achieved without breaking the structure symmetry. Further investigations have shown that the single transparency window in the proposed quadrupole slot structure is more likely originated from the quantum effect of Autler-Townes splitting. Then, by introducing a dipole slot to the quadrupole slot structure to form the dolmen-like slot structure, an additional transmission dip could occur in the transmission spectrum, thus, a multiple-transparency window system can be achieved (for the first time for graphene-based devices). More importantly, the transparency windows for both the quadrupole slot and the dolmen-like slot structures can be dynamically controlled over a broad frequency range by varying the Fermi energy levels of the graphene layer (through electrostatic gating). The proposed slot metamaterial structures with tunable single and multiple transparency windows could find potential applications in many areas such as multiple-wavelength slow-light devices, active plasmonic switching, and optical sensing. PMID- 25146673 TI - Evaluation of low-dose limits in 3D-2D rigid registration for surgical guidance. AB - An algorithm for intensity-based 3D-2D registration of CT and C-arm fluoroscopy is evaluated for use in surgical guidance, specifically considering the low-dose limits of the fluoroscopic x-ray projections. The registration method is based on a framework using the covariance matrix adaptation evolution strategy (CMA-ES) to identify the 3D patient pose that maximizes the gradient information similarity metric. Registration performance was evaluated in an anthropomorphic head phantom emulating intracranial neurosurgery, using target registration error (TRE) to characterize accuracy and robustness in terms of 95% confidence upper bound in comparison to that of an infrared surgical tracking system. Three clinical scenarios were considered: (1) single-view image+guidance, wherein a single x-ray projection is used for visualization and 3D-2D guidance; (2) dual-view image+guidance, wherein one projection is acquired for visualization, combined with a second (lower-dose) projection acquired at a different C-arm angle for 3D 2D guidance; and (3) dual-view guidance, wherein both projections are acquired at low dose for the purpose of 3D-2D guidance alone (not visualization). In each case, registration accuracy was evaluated as a function of the entrance surface dose associated with the projection view(s). Results indicate that images acquired at a dose as low as 4 MUGy (approximately one-tenth the dose of a typical fluoroscopic frame) were sufficient to provide TRE comparable or superior to that of conventional surgical tracking, allowing 3D-2D guidance at a level of dose that is at most 10% greater than conventional fluoroscopy (scenario #2) and potentially reducing the dose to approximately 20% of the level in a conventional fluoroscopically guided procedure (scenario #3). PMID- 25146674 TI - Masticatory function induced changes, at subnanostructural level, in proteins and mineral at the resin-dentine interface. AB - OBJECTIVE: This study evaluated the ability of different in vitro mechanical loading tests to promote new mineral formation at the bonded dentine interfaces created with a two-step self-etching resin adhesive. METHODOLOGY: Restored teeth were divided in the following groups: (1) unloaded, load cycling with (2) sine waveform, (3) square waveform, and hold waveform for (4) 24h, and (5) 72 h. Raman spectroscopy and cluster analysis were used to assess the resin-dentine interface. RESULTS: Mechanical loading in CSEB-treated samples promoted a generalized increase of relative presence of minerals and ratio of phosphate peaks, except in square waveform, where the nature of collagen resulted damaged. Crystallinity of carbonate was higher than phosphate. The organic component showed, in general terms, an increase in crosslinking. Molecular orientation (alpha-helices) peaks augmented in all tests. Pentosidine vibration increases in all tests, except in hold 72 h. Ratios amide I and II/CH2 incremented, in general. Non uniform parameters of Bis-GMA and adhesive penetration were encountered, as both increased at the bottom of the hybrid layer when loading square and hold 72 h were applied. SIGNIFICANCE: Functional remineralisation at the resin-dentine interface was attained after in vitro mechanical stimuli application. When loading in square waveform, the lowest vibrations to favor remineralisation were attained. PMID- 25146675 TI - Micromechanical characterization of prismless enamel in the tuatara, Sphenodon punctatus. AB - Dental enamel - a naturally occurring biocomposite of mineral and protein - has evolved from a simple prismless to an advanced prismatic structure over millions of years. Exploring the mechanical function of its structural features with differing characteristics is of great importance for evolutionary developmental studies as well as for material scientists seeking to model the mechanical performance of biological materials. In this study, mechanical properties of prismless tuatara Sphenodon punctatus enamel were characterized. Using micro cantilever bending samples the fracture strength and elastic modulus were found to be 640 +/- 87 MPa and 42 +/- 6 GPa, respectively in the orientation parallel to the crystallite long axis, which decreased in the orthogonal direction. The intrinsic fracture toughness of tuatara enamel ranged from 0.21 MPa m(1/2) and 0.32 MPa m(1/2). These values correspond to the lower limit of the range of values observed in prismatic enamel at the hierarchical level 1. PMID- 25146676 TI - Effects of proliferation and differentiation of mesenchymal stem cells on compressive mechanical behavior of collagen/beta-TCP composite scaffold. AB - The primary aim of this study is to characterize the effects of cell culture on the compressive mechanical behavior of the collagen/beta-tricalcium phosphate (TCP) composite scaffold. The composite and pure collagen scaffolds were fabricated by the solid-liquid phase separation technique and the subsequent freeze-drying method. Rat bone marrow mesenchymal stem cells (rMSCs) were then cultured in these scaffolds up to 28 days. Compression test of the scaffolds with rMSCs were conducted periodically. Biological properties such as cell number, alkaline phosphatase (ALP) activity, and gene expressions of osteogenetic bone markers were evaluated during cell culture. The microstructural changes in the scaffolds during cell culture were also examined using a scanning electron microscope. The compressive elastic modulus was then correlated with those of the biological properties and microstructures to understand the mechanism of variational behavior of the macroscopic elastic property. The composite scaffold exhibited higher ALP activity and more active generation of osteoblastic markers than the collagen scaffold, indicating that beta-TCP can activate the differentiation of rMSCs into osteoblasts and extracellular matrix (ECM) formation such as type I collagen and the following mineralization. The variational behavior of the compressive modulus of the composite scaffold was affected by both the material degradation and the proliferation of cells and the ECM formation. In the first stage, the modulus of the composite scaffold tended to increase due to cell proliferation and the following formation of network structure. In the second stage, the modulus tended to decrease because the material degradation such as ductile deformation of collagen and decomposition of beta-TCP were more effective on the property than the ECM formation. In the third stage, active calcification by formation and growth of mineralized nodules resulted in the recovery of modulus. It is concluded that the introduction of beta-TCP powder into the porous collagen matrix is very effective to improve the mechanical and biological properties of collagen scaffold prepared for bone tissue engineering. Furthermore, the compressive modulus of the composite scaffold is strongly affected by the material degradation and the ECM formation by stem cells under in vitro culture condition. PMID- 25146677 TI - Fracture and fatigue in osteocytes. AB - Fatigue is a common mode of mechanical failure which occurs when a material is subjected to repeated cycles at a strain level less than that needed for monotonic fracture. Fatigue has been observed and measured in many different materials but, until recently, not in cells. We devised a novel experiment which allowed us to create both monotonic failure and fatigue in the cellular processes of osteocytes within samples of bone (Dooley et al., European Cells and Materials 2014). In the present paper, we describe the results of further experiments and a computer simulation, which has allowed us to estimate the strain history of each sample tested and thus present, for the first time, strain/life data for cells. Failure occurred during the first cycle at strains of 0.1-0.2; at lower strains failure occurred after a number of cycles which depended inversely on the applied strain range. Scatter in the strain/life data was reduced when we allowed for the effects of mean stress using the Smith-Watson-Topper parameter. We confirmed that aspects of our experimental method (the types of microcrack used and the testing of fresh versus frozen samples) did not affect the results. Such information is useful because many cell types, including the cellular processes of osteocytes, experience cyclic strain in vivo. PMID- 25146678 TI - Mechanical properties and corrosion behavior of Mg-HAP composites. AB - Mg and Mg-HAP composites containing 5, 10 and 15 wt% of hydroxyapatite have been produced following a powder metallurgy route that consists of mixing raw powders and consolidation by extrusion. The microstructure, texture, mechanical behavior and resistance to corrosion under a PBS solution have been studied. Addition of HAP increases the microhardness of the composites, however the yield strength under compression slightly decreases. Texture analyses reveal a fiber texture for pure Mg that is weakened increasing the HAP fraction. This texture promotes twinning and softening of Mg and Mg-5HAP during the initial deformation stages. Mg-10HAP and Mg-15HAP present a strain-hardening dependence showing no softening. The volume fraction of HAP particles weakens the texture and favors the activation of secondary slip systems. Corrosion experiments in PBS solution have shown that Mg-5HAP exhibits the best resistance to corrosion. Texture and porosity appear to be the main material features controlling the corrosion rates of Mg-HAP composites under the present conditions. PMID- 25146679 TI - [Incidental bronchoscopic findings]. AB - Inflexible and flexible bronchoscopy represents a standard diagnostic procedure in pneumology. Besides lung carcinomas, which is the most frequent indication for diagnostic bronchoscopy, a plethora of clinical symptoms such as chronic persistent cough, hoarseness, unexplained dyspnea, hemoptysis, and suspicious findings on auscultation require further endoscopic evaluation. Moreover, bronchoscopy plays a central role in the diagnostic work-up of interstitial lung diseases and persistent lung infiltrates, in particular those of infectious origin (e.g., fungal, viral, tuberculous, and Pneumocystis jiroveci infections). In addition, diagnostic bronchoscopy has more recently been complemented by endobronchial ultrasound (EBUS). EBUS is predominantly employed for the accurate diagnosis and mediastinal staging of lung carcinomas, and the assessment of lympadenopathy-associated diseases such as sarcoidosis.Since endoscopic evaluation is typically preceded by computed tomography (CT) of the chest, genuine incidental findings occur relatively seldom and usually account for pathological findings that have been missed on conventional imaging approaches. For instance, characteristic incidental findings include benign and malignant tumors in the area of the endoscopic access and central airways, anatomical variations and (vascular) malformations, tracheal and bronchial airway alterations, and aspirated objects. This review focuses on bronchoscopic findings that have either been completely missed by conventional imaging or differently interpreted due to its radiologic morphology. PMID- 25146680 TI - Increased sensitivity of 31P MRSI using direct detection integrated with multi echo polarization transfer (DIMEPT). AB - Here, we show that the sensitivity of (31)P MRSI of (31)P spins J-coupled to protons can be increased by almost a factor of three when compared with an optimal direct detection free induction decay. By direct detection integrated with multi-echo polarization transfer (DIMEPT), multiple signals from polarization transfer and direct detection can be acquired in one repetition time, with minimal mutual interference, provided that the number of refocusing pulses in the multi-echo polarization transfer part is even. The DIMEPT sequence was implemented on a 7-T body scanner and tested on a phantom and on the breasts of five healthy volunteers. The in vivo signal-to-noise ratio (SNR) enhancement for the J-coupled phosphomonoesters was 270% when compared with an Ernst angle pulse-acquire sequence. However, the phosphodiester signals, presumably mainly mobile phospholipids, had T2 values that were too short to be enhanced. Uncoupled (31)P spins, with sufficiently long T2 values, such as inorganic phosphate, were SNR enhanced by a factor of 1.9 relative to an Ernst-angle excitation pulse acquire sequence by multi-echo direct detection. PMID- 25146681 TI - A triterpenoid saponin from Adenophora triphylla var. japonica suppresses the growth of human gastric cancer cells via regulation of apoptosis and autophagy. AB - In the present study, we investigated the effects of 3-O-beta-D-galactopyranosyl (1 -> 2)-[beta-D-xylopyranosyl-(1 -> 3)]-beta-D-glucuronopyranosyl-28-O-[alpha-L arabinopyranosyl-(1 -> 4)-alpha-L-arabinopyranosyl-(1 -> 3)-beta-D-xylopyranosyl (1 -> 4)-alpha-L-rhamnopyranosyl-(1 -> 2)-beta-D-fucopyranosyl] quillaic acid, named compound 1, on the induction of apoptosis and autophagy in human gastric cancer AGS cells. Compound 1, a triterpenoid saponin isolated from the root of Adenophora triphylla var. japonica, effectively inhibited the growth of AGS cells by inducing apoptosis, as well as autophagy. Apoptosis by compound 1 treatment was associated with activation of caspases, release of cytochrome c, and increased ratio of Bax/Bcl-2. Autophagy by compound 1 treatment was indicated by LC3-II protein expression. We also found an increase in phosphorylation of p38 and JNK and a decrease in phosphorylation of ERK and Akt after compound 1 treatment. Furthermore, pretreatment with p38 inhibitor SB202190 completely inhibited compound 1-induced activation of caspases and cleavage of PARP1, whereas pretreatment with SB202190 synergistically increased the protein expression of LC3-II. These results suggest that compound 1 distinctly induces apoptotic and autophagic cell death and the increased autophagy by SB202190 protects compound 1-induced AGS cell death. Our findings provide an important clue for exploring the potential anticancer role of compound 1. PMID- 25146682 TI - Contribution of cyclin D1 (CCND1) and E-cadherin (CDH1) alterations to colorectal cancer susceptibility: a case-control study. AB - Cyclin D1 (CCND1) and E-cadherin (CDH1) are two important genes of the beta catenin/LEF pathway that is involved in tumorigenesis of various cancers including colorectal cancer (CRC). However, studies of the association between genetic variants of these two genes and CRC have shown conflicting results. We conducted a genetic association study in South Indian population (cases, 103; controls, 107) to assess the association of CCND1 870G/A and CDH1 -160C/A single nucleotide polymorphisms (SNPs) with CRC risk. Genotyping of SNPs was performed by PCR sequencing analysis. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D') for pair-wise linkage disequilibrium (LD) were assessed by Haploview Software. In addition, to better understand the role of CCND1 and CDH1 in the pathophysiology of CRC, the expression pattern was evaluated in analogous tumor and adjacent normal tissues from 23 CRC patients by Western blot analysis. The frequencies of CCND1 870A/A (P = 0.045) genotype, CDH1 -160A allele (P = 0.042), and 870A/-160A haplotype (P = 0.002) were significantly higher in patients as compared with controls. Strong LD was observed between 870G/A and -160C/A SNPs in cases (D' = 0.76) as compared to controls (D' = 0.32). Furthermore, elevated CCND1 and diminished CDH1 expression was observed in tumor tissue as compared with analogous normal tissue of CRC patients. Interestingly, advanced-stage tumors showed wider expression alterations than in early-stage tumors. In conclusion, CCND1 870G/A and CDH1 -160C/A SNPs may modify the risk of CRC susceptibility in South Indian population. In addition, elevated CCND1 and diminished CDH1 expression appears to be useful prognostic markers for CRC. PMID- 25146683 TI - IL-27 -964A>G polymorphism and the risk of breast cancer: a case-control study. AB - Interleukin-27 (IL-27) is a new member of the IL-12 family which plays a key role in antitumor immunity. The aim of the present study was to investigate the association between a potentially functional polymorphism (rs153109, -964A>G) at the promoter of IL-27 and the risk of breast cancer in a Chinese population. We determined the genotypes of 326 breast cancer cases and 460 healthy controls by using polymerase chain reaction-restriction fragment length polymorphism analysis. Logistic regression was used to analyze the association between -964A>G polymorphism and breast cancer susceptibility. There was no significant association between IL-27 -964A>G polymorphism and the risk of breast cancer. However, in the stratified analysis by menopausal history, IL-27 -964A>G polymorphism was associated with a decreased risk of breast cancer in premenopausal women (GG vs. AA: OR = 0.48, 95 % CI = 0.26-0.89; G vs. A: OR = 0.75, 95 % CI = 0.59-0.97). Taken together, our study suggested that IL-27 964A>G polymorphism may be a protective factor for breast cancer in premenopausal women. PMID- 25146684 TI - Synthesis and structure-activity relationship studies of 2-(1,3,4-oxadiazole 2(3H)-thione)-3-amino-5-arylthieno[2,3-b]pyridines as inhibitors of DRAK2. AB - In recent years, DAPK-related apoptosis-inducing protein kinase 2 (DRAK2) has emerged as a promising target for the treatment of a variety of autoimmune diseases and for the prevention of graft rejection after organ transplantation. However, medicinal chemistry optimization campaigns for the discovery of novel small-molecule inhibitors of DRAK2 have not yet been published. Screening of a proprietary compound library led to the discovery of a benzothiophene analogue that displays an affinity constant (Kd) value of 0.25 MUM. Variation of the core scaffold and of the substitution pattern afforded a series of 5-arylthieno[2,3 b]pyridines with strong binding affinity (Kd = 0.008 MUM for the most potent representative). These compounds also show promising activity in a functional biochemical DRAK2 enzyme assay, with an IC50 value of 0.029 MUM for the most potent congener. Selectivity profiling of the most potent compounds revealed that they lack selectivity within the DAPK family of kinases. However, one of the less potent analogues is a selective ligand for DRAK2 and can be used as starting point for the synthesis of selective and potent DRAK2 inhibitors. PMID- 25146685 TI - Large size three-dimensional video by electronic holography using multiple spatial light modulators. AB - In this paper, we propose a new method of using multiple spatial light modulators (SLMs) to increase the size of three-dimensional (3D) images that are displayed using electronic holography. The scalability of images produced by the previous method had an upper limit that was derived from the path length of the image readout part. We were able to produce larger colour electronic holographic images with a newly devised space-saving image-readout optical system for multiple reflection-type SLMs. This optical system is designed so that the path length of the image-readout part is half that of the previous method. It consists of polarization beam splitters (PBSs), half-wave plates (HWPs), and polarizers. We used 16 (4 * 4) 4K*2K-pixel SLMs for displaying holograms. The experimental device we constructed was able to perform 20 fps video reproduction in colour of full-parallax holographic 3D images with a diagonal image size of 85 mm and a horizontal viewing-zone angle of 5.6 degrees. PMID- 25146686 TI - Asymmetric alkynylation/lactamization cascade: an expeditious entry to enantiomerically enriched isoindolinones. AB - An unprecedented Cu(I)-pybox-diPh-catalyzed highly enantioselective (up to >99% ee) alkynylation/lactamization cascade has been developed as a general catalytic system for the synthesis of diversely substituted isoindolinones of immense biological importance. The cascade effects one C-C and two C-N bond-forming events in one reaction vessel under operationally simple, additive-free reaction conditions in good to excellent yields. The methodology was further extended to the synthesis of tetrahydroisoquinoline scaffolds common to several biologically active natural products in a two-step sequence with remarkable selectivity (up to 94% ee). PMID- 25146687 TI - The need to improve current psychopharmacotherapy before developing new drugs. AB - CNS research has become unprofitable, and several pharmaceutical companies have reduced financial support for developing new CNS drugs. Until the situation can be changed, it is our duty to optimize the usage of the currently available psychoactive drugs. Several tools for optimizing pharmacotherapy are available, such as therapeutic drug monitoring and genotyping and phenotyping CYP enzymes. Further medical treatment and healthcare provision for patients with severe mental disorders should be improved. Knowledge of psychopharmacotherapy influences the choices of medication and outcomes; therefore, future psychiatrists should have a greater knowledge of pharmacodynamics, pharmacokinetics and pharmacogenetics. PMID- 25146688 TI - Cell cycle-dependent O-GlcNAc modification of tobacco histones and their interaction with the tobacco lectin. AB - The Nicotiana tabacum agglutinin or Nictaba is a nucleocytoplasmic lectin that is expressed in tobacco after the plants have been exposed to jasmonate treatment or insect herbivory. Nictaba specifically recognizes GlcNAc residues. Recently, it was shown that Nictaba is interacting in vitro with the core histone proteins from calf thymus. Assuming that plant histones - similar to their animal counterparts - undergo O-GlcNAcylation, this interaction presumably occurs through binding of the lectin to the O-GlcNAc modification present on the histones. Hereupon, the question was raised whether this modification also occurs in plants and if it is cell cycle dependent. To this end, histones were purified from tobacco BY-2 suspension cells and the presence of O-GlcNAc modifications was checked. Concomitantly, O-GlcNAcylation of histone proteins was studied. Our data show that similar to animal histones plant histones are modified by O-GlcNAc in a cell cycle-dependent fashion. In addition, the interaction between Nictaba and tobacco histones was confirmed using lectin chromatography and far Western blot analysis. Collectively these findings suggest that Nictaba can act as a modulator of gene transcription through its interaction with core histones. PMID- 25146689 TI - Effective light absorption and absolute electron transport rates in the coral Pocillopora damicornis. AB - Pulse Amplitude Modulation (PAM) fluorometry has been widely used to estimate the relative photosynthetic efficiency of corals. However, both the optical properties of intact corals as well as past technical constrains to PAM fluorometers have prevented calculations of the electron turnover rate of PSII. We used a new Multi-colour PAM (MC-PAM) in parallel with light microsensors to determine for the first time the wavelength-specific effective absorption cross section of PSII photochemistry, sigmaII(lambda), and thus PAM-based absolute electron transport rates of the coral photosymbiont Symbiodinium both in culture and in hospite in the coral Pocillopora damicornis. In both cases, sigmaII of Symbiodinium was highest in the blue spectral region and showed a progressive decrease towards red wavelengths. Absolute values for sigmaII at 440 nm were up to 1.5-times higher in culture than in hospite. Scalar irradiance within the living coral tissue was reduced by 20% in the blue when compared to the incident downwelling irradiance. Absolute electron transport rates of P. damicornis at 440 nm revealed a maximum PSII turnover rate of ca. 250 electrons PSII(-1) s(-1), consistent with one PSII turnover for every 4 photons absorbed by PSII; this likely reflects the limiting steps in electron transfer between PSII and PSI. Our results show that optical properties of the coral host strongly affect light use efficiency of Symbiodinium. Therefore, relative electron transport rates do not reflect the productivity rates (or indeed how the photosynthesis-light response is parameterised). Here we provide a non-invasive approach to estimate absolute electron transport rates in corals. PMID- 25146691 TI - Microwave spectroscopic investigation and structural determination of the Ar difluoropyridine van der Waals complexes. AB - The ground state rotational spectra of the van der Waals dimers of 2,3-, 2,4-, 2,5-, 2,6-, and 3,5-difluoropyridine with argon were investigated in the range of 4 to 26 GHz using both Fourier transform microwave (FTMW) and chirped pulse Fourier transform microwave (cp-FTMW) spectroscopy. The spectroscopic parameters derived from fitting the observed transitions were used to estimate the van der Waals coordinates of the five weakly bound complexes and to quantitatively describe their internal dynamics using a pseudodiatomic model. The experimental structures are in fair agreement with MP2 calculations (6-311++G(2d, 2p)) and have the centers of mass of the two moieties separated by 3.486 to 3.545 A with the Ar atom lying 2-10 degrees from the c' axis of the ring monomer. PMID- 25146690 TI - Impact of Sod on the expression of stress-related genes in Listeria monocytogenes 4b G with/without paraquat treatment. AB - Listeria monocytogenes is a foodborne pathogen that causes listeriosis. Paraquat can generate reactive oxygen species (ROS) in cells, which results in oxidative stress. It was first shown that 1 mM of paraquat inhibited the growth rate of a superoxide dismutase (sod)-deletion mutant (?sod) generated from L. monocytogenes 4b G but not in the wild-type, and induced the expression of other resistance genes (kat, fri, perR, sigB, and recA) as well as sod in the wild type. Interestingly, without paraquat treatment the expression of all the 5 genes were repressed in ?sod compared to the wild type, while the expression of recA triggering SOS response, a global response to DNA damage, was increased in ?sod in the presence of 1 mM paraquat. Taken together, these results suggest that SOD plays a central role in oxidant defense of L. monocytogenes 4b G, and SOS probably significantly impacts ?sod survival under oxidative stress. PMID- 25146693 TI - Measurement of statin exposure in the absence of information on prescribed doses. PMID- 25146692 TI - Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir. AB - PURPOSE: Dolutegravir (DTG) is an unboosted, integrase inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects. METHODS: The first study was an open-label crossover where 12 subjects received DTG 50 mg every 24 hours (q24h) for 5 days, followed by DTG 50 mg and EFV 600 mg q24h for 14 days. The second study was an open-label crossover where 18 subjects received DTG 50 mg q24h for 5 days followed by TPV/r 500/200 mg every 12 hours (q12h) for 7 days and then DTG 50 mg q24h and TPV/r 500/200 mg q12h for a further 5 days. Safety assessments and serial PK samples were collected. Non compartmental PK analysis and geometric mean ratios and 90% confidence intervals were generated. RESULTS: The combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75% in DTG AUC(0-tau), Cmax and Ctau, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76% in DTG AUC(0-tau), Cmax and Ctau, respectively. CONCLUSIONS: Given the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50 mg twice daily when co administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients. PMID- 25146694 TI - Analysis of rat testicular proteome following 30-day exposure to 900 MHz electromagnetic field radiation. AB - The use of electromagnetic field (EMF) generating apparatuses such as cell phones is increasing, and has caused an interest in the investigations of its effects on human health. We analyzed proteome in preparations from the whole testis in adult male Sprague-Dawley rats that were exposed to 900 MHz EMF radiation for 1, 2, or 4 h/day for 30 consecutive days, simulating a range of possible human cell phone use. Subjects were sacrificed immediately after the end of the experiment and testes fractions were solubilized and separated via high-resolution 2D electrophoresis, and gel patterns were scanned, digitized, and processed. Thirteen proteins, which were found only in sham or in exposure groups, were identified by MALDI-TOF/TOF-MS. Among them, heat shock proteins, superoxide dismutase, peroxiredoxin-1, and other proteins related to misfolding of proteins and/or stress were identified. These results demonstrate significant effects of radio frequency modulated EMFs exposure on proteome, particularly in protein species in the rodent testis, and suggest that a 30-day exposure to EMF radiation induces nonthermal stress in testicular tissue. The functional implication of the identified proteins was discussed. PMID- 25146695 TI - The impact of childhood parental loss on risk for mood, anxiety and substance use disorders in a population-based sample of male twins. AB - Previous studies have identified the relationship between parental loss and psychopathology later in life. However, this relationship varied depending on the kind of loss, the parent involved, and the type of psychopathology. In the present study, we examined the association between parental loss (any loss, death, and separation) during childhood and lifetime risk for seven common psychiatric and substance use disorders in a sample of 2605 male twins from the Virginia population-based twin registry. Using structural equation modeling (SEM), we also examined the extent to which the influence of parental loss contributes to adult psychopathology. Parental separation was associated with a wide range of adult psychopathology, whereas parental death was specifically associated with phobia and alcohol dependence. Maternal and paternal separations were almost equally associated with most forms of psychopathology. SEM suggested that parental loss accounted for about 10% of the variance of adult psychopathology, of which parental separation had the strongest impacts on risk for depression and drug abuse/dependence (11% of the total variance). Our findings suggest that early parental separation has stronger and wider effects on adult psychopathology than parental death. PMID- 25146696 TI - Association of KIBRA rs17070145 polymorphism with episodic memory in the early stages of a human neurodevelopmental disorder. AB - A common T/C polymorphism within the ninth intron of the KIBRA gene (rs17070145) is thought to influence memory in humans. Since cognitive impairment, including memory, is a core feature of schizophrenia, we attempted to investigate this association in an independent sample of adolescent patients with early-onset schizophrenia (EOS; onset before age 18) probands and their healthy siblings. In a sample of 25 pairs of EOS proband-healthy full sibling, we sought to investigate the association of KIBRA with memory performance. Episodic memory was measured using immediate and delayed recall measures of the California Verbal Learning Test. EOS underperformed at immediate and delayed recall compared with siblings. In a combined analysis (TT vs. TC/CC) assuming a C dominant model of inheritance, we found a main effect of genotype where individuals with TT genotype outperformed non-TT-carriers at immediate and delayed recall. A genotype by group interaction showed that EOS with TT genotype did not show a memory advantage over siblings with TT or non-TT-carriers at immediate or delayed recall. Siblings with TT genotype showed enhanced immediate recall (not delayed recall) compared with non-TT-carriers. This study demonstrates an association between the KIBRA gene and episodic memory (immediate free recall) and suggests a differential effect of this genetic variant in EOS and healthy siblings. PMID- 25146697 TI - Advanced Nanomedicines for the Treatment and Diagnosis of Myocardial Infarction and Heart Failure. AB - Nanotechnology has impacted tremendously the medical research with increasing importance in the development of new therapeutic approaches and applications. Among these applications, the use of nanocarriers has gained particular interest in order to achieve successful delivery of therapeutics and imaging agents for the treatment and diagnostics of different diseases, such as cancer, infections, diabetes, lung, brain and cardiovascular diseases. Heart failure (HF) is a complex clinical syndrome derived from multiple causes that arise from secondary to inherited or acquired abnormalities of cardiac structure and/or function. Myocardial infarction (MI), the major cause of HF, continues to be an increasing problem in terms of morbidity, mortality and healthcare costs worldwide. Currently, established pharmacological drugs have proven to be effective in reducing hypertrophy, remodeling of the myocardium, and in reducing morbidity and mortality in patients with HF. However, despite optimal treatment with existing drugs, the prognosis of HF is poor and also the possible deleterious effects of therapeutic agents must be considered when used at doses required for the desired therapeutic effect. Therefore, novel therapeutic strategies are urgently needed to prevent high morbidity and mortality associated with MI and HF. In this review, we will present recent developments in nanomedicine research envisaged to have an important impact on the treatment of cardiovascular diseases, particularly MI. In addition, we will discuss the use of different advanced modified nanosystems for molecular imaging and therapeutics of MI, presenting several in vitroand in vivoexamples. Finally, we will conclude with an overview of the potential of nanomedicines in the future for the treatment of cardiovascular diseases. PMID- 25146698 TI - Management of inflammatory bowel disease patients with a cancer history. AB - In inflammatory bowel disease (IBD) patients, thiopurines promote carcinogenesis of Epstein-Barr Virus (EBV)-related lymphomas, non-melanoma skin cancers and urinary tract cancers, while anti-TNF agents could promote carcinogenesis of melanomas. Patients with IBD and previous cancer are at a higher risk of developing new or recurrent cancer than IBD patients without a history of cancer, irrespective of the use of immunosuppressants. In transplant recipients, the use of thiopurines is associated with a high rate of cancer recurrence, particularly within the first two years following transplantation. In patients with chronic inflammatory disease, limited data suggest that no dramatic incidence of cancer recurrence is associated with the use of thiopurines or anti-TNF agents. However, there is a rationale for a two-year drug holiday from immunosuppressants after the diagnosis and treatment of the majority of incident cancers, as often as possible. Extending the duration of the immunosuppressant drug holiday to 5 years in patients with previous cancers associated with a high risk of recurrence in the post-transplant state should be considered. The immunosuppressants that can be initiated or resumed after cancer treatment should be chosen according to the type of the previous cancer. All individual decisions should be made on a case-by case basis, together with the oncologist, according to characteristics and expected evolution of the index cancer, expected impact of the immunosuppressants on cancer evolution, and intrinsic severity of IBD, with its associated risks. PMID- 25146700 TI - Molecular function of counting the numbers 1 and 2 exhibited by a sulfoneamidohelicene tetramer. AB - The sulfoneamidohelicene tetramer in solution exhibits different molecular responses to the same cooling stimulus delivered once and twice under thermal hysteresis conditions. Its random-coil state at a high temperature was cooled and maintained at a given temperature for which its molecules remained in a random coil (first cooling); the resulting solution was heated and cooled, after which a helix dimer formed (second cooling). Such a property can be regarded as a molecular function of counting the numbers 1 and 2. PMID- 25146699 TI - Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema. AB - Cerebral edema is a potentially life-threatening illness, but knowledge of its underlying mechanisms is limited. Here we report that hypobaric hypoxia induces rat cerebral edema and neuronal apoptosis and increases the expression of corticotrophin releasing factor (CRF), CRF receptor type 1 (CRFR1), aquaporin-4 (AQP4), and endothelin-1 (ET-1) in the cortex. These effects, except for the increased expression of CRF itself, could all be blocked by pretreatment with an antagonist of the CRF receptor CRFR1. We also show that, in cultured primary astrocytes: (i) both CRFR1 and AQP4 are expressed; (ii) exogenous CRF, acting through CRFR1, triggers signaling of cAMP/PKA, intracellular Ca(2+), and PKCepsilon; and (iii) the up-regulated cAMP/PKA signaling contributes to the phosphorylation and expression of AQP4 to enhance water influx into astrocytes and produces an up-regulation of ET-1 expression. Finally, using CHO cells transfected with CRFR1(+) and AQP4(+), we show that transfected CRFR1(+) contributes to edema via transfected AQP4(+). In conclusion, hypoxia triggers cortical release of CRF, which acts on CRFR1 to trigger signaling of cAMP/PKA in cortical astrocytes, leading to activation of AQP4 and cerebral edema. PMID- 25146701 TI - Effects of dorsal periaqueductal gray CRF1- and CRF2-receptor stimulation in animal models of panic. AB - An increasing amount of evidence suggests that dysregulation of corticotrophin releasing factor (CRF) signaling may contribute to the etiology of anxiety disorders such as post-traumatic stress disorder and panic. The dorsal periaqueductal gray matter (dPAG) in the midbrain has been considered a key region involved in the physiopathology of anxiety and panic. Administration of CRF in this structure enhances the expression of anxiety-related defensive behaviors in different animal models. Controversial results have been obtained regarding the involvement of CRF1 and CRF2 receptors in the regulation of panic related responses. We report here that CRF (0.0625-1 MUg) in the dPAG facilitates escape expression in two animal models that associate this behavior with panic, the elevated T-maze and the electrical stimulation of the dPAG. This effect, equally observed after CRF injection in the dorsomedial and dorsolateral columns of the PAG, is due to the activation of CRF1 receptors as revealed by its blockade by the CRF1 receptor antagonist antalarmin. In the elevated T-maze, CRF also facilitates inhibitory avoidance acquisition, suggesting an anxiogenic effect. Local administration of urocortin 2 (0.01-0.1 MUg), a preferential CRF2 receptor agonist, failed to change escape expression, but impaired avoidance learning, indicating an anxiolytic effect. The results indicate that CRF1 receptors in the dPAG play a pervasive role in the regulation of defensive responses associated with both generalized anxiety and panic. Recruitment of CRF2 receptors only impacts upon the former type of behaviors, leading to an effect opposed to that caused by CRF1 receptor activation. PMID- 25146702 TI - Implantable defibrillators for secondary prevention of sudden cardiac death in cardiac surgery patients with perioperative ventricular arrhythmias. AB - BACKGROUND: Randomized studies of implantable cardioverter defibrillators (ICD) have excluded sudden cardiac death survivors who had revascularization before or after an arrhythmic event. To evaluate the role of ICD and the effects of clinical variables including degree of revascularization, we studied cardiac surgery patients who had an ICD implanted for sustained perioperative ventricular arrhythmias. METHODS AND RESULTS: The electronic database for Southern California Kaiser Foundation hospitals was searched for patients who had cardiac surgery between 1999 and 2005 and an ICD implanted within 3 months of surgery. One hundred sixty-four patients were identified; 93/164 had an ICD for sustained pre- or postoperative ventricular tachycardia or fibrillation requiring resuscitation. Records were reviewed for the following: presenting arrhythmia, ejection fraction, and degree of revascularization. The primary end point was total mortality (TM) and/or appropriate ICD therapy (ICD-T), and secondary end points are TM and ICD-T. During the mean follow up of 49 months, the primary endpoint of TM+ICD-T and individual end points of TM and ICD-T were observed in 52 (56%), 35 (38%), and 28 (30%) patients, respectively, with 55% of TM, and 23% of ICD-T occurring within 2 years of implant. In multivariate risk analysis, none of the following was associated with any of the end points: incomplete revascularization, presenting ventricular arrhythmia, and timing of arrhythmias. CONCLUSION: Our data supports the recent guidelines for ICD in this cohort of patients, as the presence of irreversible substrate and triggers of ventricular arrhythmias, cannot be reliably excluded even with complete revascularization. Further studies are needed to understand this complex group of patients. PMID- 25146703 TI - Automated quantification of myocardial salvage in a rat model of ischemia reperfusion injury using 3D high-resolution magnetic resonance imaging (MRI). AB - BACKGROUND: Quantification of myocardial "area at risk" (AAR) and myocardial infarction (MI) zone is critical for assessing novel therapies targeting myocardial ischemia-reperfusion (IR) injury. Current "gold-standard" methods perfuse the heart with Evan's Blue and stain with triphenyl tetrazolium chloride (TTC), requiring manual slicing and analysis. We aimed to develop and validate a high-resolution 3-dimensional (3D) magnetic resonance imaging (MRI) method for quantifying MI and AAR. METHODS AND RESULTS: Forty-eight hours after IR was induced, rats were anesthetized and gadopentetate dimeglumine was administered intravenously. After 10 minutes, the coronary artery was re-ligated and a solution containing iron oxide microparticles and Evan's Blue was infused (for comparison). Hearts were harvested and transversally sectioned for TTC staining. Ex vivo MR images of slices were acquired on a 9.4-T magnet. T2* data allowed visualization of AAR, with microparticle-associated signal loss in perfused regions. T1 data demonstrated gadolinium retention in infarcted zones. Close correlation (r=0.92 to 0.94; P<0.05) of MRI and Evan's Blue/TTC measures for both AAR and MI was observed when the combined techniques were applied to the same heart slice. However, 3D MRI acquisition and analysis of whole heart reduced intra-observer variability compared to assessment of isolated slices, and allowed automated segmentation and analysis, thus reducing interobserver variation. Anatomical resolution of 81 MUm(3) was achieved (versus ~2 mm with manual slicing). CONCLUSIONS: This novel, yet simple, MRI technique allows precise assessment of infarct and AAR zones. It removes the need for tissue slicing and provides opportunity for 3D digital analysis at high anatomical resolution in a streamlined manner accessible for all laboratories already performing IR experiments. PMID- 25146704 TI - Cardioprotection by controlling hyperamylinemia in a "humanized" diabetic rat model. AB - BACKGROUND: Chronic hypersecretion of the pancreatic hormone amylin is common in humans with obesity or prediabetic insulin resistance and induces amylin aggregation and proteotoxicity in the pancreas. We recently showed that hyperamylinemia also affects the cardiovascular system. Here, we investigated whether amylin aggregates interact directly with cardiac myocytes and whether controlling hyperamylinemia protects the heart. METHODS AND RESULTS: By Western blot, we found abundant amylin aggregates in lysates of cardiac myocytes from obese patients, but not in controls. Aggregated amylin was elevated in failing hearts, suggesting a role in myocyte injury. Using rats overexpressing human amylin in the pancreas (HIP rats) and control myocytes incubated with human amylin, we show that amylin aggregation at the sarcolemma induces oxidative stress and Ca(2+) dysregulation. In time, HIP rats developed cardiac hypertrophy and left-ventricular dilation. We then tested whether metabolites with antiaggregation properties, such as eicosanoid acids, limit myocardial amylin deposition. Rats were treated with an inhibitor of soluble epoxide hydrolase, the enzyme that degrades endogenous eicosanoids. Treatment doubled the blood concentration of eicosanoids, which drastically reduced incorporation of aggregated amylin in cardiac myocytes and blood cells, without affecting pancreatic amylin secretion. Animals in the treated group showed reduced cardiac hypertrophy and left-ventricular dilation. The cardioprotective mechanisms included the mitigation of amylin-induced cardiac oxidative stress and Ca(2+) dysregulation. CONCLUSIONS: The results suggest blood amylin as a novel therapeutic target in diabetic heart disease and elevating blood levels of antiaggregation metabolites as a pharmacological strategy to reduce amylin aggregation and amylin-mediated cardiotoxicity. PMID- 25146705 TI - Association between thoracic aortic disease and inguinal hernia. AB - BACKGROUND: The study hypothesis was that thoracic aortic disease (TAD) is associated with a higher-than-expected prevalence of inguinal hernia. Such an association has been reported for abdominal aortic aneurysm (AAA) and hernia. Unlike AAA, TAD is not necessarily detectable with clinical examination or ultrasound, and there are no population-based screening programs for TAD. Therefore, conditions associated with TAD, such as inguinal hernia, are of particular clinical relevance. METHODS AND RESULTS: The prevalence of inguinal hernia in subjects with TAD was determined from nation-wide register data and compared to a non-TAD group (patients with isolated aortic stenosis). Groups were balanced using propensity score matching. Multivariable statistical analysis (logistic regression) was performed to identify variables independently associated with hernia. Hernia prevalence was 110 of 750 (15%) in subjects with TAD versus 29 of 301 (9.6%) in non-TAD, P=0.03. This statistically significant difference remained after propensity score matching: 21 of 159 (13%) in TAD versus 14 of 159 (8.9%) in non-TAD, P<0.001. Variables independently associated with hernia in multivariable analysis were male sex (odds ratio [OR] with 95% confidence interval [95% CI]) 3.4 (2.1 to 5.4), P<0.001; increased age, OR 1.02/year (1.004 to 1.04), P=0.014; and TAD, OR 1.8 (1.1 to 2.8), P=0.015. CONCLUSIONS: The prevalence of inguinal hernia (15%) in TAD is higher than expected in a general population and higher in TAD, compared to non-TAD. TAD is independently associated with hernia in multivariable analysis. Presence or history of hernia may be of importance in detecting TAD, and the association warrants further study. PMID- 25146706 TI - Reliability of noninvasive assessment of systolic pulmonary artery pressure by Doppler echocardiography compared to right heart catheterization: analysis in a large patient population. AB - BACKGROUND: Pulmonary artery pressure (PAP) is an important marker in cardiovascular disorders, being closely associated with morbidity and mortality. Noninvasive assessment by Doppler echocardiography is recommended by current guidelines. So far, the reliability of this method has been assessed only in small studies with contradictory results. Therefore, the aim of this study was to analyze the reliability of noninvasive PAP assessment by Doppler echocardiography compared to invasive measurements in a large patient population. METHODS AND RESULTS: We retrospectively analyzed data from a large tertiary cardiology department over 6 years in order to compare invasively measured PAP to estimated PAP from echocardiography examinations. N=15 516 patients fulfilled inclusion criteria and n=1695 patients with timely matched examinations (within 5 days) were analyzed. In n=1221 (72%) patients, pulmonary hypertension (PH) was diagnosed invasively (postcapillary PH: n=1122 [66%]; precapillary PH: n=99 [6%]). Systolic pulmonary artery pressure (sPAP) was 45.3+/-15.5 mm Hg by Doppler echocardiography and 47.4+/-16.4 mm Hg by right heart catheterization. Pearson's correlation coefficient was r=0.87 (P<0.0001). Mean right atrial pressure (RAP) was 12.0+/-5.7 mm Hg by right heart catheterization and was estimated to be 12.1+/-6.6 mm Hg by echocardiography (r=0.82, P<0.0001). Bland-Altman analysis showed a bias of -2.0 mm Hg for sPAP (95% limits of agreement -18.1 to +14.1 mm Hg) and +1.0 mm Hg for RAP (95% limits of agreement +0.1 to +1.9 mm Hg). Noninvasive diagnosis of pulmonary hypertension with Doppler echocardiography had a good sensitivity (87%) and specificity (79%), positive and negative predictive values (91% and 70%), as well as accuracy (85%) for a sPAP cut-off value of 36 mm Hg (AUC 0.91, P<0.001, CI 0.90 to 0.93). CONCLUSIONS: In this study, Doppler echocardiography proved to be a reliable method for the assessment of sPAP, being well suited to establish the noninvasive diagnosis of pulmonary hypertension in patients with cardiac diseases. PMID- 25146707 TI - Benefit of clopidogrel therapy in patients with myocardial infarction and chronic kidney disease-a Danish nation-wide cohort study. AB - BACKGROUND: The aim of the present study was to evaluate clopidogrel treatment after incident myocardial infarction (MI) in patients with and without chronic kidney disease (CKD). METHODS AND RESULTS: By linking nation-wide registries, information about patients admitted with incident MI was found. Primary endpoints were all-cause and cardiovascular (CV) mortality, a composite of all-cause mortality and recurrent MI, and a composite of fatal and nonfatal bleedings. Effect of clopidogrel use versus clopidogrel nonuse was estimated using an adjusted Cox's regression model stratified according to percutaneous coronary intervention (PCI) treatment.A total of 69 082 incident MI patients in the period 2002-2011 were included. Clopidogrel treatment was associated with hazard ratios (HRs) for the combined endpoint of all-cause mortality and recurrent MI in PCI treated patients of 0.90 (95% confidence interval [CI], 0.47 to 1.72) in renal replacement therapy (RRT) patients, 0.59 (95% CI: 0.40 to 0.88) in non-end-stage CKD patients and 0.69 (95% CI, 0.61 to 0.77) in patients without kidney disease (P for interaction=0.60). In patients not treated with PCI, HRs were 0.90 (95% CI, 0.68 to 1.21) in RRT patients, 0.86 (95% CI, 0.75 to 0.99) in non-end-stage CKD patients, and 0.91 (95% CI, 0.87 to 0.95) in patients without kidney disease (P for interaction=0.74). An increase in bleeding events (not significant) was noted for clopidogrel-treated patients not undergoing PCI and for non-end-stage CKD patients undergoing PCI, whereas clopidogrel was associated with less bleedings in PCI-treated RRT patients and patients without kidney disease. CONCLUSIONS: During a 1-year follow-up, after MI, clopidogrel was associated with improved outcomes in patients with non-end-stage CKD. Even though no effect difference, compared to patients without CKD, was observed, the benefit associated with the use of clopidogrel after MI in patients requiring RRT is less clear. PMID- 25146708 TI - Impact of revascularization for patients who survive life-threatening ventricular arrhythmias. PMID- 25146709 TI - Imaging the area at risk in myocardial infarction with cardiovascular magnetic resonance. PMID- 25146710 TI - Aspirin for primary prevention: a challenging decision. PMID- 25146711 TI - Development and validation of an ion-exchange chromatography method for heparin and its impurities in heparin products. AB - An anion-exchange liquid chromatography method for the determination of heparin and its impurities (dermatan sulfate and oversulfated chondroitin sulfate) was developed using chemometric-assisted optimization, including multivariate experimental design and response surface methodology. The separation of heparin, dermatan sulfate, and oversulfated chondroitin sulfate (Rs above 2.0) was achieved on a Dionex RF IC IonPac AS22 column with a gradient elution of 10-70% of 2.5 M sodium chloride and 20 mM Tris phosphate buffer (pH 2.1) at a flow rate of 0.6 mL/min and UV detection at 215 nm. Method validation shows good linearity (r > 0.99), acceptable precision (%relative standard deviations <11.4%) and trueness (%recovery of 92.3-103.9%) for all analytes. The limits of detection for dermatan sulfate and oversulfated chondroitin sulfate are equivalent to 0.11% w/w (10.5 MUg/mL) and 0.07% w/w (7.2 MUg/mL), while the limits of quantification are 0.32% w/w (31.5 MUg/mL) and 0.22% w/w (22.0 MUg/mL) relative to heparin, respectively. The method is specific for heparin, dermatan sulfate, and oversulfated chondroitin sulfate without interference from mobile phase and sample matrices and could be used for accurate quantitation the drug and its impurities in a single run. Applications of the method reveal contents of heparin between 90.3 and 97.8%. Dermatan sulfate and oversulfated chondroitin sulfate were not detected in any of the real-life samples. PMID- 25146712 TI - The social cost of cold homes in an English city: developing a transferable policy tool. AB - BACKGROUND: Although there is substantial epidemiological evidence implicating cold homes in death and morbidity, evidence for the UK on the nature and scale of the costs involved is fragmentary. Policy making in this area is thus not well informed of the benefit of interventions which arises in the form of costs averted. METHODS: This pilot study presents estimates of the social cost of harms to health caused by cold homes in the City of Sheffield. All costs are monetized and are for 1 year. Different elements of social cost are distinguished as are different types of harms to health. Because all estimates are derived from readily available secondary data the estimating framework is readily transferable to any other English local authority area. RESULTS: The social cost arising from losses of well-being are shown to dominate other elements of social cost including National Health Service and Social Care costs, and the social cost arising from mental illness is shown to dominate that arising from other harms to health including death. DISCUSSION: The implications of the results for the application of fiscal rate-of-return and social cost-benefit tests are discussed. Several areas are identified in which research reported in this pilot study could be improved on and expanded. PMID- 25146713 TI - Does screening for Down's syndrome cause anxiety in pregnant women? A systematic review. AB - BACKGROUND: Prenatal screening for Down's syndrome and other chromosomal abnormalities is included in prenatal care programs in many countries. However, the potential association between prenatal screening and maternal anxiety remains an issue of debate. OBJECTIVE: To systematically review and summarize the current scientific evidence on whether screening for Down's syndrome might cause anxiety in pregnant women with a negative or a false-positive screening result. METHODS: Five databases (PubMed, Embase, Cinahl, PsychInfo and Cochrane) were systematically searched for randomized controlled trials or cohort studies comparing screening and no screening, or comparing different types of screening for Down's syndrome. The search was limited to studies published between September 2001 and April 2013. In all, 316 studies were identified through search of databases and 40 were included for full-text assessment. Two observers independently screened the articles and seven studies satisfied the inclusion criteria. They were subsequently assessed for risk of bias and level of evidence. MAIN OUTCOME MEASURES: Quantitative measurements of maternal anxiety or worry. RESULTS: Two studies compared anxiety in pregnant women who accepted or declined screening and showed no difference between groups. All studies described a decrease in anxiety following a screen-negative result. Four studies reported that women's anxiety levels increased significantly upon receiving a screen positive result. However, after a normal diagnostic result, anxiety levels declined to the same level as for screen-negative women. CONCLUSION: Studies using quantitative, validated measures to estimate anxiety showed no association between screening and residual anxiety. PMID- 25146714 TI - Photoactive nanocrystals by low-temperature welding of copper sulfide nanoparticles and indium sulfide nanosheets. AB - We successfully utilize the concept of coalescence and room-temperature sintering to prepare morphologically different nanoparticles. n-Type chalcogenide (CuIn5 S8 ) nanocrystals are synthesized at room temperature by simple mixing of oppositely charged precursor nanoparticles. The coalescence of polycation-coated CuS nanoparticles and negatively charged In2 S3 nanoplates is driven by close contact of the particles due to electrostatic interactions. Analysis by X-ray diffraction, transmission electron microscopy (TEM) imaging, and Raman spectroscopy confirms the formation of single-phase CuIn5 S8 without traceable secondary phase. In a photovoltaic device, the use of the coalesced particles yields a power conversion efficiency of 1.8%. PMID- 25146715 TI - Managing patient complaints in China: a qualitative study in Shanghai. AB - OBJECTIVES: To examine the handling system for patient complaints and to identify existing barriers that are associated with effective management of patient complaints in China. SETTING: Key stakeholders of the handling system for patient complaints at the national, Shanghai municipal and hospital levels in China. PARTICIPANTS: 35 key informants including policymakers, hospital managers, healthcare providers, users and other stakeholders in Shanghai. PRIMARY AND SECONDARY OUTCOME MEASURES: Semistructured interviews were conducted to understand the process of handling patient complaints and factors affecting the process and outcomes of patient complaint management. RESULTS: The Chinese handling system for patient complaints was established in the past decade. Hospitals shoulder the most responsibility of patient complaint handling. Barriers to effective management of patient complaints included service users' low awareness of the systems in the initial stage of the process; poor capacity and skills of healthcare providers, incompetence and powerlessness of complaint handlers and non-transparent exchange of information during the process of complaint handling; conflicts between relevant actors and regulations and unjustifiable complaints by patients during solution settlements; and weak enforcement of regulations, deficient information for managing patient complaints and unwillingness of the hospitals to effectively handle complaints in the postcomplaint stage. CONCLUSIONS: Barriers to the effective management of patient complaints vary at the different stages of complaint handling and perspectives on these barriers differ between the service users and providers. Information, procedure design, human resources, system arrangement, unified legal system and regulations and factors shaping the social context all play important roles in effective patient complaint management. PMID- 25146716 TI - Efficacy of a dual-ring wound protector for prevention of incisional surgical site infection after Whipple's procedure (pancreaticoduodenectomy) with preoperatively-placed intrabiliary stents: protocol for a randomised controlled trial. AB - INTRODUCTION: Among surgical oncology patients, incisional surgical site infection is associated with substantially increased morbidity, mortality and healthcare costs. Moreover, while adults undergoing pancreaticoduodenectomy with preoperative placement of an intrabiliary stent have a high risk of this type of infection, and wound protectors may significantly reduce its risk, no relevant studies of wound protectors yet exist involving this patient population. This study will evaluate the efficacy of a dual-ring wound protector for prevention of incisional surgical site infection among adults undergoing pancreaticoduodenectomy with preoperatively-placed intrabiliary stents. METHODS AND ANALYSIS: This study will be a parallel, dual-arm, randomised controlled trial that will utilise a more explanatory than pragmatic attitude. All adults (>=18 years) undergoing a pancreaticoduodenectomy at the Foothills Medical Centre in Calgary, Alberta, Canada with preoperative placement of an intrabiliary stent will be considered eligible. Exclusion criteria will include patient age <18 years and those receiving long-term glucocorticoids. The trial will employ block randomisation to allocate patients to a commercial dual-ring wound protector (the Alexis Wound Protector) or no wound protector and the current standard of care. The main outcome measure will be the rate of surgical site infection as defined by the Centers for Disease Control and Prevention criteria within 30 days of the index operation date as determined by a research assistant blinded to treatment allocation. Outcomes will be analysed by a statistician blinded to allocation status by calculating risk ratios and 95% CIs and compared using Fisher's exact test. ETHICS AND DISSEMINATION: This will be the first randomised trial to evaluate the efficacy of a dual-ring wound protector for prevention of incisional surgical site infection among patients undergoing pancreaticoduodenectomy. Results of this study are expected to be available in 2016/2017 and will be disseminated using an integrated and end-of-grant knowledge translation strategy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT01836237. PMID- 25146717 TI - Long-term mortality after community-acquired pneumonia--impacts of diabetes and newly discovered hyperglycaemia: a prospective, observational cohort study. AB - OBJECTIVES: Community-acquired pneumonia is associated with a significant long term mortality after initial recovery. It has been acknowledged that additional research is urgently needed to examine the contributors to this long-term mortality. The objective of the present study was to assess whether diabetes or newly discovered hyperglycaemia during pneumonia affects long-term mortality. DESIGN: A prospective, observational cohort study. SETTING: A single secondary centre in eastern Finland. PARTICIPANTS: 153 consecutive hospitalised patients who survived at least 30 days after mild-to-moderate community-acquired pneumonia. INTERVENTIONS: Plasma glucose levels were recorded seven times during the first day on the ward. Several possible confounders were also recorded. The surveillance status and causes of death were recorded after median of 5 years and 11 months. RESULTS: In multivariate Cox regression analysis, a previous diagnosis of diabetes among the whole population (adjusted HR 2.84 (1.35-5.99)) and new postprandial hyperglycaemia among the non-diabetic population (adjusted HR 2.56 (1.04-6.32)) showed independent associations with late mortality. New fasting hyperglycaemia was not an independent predictor. The mortality rates at the end of follow-up were 54%, 37% and 10% among patients with diabetes, patients without diabetes with new postprandial hyperglycaemia and patients without diabetes without postprandial hyperglycaemia, respectively (p<0.001). The underlying causes of death roughly mirrored those in the Finnish general population with a slight excess in mortality due to chronic respiratory diseases. Pneumonia was the immediate cause of death in just 8% of all late deaths. CONCLUSIONS: A previous diagnosis of diabetes and newly discovered postprandial hyperglycaemia increase the risk of death for several years after community-acquired pneumonia. As the knowledge about patient subgroups with an increased late mortality risk is gradually gathering, more studies are needed to evaluate the possible postpneumonia interventions to reduce late mortality. PMID- 25146718 TI - Developing a service user informed intervention to improve participation and ability to perform daily activities in primary Sjogren's syndrome: a mixed methods study protocol. AB - INTRODUCTION: A significant proportion of patients with primary Sjogren's syndrome (PSS) is functionally impaired and experience difficulties participating in various aspects of everyday life. There is currently no evidence of efficacy for non-pharmacological interventions aimed specifically at supporting the patients with PSS to improve their participation and ability to perform daily activities. This paper describes a research protocol for a mixed-methods study to develop an intervention to improve these outcomes. The protocol follows the Medical Research Council framework for complex interventions. METHODS AND ANALYSIS: We will use group concept mapping with the patients, adults who live with them and healthcare professionals to identify factors which prevent people with PSS from participating in daily life and performing daily activities. The factors will be prioritised by participants for importance and feasibility and will inform an intervention to be delivered within a National Health Service (NHS) setting. Evidence-based intervention techniques will be identified for the prioritised factors and combined into a deliverable intervention package. Key stakeholders will comment on the intervention content and mode of delivery through focus groups, and the data will be used to refine the intervention. The acceptability and feasibility of the refined intervention will be evaluated in a future study. ETHICS AND DISSEMINATION: The study has been approved by an NHS Research Ethics Committee, REC Reference: 13/NI/0190. The findings of this study will be disseminated in peer-reviewed journals and through presentation at national and international conferences. TRIAL REGISTRATION NUMBER: UKCRN Study ID: 15939. PMID- 25146719 TI - HISTONE DEACETYLASE 9 represses seedling traits in Arabidopsis thaliana dry seeds. AB - Plant life is characterized by major phase changes. We studied the role of histone deacetylase (HDAC) activity in the transition from seed to seedling in Arabidopsis. Pharmacological inhibition of HDAC stimulated germination of freshly harvested seeds. Subsequent analysis revealed that histone deacetylase 9 (hda9) mutant alleles displayed reduced seed dormancy and faster germination than wild type plants. Transcriptome meta-analysis comparisons between the hda9 dry seed transcriptome and published datasets demonstrated that transcripts of genes that are induced during imbibition in wild-type prematurely accumulated in hda9-1 dry seeds. This included several genes associated with photosynthesis and photoautotrophic growth such as RuBisCO and RuBisCO activase (RCA). Chromatin immunoprecipitation experiments demonstrated enhanced histone acetylation levels at their loci in young hda9-1 seedlings. Our observations suggest that HDA9 negatively influences germination and is involved in the suppression of seedling traits in dry seeds, probably by transcriptional repression via histone deacetylation. Accordingly, HDA9 transcript is abundant in dry seeds and becomes reduced during imbibition in wild-type seeds. The proposed function of HDA9 is opposite to that of its homologous genes HDA6 and HDA19, which have been reported to repress embryonic properties in germinated seedlings. PMID- 25146720 TI - Addition of bortezomib to standard dose chop chemotherapy improves response and survival in relapsed mantle cell lymphoma. AB - The proteasome inhibitor, bortezomib, potentially increases cell sensitivity to chemotherapy. This study was performed to determine the overall response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicity of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) compared to CHOP + bortezomib chemotherapy in mantle cell lymphoma (MCL) patients at first relapse. Forty-six patients were randomly assigned to standard dose CHOP +/- bortezomib 1.6 mg/m(2) given on a 21-d cycle for up to eight cycles of treatment. Median age was 71 years (CHOP arm) and 69 years (CHOP-bortezomib arm). Median Eastern Cooperative Oncology Group performance status was 1 (CHOP) and 0 (CHOP bortezomib) with 65% and 52%, respectively, having a disease stage of IV. ORR was 47.8% (CHOP) and 82.6% (CHOP-bortezomib). Complete response rate was 21.7% (CHOP) vs. 34.8% (CHOP-bortezomib); partial response rate was 26.1% (CHOP) vs. 47.8% (CHOP-bortezomib). Median OS was 11.8 months (CHOP) and 35.6 months (CHOP bortezomib) (P = 0.01, Hazard ratio [HR] 0.37 [95% confidence interval (CI) 0.16 0.83)] and there was a non-significant improvement in PFS: 8.1 months (CHOP) and 16.5 months (CHOP-bortezomib) [P = 0.12, HR 0.60 (95% CI 0.31-1.15)]. Severe (>=grade 3) sensory neuropathy was similar in both arms (4.3% CHOP vs. 6.5% CHOP bortezomib). We conclude that the addition of bortezomib to CHOP chemotherapy for relapsed MCL significantly improves outcome with a manageable increase in toxicity. PMID- 25146721 TI - The CROWN initiative: journal editors invite researchers to develop core outcomes in women's health. PMID- 25146722 TI - Prevalence of low back pain by anatomic location and intensity in an occupational population. AB - BACKGROUND: Low Back Pain (LBP) is a common and costly problem, with variation in prevalence. Epidemiological reports of rating of pain intensity and location within the low back area are rare. The objective is to describe LBP in a large, multi-center, occupational cohort detailing both point and 1-month period prevalence of LBP by location and intensity measures at baseline. METHODS: In this cross-sectional report from a prospective cohort study, 828 participants were workers enrolled from 30 facilities performing a variety of manual material handling tasks. All participants underwent a structured interview detailing pain rating and location. Symptoms in the lower extremities, demographic and other data were collected. Body mass indices were measured. Outcomes are pain rating (0 10) in five defined lumbar back areas (i) LBP in the past month and (ii) LBP on the day of enrollment. Pain ratings were reported on a 0-10 scale and subsequently collapsed with ratings of 1-3, 4-6 and 7-10 classified as low, medium and high respectively. RESULTS: 172 (20.8%) and 364 (44.0%) of the 828 participants reported pain on the day of enrollment or within the past month, respectively. The most common area of LBP was in the immediate paraspinal area with 130 (75.6%) participants with point prevalence LBP and 278 (77.4%) with 1 month period prevalence reported having LBP in the immediate paraspinal area. Among those 364 reporting 1-month period prevalence pain, ratings varied widely with 116 (31.9%) reporting ratings classified as low, 170 (46.7%) medium and 78 (21.4%) providing high pain ratings in any location. Among the 278 reporting 1 month period prevalence pain in the immediate paraspinal area, 89 (32.0%) reported ratings classified as low, 129 (46.4%), medium and 60 (21.6%) high pain ratings. CONCLUSIONS: Pain ratings varied widely, however less variability was seen in pain location, with immediate paraspinal region being the most common. Variations may suggest different etiological factors related to LBP. Aggregation of different locations of pain or different intensities of pain into one binary classification of LBP may result in loss of information which may potentially be useful in prevention or treatment of LBP. PMID- 25146724 TI - Polymerization kinetics in three-dimensional direct laser writing. AB - By in-situ measuring the scattered light during microstructure formation, the polymerization kinetics of three-dimensional direct laser writing are investigated in detail. Oxygen quenching, oxygen diffusion, and inhibitor depletion are shown to have substantial impact on the kinetic behavior. For typical photoresists based on multifunctional acrylates, the polymerization occurs in less than a millisecond. PMID- 25146723 TI - Functional high-throughput screening identifies the miR-15 microRNA family as cellular restriction factors for Salmonella infection. AB - Increasing evidence suggests an important role for miRNAs in the molecular interplay between bacterial pathogens and host cells. Here we perform a fluorescence microscopy-based screen using a library of miRNA mimics and demonstrate that miRNAs modulate Salmonella infection. Several members of the miR 15 miRNA family were among the 17 miRNAs that more efficiently inhibit Salmonella infection. We discovered that these miRNAs are downregulated during Salmonella infection, through the inhibition of the transcription factor E2F1. Analysis of miR-15 family targets revealed that derepression of cyclin D1 and the consequent promotion of G1/S transition are crucial for Salmonella intracellular proliferation. In addition, Salmonella induces G2/M cell cycle arrest in infected cells, further promoting its replication. Overall, these findings uncover a mechanism whereby Salmonella renders host cells more susceptible to infection by controlling cell cycle progression through the active modulation of host cell miRNAs. PMID- 25146726 TI - Don't drop the anchor. PMID- 25146727 TI - Benchmarks and outcomes in surgical oncology: an introduction and current perspective. PMID- 25146725 TI - Beliefs and perceptions about the causes of breast cancer: a case-control study. AB - BACKGROUND: Attributions of causality are common for many diseases, including breast cancer. The risk of developing breast cancer can be reduced by modifications to lifestyle and behaviours to minimise exposure to specific risk factors, such as obesity. However, these modifications will only occur if women believe that certain behaviours/lifestyle factors have an impact on the development of breast cancer. METHOD: The Breast Cancer, Environment and Employment Study is a case-control study of breast cancer conducted in Western Australia between 2009 and 2011. As part of the study 1109 women with breast cancer and 1633 women without the disease completed a Risk Perception Questionnaire in which they were asked in an open-ended question for specific cause/s to the development of breast cancer in themselves or in others. The study identified specific causal beliefs, and assessed differences in the beliefs between women with and without breast cancer. RESULTS: The most common attributions in women without breast cancer were to familial or inherited factors (77.6%), followed by lifestyle factors, such as poor diet and smoking (47.1%), and environmental factors, such as food additives (45.4%). The most common attributions in women with breast cancer were to mental or emotional factors (46.3%), especially stress, followed by lifestyle factors (38.6%) and physiological factors (37.5%), particularly relating to hormonal history. CONCLUSIONS: While the majority of participants in this study provided one or more causal attributions for breast cancer, many of the reported risk factors do not correspond to those generally accepted by the scientific community. These misperceptions could be having a significant impact on the success of prevention and early detection programs that seek to minimise the pain and suffering caused by this disease. In particular, women who have no family history of the disease may not work to minimise their exposure to the modifiable risk factors. PMID- 25146728 TI - Opposite face sensitivity of CeO2 in hydrogenation and oxidation catalysis. AB - The determination of structure-performance relationships of ceria in heterogeneous reactions is enabled by the control of the crystal shape and morphology. Whereas the (100) surface, predominantly exposed in nanocubes, is optimal for CO oxidation, the (111) surface, prevalent in conventional polyhedral CeO2 particles, dominates in C2H2 hydrogenation. This result is attributed to the different oxygen vacancy chemistry on these facets. In contrast to oxidations, hydrogenations on CeO2 are favored over low-vacancy surfaces owing to the key role of oxygen on the stabilization of reactive intermediates. The catalytic behavior after ageing at high temperature confirms the inverse face sensitivity of the two reaction families. PMID- 25146729 TI - Slr0151 in Synechocystis sp. PCC 6803 is required for efficient repair of photosystem II under high-light condition. AB - Cyanobacteria are ancient photosynthetic prokaryotes that have adapted successfully to adverse environments including high-light irradiation. Although it is known that the repair of photodamaged photosystem II (PSII) in the organisms is a highly regulated process, our knowledge of the molecular components that regulate each step of the process is limited. We have previously identified a hypothetical protein Slr0151 in the membrane fractions of cyanobacterium Synechocystis sp. PCC 6803. Here, we report that Slr0151 is involved in PSII repair of the organism. We generated a mutant strain (Deltaslr0151) lacking the protein Slr0151 and analyzed its characteristics under normal and high-light conditions. Targeted deletion of slr0151 resulted in decreased PSII activity in Synechocystis. Moreover, the mutant exhibited increased photoinhibition due to impairment of PSII repair under high-light condition. Further analysis using in vivo radioactive labeling and 2-D blue native/sodium dodecylsulfate polyacrylamide gel electrophoresis indicated that the PSII repair cycle was hindered at the levels of D1 synthesis and disassembly and/or assembly of PSII in the mutant. Protein interaction assays demonstrated that Slr0151 interacts with D1 and CP43 proteins. Taken together, these results indicate that Slr0151 plays an important role in regulating PSII repair in the organism under high-light stress condition. PMID- 25146730 TI - Aip1p dynamics are altered by the R256H mutation in actin. AB - Mutations in actin cause a range of human diseases due to specific molecular changes that often alter cytoskeletal function. In this study, imaging of fluorescently tagged proteins using total internal fluorescence (TIRF) microscopy is used to visualize and quantify changes in cytoskeletal dynamics. TIRF microscopy and the use of fluorescent tags also allows for quantification of the changes in cytoskeletal dynamics caused by mutations in actin. Using this technique, quantification of cytoskeletal function in live cells valuably complements in vitro studies of protein function. As an example, missense mutations affecting the actin residue R256 have been identified in three human actin isoforms suggesting this amino acid plays an important role in regulatory interactions. The effects of the actin mutation R256H on cytoskeletal movements were studied using the yeast model. The protein, Aip1, which is known to assist cofilin in actin depolymerization, was tagged with green fluorescent protein (GFP) at the N-terminus and tracked in vivo using TIRF microscopy. The rate of Aip1p movement in both wild type and mutant strains was quantified. In cells expressing R256H mutant actin, Aip1p motion is restricted and the rate of movement is nearly half the speed measured in wild type cells (0.88 +/- 0.30 MUm/sec in R256H cells compared to 1.60 +/- 0.42 MUm/sec in wild type cells, p < 0.005). PMID- 25146731 TI - Amyloid-beta precursor protein synthesis inhibitors for Alzheimer's disease treatment. PMID- 25146732 TI - Rationale and Design of FIRE AND ICE: A multicenter randomized trial comparing efficacy and safety of pulmonary vein isolation using a cryoballoon versus radiofrequency ablation with 3D-reconstruction. AB - BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia imposing substantial morbidity and mortality. Catheter-based pulmonary vein isolation (PVI) using radiofrequency current (RFC) has become a standard treatment for drug-resistant and symptomatic paroxysmal AF (PAF). In recent years, the cryoballoon-based technique is increasingly used as a promising alternative with a short learning curve. METHODS: The FIRE AND ICE trial is a prospective, randomized, controlled, open, blinded outcome assessment, noninferiority trial comparing cryoballoon-, and RFC-based PVI. Patients with drug-resistant PAF will be randomized in a 1:1 matrix in multiple European centers. The primary hypothesis is that cryoballoon ablation is not inferior to RFC ablation using 3-dimensional mapping with respect to clinical efficacy. The primary endpoint is defined as the time to first documented clinical failure, including: (1) recurrence of AF; (2) atrial flutter or atrial tachycardia; (3) prescription of class I or III antiarrhythmic drugs; or (4) re-ablation, whichever comes first, following a blanking period of 3 months after the index ablation procedure. The primary safety endpoint is a composite of death, stroke/transient ischemic attack, cardiac arrhythmias (apart from AF recurrence) causally related to the therapeutic intervention, and procedure-related serious adverse events. CONCLUSION: The FIRE AND ICE trial compares 2 different technologies to perform catheter ablation of PAF with respect to efficacy and safety. It aims at providing objective data to guide selection and usage of ablation catheters in the treatment of AF. PMID- 25146733 TI - A mouse polyomavirus-encoded microRNA targets the cellular apoptosis pathway through Smad2 inhibition. AB - Some viruses and most eukaryotic cells have microRNAs that regulate the expression of many genes. Although many viral miRNAs have been identified, only a few have been included in in vivo functional studies. Here we show that a Py encoded miRNA downregulates the expression of the pro-apoptotic factor Smad2, resulting in the suppression of the apoptosis pathway. To study the Py miRNA in an in vivo context, a miRNA-deficient mutant virus was created on the background of the LID virus strain which establishes a rapid and lethal infection in newborn mice. Apoptosis analysis on kidney tissues indicates that the pro-apoptotic pathway is targeted in the infected host as well. Suppression of apoptosis through targeting of Smad2 by the Py miRNA is expected to synergize with anti apoptotic effects previously attributed to the polyoma tumor antigens in support of virus replication in the natural host. PMID- 25146734 TI - Synthesis, structure, and catecholase activity of bispyrazolylacetate copper(II) complexes. AB - A series of six-coordination copper(ii) complexes containing bis(3,5-di-t butylpyrazol-1-yl)acetate (bdtbpza) and N-heterocycles or chelating aliphatic ligands have been synthesized. The steric bulkiness of bis(pyrazol-1-yl)acetate anchors two bdtbpza to situate a trans position and to adopt an O-bound monodentate coordination mode with other nitrogen bases occupying the basal plane. Five mononuclear mixed ligand complexes, [Cu(bdtbpza)2(py)4] , [Cu(bdtbpza)2(t-Bupy)4] , [Cu(bdtbpza)2(pym)2(MeOH)2] , [Cu(bdtbpza)2(eda)2] , [Cu(bdtbpza)2(tmeda)(H2O)2] , where py = pyridine, t-Bupy = tert-butylpyridine, pym = pyrimidine, eda = ethylenediamine, and tmeda = tetramethylethylenediamine, were isolated and thoroughly characterized. Intriguingly, the heteroleptic complex , which has two aquo-ligands oriented in the cis positions, demonstrates higher catecholase-like activity in performing aerial oxidation of 3,5-di-tert butylcatechol (3,5-DTBC) to 3,5-di-tert-butylquinone (3,5-DTBQ) than other bis(pyrazolyl)acetate-embedded copper complexes reported herein, which suggests the essential role of labile cis-aquo ligands to promote the catalytic reaction. PMID- 25146735 TI - Type I procollagen C-propeptide defects: study of genotype-phenotype correlation and predictive role of crystal structure. AB - The type I procollagen carboxyterminal(C-)propeptides are crucial in directing correct assembly of the procollagen heterotrimers. Defects in these domains have anecdotally been reported in patients with Osteogenesis Imperfecta (OI) and few genotype-phenotype correlations have been described. To gain insight in the functional consequences of C-propeptide defects, we performed a systematic review of clinical, molecular, and biochemical findings in all patients in whom we identified a type I procollagen C-propeptide defect, and compared this with literature data. We report 30 unique type I procollagen C-propeptide variants, 24 of which are novel. The outcome of COL1A1 nonsense and frameshift variants depends on the location of the premature termination codon. Those located prior to 50-55 nucleotides upstream of the most 3' exon-exon junction lead to nonsense mediated mRNA decay (NMD) and cause mild OI. Those located beyond this boundary escape NMD, generally lead to production of stable, overmodified procollagen chains, which may partly be retained intracellularly, and are usually associated with severe-to-lethal OI. Proalpha1(I)-C-propeptide defects that permit chain association result in more severe phenotypes than those inhibiting chain association. We demonstrate that the crystal structure of the proalpha1(III)-C propeptide is a reliable tool to predict phenotypic severity for most COL1A1-C propeptide missense variants, whereas for COL1A2-C-propeptide variants, the phenotypic outcome is milder than predicted. PMID- 25146736 TI - [Liver cancer: new strategy of molecular pathological diagnosis and new mode of clinical therapy]. PMID- 25146737 TI - [Comparison of hepatic resection and transarterial chemoembolization for hepatocellular carcinoma within the Milan criteria]. AB - OBJECTIVE: To compare the long-term survival of hepatocellular carcinoma (HCC) patients within the Milan criteria who underwent hepatic resection (HR) or transarterial chemoembolization (TACE). METHODS: A total of 159 HR and 42 TACE patients with HCC within the Milan criteria were retrospectively evaluated. Propensity-score matching (PSM) was used to generate matched controls. Long-term survival was evaluated by the Kaplan-Meier method. And independent prognostic predictors were determined by the Cox proportional hazard model. RESULTS: After adjusting for baseline differences, 84 HR and 42 TACE patients were selected. Median survival time was 42.9 months in HR group versus 34.8 months in TACE group. The 1, 3 and 5-years survival rates were significantly higher in HR group (87.8%, 64.0%, 41.9%) than those in TACE group (85.7%, 47.6%, 26.0%; P = 0.028). Subgroup analysis showed that the patients with single-tumor HCC <= 5 cm had 1, 3 and 5-year overall survival rates of 86.3%, 61.3% and 42.9% after HR versus 90.3%, 61.3% and 33.2% after TACE (P = 0.332). Among those with multinodular HCC involving 2-3 tumors <= 3 cm, 1, 3 and 5-years survival rates were 93.8%, 75.0% and 39.3% after HR versus 72.7%, 45.5% and 9.1% after TACE (P = 0.002). Body mass index >= 23 kg/m(2), serum level of alpha-fetoprotein (AFP) >= 400 ug/L and TACE treatment significantly predicted poor survival according to the Cox proportional hazard model (all P < 0.05). CONCLUSIONS: Hepatic resection provides better long term survival than TACE for HCC patients within the Milan Criteria. In fact, HR provides significant long-term survival benefits for patients with multinodular HCC involving 2-3 tumors <= 3 cm. In contrast, both HR and TACE have similar survival rates among patients with single-tumor HCC <= 5 cm. PMID- 25146738 TI - [Expression of novel metastasis-promoting gene 1 and its clinical significance in hepatocellular carcinoma]. AB - OBJECTIVE: To explore the expression of NVM-1(novel metastasis-promoting gene 1) in hepatocellular carcinoma (HCC) tissue and examine its clinical significance. METHODS: The expression of NVM-1 in 92 cases of HCC tumor tissues and non-tumor tissues was detected by immunohistochemical staining with SP (streptavidin perosidase). And its clinical significance was evaluated. RESULTS: The staining of NVM-1 was predominantly located in the nucleus of HCC tumor tissue. The positive rate of NVM-1 was 52.2% in all detected cancers and it was higher than that in control non-tumor tissues (28.3%) and benign hepatic lesions (0) . A significant difference of positive rates existed between tumor and non-tumor tissues (P < 0.05). The expression of NVM-1 in HCC was not correlated with hepatic B virus (HBV), size, amount or cirrhosis, etc. However, it was correlated with TNM (P = 0.016), BCLC stage (P = 0.015), poor differentiation (P = 0.000), intrahepatic metastasis (P = 0.002), portal vein tumor thrombus (P = 0.023) and recurrence (P = 0.001). By Kaplan-Meier analysis, the median tumor-free survival time was 5 months in positive expression group and it was significantly shorter than 13 months in negative expression group (P = 0.001). CONCLUSION: There is probably a close relation between recurrence and metastasis and the expression of NVM-1 in HCC. PMID- 25146739 TI - [Activation of p21(WAF1/CIP1) by small activating RNA inhibits cell proliferation and induces apoptosis in BEL-7402 hepatoma cell]. AB - OBJECTIVE: To evaluate the anti neoplastic effects of p21(WAF1/CIP1) transcriptional activation induced by duplex RNAs in hepatocellular carcinoma (HCC) cell line BEL-7402. METHODS: Cells were treated with dsRNAs complementary to promoter sequences of p21(WAF1/CIP1). Quantitative polymerase chain reaction (qPCR) and Western blot were employed to detect the expression of p21. At various timepoints post-transfection, cell viability assay and apoptosis analysis were used to determine the effect of RNA activation. After transfection Western blot was also performed to detect the expression of Bcl-xL, cleaved caspase-3, cleaved caspase-9 and cleaved PARP. RESULTS: DsP21-322 transfection significantly inhibited cell viability. And, at Day 5, dsP21-322 inhibited cell growth by 65.84% versus control. Flow cytometry revealed that dsP21-322 caused a significant increase of cell apoptosis. The total percent of apoptotic cells (UR+LR) increased to 36.86% versus 11.51% and 14.06% in mocks and controls respectively. Such phenomena correlated with a decrease of anti-apoptotic protein Bcl-xL and an increase of cleaved caspase-3, cleaved caspase-9 and cleaved PARP. CONCLUSION: Activation of p21 gene expression by saRNA may offer therapeutic benefits for HCC and other cancers. PMID- 25146740 TI - [Association between serum interleukin-17 level and abnormal cellular immunological status in patients with severe aplastic anemia]. AB - OBJECTIVE: To explore the role of interleukin-17 (IL-17) in the pathogenesis of severe aplastic anemia (SAA). METHODS: Peripheral blood samples were obtained from 40 SAA patients (25 untreated, 15 recovery) and 10 normal controls from October 2012 to October 2013. The level of IL-17 in peripheral blood was measured with cytometric bead array (CBA). The correlations between IL-17 and T cells subset (CD4(+)/CD8(+)), dendritic cells (DC) subset (mDC/pDC), regulatory T cells (Treg) and hemogram were analyzed. RESULTS: The serum level of IL-17 in untreated patients was higher than that in recovery patients and normal controls ((17.07 +/ 15.18) vs (7.09 +/- 3.84) and (3.53 +/- 2.08) ng/L, both P < 0.01). Also significant differences existed between the latter two groups (P < 0.05). The ratio of CD4(+)/CD8(+) was (0.32 +/- 0.08) in untreated patients and it was lower than that in recovery patients (1.11 +/- 0.31, P < 0.01) and normal controls (1.07 +/- 0.26, P < 0.01). The ratio of mDC/pDC was (3.16 +/- 0.55) in untreated patients was higher than that in recovery patients (1.60 +/- 0.43, P < 0.01)and normal controls (1.43 +/- 0.38, P < 0.01). The percentage of Tregs in peripheral blood lymphocyte (CD4(+)CD25(+)CD127(dim)/PBL) was 0.80% +/- 0.31% in untreated patients and it was lower than that in recovery patients (1.78% +/- 0.69%, P < 0.01) and normal controls (2.23% +/- 0.66%, P < 0.01). The serum level of IL-17 in untreated SAA patients was related positively with mDC/pDC ratio (r = 0.414, P < 0.05) and negatively with CD4(+)/CD8(+) ratio (r = -0.421, P < 0.05) and CD4(+)CD25(+)CD127(dim)/PBL(r = -0.650, P < 0.01). And significant negative correlations existed between serum IL-17 and white blood cells in untreated patients (r = -0.689, P < 0.01) and recovery patients (r = -0.640, P < 0.05). CONCLUSION: The elevated serum level of IL-17 in SAA is related with the immunological status and disease severity. PMID- 25146741 TI - [Level of soluble programmed death ligand 1 in pleural effusion and peripheral blood of patients with tuberculous pleural effusion and its clinical implications]. AB - OBJECTIVE: To explore the level of soluble programmed death ligand 1 (sPD-L1) in pleural effusion and peripheral blood of patients with tuberculous pleural effusion (TPE) and elucidate its clinical implications. METHODS: Patients with newly diagnosed pleural effusion at the Second Affiliated Hospital of Soochow University from June 2012 to March 2013 were enrolled and divided into 3 groups of TPE, malignant pleural effusion (MPE) and non-tuberculous non-malignant pleural effusion (non-TPE non-MPE) according to the nature of pleural effusion. The level of sPD-L1 in pleural effusion and peripheral blood was analyzed by enzyme linked immunosorbent assay (ELISA) kit. Flow cytometry was used to detect the changes of immune cell subsets in pleural effusion. And the gene expressions of programmed death ligand 1 (PD-L1) and matrix metalloproteinase-3 (MMP-3) were detected in different effusions by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: A total of 77 newly diagnosed patients with pleural effusion were enrolled, 24 patients with TPE, 39 patients with MPE, 14 patients with non-TPE non-MPE. The level of sPD-L1 in TPE was higher than that in MPE and non-TPE non-MPE (4.2 (2.6-6.3), 1.4 (0.8-2.1), 1.8 (1.2-2.6) ug/L, P < 0.001). No significant difference existed in the levels of sPD-L1 in peripheral blood samples (P = 0.811). The average content of sPD-L1 in pleural effusion in all patients was statistically higher than that in peripheral blood (2.0 (1.4-3.7), 1.5 (1.0-2.0) ug/L, P = 0.004). The proportion of CD8 subset, PD-L1 on CD14(+) monocytes and the mRNA level of PD-L1, MMP-3 in TPE were higher than in MPE and non-TPE non-MPE (P = 0.001, P < 0.001, P < 0.001), and the mRNA level of PD-L1 in TPE was positively correlated with the level of MMP-3 (r = 0.887, P < 0.001). Receiver operating characteristic (ROC) curve analysis showed that sPD-L1 had a sensitivity of 82.6%, a specificity of 83.8% and an area under curve (AUC) of 0.854 for differential diagnosis of TPE from other conditions. Combinations of sPD-L1, PD-L1 on CD14(+) monocytes and adenosine deaminase (ADA) measurements further increased the sensitivity up to 91.3%, specificity up to 89.2% and AUC up to 0.989. CONCLUSION: The elevated expression of sPD-L1 in tuberculous pleural effusion may aid the diagnosis of TPE. PMID- 25146742 TI - [Long-term follow-ups of comprehensive therapies for stage 4 neuroblastoma]. AB - OBJECTIVE: To evaluate the long-term outcomes of childhood stage 4 neuroblastoma (NB) and its correlative prognostic factors. METHODS: Comprehensive protocols including tumor resection, intensive chemotherapy, radiotherapy, autologous bone marrow transplantation and 13-cis-retinoid were designed and implemented. A total of 112 newly diagnosed NB stage 4 patients at Shanghai Children's Medical Center collected from June 1998 to December 2010 were treated. Their clinical features, therapeutic efficacies, long-term outcomes and prognostic factors were analyzed. RESULTS: There were 69 males and 43 females with an age range of 4 months to 15 years. Among them, 12 improving patients didn't complete treatment because of parental decisions. Among those completing the comprehensive protocols, 62 cases (62.0%) achieved very good partial remission (VGPR), 20 (20.0%) achieved partial remission (PR) while another 18 (18.0%) progressed during treatment. The efficiency rate (including VGPR+PR) of treatment was 82.0 % (n = 82). The median follow-up period was 78 (56, 120) months. And 13 cases were lost after a median follow-up of 16 months. The 2, 3, 5-year event-free survival (EFS) was 56.2% (59/105) , 40.8% (40/98) and 21.1% (19/90) respectively. Age (>18 months), poor curative effect (achieving no VGPR at the end of treatment), elevated level of lactate dehydrogenase (LDH) (> 5 times normal value), bone marrow involvement and brain metastasis were poor prognostic factors (chi(2) = 12.01, 13.66, 6.29, 5.44, 16.18, all P < 0.05) . According to the multivariate estimates of hazards, age, high levels of LDH, poor curative effect and brain metastasis were associated with a worse survival (OR = 3.54, 1.89, 3.08, 3.45, all P < 0.05) . Brain metastasis predicted a worse outcome with 100% mortality rate (n = 6). Compared to traditional chemotherapy, topotecan-based chemotherapy could not improved the efficiency (52.6% (10/19) vs 63.2% (36/57) , P > 0.05) and long-term outcome (2 ys-EFS 42.1% (8/19) vs 56.4% (31/55) , P > 0.05). CONCLUSIONS: The prognosis remains poor for neuroblastoma of stage 4. Age (>18 months), poor curative effect (achieving no VGPR at the end of treatment), elevated LDH level (>5 times normal value) and bone marrow infiltration are associated with worse prognosis. Brain metastasis predicts the worst with 100% death rate. Topotecan included chemotherapy can not be proved more effective in this study. PMID- 25146743 TI - [Retrospective analysis of correlative factors between digestive system injury and anticoagulant or antiplatelet-agents]. AB - OBJECTIVE: To explore the correlative factors and clinical characteristics of digestive system injury during the treatment of anticoagulant and (or) antiplatelet-agents. METHODS: A total of 1 443 hospitalized patients on anticoagulant and (or) antiplatelet-agents from January 2010 to December 2013 at Renmin Hospital of Wuhan University were analyzed retrospectively. RESULTS: Their length of hospital stay was from 5 to 27 days. Most of them were elderly males (n = 880, 61.0%) with an average age of (62 +/- 6) years. 1 138 patients (78.9%) were farmers, workers or someone without a specific occupation. During the treatment of anticoagulant/antiplatelet-agents, statistical difference existed (P = 0.01) between positively and negatively previous digestive disease groups for actively newly occurring digestive system injury (16.0% (41/256) vs 15.9% (189/1 187)). After the dosing of anticoagulant and (or) antiplatelet-agents, 57 (66.3%, 57/86) patients were complicated by hemorrhage of digestive tract, taking 62.9% (61/97) of all positive result patients for Helicobacter pylori test. Comparing preventive PPI group with no PPI group, there was no marked statistical differences (P = 2.67) for digestive system complication (including hemorrhage of digestive tract) while receiving anticoagulant and (or) antiplatelet-agents (13.9% (74/533) vs 17.1% (156/910)). During anticoagulant and/or antiplatelet agent therapy, 185 patients (12.8%) were complicated by peptic ulcer or peptic ulcer with bleeding, 40 patients (2.8%) had erosive gastritis and 5 (0.3%) developed acute gastric mucosal lesions. And 42 of 76 patients complicated by hemorrhage of digestive tract underwent endoscopic hemostasis while 2 patients were operated. Ninety-seven patients (6.7%) died, including 61 (62.9%, 61/97) from hemorrhage of digestive tract. The remainder became cured, improved and discharged. Moreover, no significant statistical differences existed (P = 2.29) among three combination group (aspirin, clopidogrel, warfarin), two combination group (aspirin, clopidogrel), exclusive aspirin group and exclusive warfarin group in short-term (<27 d) mortality. CONCLUSIONS: It is necessary to clearly dictate the details of medication to the patients not highly educated. Elder, male, history of digestive system disease and Helicobacter pylori infection are possibly highly risk correlative factors for digestive system complications during anticoagulant/antiplatelet-agent therapy. The short-term protective effect of routine dose of PPI is inconspicuous. No significant correlation exists between short-term mortality and the dosage (or type) of anticoagulant/antiplatelet-agents. PMID- 25146744 TI - [CD160 characterization and its association with disease progression in patients with chronic HIV-1 infection]. AB - OBJECTIVE: To explore the expression of CD160, a costimulator, on CD4(+) and CD8(+) T cells in chronic human immunodeficiency virus-1 (HIV-1) infected patients. METHODS: A total of 23 chronic HIV-1 infected patients were enrolled into 302 Hospital of People's Liberation Army from January 2010 to December 2011. Meanwhile, 20 healthy individuals were selected as healthy controls (HC). Peripheral blood was collected, peripheral blood mononuclear cells (PBMC) were isolated by density gradient centrifugation and CD160 was stained with fluorescent antibody. The expressions of CD160 on CD4(+) and CD8(+) T cell subsets were detected by flow cytometry and its correlation with CD4(+) T cell absolute number and HIV RNA viral load were analyzed. RESULTS: The expressions of CD160 on CD4(+) and CD8(+) T cell increased versus HC (on CD4(+) T cells, percentage: (14.3 +/- 7.5)% vs (3.9 +/- 2.2)%, median fluorescent intensity (MFI): 26.4 +/- 11.0 vs 12.4 +/- 2.9; on CD8(+) T cells, percentage: (40.9 +/- 13.2)% vs (12.9 +/- 6.6)%, MFI: 52.5 +/- 17.4 vs 18.2 +/- 5.0). Furthermore, the expression of CD160 on CD4(+) T cells was negatively correlated with CD4(+) T cell absolute number (r = -0.550, P = 0.010) and positively with HIV RNA load (r = 0.522, P = 0.015). However, the expression of CD160 on CD8(+) T cells was not correlated with CD4(+) T cell absolute number or HIV RNA load. The expressions of CD160 on CD8(+) T cell subsets Tn, Tcm and Tem in patients with chronic HIV-1 infection increased compared with HC (25.3 +/- 17.6 vs 5.0 +/- 3.1, 45.8 +/- 13.0 vs 20.4 +/- 4.3, 37.0 +/- 13.6 vs 20.0 +/- 10.8). In addition, Tn subset decreased while Tcm subset increased in CD160(+) CD8(+) T cell subset distribution in patients with HIV-1 infection compared with HC subjects. CONCLUSION: CD160 may contribute to the exhaustion of CD4(+) and CD8(+) T cells and influence the distribution of memory CD8(+) T cell subsets. PMID- 25146745 TI - [Effects of ribavirin aerosol on viral exclusion of patients with hand-foot-mouth disease]. AB - OBJECTIVE: To explore the roles of ribavirin aerosol in the prevention and treatment of hand-foot-mouth disease (HFMD). METHODS: For this prospective, multicenter, randomized, double-blind and placebo-controlled trial, a total of 300 HFMD outpatients from 3 class 3A hospitals from July 2011 to June 2013 were divided into treatment (ribavirin aerosol) and control (placebo) groups (n = 150 each). The age range was 6 months to 6 years. The proportion of male and female was 1.5: 1. Temperature, herpes of mouth and skin rash were observed before and after treatments. Before treatment and 6-7 days after, their specimens of throat swab were collected and the levels of EV71 and CA16 detected with reverse transcription (RT)-PCR. The software SAS 9.2 was used for statistic data analyses. RESULTS: Before treatment, no significant statistical difference existed in parameters between treatment and control groups (all P > 0.05). After treatment, the degree of herpes of mouth and papulovesicle of skin in treatment group was better than that in control group (100.0% (147/147) vs 83.9% (120/143), chi(2) = 109.21, P < 0.01); (100.0% (147/147) vs 95.9% (139/145) , chi(2) = 6.38, P < 0.05) . The virus negative conversion rates had significant inter-group difference (80.0% (102/110) vs 41.8% (41/98) , chi(2) = 37.06, P < 0.01). The temperature, compliance and differences were not significant (all P > 0.05). The effective rate of comprehensive efficacy in treatment group was higher than that in control group (93.9% (122/130) vs 52.0% (64/123), chi(2) = 111.08, P < 0.01). No obvious adverse drug reaction was observed. CONCLUSIONS: Ribavirin aerosol has multiple advantages of lower dose, quicker onset, higher local concentration, better clinical efficacy and fewer side-effects. Its therapeutic effect for local lesion is better than that for systemic lesion. Thus it may shorten the duration of oropharyngeal and skin lesions and lower the number and time of viral release. PMID- 25146746 TI - [Early screening of developmental dysplasia of the hip among hospitalized children]. AB - OBJECTIVE: To summarize retrospectively developmental dysplasia of the hip (DDH) screening of children within 36 months. METHODS: Newborn infants underwent initial DDH screening at First Affiliated Hospital, Zhengzhou University from September 2011 to May 2013. The examinations included double hip function, abduction test and Ortolani/Barlow test. After initial DDH screening, suspected and abnormal infants were transferred to our department for re-screening. And clinical physical examinations, type B ultrasound or radiological imaging were performed for confirmation or elimination. RESULTS: A total of 10 428 children were DDH screened. And 1 260 children were examined with ultrasound and 346 suspected and abnormal children (445 hips) were transferred for further assessments. Among them, 33 children (49 hips) were positive with Ortolani or Barlow test, 61 children (88 hips) had dysplasia of hip and 48 children (14 boys, 34 girls) (69 hips) received a final diagnosis of DDH. Left (n = 52) and right hip (n = 17) were involved with a disease incidence of DDH at 0.46%. CONCLUSIONS: Ultrasonic examination is both simple and cost-effective for DDH screening of children within 6 months. And meticulous medical examinations and imaging studies are effective DDH screening for children from 6 to 36 months. PMID- 25146747 TI - [Intensive care unit survey of cognition status of donation after brain death]. AB - OBJECTIVE: To explore the development approach of donation after brain death through analyzing the cognition status of donation after brain death among medical staff and potential donor (PD) family members of intensive care unit (ICU). METHODS: Analysis was conducted for the cognition of donation after brain death among 149 ICU professionals and 879 PD family members at 89 hospitals from July 2011 to April 2013. RESULTS: Medical staff: 100% (149/149) recognized the significance of donation after brain death, 96.6% (144/149) approved of donation after brain death, 85.9% (128/149) knew about brain death criteria, 94.0% (140/149) accepted the equivalence of brain death as death. Awareness of standard of potential donor: 13.4% (20/149) were aware of donation age, 40.9% (61/149) familiar with the donation criteria of liver and kidney function and 44.3% (66/149) knew the hepatitis B donation criteria. Necessity of brain death legislation: 79.2% (118/149) considered it necessary, 14.8% (22/149) unimportant and 6.0% (9/149) not necessary. How to manage donation after brain death: 43.6% (65/149) did not know how, 79.2% (118/149) were afraid and 30.9% (46/149) never considered. Family members: 0/879 knew about brain death, 98.6% (867/879) accepted the equivalence of brain death as death, 99.5% (875/879) approved the significance of donation after brain death and 47.0% (413/879) agreed with donation after brain death. The reasons for approving the significance of donation after brain death but not agreeing with donation: 80.5% (372/462) required a full corpse after death and 19.5% (90/462) for other reasons. Reasons for agreeing with donation but refuse: 50.1% (207/413) were opposed by other family members, 11.4% (47/413) beware of neighbors' chat about their organ trading, 9.2% (38/413) hoped to be paid and 8.0% (33/413) for the others. CONCLUSIONS: The cognitive deficits of donation after brain death for medical staff and family members, medical staff's worries about brain death legislation and traditional thoughts of family members are the main reasons for a low conversion rate of PD. A professional transplant coordinating team should be built for national organ donation knowledge education. PMID- 25146748 TI - [Effects of continuous sedation with propofol on peripheral blood mononuclear cell and intercellular adhesion molecule in beagles with combined burn-blast injuries]. AB - OBJECTIVE: To observe the effects of continuous sedation with propofol on peripheral blood mononuclear cell (PBMC) and intercellular adhesion molecule 1 (ICAM-1) in beagles with combined burn-blast injuries. METHODS: A total of 32 male beagles were randomly divided into 4 groups of normal control (NC), combined injury control (CC), propofol 1 (P1) and propofol 2 (P2) (n = 8 each). Except for NC group, the other 3 groups were subject to severe combined burn-blast injury. And sodium lactate Ringer's solution was infused after trauma according to the Parkland formula, including NC group. At the same time, P1 and P2 groups received continuous intravenous infusions of 2 mg*kg(-1)*h(-1), 5 mg*kg(-1)*h(-1) doses of propofol respectively for 72 hours. The serum concentrations of ICAM-1 and lymphocyte function associated antigen-1 (LFA-1) were measured by enzyme-linked immunosorbent assay (ELISA) at 6, 24, 48, 72 h post-injury. Flow cytometry was used to detect the major histocompatibility complex (MHC) antigen expression on CD14(+) monocytes, CD4(+)/CD8(+) T lymphocyte rate and PBMC apoptosis rate. RESULTS: The level of ICAM-1 in CC group ((10.5 +/- 1.1), (10.8 +/- 1.3), (12.3 +/- 1.4) ng/ml) was significantly higher than that in NC group ((7.4 +/- 1.4), (7.4 +/- 1.1), (7.4 +/- 1.6) ng/ml) at 12, 24, 48 h post-injury (all P < 0.05). The level of ICAM-1 in P1 group was significantly lower than that in CC group ((10.7 +/- 1.3) vs (12.3 +/- 1.4) ng/ml) while the level of ICAM-1 in P2 group was significantly lower than that in P1 group at 72 h post-injury ((8.8 +/- 1.4) vs (10.7 +/- 1.3) ng/ml) (both P < 0.05). The level of LFA-1 in CC group ((7.3 +/ 1.3), (8.4 +/- 1.3), (9.6 +/- 1.7) ng/ml) was significantly higher than that in NC group ((5.1 +/- 1.2), (5.4 +/- 1.3), (5.8 +/- 1.2) ng/ml) at 24, 48, 72 h post injury (all P < 0.05). MHC antigen expression on the CD14(+) monocytes of P2 group was obviously higher than that of CC and P1 groups ((46 +/- 13)% vs (26 +/- 15)% and (32 +/- 12)%, both P < 0.05). The CD4/CD8 rate in P1 and P2 was significantly higher than that in CC group (1.71 +/- 0.26, 1.82 +/- 0.31 and 1.81 +/- 0.24, 1.96 +/- 0.24 vs 1.41 +/- 0.34, 1.34 +/- 0.26) at 48, 72 h post-injury (all P < 0.05). At 72 h post injury, the PBMC apoptosis rate in CC and P1 group was obviously higher than that of the NC group ((2.57 +/- 0.21)% and (1.64 +/- 0.10)% vs (0.81 +/- 0.11)%) (both P < 0.01); the apoptosis rate in P2 group was significantly lower than that in P1 group ((1.09 +/- 0.15)% vs (1.64 +/- 0.10)%) (P < 0.01). CONCLUSION: Propofol may improve the immune function after combined burn-blast injuries through suppressing an excessive release of ICAM-1 and PBMC apoptosis in a concentration-dependent manner. PMID- 25146749 TI - [Effects of postconditioning on autophagy of lung ischemic reperfusion injury in rats]. AB - OBJECTIVE: To explore the effects of postconditioning on autophagy of lung injury in situ during lung ischemic reperfusion. METHODS: Twenty-four male Sprague Dawley rats were randomly divided into 3 groups of sham-operated (S), ischemic reperfusion (I/R) and ischemic postconditioning (IpostC) (n = 8 each). All underwent left thoracotomy after anesthesia. In the S group, a line was only placed around left hilum but not fastened. In the I/R group, a line was fastened to block the blood flow of left lung for 30 min and then loosened for reperfusion for 120 min. In the IpostC group, after blocking the blood flow of left lung for 30 min, left hilum was fastened for 30 sec and loosened for 30 sec. Lung tissues were measured by Western blot. Histopathological changes of lung tissues were observed, lung injury scores calculated and autophagic vacuoles determined by electron microscope. RESULTS: The relative expression levels of mammalian target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR) in group I/R (0.40 +/- 0.03, 0.33 +/- 0.10) were not different with those of group S (0.37 +/- 0.07, 0.31 +/- 0.10) (both P > 0.05). However, both significantly increased in group IpostC (0.46 +/- 0.09, 0.55 +/- 0.07) (both P < 0.05). As compared with group S, the relative expression level of LC3-IIand lung injury score significantly increased in groups I/R and IpostC (0.53 +/- 0.08, 0.38 +/- 0.03 vs 0.25 +/- 0.06; 15.79 +/ 1.33, 11.67 +/- 1.55 vs 5.58 +/- 0.39) while obviously declined in group IpostC versus group I/R (all P < 0.05). In group I/R, neutrophil infiltration, interstitial edema, atelectasis and hyaline membrane formation were observed microscopically in lung tissues and the formation of autophagic vacuoles was evident under electron microscope. The changes of group IpostC were milder than those of group I/R. CONCLUSIONS: Ischemic postconditioning has protective effects on lung ischemic reperfusion injury by attenuating autophagy. It may be related with strengthening mTOR. PMID- 25146750 TI - [Mechanism of endocannabinoids system in glucose metabolism of rats with chronic intermittent hypoxia]. AB - OBJECTIVE: To explore the mechanism of endocannabinoids system (ECS) in glucose metabolism of rats with chronic intermittent hypoxia (CIH). METHODS: According to random permutation table and experiment time, a total of 48 Wistar rats were randomly divided into 6 groups of 4/6-week control (filling with compressed air with 21% oxygen), 4/6-week CIH (CIH exposure for 8 hours per day) and 4/6-week CIH plus rimonabant group [an intraperitoneal injection of CB1 receptor antagonist rimonabant into liver (1 mg*kg(-1)*d(-1)) before CIH exposure] (n = 8 each). The levels of fasting plasma glucose, serum insulin, serum C-peptide and the expression of CB1 receptor in liver were detected after 4/6 weeks to evaluate the effects of CIH on the indices of glucose metabolism. RESULTS: The levels of the following indices in 4/6-week CIH group were significantly higher than those in 4/6-week control group: fasting plasma glucose (8.91 +/- 0.40), (10.61 +/- 0.36) vs (6.48 +/- 0.23), (6.51 +/- 0.25) mmol/L; serum insulin (16.72 +/- 3.76), (20.25 +/- 3.64) vs (9.02 +/- 2.05), (9.19 +/- 2.35) U/L; serum C-peptide (3.53 +/- 0.26), (5.23 +/- 0.29) vs (1.37 +/- 0.26), (1.41 +/- 0.41) ug/L; the expression of CB1 receptor in liver (0.290 +/- 0.026), (0.342 +/- 0.030) vs (0.214 +/- 0.023), (0.221 +/- 0.026) (all P < 0.05). Notably 6-week CIH group was significantly higher than 4-week CIH group (P < 0.05). And the above indices in 4/6-week CIH plus rimonabant group were significantly lower than others (both P < 0.05). The level of CB1 was significantly positively correlated with the levels of fasting plasma glucose, serum insulin and serum C-peptide (r = 0.856, 0.758, 0.827, all P < 0.05). CONCLUSION: ECS may contribute to abnormal glucose metabolism caused by CIH. PMID- 25146751 TI - [Roles of CXCL9 and CXCL10 in acute rejection after retransplantation in mice]. AB - OBJECTIVE: To observe the effects of chemokines CXCL9 and CXCL10 on cardiac allograft acute rejection mediated by alloreactive memory T cells in a retransplantation model. METHODS: Heart transplantation was performed 6 weeks after skin grafting. The mice were divided into 3 groups of control (direct heterotopic heart transplantation without skin grafting); experimental (heart transplantation after skin grafting) and syngraft (C57BL/6->C57BL/6, heterotopic heart transplantation) (n = 12 each). Graft survival and the pathological changes of cardiac graft were observed. And related gene expression in cardiac grafts and serum concentration of CXCL9/CXCL10 were detected. RESULTS: The mean survival time of control and experimental groups was 7.75 and 3.25 days respectively (P < 0.01).Serum concentrations of CXCL9 and CXCL10 in recipient mice were higher in the experimental group than those in the control group. Compared with the control group, the relative gene expressions of CXCL9 and CXCL10 were higher in the experimental group. According to pathological examinations, the histological rank of cardiac allograft was Grade 2.27 +/- 0.25 in the control group versus Grade 4.12 +/- 0.03 in the experimental group (P < 0.01). CONCLUSIONS: CXCL9 and CXCL10 play critical roles in retransplantation mediated by alloreactive memory T cells. And acute rejection of cardiac allograft is more extensive in retransplantation. PMID- 25146752 TI - A pre- and post-intervention study of infection control in equine hospitals in Sweden. AB - BACKGROUND: Detection of nosocomial methicillin-resistant Staphylococcus aureus infections in horses in Sweden has increased attention on infection control (IC) in equine hospitals. This study established baseline data on IC programmes within such settings, evaluated compliance with some IC procedures before and after an education intervention, and examined barriers to compliance.The study was carried out between 2008 and 2011 in four Swedish equine hospitals. Data on current IC of each hospital, purchase data on hand sanitisers and disposable gloves per patient, and direct observations of compliance with procedures were monitored pre and post-intervention. The intervention comprised a lecture on common IC and a review of each hospital's current procedures. For comparison, retrospective purchase data were reviewed. A questionnaire on individual compliance, experiences and opinions of IC was issued to employees. RESULTS: Three hospitals completed the study, while the fourth reported its IC procedures and completed the questionnaire. Actual numbers of procedures, content and level of documentation differed among the hospitals. Similarities were poor or absent IC implementation strategy, lack of active surveillance of compliance with procedures and no monitoring of such as nosocomial infections. Among the hospitals which completed the study, two reported pre-intervention observation of compliance, while all three reported post-intervention observations. The purchase data showed trends for changes over time, although not uniformly related to the intervention. One hospital demonstrated a significant post-intervention increase in compliance with glove procedures, accompanied by a non-significant post intervention increase in purchases figures. Compliance with dress code and personal appearance was high in all three hospitals (92-100%), while compliance with hand hygiene procedures was generally poorer. Barriers to compliance cited in the questionnaire (data from four hospitals) included insufficient supplies of hygiene products, lack of readily accessible places for cleaning, insufficient knowledge and high workload. CONCLUSIONS: Potential for easily attainable improvements in IC, such as traceability of documents, implementation strategies and surveillance of efficacy, was revealed. Attention to hand hygiene implementation and improvement of logistics appeared important. Data on purchases per patient were readily available and therefore applicable for intra-hospital surveillance of IC trends over time. PMID- 25146753 TI - Paradox and promise: research on the role of recent advances in paleodemography and paleoepidemiology to the study of "health" in Precolumbian societies. AB - Bioarcheology has made tremendous strides since the subdiscipline's inception, subsequent syntheses, the standardization of data collection methods, and analytical advances ranging from molecular analyses through age-estimation and biodistance. Concurrently, health and the adaptive success of past populations have remained primary concerns. However, questions are routinely raised about lesions and whether or not changing frequencies are synonymous with increases or decreases in stress, morbidity, and overall health. These include how and why healed lesions can simultaneously represent stress and survival, demanding that researchers understand how population dynamics influence skeletal sample formation. In this study, methods to analyze age- and sex-specific mortality patterns prior to, and in conjunction with, the analysis of linear enamel hypoplasias are demonstrated. Paleodemographic and paleoepidemiological models are presented for late Pre-Columbian skeletal samples from the Eastern Woodlands. Results of hazard modeling demonstrate that elevated mortality rates were commonplace during the latter half of the Mississippian period (AD 1200-1450) with reproductive-age females experiencing high age-specific risk of death attributed to the development of fortified villages and novel environments for increased pathogen loads. Corollary results are presented for the age-specificity of linear enamel hypoplasias in the central Illinois River valley. The epidemiological models demonstrate that the relationship between adult mortality and early childhood stress varied through space, culture, and time. These findings highlight the need to effectively operationalize measurements related to health and stress in past populations and support the adoption of selective mortality and heterogeneity in frailty as key concepts in bioarcheological research. Am J Phys Anthropol 155:268-280, 2014. (c) 2014 Wiley Periodicals, Inc. PMID- 25146754 TI - Circulating miR-1, miR-133a, and miR-206 levels are increased after a half marathon run. AB - CONTEXT: Circulating miRNAs are potential biomarkers that can be important molecules driving cell-to-cell communication. OBJECTIVE: To investigate circulating muscle-specific miRNAs in recreational athletes. MATERIALS AND METHODS: Three miRNAs from whole plasma before and after a half-marathon were analyzed by qPCR. RESULTS: MiR-1, -133a, and -206 significantly increased after the race. DISCUSSION: Increased levels of miRNAs after exercise point to potential biomarkers and to the possibility of being functional players following endurance training. CONCLUSION: These miRNAs are potential biomarkers of muscle damage or adaptation to exercise. PMID- 25146755 TI - A video protocol of retroviral infection in primary intestinal organoid culture. AB - Lgr5-positive stem cells can be supplemented with the essential growth factors Egf, Noggin, and R-Spondin, which allows us to culture ever-expanding primary 3D epithelial structures in vitro. Both the architecture and physiological properties of these 'mini-guts', also called organoids, closely resemble their in vivo counterparts. This makes them an attractive model system for the small intestinal epithelium. Using retroviral transduction, functional genetics can now be performed by conditional gene overexpression or knockdown. This video demonstrates the procedure of organoid culture, the generation of retroviruses, and the retroviral transduction of organoids to assist phenotypic analysis of the small intestinal epithelium in vitro. This novel organotypic model system in combination with retroviral mediated gene expression provides a valuable tool for rapid analysis of gene function in vitro without the need of costly and time consuming generation for transgenic animals. PMID- 25146756 TI - Effects of maropitant citrate or acepromazine on the incidence of adverse events associated with hydromorphone premedication in dogs. AB - BACKGROUND: Vomiting is a common complication associated with the use of hydromorphine for pre-emptive analgesia in dogs. The ideal anti-emetic protocol for prevention of this complication has not been established. HYPOTHESIS: Maropitant administered concurrently or before hydromorphone would reduce the incidence of vomiting, signs of nausea, ptyalism, and increased panting compared to administration of acepromazine or a 0.9% saline control. ANIMALS: Sixty mixed breed female dogs scheduled for ovariohysterectomy. METHODS: Randomized, blinded, placebo-controlled experimental study. Dogs were assigned to 4 experimental groups with 15 dogs per group. All groups received 0.2 mg/kg of hydromorphone IM. Group "Control" received 0.1 mL/kg saline SC 30-45 minutes before hydromorphone, group "Marop1" received 1 mg/kg maropitant SC 30-45 minutes before hydromorphone, group "Ace" received 0.02 mg/kg IM acepromazine 30-45 minutes before hydromorphone, and group "Marop2" received 1 mg/kg SC maropitant concurrently with hydromorphone. A trained and blinded observer documented adverse events from the time hydromorphone was administered until the time dogs were induced for surgery. RESULTS: Marop1 had significantly less vomiting (0%) compared to Control (87%; P < .01) and Ace (53%; P < .01). Marop2 had significantly less vomiting (27%) compared to Control (P < .01). Marop1 had significantly greater incidence of ptyalism (73%) compared to Ace (P < .01; 20%). Ace showed significantly less panting (33%) compared to Marop2 (93%; P < .01). CONCLUSIONS AND CLINICAL IMPORTANCE: In healthy dogs, maropitant citrate administered before hydromorphone significantly decreases the incidence of vomiting in dogs but does not improve signs of nausea, ptyalism, or increased panting. PMID- 25146757 TI - Ultrasound-guided transthoracic intramyocardial injection in mice. AB - Murine models of cardiovascular disease are important for investigating pathophysiological mechanisms and exploring potential regenerative therapies. Experiments involving myocardial injection are currently performed by direct surgical access through a thoracotomy. While convenient when performed at the time of another experimental manipulation such as coronary artery ligation, the need for an invasive procedure for intramyocardial delivery limits potential experimental designs. With ever improving ultrasound resolution and advanced noninvasive imaging modalities, it is now feasible to routinely perform ultrasound-guided, percutaneous intramyocardial injection. This modality efficiently and reliably delivers agents to a targeted region of myocardium. Advantages of this technique include the avoidance of surgical morbidity, the facility to target regions of myocardium selectively under ultrasound guidance, and the opportunity to deliver injectate to the myocardium at multiple, predetermined time intervals. With practiced technique, complications from intramyocardial injection are rare, and mice quickly return to normal activity on recovery from anesthetic. Following the steps outlined in this protocol, the operator with basic echocardiography experience can quickly become competent in this versatile, minimally invasive technique. PMID- 25146758 TI - The Chlamydia protease CPAF: caution, precautions and function. PMID- 25146759 TI - Cytotoxic and nitric oxide production-inhibitory activities of limonoids and other compounds from the leaves and bark of Melia azedarach. AB - Nine limonoids, 1-9, one apocarotenoid, 11, one alkaloid, 12, and one steroid, 13, from the leaf extract; and one triterpenoid, 10, five steroids, 14-18, and two flavonoids, 19 and 20, from the bark extract of Melia azedarach L. (Chinaberry tree; Meliaceae) were isolated. Among these compounds, three compounds, 4-6, were new, and their structures were established as 3-deacetyl-28 oxosalannolactone, 3-deacetyl-28-oxosalanninolide, and 3-deacetyl-17-defurano 17,28-dioxosalannin, respectively, on the basis of extensive spectroscopic analyses and comparison with literature data. All of the isolated compounds were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines. 3-Deacetyl-4'-demethyl 28-oxosalannin (3) against HL60 and AZ521 cells, and methyl kulonate (10) against HL60 cells exhibited potent cytotoxicities with IC50 values in the range of 2.8 5.8 MUM. In addition, upon evaluation of compounds 1-13 against production of nitric oxide (NO) in mouse macrophage RAW 264.7 cells induced by lipopolysaccharide (LPS), seven, i.e., trichilinin B (1), 4, ohchinin (7), 23 hydroxyohchininolide (8), 21-hydroxyisoohchininolide (9), 10, and methyl indole 3 carboxylate (12), inhibited production of NO with IC50 values in the range of 4.6 87.3 MUM with no, or almost no, toxicity to the cells (IC50 93.2-100 MUM). Western blot analysis revealed that compound 7 reduced the expression levels of the inducible NO synthase (iNOS) and COX-2 proteins in a concentration-dependent manner. Furthermore, compounds 5, 6, 13, and 18-20 exhibited potent inhibitory effects (IC50 299-381 molar ratio/32 pmol TPA) against Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cell line. PMID- 25146760 TI - Adsorbents for apheresis prepared from polysaccharides of algae that threaten ecosystem services. AB - In this work, we investigated whether materials isolated from algae that threaten ecosystems can be used for human benefit. We converted acidic polysaccharides (ulvan) from the alga Ulva pertusa into soft hydrogel materials. In addition to ulvan, the hydrogels also contained alginate in a polyion complex with chitosan. Cross-linking the hydrogel with glutaraldehyde reduced polysaccharide elution from the polyion complex gel. We also found that both ulvan-chitosan and alginate chitosan gels were able to remove urea and heavy metals from aqueous solution. This is clinically significant, since during apheresis, toxic compounds such as urea have to be removed from the bloodstream of patients. Importantly, albumin was not removed by the hydrogels, implying that this vital protein can be returned to the bloodstream following dialysis. PMID- 25146761 TI - Binding pockets and pathways for dioxygen through the KijD3 N-oxygenase in complex with flavin mononucleotide cofactor and a 3-aminoglucose substrate: predictions from molecular dynamics simulations. AB - In this work, two protein systems, Kij3D-FMN-AKM-O2 and Kij3D-FMN-O2 , made of KijD3 N-oxygenase, flavin mononucleotide (FMN) cofactor, dTDP-3-amino-2,3,6 trideoxy-4-keto-3-methyl-D-glucose (AKM) substrate, and dioxygen (O2), have been assembled by adding a molecule of O2, and removing (or not) AKM, to crystal data for the Kij3D-FMN-AKM complex. Egress of AKM and O2 from these systems was then investigated by applying a tiny external random force, in turn, to their center of mass in the course of molecular dynamics in explicit H2 O. It turned out that the wide AKM channel, even when emptied, does not constitute the main route for O2 egress. Other routes appear to be also viable, while various binding pockets (BPs) outside the active center are prone to trap O2. By reversing the reasoning, these can also be considered as routes for uptake of O2 by the protein, before or after AKM uptake, while BPs may serve as reservoirs of O2. This shows that the small molecule O2 is capable of permeating the protein by exploiting all nearby interstices that are created on thermal fluctuations of the protein, rather than having necessarily to look for farther, permanent channels. PMID- 25146762 TI - Solution synthesis, conformational analysis, and antimicrobial activity of three alamethicin F50/5 analogs bearing a trifluoroacetyl label. AB - We prepared, by solution-phase methods, and fully characterized three analogs of the membrane-active peptaibiotic alamethicin F50/5, bearing a single trifluoroacetyl (Tfa) label at the N-terminus, at position 9 (central region) or at position 19 (C-terminus), and with the three Gln at positions 7, 18, and 19 replaced by Glu(OMe) residues. To add the Tfa label at position 9 or 19, a gamma trifluoroacetylated alpha,gamma-diaminobutyric acid (Dab) residue was incorporated as a replacement for the original Val(9) or Glu(OMe)(19) amino acid. We performed a detailed conformational analysis of the three analogs (using FT-IR absorption, CD, 2D-NMR, and X-ray diffraction), which clearly showed that Tfa labeling does not introduce any dramatic backbone modification in the predominantly alpha-helical structure of the parent peptaibiotic. The results of an initial solid-state (19)F-NMR study on one of the analogs favor the conclusion that the Tfa group is a very promising reporter for the analysis of peptaibiotic?membrane interactions. Finally, we found that the antimicrobial activities of the three newly synthesized analogs depend on the position of the Tfa label in the peptide sequence. PMID- 25146763 TI - Insecticidal metabolites from the rhizomes of Veratrum album against adults of Colorado potato beetle, Leptinotarsa decemlineata. AB - The dried rhizomes of Veratrum album were individually extracted with CHCl3 , acetone, and NH4 OH/benzene to test the toxic effects against the Colorado potato beetle, Leptinotarsa decemlineata, which is an important agricultural pest. Fifteen compounds in various amounts were isolated from the extracts using column and thin-layer chromatography. The chemical structures of 14 compounds were characterized as octacosan-1-ol (1), beta-sitosterol (2), stearic acid (3), diosgenin (4), resveratrol (5), wittifuran X (6), oxyresveratrol (7), beta sitosterol 3-O-beta-D-glucopyranoside (8), diosgenin 3-O-alpha-L-rhamnopyranosyl (1 -> 2)-beta-D-glucopyronoside (9), oxyresveratrol 3-O-beta-D-glucopyranoside (10), jervine (11), pseudojervine (13), 5,6-dihydro-1-hydroxyjervine (14), and saccharose (15) using UV, IR, MS, (1) H- and (13)C-NMR, and 2D-NMR spectroscopic methods. However, the chemical structure of 12, an oligosaccharide, has not fully been elucidated. Compounds 4, 6, 9, and 10 were isolated from V. album rhizomes for the first time in the current study. The toxic effects of three extracts (acetone, CHCl3 , and NH4 OH/benzene) and six metabolites, 2, 2+4, 5, 7, 8, and 11, were evaluated against the Colorado potato beetle. The assay revealed that all three extracts, and compounds 7, 8, and 11 exhibited potent toxic effects against this pest. This is the first report on the evaluation of the toxic effects of the extracts and secondary metabolites of V. album rhizomes against L. decemlineata. Based on these results, it can be concluded that the extracts can be used as natural insecticides. PMID- 25146764 TI - Essential-oil diversity of Salvia tomentosa Mill. in Greece. AB - Salvia tomentosa essential oils from Greece were studied for the first time here. The oils from five populations growing in Mediterranean pine forests on the island of Thassos (northern Aegean Sea) and from 14 populations situated in deciduous forests in Thrace (northeastern Greek mainland) were investigated. Their essential-oil contents ranged from 1.1 to 3.3% (v/w, based on the dry weight of the plant material). The populations from Thassos had high contents of alpha-pinene (18.0 +/- 2.9%), 1,8-cineole (14.7 +/- 3.0%), cis-thujone (14.0 +/- 6.9%), and borneol (12.8 +/- 2.2%) and smaller amounts of camphene, camphor, and beta-pinene, whereas the populations from Thrace showed high alpha-pinene (16.7 +/- 4.0%), beta-pinene (22.8 +/- 4.5%), camphor (18.3 +/- 4.3%), and camphene (10.3 +/- 2.4%) contents, much lower 1,8-cineole and borneol amounts, while cis thujone was completely lacking. The comparison of the present results with published data showed that oils having cis-thujone as one of the main compounds were reported for the first time here. Multivariate statistical analyses indicate that the observed essential-oil variation was related to geographical and environmental factors. PMID- 25146765 TI - Chemical composition and phytotoxic effects of essential oils obtained from Ailanthus altissima (Mill.) swingle cultivated in Tunisia. AB - Ailanthus altissima Mill. Swingle (Simaroubaceae), also known as tree of heaven, is used in the Chinese traditional medicine as a bitter aromatic drug for the treatment of colds and gastric diseases. In Tunisia, Ailanthus altissima is an exotic tree, which was introduced many years ago and used particularly as a street ornamental tree. Here, the essential oils of different plant parts of this tree, viz., roots, stems, leaves, flowers, and samaras (ripe fruits), were obtained by hydrodistillation. In total, 69 compounds, representing 91.0-97.2% of the whole oil composition, were identified in these oils by GC-FID and GC/MS analyses. The root essential oil was clearly distinguishable for its high content in aldehydes (hexadecanal (1); 22.6%), while those obtained from flowers and leaves were dominated by oxygenated sesquiterpenes (74.8 and 42.1%, resp.), with caryophyllene oxide (4) as the major component (42.5 and 22.7%, resp.). The samara oil was rich in the apocarotenoid derivative hexahydrofarnesyl acetone (6; 58.0%), and the oil obtained from stems was characterized by sesquiterpene hydrocarbons (54.1%), mainly beta-caryophyllene (18.9%). Principal component and hierarchical cluster analyses separated the five essential oils into four groups, each characterized by the major oil constituents. Contact tests showed that the germination of lettuce seeds was totally inhibited by all the essential oils except of the samara oil at a dose of 1 mg/ml. The flower oil also showed a significant phytotoxic effect against lettuce germination at 0.04 and 0.4 mg/ml ( 55.0 +/- 3.5 and -85.0 +/- 0.7%, resp.). Moreover, the root and shoot elongation was even more affected by the oils than germination. The inhibitory effect of the shoot and root elongation varied from -9.8 to -100% and from -38.6 to -100%, respectively. Total inhibition of the elongation (-100%) at 1 mg/ml was detected for all the oils, with the exception of the samara oil (-74.7 and -75.1% for roots and shoots, resp.). PMID- 25146766 TI - Essential oil from black currant buds as chemotaxonomy marker and antimicrobial agent. AB - Dormant buds are recognized as valuable side product of the blackcurrant cultivation. Four blackcurrant varieties cultivated in Serbia, i.e., Ben Sarek, Ometa, Ben Lomond, and Ben Nevis, were evaluated for the content, chemical composition, and antimicrobial activity of their bud essential oils. The oil yields of buds harvested during two different growth periods ranged from 1.2 2.0%, and the variety Ometa had the highest yield among the tested varieties. GC FID and GC/MS analysis of the oils allowed the identification of eight main components, i.e., alpha-pinene (1.6-5.4%), sabinene (1.9-38.4%), delta-car-3-ene (13.0-50.7%), beta-phellandrene (2.9-18.0%), terpinolene (6.6-11.9%), terpinen-4 ol (0.9-6.6%), beta-caryophyllene (3.8-10.4%), and alpha-humulene (0.2-4.1%). In addition, the similarity degree of the essential-oil compositions of buds harvested from the upper and lower parts of the shrubs was investigated by hierarchical clustering. All essential oils originating from the same genotype were grouped in the same cluster, indicating the reliability of essential oils as chemotaxonomic markers. For more detailed chemotaxonomic investigations, the three compounds with the greatest variance were chosen, i.e., sabinene, delta-car 3-ene, and beta-phellandrene, which proved to be efficient for the variety distinction. Factor analysis showed that the essential-oil composition as chemotaxonomic marker in blackcurrants was more reliable for variety Ben Sarek than for variety Ben Nevis. Moreover, it was demonstrated that the essential oils had very strong inhibitory activity against all tested microorganisms. Fungi were more sensitive than bacteria; indeed their growth was completely inhibited at much lower concentrations. In comparison to commercial antibiotics, significantly lower concentrations of the oils were necessary for the complete inhibition of fungal growth. PMID- 25146767 TI - Microjaponin, a new dihydroagarofuranoid sesquiterpene from the stem of Microtropis japonica with antituberculosis activity. AB - A new dihydroagarofuran-based sesquiterpene, microjaponin (1), was isolated from the stem of Microtropis japonica. Its structure was determined by in-depth spectroscopic and mass-spectrometric analyses. Microjaponin (1) exhibited potent in vitro antituberculosis activity, with an MIC value of 12.5 MUg/ml against Mycobacterium tuberculosis H37 Rv. PMID- 25146768 TI - Phytotoxic potential of Onopordum acanthium L. (Asteraceae). AB - Onopordum acanthium L. (Asteraceae) is a plant native to southern Europe and southwestern Asia, but it is invasive in disturbed areas and agricultural fields around the world, causing many agronomic problems by interfering with crops or preventing animals from grazing on pastures. Allelopathy could be one of the reasons that this plant has spread over different continents. The aim of the present study was to bioprospect O. acanthium leaf extracts through the isolation and purification of allelopathic secondary metabolites with phytotoxicity to explain their invasive behavior. Phytotoxic activity was tested using etiolated wheat coleoptiles. The most active extract was selected to perform a bioassay guided isolation of two flavonoids, pectolarigenin (1) and scutellarein 4'-methyl ether (2), and two sesquiterpene lactones, elemanolide 11(13)-dehydromelitensin beta-hydroxyisobutyrate (3) and acanthiolide (4). All compounds were isolated for the first time from O. acanthium, and acanthiolide (4) is described for the first time. Compound 3 strongly inhibited the growth of wheat coleoptiles and 1 showed an intermediate effect. The results indicate that these compounds could contribute to the invasion of O. acanthium in ecological systems and agricultural fields. PMID- 25146769 TI - Structure-activity relationships of strychnine analogs at glycine receptors. AB - Nine strychnine derivatives including neostrychnine, strychnidine, isostrychnine, 21,22-dihydro-21-hydroxy-22-oxo-strychnine, and several hydrogenated analogs were synthesized, and their antagonistic activities at human alpha1 and alpha1beta glycine receptors were evaluated. Isostrychnine has shown the best pharmacological profile exhibiting an IC50 value of 1.6 MUM at alpha1 glycine receptors and 3.7-fold preference towards the alpha1 subtype. SAR Analysis indicates that the lactam moiety and the C(21) = C(22) bond in strychnine are essential structural features for its high antagonistic potency at glycine receptors. PMID- 25146770 TI - Total mercury in sediments, macrophytes, and fish from a shallow steppe lake in eastern Austria. AB - During summer 2011, samples of sediment, macrophytes, and fish tissues from the shallow, slightly alkaline Lake Neusiedl, Austria, were evaluated for their total Hg content. This is the first report of Hg levels from this lake. Sediments displayed Hg contents between 0.025 and 0.113 MUg g(-1) dw (dry weight), significantly correlating with the proportion of organic components pointing to a small anthropogenic impact on the lake's Hg content. Hg Levels in plants and fish were unexpectedly high: both investigated submerged plant species, Potamogeton pectinatus and Myriophyllum spicatum, showed mean values of 0.245 +/- 0.152 and 0.298 +/- 0.115 MUg g(-1) dw, respectively. Biomagnification was evident when comparing muscle samples of the planktivorous fish species rudd Scardinus erythrophthalmus (n = 10, mean = 0.084 MUg g(-1) ww (wet weight)) with the piscivorous perch Perca fluviatilis (n = 21, mean = 0.184 MUg g(-1) ww) or pike perch Sander lucioperca (n = 9, mean = 0.205 MUg g(-1) ww). Significantly lower values were found in the muscle of the piscivorous pike Esox lucius (n = 25, mean = 0.135 MUg g(-1) ww), pointing to a specific Hg metabolism of this fish, presumably under the particular physicochemical properties of the lake. Hg Concentrations in fish could pose a risk to piscivorous birds in this protected wetland system. PMID- 25146771 TI - [Comments to the article: "Endobronchial stent for the treatment of atraumatic rupture of the left bronchial due to a bull horn. Anesthetic implications"]. PMID- 25146772 TI - [Perioperative considerations for performing a brain biopsy on a patient with subtype VV2 sporadic Creutzfeldt-Jakob disease]. AB - Creutzfeldt-Jakob disease (CJD) is the most common transmissible spongiform encephalopathy. It is an infectious, progressive, degenerative neurological disorder, with a presumably long incubation period, but a rapid fatal course. CJD is transmitted by a proteinaceous infectious agent, or "prion". Because the prions are difficult to eradicate and are resistant to the currently used sterilization methods, special precautions must be taken with all surgical instruments. It is recommended the single-use equipment, destruction of contaminated equipment, decontamination of reusable instruments, use of protective clothing, and storing and quarantining surgical instruments. The single-use equipment and some tissues and body fluids from the patient with CJD are highly infectious and must be incinerated. We report a case of a patient who had undergone brain biopsy for suspected of CJD, being confirmed to have sporadic CJD. Specific preventive measures were taken to reduce the risk of transmission to healthcare workers. PMID- 25146773 TI - [Preoperative tests recommendations in adult patients for ambulatory surgery]. AB - Anesthetic assessment traditionally included a series of laboratory tests intended to detect undiagnosed diseases, and to ensure that the patient undergoes surgery following safety criteria. These tests, without a specific clinical indication, are expensive, of questionable diagnostic value and often useless. In the context of outpatient surgery, recent evidence suggests that patients of any age without significant comorbidity, ASA physical status gradei and grade ii, do not need additional preoperative tests routinely. The aim of the present recommendations is to determine the general indications in which these tests should be performed in ASA gradei and grade ii patients undergoing ambulatory surgery. PMID- 25146774 TI - Renal and hepatic integrity in long-term sevoflurane sedation using the anesthetic conserving device: a comparison with intravenous propofol sedation in an animal model. AB - INTRODUCTION: Critically ill patients are sedated with intravenous agents because the use of inhaled agents is limited by their potential risk of toxicity. Increasing levels of inorganic fluorides after the metabolism of these agents have been considered potentially nephrotoxic. However, hepatic involvement after prolonged administration of sevoflurane has not yet been studied. The present study evaluated the potential renal and hepatic toxicity caused by prolonged administration (72h) of sevoflurane. METHODS: For this experimental, prospective, randomized, controlled trial, 22 Landrace x Large-White female pigs were randomly assigned to two groups: intravenous propofol (P) or inhaled sevoflurane via the AnaConDaTM device (S, end-tidal 2.5 vol%). The P group remained sedated for 108h with propofol. In the S group, sevoflurane was administered for 72h and then changed to propofol for the remaining 36h in order to observe the kinetics of fluoride after discontinuation of sevoflurane. Serum creatinine was the primary outcome variable, but inorganic fluoride concentrations and other renal, hepatic, and cardiorespiratory variables were also measured. RESULTS: Both groups of animals were comparable at baseline. No differences were found between the two groups for plasma creatinine and urea or creatinine clearance throughout the study. Fluoride levels were significantly higher in the sevoflurane group. No correlation was found between inorganic fluoride and serum creatinine values. No significant differences were observed for hepatic function. Hemodynamic, respiratory, and blood gas variables were comparable between the groups. CONCLUSIONS: Long-term sedation with sevoflurane using AnaConDaTM or propofol does not negatively affect renal or hepatic function. PMID- 25146775 TI - [Comment on perioperative managment of ACE inhibitors and ARBs]. PMID- 25146776 TI - [Anatomical description of laryngeal ultrasound windows]. PMID- 25146777 TI - All in the mind. PMID- 25146778 TI - Pragmatic not defeatist. PMID- 25146779 TI - Orthotropics: Will we never be free? PMID- 25146780 TI - Cherry-picked references. PMID- 25146781 TI - ARF hike: Together we are stronger. PMID- 25146782 TI - Eschewing science. PMID- 25146783 TI - Raising standards. PMID- 25146784 TI - Oral surgery: The role of microbiology. PMID- 25146785 TI - Fitness to practise: Unbelievably arrogant. PMID- 25146786 TI - Antibiotic resistance: Educate your colleagues. PMID- 25146787 TI - Facial burns: Reducing risks. PMID- 25146789 TI - Meet your MP and voice your concerns. PMID- 25146790 TI - Dental art: Dentistry through art. Part 7. PMID- 25146791 TI - All clinical trials should be registered prospectively. PMID- 25146792 TI - Recording jaw injuries in wartime. PMID- 25146793 TI - The face of dentistry in Wales retires. PMID- 25146796 TI - Prehistoric plaque proves plant processing. PMID- 25146802 TI - Response to the 2014 Malcolm Pendlebury lecture. AB - On 12 June, General Dental Council Chair, Bill Moyes addressed the Faculty of General Dental Practice (UK) at its Malcolm Pendlebury lecture. Its contents have been subject to scrutiny, following the proposed substantial increase of the annual retention fee (ARF) and advertisements encouraging patient complaints. This article seeks to address concerns regarding the GDC's role and responsibilities. PMID- 25146803 TI - Pre- and post-operative management of dental implant placement. Part 2: management of early-presenting complications. AB - Despite morbidity factors that include pain and complications with healing, there is currently little available guidance regarding optimal pre-and post-operative protocols for dental implant placement. While the first paper of this two-part series discussed the management of post-operative pain, the second instalment reviews pre- and post-operative means of managing early complications associated with dental implant placement. PMID- 25146804 TI - Planning for future provision of dental services in prison: an international proposal of two systems. AB - This article describes a proposal for the future organisation of the delivery of dental and oral health services for prisoners. This vision is based on an analysis of the existing prison dental programmes in England and the United States (Federal Bureau of Prisons, [FBOP]), together with discussions from two key individuals from both countries who championed changes to prison dental services and have published in the field of prison dental services. Both countries have similar visions. Some of the suggested work has already been addressed in the past (for example, introduction of state of the art dental facilities in the UK prison setting), some are in process (for example, electronic patients' records) and some may be addressed in the near future (for example, prisoners' involvement with the services provided for them). Some of the expressed visions for the future in this article are driven by evidence-based literature and dental workforce policy. PMID- 25146809 TI - Summary of: Reporting of occupational exposures to blood and body fluids in the primary dental care setting in Scotland: an evaluation of current practice and attitudes. PMID- 25146810 TI - Summary of: The fluoride contents of commercially-available soya milks in the UK. PMID- 25146811 TI - Update on guidelines for selecting appropriate patients to receive treatment with dental implants: priorities for the NHS--the position after 15 years. AB - In 1997 the Faculty of Dental Surgery (Royal College of Surgeons, England) as part of a wider publication produced guidance on prioritisation for the selection of patients to receive treatment with dental implants within the NHS in the UK (http://www.rcseng.ac.uk/fds/publications-clinical guidelines/clinical_guidelines/index.html). This update considers eight main groups who may benefit from treatment with osseointegrated implants. Where patients are being considered for implant-based rehabilitation, treatment plans must be weighed up against the risks, benefits and outcomes outlined in evidence based research. PMID- 25146812 TI - Evidence-based dentistry--overcoming the challenges for the UK's dental practitioners. AB - This paper describes the historical origins and purpose of 'evidence-based practice' and describes the barriers to the growth of evidence-based practice within dentistry. It describes a new research agenda-setting process for dentistry, which includes identifying and prioritising the topics of most relevance to the work of primary dental care practitioners. By undertaking the work described in this paper we were striving to make research more relevant to the day to day decisions made by dentists in practice by introducing a new process, the intention being to promote and promulgate the practice of evidence based dentistry. PMID- 25146830 TI - Reporting of occupational exposures to blood and body fluids in the primary dental care setting in Scotland: an evaluation of current practice and attitudes. AB - OBJECTIVES: To evaluate experience, practice and beliefs regarding occupational exposures to blood and oral fluids among a random sample of 300 dentists working in Scotland's NHS primary dental services. METHOD: A cross-sectional postal survey assessed occupational exposure policies and procedures, recent occupational exposure incidence and current management. Beliefs were measured using constructs from the theory of planned behaviour, shown to influence behaviour in this population. RESULTS: Forty-two percent of dentists responded. Fourteen percent had sustained an occupational exposure in the previous 12 months; of those, 35% did not report their exposure. All respondents' practices had protocols in place for managing and reporting dental team member sharps injuries. Most (82%) had protocols for mucocutaneous exposures. Less than half (48%) had a protocol for managing and reporting patient exposures to blood or saliva. Dentists placed significantly more importance (z-score -4.44, p value <0.001) and necessity (z-score -4.17, p value <0.001) on reporting patient exposure than dentist occupational exposure. CONCLUSION: This study suggests that while dentists generally have positive beliefs about reporting occupational exposures, there are gaps in practice. PMID- 25146831 TI - The fluoride contents of commercially-available soya milks in the UK. AB - BACKGROUND: In some parts of the world, soya milks are found to be a significant source of fluoride (F). Among western commercial markets, although there has been a sustained increase in soya milk products available for purchase, there are limited data on their F content. OBJECTIVE: To determine the F content of soya milk products available in the UK market including fresh and ultra-high temperature products in addition to sweetened and unsweetened soya milks. MATERIALS AND METHODS: Fifty-two traditional and UK-produced soya milk samples commercially available in northeast England were analysed to determine their F concentration using a modified hexamethyldisiloxane-facilitated diffusion method with a F-ion-selective electrode coupled to a potentiometer. RESULTS: The median F concentration of all products was 0.293 MUg/ml ranging from 0.015 MUg/ml to 0.964 MUg/ml. The median F concentration of ultra-high temperature (UHT) (n = 42) milks was 0.272 MUg/ml lower than 0.321 MUg/ml obtained for fresh (n = 10) soya milks. Organic soya milks contained less F compared with non-organic for sweetened and unsweetened categories. CONCLUSION: Commercially available soya milks in the UK do not pose an increased risk for dental fluorosis development. Further research is necessary into the manufacturing process of soya milks, which may influence the overall F content of the end product. PMID- 25146832 TI - Regulation of competence and gene expression in Streptococcus mutans by the RcrR transcriptional regulator. AB - An intimate linkage between the regulation of biofilm formation, stress tolerance and genetic competence exists in the dental caries pathogen Streptococcus mutans. The rcrRPQ genes encode ABC exporters (RcrPQ) and a MarR-family transcriptional repressor of the rcr operon (RcrR) that play a dominant role in the regulation of the development of genetic competence and connect competence with stress tolerance and (p)ppGpp production in S. mutans. Here we identify the target for efficient RcrR binding in the rcr promoter region using purified recombinant RcrR (rRcrR) protein in electrophoretic mobility shift assays and show that DNA fragments carrying mutations in the binding region were not bound as efficiently by rRcrR in vitro. Mutations in the RcrR binding site impacted expression from the rcrR promoter in vivo and elicited changes in transformation efficiency, competence gene expression, and growth inhibition by competence-stimulating peptide; even when the changes in rcrRPQ transcription were minor. An additional mechanistic linkage of RcrR with competence and (p)ppGpp metabolism was identified by showing that the rRcrR protein could bind to the promoter regions of comX, comYA and relP, although the binding was not as efficient as to the rcrRPQ promoter under the conditions tested. Hence, tightly controlled autogenous regulation of the rcrRPQ operon by RcrR binding to specific target sites is essential for cellular homeostasis, and RcrR contributes to the integration of genetic competence, (p)ppGpp metabolism, and acid and oxidative stress tolerance in S. mutans through both direct and indirect mechanisms. PMID- 25146833 TI - Epithelial dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness. AB - BACKGROUND: Gastric dysplasia is classified as adenomatous/type I (intestinal phenotype) and foveolar or pyloric/type II (gastric phenotype) according to morphological (architectural and cytological) features. The immunophenotypic classification of dysplasia, based on the expression of the mucins, CD10 and CDX2, recognizes the following immunophenotypes: intestinal (MUC2, CD10, and CDX2); gastric (MUC5AC and/or MUC6, absence of CD10, and absent or low expression of CDX2); hybrid (gastric and intestinal markers); and null. METHODS: Sixty-six cases of nonpolypoid epithelial dysplasia of the stomach were classified according to morphological features (histotype and grade) and immunophenotype. Immunohistochemical staining was performed with antibodies against MUC2, MUC5AC, MUC6, CD10, CDX2, chromogranin, synaptophysin, Ki-67, and TP53. HER2 alterations were analyzed by immunohistochemistry and silver-enhanced in situ hybridization. RESULTS: By conventional histology, dysplasia was classified as adenomatous/intestinal (n = 42; 64 %) and foveolar or pyloric/gastric (n = 24; 36 %) and graded as low grade (n = 37; 56 %) or high grade (n = 29; 44 %). Immunophenotypic classification showed intestinal (n = 22; 33.3 %), gastric (n = 25; 37.9 %), hybrid (n = 17; 25.8 %), or null (n = 2; 3.0 %) phenotypes. In 20 cases a coexistent intramucosal carcinoma was identified. The intestinal immunophenotype was shown to be significantly associated with low-grade dysplasia (p = 0.001), high expression of CDX2 (p = 0.015), TP53 (p = 0.034), synaptophysin (p = 0.003), and chromogranin (p < 0.0001); the gastric immunophenotype was significantly associated with high-grade dysplasia (p = 0.001), high Ki-67 proliferative index (p = 0.05), and coexistence of intramucosal carcinoma (p = 0.013). HER2 amplification was observed in 3 cases, typed as gastric or hybrid. CONCLUSIONS: Epithelial nonpolypoid dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness and may represent the putative precursor lesion in a pathway of gastric carcinogenesis originated de novo from the native gastric mucosa, leading to gastric-type adenocarcinoma. PMID- 25146834 TI - Comment to the paper: The response and survival of children with recurrent diffuse intrinsic pontine glioma based on phase II study of antineoplastons A10 and AS2-1 in patients with brainstem glioma : Stanislaw R. Burzynski, Tomasz J. Janicki, Gregory S. Burzynski, Ania Marszalek. PMID- 25146835 TI - Ventricular access device infection rate: a retrospective study and review of the literature. AB - PURPOSE: Ventricular access devices (VAD) are often used for treatment of posthemorrhagic hydrocephalus (PHH) in preterm infants. The reported rates of infection have varied and range from 0 to 22 %. The objective of our study is to present our VAD associated infection at our institution. METHODS: The charts for patients that had VADs inserted between May 1, 2009 and October 31, 2013 at a single institution (Children's Healthcare of Atlanta) were retrospectively reviewed. The number of VAD infections, defined as either cerebrospinal fluid (CSF)-positive cultures or wound complication, was recorded. Of patients that survived, the number of VAD to shunt conversions was also examined. The data from 15 previously published studies were pooled to determine overall VAD infection and VAD to shunt conversion rates. RESULTS: A total of 142 VADs were placed. There were 13 infections (9.2 %), 11 of which had CSF-positive cultures (7.7 %). There were two wound complications with negative CSF cultures. Six patients died after VAD placement for reasons unrelated to their VAD surgeries (4.2 %). In the remaining patients, there were 113 VAD to shunt conversions (83.1 %). Fifteen studies that reported VAD infections were analyzed; an overall infection rate of 7.0 % and VAD to shunt conversion rate of 79 % were calculated. CONCLUSIONS: While VAD is a valuable tool to treat PHH, it remains a procedure with an infection rate between 7.0 and 8.0 %. Close follow-up is needed to capture these adverse events as early as possible. Approximately 80 % of patients with PHH will require permanent CSF diversion. PMID- 25146836 TI - Early childhood diarrhoeal diseases and cognition: are we missing the rest of the iceberg? AB - Risk factors which interfere with cognitive function are especially important during the first 2 years of life - a period referred to as early child development and a time during which rapid growth and essential development occur. Malnutrition, a condition whose effect on cognitive function is well known, has been shown to be part of a vicious cycle with diarrhoeal diseases, and the two pathologies together continue to be the leading cause of illness and death in young children in developing countries. This paper reviews the burden of early childhood diarrhoeal diseases globally and the emerging evidence of their relationship with global disparities in neurocognitive development. The strength of evidence which indicates that the severe childhood diarrhoeal burden may be implicated in cognitive impairment of children from low- and middle-income counties is discussed. Findings suggest that greater investment in multi-site, longitudinal enteric infection studies that assess long-term repercussions are warranted. Furthermore, economic analyses using the concept of human capital should play a key role in advancing our understanding of the breadth and complexities of the health, social and economic ramifications of early childhood diarrhoeal diseases and enteric infections. This broadened awareness can serve to help advocate for more effective interventions, particularly in developing economies. PMID- 25146837 TI - Relationship between leisure time screen activity and aggressive and violent behaviour in Iranian children and adolescents: the CASPIAN-IV Study. AB - Background: This study aimed to assess the relationship between leisure time spent watching television (TV) and at a computer and aggressive and violent behaviour in children and adolescents. Methods: In this nationwide study, 14,880 school students, aged 6-18 years, were selected by cluster and stratified multi stage sampling method from 30 provinces in Iran. The World Health Organization Global School-based Health Survey questionnaire (WHO-GSHS) was used. Results: Overall, 13,486 children and adolescents (50.8% boys, 75.6% urban residents) completed the study (participation rate 90.6%). The risk of physical fighting and quarrels increased by 29% (OR 1.29, 95% CI 1.19-1.40) with watching TV for >2 hr/day, by 38% (OR 1.38, 95% CI 1.21-1.57) with leisure time computer work of >2 hr/day, and by 42% (OR 1.42, 95% CI 1.28-1.58) with the total screen time of >2 hr/day. Watching TV or leisure time spent on a computer or total screen time of >2 hr/day increased the risk of bullying by 30% (OR 1.30, 95% CI 1.18-1.43), 57% (1.57, 95% CI 1.34-1.85) and 62% (OR 1.62, 95% CI 1.43-1.83). Spending >2 hr/day watching TV and total screen time increased the risk of being bullied by 12% (OR 1.12, 95% CI 1.02-1.22) and 15% (OR 1.15, 95% CI 1.02-1.28), respectively. This relationship was not statistically significant for leisure time spent on a computer (OR 1.10, 95% CI 0.9-1.27). Conclusions: Prolonged leisure time spent on screen activities is associated with violent and aggressive behaviour in children and adolescents. In addition to the duration of screen time, the association is likely to be explained also by the media content. PMID- 25146838 TI - More favorable response to cardiac resynchronization therapy in women than in men. AB - BACKGROUND: Data on sex difference in response to cardiac resynchronization therapy (CRT) remain controversial. We conducted a meta-analysis to summarize all published studies to determine whether sex-based differences in response to CRT exist. METHODS AND RESULTS: We performed a literature search using MEDLINE (source PubMed; January 1966 to March 2014) and EMBASE (January 1980 to March 2014) with no restrictions. Pooled effect estimates were obtained by using random effects meta-analysis. Seventy-two studies involving 33 434 patients were identified. Overall, female patients had better outcomes from CRT compared with male patients, with a significant 33% reduction in the risk of death from any cause (hazard ratio, 0.67; 95% confidence interval, 0.61-0.74; P<0.001), 20% reduction in death or hospitalization for heart failure (hazard ratio, 0.80; 95% confidence interval, 0.71-0.90; P<0.001), 41% reduction in cardiac death (hazard ratio, 0.59; 95% confidence interval, 0.42-0.84; P<0.001), and 41% reduction in ventricular arrhythmias or sudden cardiac death (hazard ratio, 0.59; 95% confidence interval, 0.49-0.70; P<0.001). These more favorable responses to CRT in women were consistently associated with greater echocardiographic evidence of reverse cardiac remodeling in women than in men. CONCLUSIONS: Women obtained greater reductions in the risk of death from any cause, cardiac cause, death or hospitalization for heart failure, and ventricular arrhythmias or sudden cardiac death with CRT therapy compared with men, with consistently greater echocardiographic evidence of reverse cardiac remodeling in women than in men. Further studies are needed to investigate the exact reasons for these results and determine whether indications for CRT in women should be different from men. PMID- 25146839 TI - A novel mutation in TFL1 homolog affecting determinacy in cowpea (Vigna unguiculata). AB - Mutations in the widely conserved Arabidopsis Terminal Flower 1 (TFL1) gene and its homologs have been demonstrated to result in determinacy across genera, the knowledge of which is lacking in cowpea. Understanding the molecular events leading to determinacy of apical meristems could hasten development of cowpea varieties with suitable ideotypes. Isolation and characterization of a novel mutation in cowpea TFL1 homolog (VuTFL1) affecting determinacy is reported here for the first time. Cowpea TFL1 homolog was amplified using primers designed based on conserved sequences in related genera and sequence variation was analysed in three gamma ray-induced determinate mutants, their indeterminate parent "EC394763" and two indeterminate varieties. The analyses of sequence variation exposed a novel SNP distinguishing the determinate mutants from the indeterminate types. The non-synonymous point mutation in exon 4 at position 1,176 resulted from transversion of cytosine (C) to adenine (A) leading to an amino acid change (Pro-136 to His) in determinate mutants. The effect of the mutation on protein function and stability was predicted to be detrimental using different bioinformatics/computational tools. The functionally significant novel substitution mutation is hypothesized to affect determinacy in the cowpea mutants. Development of suitable regeneration protocols in this hitherto recalcitrant crop and subsequent complementation assay in mutants or over expressing assay in parents could decisively conclude the role of the SNP in regulating determinacy in these cowpea mutants. PMID- 25146840 TI - An evaluation of the ecological relationship between Drosophila species and their parasitoid wasps as an opportunity for horizontal transposon transfer. AB - Evidences of horizontal transfer, the exchange of genetic material between reproductively isolated species, have accumulated over the last decades, including for multicellular eukaryotic organisms. However, the mechanisms and ecological relationships that promote such phenomenon is still poorly known. Host parasite interaction is one type of relationship usually pointed in the literature that could potentially increase the probability of the horizontal transfer between species, because the species involved in such relationships are generally in close contact. Transposable elements, which are well-known genomic parasites, are DNA entities that tend to be involved in horizontal transfer due to their ability to mobilize between different genomic locations. Using Drosophila species and their parasitoid wasps as a host-parasite model, we evaluated the hypothesis that horizontal transposon transfers (HTTs) are more frequent in this set of species than in species that do not exhibit a close ecological and phylogenetic relationship. For this purpose, we sequenced two sets of species using a metagenomic and single-species genomic sampling approach through next-generation DNA sequencing. The first set was composed of five generalist Drosophila (D. maculifrons, D. bandeirantorum, D. polymorpha, D. mercatorum and D. willistoni) species and their associated parasitoid wasps, whereas the second set was composed of D. incompta, which is a flower specialist species, and its parasitoid wasp. We did not find strong evidence of HTT in the two sets of Drosophila and wasp parasites. However, at least five cases of HTT were observed between the generalist and specialist Drosophila species. Moreover, we detected an HT event involving a Wolbachia lineage between generalist and specialist species, indicating that these endosymbiotic bacteria could play a role as HTT vectors. In summary, our results do not support the hypothesis of prevalent HTT between species with a host-parasite relationship, at least for the studied wasp-Drosophila pairs. Moreover, it suggests that other mechanisms or parasites are involved in promoting HTT between Drosophila species as the Wolbachia endosymbiotic bacteria. PMID- 25146841 TI - Infliximab leading to autoimmune hepatitis: an increasingly recognized side effect. PMID- 25146842 TI - Fluoxetine inhibits hyperresponsive lamina propria mononuclear cells and bone marrow-derived dendritic cells, and ameliorates chronic colitis in IL-10 deficient mice. AB - BACKGROUND/AIMS: We aimed to study the effect of fluoxetine on chronic colitis and its anti-inflammatory mechanism in interleukin-10-deficient (IL-10(-/-)) mice. METHODS: IL-10(-/-) mice were administered with either the vehicle or one of the two dosages of fluoxetine (1 or 5 mg/kg) by oral gavage daily for 2 weeks. Lamina propria mononuclear cells (LPMCs) were isolated from IL-10(-/-) mice treated with or without fluoxetine, and cytokine expression was measured. Bone marrow-derived dendritic cells (BMDCs) isolated from IL-10(-/-), and wild-type mice were pretreated with fluoxetine and then stimulated with lipopolysaccharide. IL-12p40 and tumor necrosis factor (TNF)-alpha gene expression was determined by real-time PCR. DNA-binding activity of nuclear factor-kappaB (NF-kappaB) was evaluated by electrophoretic mobility shift assay. RESULTS: Fluoxetine significantly reduced intestinal inflammation as assessed by body weight, colon length, and histopathological grading, and it inhibited the level of TNF-alpha gene expression in IL-10(-/-) mice. LPMCs were isolated from IL-10(-/-) mice, and cellular expression of IL-12p40 and interferon-gamma was suppressed by fluoxetine treatment. Fluoxetine significantly inhibited IL-12p40 and TNF-alpha gene expression and protein secretion in BMDCs from IL-10(-/-) mice. DNA-binding activity of NF-kappaB was suppressed by fluoxetine pretreatment. CONCLUSIONS: These results indicate that fluoxetine ameliorates intestinal inflammation in IL 10(-/-) mice and inhibits hyperresponsive LPMCs and BMDCs, which suggests that fluoxetine could be a potential therapeutic agent for inflammatory bowel disease. PMID- 25146843 TI - A rapid and accurate method to detect active small bowel gastrointestinal bleeding on video capsule endoscopy. AB - BACKGROUND: Video capsule endoscopy (VCE) is indicated to evaluate for suspected small bowel bleeding, but "standard view" (SV) evaluation is time-consuming. Rapid Reader 6.0 software (Given Imaging, Duluth GA) contains two computer algorithmic systems: (1) "Quickview" (QV) which automatically skips similar images and (2) a pixel analysis program that identifies suspected blood (SBI). Combining the two modalities (QV + SBI) may provide a faster modality to assess for active small bowel bleeding. AIMS: This study was designed to assess the accuracy of QV + SBI for small bowel bleeding compared to SV findings. METHODS: This is a retrospective, case-control study at a single tertiary care referral hospital including all patients with VCE performed for suspected small bowel bleeding from 4/2007 to 3/2011. All studies were previously read using SV by one of two experienced faculty (CS, DR). The primary outcome was diagnostic accuracy of QV + SBI in assessing for active small bowel bleeding compared to SV. RESULTS: A total of 116 VCE were included, 28 with active small bowel bleeding identified by original SV. Using QV + SBI, all 28 VCEs with active small bowel bleeding were identified. The sensitivity of QV + SBI to detect active bleeding was 100%, while the specificity was 93-94%. The mean time to identify landmarks and read the entire study was 3 min 20 s. CONCLUSIONS: The QV + SBI reading format of VCE is an efficient, highly sensitive modality to assess for potential small bowel bleeding. PMID- 25146844 TI - Influence of post-transplant immunosuppressive therapy on gastrointestinal transit using biomagnetic method: a pilot study. AB - BACKGROUND: Immunosuppressive therapy after kidney transplant is necessary to prevent allograft rejection and it is the cause of several gastrointestinal (GI) disorders that have been scantily studied. OBJECTIVES: This study was aimed at investigating the influence of triple immunosuppressive therapy on GI transit in renal transplant patients by employing a biomagnetic technique. METHODS: Twenty one renal transplant patients underwent triple therapy, which included either tacrolimus (TAC) or cyclosporin A (CsA) associated with prednisone and azathioprine. They were all evaluated, and fifteen other healthy individuals formed the control group. After a standardized meal, GI transit of magnetic markers was assessed using Alternating Current Biosusceptometry (ACB). RESULTS: Patients taking TAC had significantly accelerated gastric emptying and colonic arrival (p <= 0.001) when compared with those taking CsA and those in the control group. However, no differences were observed in small bowel transit among the groups studied. Overall, the inter-subject coefficients of variation for gastrointestinal transit parameters were higher for the TAC group and similar for the CsA and control groups. CONCLUSION: This study demonstrated that ACB is a suitable methodology when evaluating the influence of different immunosuppressive therapies on gastrointestinal transit after renal transplantation. Pronounced inter-individual variation was found in patients treated with tacrolimus, thus showing the prokinetic effect of this drug on GI motility. Studies of motility patterns in this population could be useful as complementary information toward determining the mechanisms and the relationship between motility and therapeutic doses. PMID- 25146845 TI - Association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma susceptibility: evidence from a meta-analysis. AB - Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. A number of studies have examined the association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma (NHL) susceptibility; however, the conclusions were contradictory. We searched available publications assessing the polymorphisms of MTHFR and NHL susceptibility from MEDLINE, EMBASE and CBM. Genotype-based mRNA expression analysis was performed using data from 270 individuals with three different ethnicities. Ultimately, a total of 7448 cases and 11146 controls from 25 studies were included for the C677T polymorphism, 6173 cases and 9725 controls from 19 studies for the A1298C polymorphism. Pooled results indicated that neither C677T nor A1298C polymorphism was associated with NHL susceptibility. However, C677T polymorphism showed a statistically significantly increased risk for Caucasians, but a decreased risk for Asians in the subgroup analysis by ethnicity. The same variants may confer increased susceptibility to develop follicular lymphoma (FL). Moreover, A1298C polymorphism was associated with increased NHL risk for Asians. This meta-analysis indicated that C677T polymorphism was associated with altered NHL susceptibility for Caucasians, Asians and FL. Increased NHL risk was also shown for A1298C among Asians. These findings warrant validation in large and well-designed prospective studies. PMID- 25146846 TI - Lactoferrin Promotes Early Neurodevelopment and Cognition in Postnatal Piglets by Upregulating the BDNF Signaling Pathway and Polysialylation. AB - Lactoferrin (Lf) is a sialic acid (Sia)-rich, iron-binding milk glycoprotein that has multifunctional health benefits. Its potential role in neurodevelopment and cognition remains unknown. To test the hypothesis that Lf may function to improve neurodevelopment and cognition, the diet of postnatal piglets was supplemented with Lf from days 3 to 38. Expression levels of selected genes and their cognate protein profiles were quantitatively determined. The importance of our new findings is that Lf (1) upregulated several canonical signaling pathways associated with neurodevelopment and cognition; (2) influenced ~10 genes involved in the brain-derived neurotrophin factor (BDNF) signaling pathway in the hippocampus and upregulated the expression of polysialic acid, a marker of neuroplasticity, cell migration and differentiation of progenitor cells, and the growth and targeting of axons; (3) upregulated transcriptional and translational levels of BDNF and increased phosphorylation of the cyclic adenosine monophosphate (cAMP) response element-binding protein, CREB, a downstream target of the BDNF signaling pathway, and a protein of crucial importance in neurodevelopment and cognition; and (4) enhanced the cognitive function and learning of piglets when tested in an eight-arm radial maze. The finding that Lf can improve neural development and cognition in postnatal piglets has not been previously described. PMID- 25146847 TI - Osteopontin Mediates Hyperbaric Oxygen Preconditioning-Induced Neuroprotection Against Ischemic Stroke. AB - Neurosurgical operations may result in surgical injury which would lead to postoperative neurological deficits. Hyperbaric oxygen preconditioning (HBO-PC) may be beneficial for such people. However, the exact mechanism underlying HBO-PC is not well known yet. The aim of this study is to explore the role of osteopontin (OPN) in HBO-PC-induced neuroprotection. The study consisted of two experiments. In experiment 1, Sprague Dawley (SD) rats were divided into four groups: sham group, HBO-PC sham group, stroke group, and HBO-PC group (HBO-PC + stroke). The animals in the second experiment were randomly assigned to one of two groups: OPN small interfering (siRNA) group (HBO-PC + stroke + OPN siRNA) and control siRNA group (HBO-PC + stroke + negative control siRNA). Neurological outcome in HBO-PC group was better than that of stroke group. After OPN siRNA was administered, neurological function aggravated compared with control siRNA group. Brain morphology and structure seen by light microscopy was diminished in stroke group and OPN siRNA group, while fewer pathological injuries occurred in HBO-PC and control siRNA group. The infarct volume in HBO-PC group was the lowest, followed by OPN siRNA group and stroke group, respectively. Preconditioning with HBO promoted expression of OPN, which reduced the expression of interleukin (IL) 1beta/nuclear factor-kappa-gene binding (NFkappaB) and augmented protein kinase B (Akt). OPN siRNA reversed these changes. OPN plays an important role in the neuroprotection elicited by HBO-PC. Pretreatment with HBO may be beneficial for people going to undertake brain surgery. PMID- 25146849 TI - Multiplexing strategies for monolithic crystal PET detector modules. AB - To reduce the number of output channels and associated cost in PET detectors, strategies to multiplex the signal channels have been investigated by several researchers. This work aims to find an optimal multiplexing strategy for detector modules consisting of a monolithic LYSO scintillator coupled to a 64-channel PMT. We apply simulated multiplexing strategies to measured data from two continuous miniature crystal element (cMiCE) detector modules. The strategies tested include standard methods such as row column summation and its variants, as well as new data-driven methods involving the principal components of measured data and variants of those components. The detector positioning resolution and bias are measured for each multiplexing strategy and the results are compared. The mean FWHM over the entire detector was 1.23 mm for no multiplexing (64 channels). Using 16 principal component channels yielded a mean FWHM resolution of 1.21 mm, while traditional row/column summation (16 channels) yielded 1.28 mm. Using 8 principal component output channels resulted in a resolution of 1.30 mm. Using the principal components of the calibration data to guide the multiplexing scheme appears to be a viable method for reducing the number of output data channels. Further study is needed to determine if the depth-of-interaction resolution can be preserved with this multiplexing scheme. PMID- 25146848 TI - Induced Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Neurodegenerative Diseases. AB - Although most neurodegenerative diseases have been closely related to aberrant accumulation of aggregation-prone proteins in neurons, understanding their pathogenesis remains incomplete, and there is no treatment to delay the onset or slow the progression of many neurodegenerative diseases. The availability of induced pluripotent stem cells (iPSCs) in recapitulating the phenotypes of several late-onset neurodegenerative diseases marks the new era in in vitro modeling. The iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in these diseases and provides a novel human stem cell platform for screening new candidate therapeutics. Modeling human diseases using iPSCs has created novel opportunities for both mechanistic studies as well as for the discovery of new disease therapies. In this review, we introduce iPSC based disease modeling in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In addition, we discuss the implementation of iPSCs in drug discovery associated with some new techniques. PMID- 25146850 TI - Decreased expression of HLA-DQ and HLA-DR on cells of the monocytic lineage in cystic fibrosis. AB - We studied HLA class II molecules on blood monocyte subsets, blood dendritic cells, sputum macrophages, and monocyte-derived macrophages at the protein (flow cytometry) and mRNA level (RT-PCR) in adult patients with cystic fibrosis (CF) and healthy control subjects as putative contributors to the CF phenotype. In healthy donors, we found a high average HLA-DQ expression of 4.35 mean specific fluorescence intensity units (DeltaMnI) on classical blood monocytes. In F508del homozygous CF patients, the average DeltaMnI was low (1.80). Patients were divided into two groups, in which 14 of these patients had HLA-DQ expression above 2 DeltaMnI (average 3.25 DeltaMnI, CF-DQ(group1)) and 36 below (average 1.24 DeltaMnI, CF-DQ(group2)). Also, the CD16-positive monocyte subset and blood dendritic cells showed much lower levels of HLA-DQ for the CF-DQ(group2) patients compared with healthy controls. In macrophages from sputum and derived from monocytes, in vitro HLA-DQ expression was dramatically decreased to background levels in CF-DQ(group2). MHC class II transcripts were reduced in CF with a sevenfold decrease in HLA-DQbeta1 for CF-DQ(group2) patients. Higher levels of the inflammation marker CRP were associated with low HLA-DQ protein expression, and in vitro treatment with the inflammatory molecule lipopolysaccharide reduced HLA-DQ expression. Interferon gamma (IFNgamma) could overcome this effect in healthy donor cells while, in CF, the IFNgamma-induced activation was impaired. Our data demonstrate a pronounced reduction of HLA-DQ expression in CF, which is associated with inflammation and a reduced response to IFNgamma. KEY MESSAGE: * CF patients show a reduced expression of MHCII molecules in monocytes and macrophages. * HLA-DQ and HLA-DR transcript levels are also reduced in CF patients. * CF patient C-reactive protein levels correlate with low HLA-DQ expression. * Reduced expression of MHC class II molecules appears to be linked to inflammation. * CF patients exhibit an impaired response to IFNgamma. PMID- 25146851 TI - Healthy Spaces in Meaningful Places: The Rural Church and Women's Health Promotion. AB - PURPOSE: The influence of place on health is beginning to be addressed in health research. Current understanding of rural places, however, remains in a state of disequilibrium, balancing between geographic and sociocultural positions. This article illuminates the significance of place for rural women's experiences of health promotion in the rural church. DESIGN: This study used a novel approach to interpretive phenomenological methodology by including the photovoice method to elicit both individual and shared experiential meanings. METHOD: Twenty-two participants took pictures, wrote in logbooks, and participated in individual and group interviews to share their experiences of health promotion in the rural church. FINDINGS: The church as a place was realized through three broad discourses: (a) an intersection of physical and geographic environments, (b) a gateway to experiential attachment and personal meaning, and (c) a connection to shared culture and beliefs. It is also suggested that place may best be interpreted with an experiential lens as it exhibits lived and felt spaces. CONCLUSIONS: Data analysis suggests that place consists of both physical and experiential realities, in addition to being a resource of culture and meaning. Implications for rural women's health promotion include fostering a deeper recognition of place-shaped experiences of health. PMID- 25146852 TI - The memory of a friend: Lorenzo Capussotti (1947-2014). PMID- 25146853 TI - In vitro antiamoebic activity evaluation and docking studies of metronidazole triazole hybrids. AB - An in-house database of 520 compounds was docked against Entamoeba histolytica thioredoxin reductase (EhTrR), a promising target for the treatment of amoebiasis. Amongst these, some metronidazole (MTZ)-triazole hybrids were ranked high, with docking scores from -10.23 to -7.56. Studies of the binding orientations and conformations show that the head groups of MTZ-triazole hybrids interact with the arginine residues within the binding pocket of EhTrR, making it clear that such is the optimal and most reliable orientation for this class of compounds. The top-ten MTZ-triazole hybrids were then selected for evaluation of their activity against the HM1:IMSS strain of amoeba. The most active compound, 2 pyridyl-(1,2,3-triazolyl)metronidazole 10, with an IC50 value of 8.4 nM, was significantly more active than the standard drug MTZ alone. Docking studies revealed that compound 10 may act as an EhTrR inhibitor with activity in the nanomolar range and satisfactory ADME properties; it is a suitable candidate to be carried forward as a potential lead in the discovery of drugs to combat amoebiasis. PMID- 25146854 TI - Systematic analysis of funding awarded for viral hepatitis-related research to institutions in the United Kingdom, 1997-2010. AB - Viral hepatitis is responsible for great health, social and economic burden both globally and in the UK. This study aimed to assess the research funding awarded to UK institutions for viral hepatitis research and the relationship of funded research to clinical and public health burden of viral hepatitis. Databases and websites were systematically searched for information on infectious disease research studies funded for the period 1997-2010. Studies specifically related to viral hepatitis research were identified and categorized in terms of funding by pathogen, disease and by a research and development value chain describing the type of science. The overall data set included 6165 studies (total investment L2.6 billion) of which L76.9 million (3.0%) was directed towards viral hepatitis across 323 studies (5.2%). By pathogen, there were four studies specifically investigating hepatitis A (L3.8 million), 69 studies for hepatitis B (21.4%) with total investment of L14.7 million (19.1%) and 236 (73.1%) hepatitis C studies (L62.7 million, 81.5%). There were 4 studies investigating hepatitis G, and none specifying hepatitis D or E. By associated area, viral hepatitis and therapeutics research received L17.0 million, vaccinology L3.1 million and diagnostics L2.9 million. Preclinical research received L50.3 million (65.4%) across 173 studies, whilst implementation and operational research received L19.4 million (25.3%) across 128 studies. The UK is engaged in much hepatology research, but there are areas where the burden is great and may require greater focus, such as hepatitis E, development of a vaccine for hepatitis C, and further research into hepatitis associated cancers. Private sector data, and funding information from other countries, would also be useful in priority setting. PMID- 25146855 TI - Effects of foot orthoses on Achilles tendon load in recreational runners. AB - BACKGROUND: Achilles tendon pathology is a frequently occurring musculoskeletal disorder in runners. Foot orthoses have been shown to reduce the symptoms of pain in runners but their mechanical effects are still not well understood. METHODS: This study aimed to examine differences in Achilles tendon load when running with and without orthotic intervention. Twelve male runners ran at 4.0 m.s(-1). Ankle joint moments and Achilles tendon forces were compared when running with and without orthotics. FINDINGS: The results indicate that running with foot orthotics was associated with significant reductions in Achilles tendon load compared to without orthotics. INTERPRETATION: In addition to providing insight into the mechanical effects of orthotics in runners, the current investigation suggests that via reductions in Achilles tendon load, foot orthoses may serve to reduce the incidence of chronic Achilles tendon pathologies in runners. PMID- 25146856 TI - Influenza: optimising control strategies for New Zealand. PMID- 25146857 TI - Lack of effect of seasonal trivalent influenza vaccine against influenza A(H3N2) infections in hospitalised patients in winter 2012. AB - AIM: This study sought to assess the effectiveness of the 2012 trivalent inactivated influenza vaccine in preventing admission with confirmed influenza A(H3N2) infection and whether vaccination status influenced the duration or outcome. METHODS: We used the CDHB Delphic Laboratory Information System to identify 100 consecutive patients with confirmed influenza A(H3N2) infection. The patients were contacted via telephone and asked whether they had received the seasonal influenza vaccine prior to their hospital admission. We collected information such as age, gender, documented co-morbidities, smoking status, ICU admission, length of stay, and final outcome of admission and compared these between the vaccinated and non-vaccinated groups. RESULTS: A total of 92 participants could be contacted and participated; 67 these reported having been vaccinated with the 2012 seasonal influenza vaccine prior to their admission. There were no significant differences in length of stay or final outcome in vaccinated and non-vaccinated patients. CONCLUSION: This audit shows that the 2012 seasonal influenza vaccine did not provide significant protection against the H3N2 influenza strain in Canterbury. Vaccination did not alter the clinical course or final outcome in patients infected with H3N2 influenza. PMID- 25146858 TI - Evaluation of the Canterbury under-18 seasonal influenza vaccination programme. AB - AIM: To evaluate the performance of the 2013 Canterbury under-18 seasonal influenza vaccination programme (Christchurch, New Zealand). METHODS: Routinely collected under 18 influenza vaccination uptake data were analysed to determine levels of vaccination uptake and equity of uptake across ethnic groups (NZ European, Maori and Pacific) and by level of deprivation. Qualitative data were collected to identify strategies that helped to achieve high uptake in primary care practices and schools. RESULTS: Overall uptake of influenza vaccination in 2013 was 32.9%, (compared to 18.5% in 2012), close to the target of 40%. Overall uptake in primary care was higher than in the school-based programme (29.2% versus 19.7%). Maori students had higher uptake than NZ European students in the school-based programme. In primary care, uptake for both Maori and Pacific children was lower than overall uptake and there was a marked gradient in uptake by socioeconomic quintile, with 30.2% uptake in the least deprived quintile compared to 21.9% uptake in the most deprived quintile. CONCLUSIONS: The cumulative effect of 3 years' consistency in offering the under-18 influenza vaccination in primary care practices, assisted by a timely media campaign and additional awareness generated by the school-based programme, has resulted in a marked increase in uptake of the vaccine in primary care in 2013. However, this was not equitably distributed. The school-based programme achieved better equity of uptake by deprivation and ethnicity. The challenge is to achieve both high and equitable uptake. PMID- 25146859 TI - New Zealanders' self-reported uptake and attitudes towards the influenza vaccine in 2012. AB - AIMS: This study sought to assess New Zealanders' uptake of the influenza vaccine in 2012, identify the demographic characteristics of people least likely to take up the vaccine, and identify the main reasons why some did not get the vaccine. METHOD: We analysed responses to questions in the 2012 Health and Lifestyles Survey (HLS) about the influenza vaccine. The 2012 HLS was an in-home survey with a nationally representative sample of 2672 New Zealanders aged 15 years and over. RESULTS: Two-thirds of New Zealanders said they did not receive the influenza vaccine in 2012. Younger adults and those who thought they were not eligible to get the vaccine for free were least likely to have received it. The most common reason for not receiving the vaccine was a low perceived susceptibility to influenza. Other common reasons were related to dislike or distrust of the vaccine. CONCLUSIONS: This study provides information that could be used by health professionals, health promoters, and government agencies to improve the targeting and effectiveness of communication messages related to the influenza vaccine. Such communications are important because they can help encourage those New Zealanders who would benefit most from receiving the vaccine to take it up. PMID- 25146860 TI - Coroners' recommendations about healthcare-related deaths as a potential tool for improving patient safety and quality of care. AB - AIMS: To describe and investigate the nature, recipients and preventive potential of New Zealand coroners' recommendations from 1 July 2007-30 June 2012. METHOD: (1) A retrospective study of coroners' recommendations during the study period was undertaken. (2) Interviews with coroners, recipients of recommendations and interested parties were conducted. RESULTS: There were 607 coronial inquiries that resulted in 1644 recommendations. There were 309 recipients of coroners' recommendations. Government organisations received the highest proportion of recommendations (121/309). Not for profit organisations received 67 recommendations, for profit organisations received 44 recommendations and individuals received 5 recommendations. There were 72 untargeted recommendations that did not specify an identifiable organisation. The Ministry of Health received the second-highest proportion of coroners' recommendations. Transport accidents, drowning, intentional self-harm and complications of medical or surgical care were the main underlying causes of death categories investigated by coroners. Fifty-eight of the 607 inquiries involved complications of medical or surgical care. The 123 interview participants reported that there have been improvements in coronial recommendations since the introduction of the Coroners Act 2006, but that the prophylactic and patient safety potential of recommendations is not being maximised. CONCLUSION: Coronial investigations provide external insight into the way that our health system works and recommendations can be used as a tool to learn from preventable deaths. Given that this was the first New Zealand study of coroners' recommendations since the introduction of the Act, more research is needed to corroborate these findings. PMID- 25146861 TI - The impact of major earthquakes on the psychological functioning of medical students: a Christchurch, New Zealand study. AB - BACKGROUND: No previous studies have systematically assessed the psychological functioning of medical students following a major disaster. AIM: To describe the psychological functioning of medical students following the earthquakes in Canterbury, New Zealand, and identify predictors of adverse psychological functioning. METHOD: 7 months following the most severe earthquake, medical students completed the Depression, Anxiety and Stress Scale (DASS), the Post Traumatic Stress Disorder Checklist, the Eysenck Personality Questionnaire, the Connor Davidson Resilience Scale, the Work and Adjustment Scale, and Likert scales assessing psychological functioning at worst and currently. RESULTS: A substantial minority of medical students reported moderate-extreme difficulties on the DASS subscales 7 months following the most severe earthquake (Depression =12%; Anxiety =9%; Stress =10%). Multiple linear modelling produced a model that predicted 27% of the variance in total scores on the DASS. Variables contributing significantly to the model were: year of medical course, presence of mental health problems prior to the earthquakes, not being New Zealand European, and being higher on retrospectively rated neuroticism prior to the earthquakes. CONCLUSION: Around 10% of medical students experienced moderate-extreme psychological difficulties 7 months following the most severe earthquake on 22 February 2011. Specific groups at high risk for ongoing psychological symptomatology were able to be identified. PMID- 25146862 TI - Can a paediatric department provide health care for vulnerable adolescents? AB - BACKGROUND: Adolescents can face multiple barriers when attempting to access primary health care and primary health providers often feel poorly placed to provide care. The Adolescent Resilience Clinic (ARC) was established to help overcome some of these difficulties. AIM: To evaluate whether goals of the ARC were achieved and identify areas for future improvement. METHODS: A retrospective review of records for all patients referred to the ARC from May 2011 to May 2012. RESULTS: A total 41 patients were seen, aged 12-18 years, the majority of whom (98%) were female. NZ Maori was the most common ethnicity (54%). Contraceptive needs and psychosocial issues were the predominant referral reasons. After consultation, most patients (81%) had multiple diagnoses. The proportion of patients participating in "risky" behaviours showed this group to be at risk of adverse outcomes. However, only 7% of patients had a complete HEeADSS assessment (an acronym guiding systematic psychosocial history taking assessing Home, Education or employment, Eating, Activities and affect, Drug use including cigarettes, Sexual risk behaviours and Suicide) documented. CONCLUSIONS: The ARC provides accessible healthcare to a vulnerable population. Further work is needed on how to accurately document HEeADSS assessments while ensuring confidentiality. PMID- 25146863 TI - In vitro comparison of four rapid antigen tests for group A streptococcus detection. AB - AIMS: To examine the analytical sensitivity of four rapid antigen tests (RADT) for detection of group A streptococcus (GAS). METHODS: The sensitivities of four RADT kits to detect clinical and reference strains of GAS at different dilutions were compared. Test results were read by two people, and differences in interpretation were settled by a third reader. RESULTS: A total of 697 tests were performed. For all kits, detection increased with increasing colony counts of GAS. One kit [ulti med Products, Deutschland, GmbH (UM)] was found to have the highest sensitivity, although there was no significant difference between it and one other kit (Testpack Plus). All kits were only faintly positive or negative at low colony counts. CONCLUSIONS: The sensitivity of RADT for detecting GAS is related to inoculum size and the faint appearance of a positive test at low colony counts contributes to inter-observer variability. Sore throats with low colony counts have been shown to be clinically relevant. PMID- 25146864 TI - The current state of ototoxicity monitoring in New Zealand. AB - AIM: To explore medical oncologists' and audiologists' knowledge and attitudes regarding ototoxicity monitoring, and to gain an understanding of monitoring currently being implemented at District Health Boards (DHBs) nationwide. We also aimed to identify ways in which audiological outcomes for patients receiving potentially ototoxic treatments could be improved, including examining whether the formulation and implementation of a national ototoxicity monitoring guideline is necessary. METHOD: Complementary telephonic interviews were conducted with 16 senior or charge audiologists and seven senior medical oncologists from DHBs across New Zealand, and their responses analysed. RESULTS: Responses indicate a comprehensive understanding of ototoxicity across both disciplines; however there is limited familiarity with ototoxicity monitoring protocols. Patients across New Zealand undergo significantly variable ototoxicity monitoring; local practices range from no routine monitoring to audiological assessment prior to each cycle of chemotherapy. No routine audiological follow up is conducted post completion of treatment at any DHB, in contrast with international guidelines. Twenty-two of 23 participants were in favour of development of a national ototoxicity monitoring guideline. CONCLUSION: There is significant discrepancy in how ototoxicity monitoring is conducted across New Zealand, and implementation of a national ototoxicity monitoring protocol may improve audiological outcomes for patients receiving ototoxic chemotherapy. PMID- 25146865 TI - Are hearing losses among young Maori different to those found in the young NZ European population? AB - AIM: This study was undertaken to determine if young Maori have more permanent bilateral hearing loss, or less severe and profound hearing loss than New Zealand (NZ) Europeans. METHODS: Data include hearing-impaired children from birth to 19 years of age from the New Zealand Deafness Notification Database (DND) and covering the periods 1982-2005 and 2009-2013. These were retrospectively analysed, as was information on children and young people with cochlear implants. RESULTS: Young Maori are more likely to be diagnosed with permanent hearing loss greater than 26 dB HL, averaged across speech frequencies, with 39-43% of hearing loss notifications listed as Maori. Maori have a lower prevalence of severe/profound losses (n=1571, chi squared=22.08, p=0.01) but significantly more bilateral losses than their NZ European peers (n=595, Chi-squared=9.05, p=0.01). The difference in severity profile is supported by cochlear implant data showing Maori are less likely to receive a cochlear implant. CONCLUSIONS: There are significant differences in the proportion of bilateral (compared to unilateral) losses and in the rates and severity profile of hearing loss among young Maori when compared with their NZ European peers. This has implications for screening and other hearing services in NZ. PMID- 25146866 TI - The potentials and challenges of electronic referrals in transforming healthcare. AB - Referrals are traditionally defined as sending a patient to another program or practitioner for services or advice. The increasing adoption of electronic referral systems (eReferrals) requires a more complex model and shared understanding of what a referral is. eReferrals are designed to support writing referrals and automating referrals processing, and sometimes triaging. The reported benefits of eReferrals include secured delivery of referrals, improved efficiency, access to care, quality of care and continuity of care, better quality of documentation and communication, as well as reduced cost. Improvement in the time to prioritise referrals, more reliable and transparent referral handling, and better-supported hospital-community communications have been observed in regional eReferral trials in New Zealand. In the authors' opinion, teleconsultation and virtual shared care relationships have the potential to transform healthcare delivery, and they can be facilitated by eReferral technology. But the opportunities introduced by information technologies for eReferrals present several complex and contentious issues. This paper explores the potential roles and models for eReferral and its challenge to what constitutes a medical consultation. Future research is needed to understand how to facilitate and fund virtual clinics, and to support mentorships among healthcare professionals as well as for health consumers. PMID- 25146867 TI - Childhood obesity in New Zealand: time to look at stronger measures? PMID- 25146868 TI - Smokefree 2025: patterns and trends in references to the smokefree goal in political speeches and press releases. PMID- 25146869 TI - Dangers of "EDTA". PMID- 25146870 TI - Pharmacy-based screening for atrial fibrillation in high-risk Maori and Pacific populations. PMID- 25146871 TI - Should New Zealand do more to help other Pacific nations become smokefree by 2025? The case of Tokelau as a potential example. PMID- 25146872 TI - An Auckland-based student acupuncture clinic patient profile and utilisation study. PMID- 25146873 TI - Working mothers are disadvantaged by limited funding for health research. PMID- 25146874 TI - Missed melanomas - comment. PMID- 25146875 TI - An update on the management of hepatitis C virus-related arthritis. AB - INTRODUCTION: Hepatitis C virus (HCV)-related arthritis is an uncommon disease belonging to the autoimmune disorders due to the chronic stimulus exerted by the virus on the immune system. It shows two clinical subsets: a symmetrical polyarthritis resembling rheumatoid arthritis but less aggressive and an intermittent mono-oligoarthritis involving the lower limbs. AREAS COVERED: We extensively review the current literature using the largest electronic databases (MEDLINE, EMBASE and COCHRANE) with regard to HCV-related arthritis (HCVrA) and studies focusing on the co-existence of HCV and other kinds of arthritides. EXPERT OPINION: The therapeutic approach to HCVrA remains largely empirical, because few studies have been published on this topic. Mainstream treatment based on the administration of hydroxychloroquine and low doses of corticosteroid is still largely preferred. Cyclosporine represents a useful alternative due to its antiviral properties. Anti-TNF agents are safe, but their hypothetic use appears excessive for a mild disorder such as HCVrA. IFN-alpha (and more recently pegylated IFN-alpha) when administered as a component of the combined (IFN-alpha + ribavirin) anti-HCV therapy can promote the appearance or the worsening of several autoimmune HCV-related disorders, including arthritis. New and forthcoming antiviral molecules will be used in the near future for a revolutionary IFN-free treatment. PMID- 25146876 TI - Multidomain hybrid hydrogels: spatially resolved photopatterned synthetic nanomaterials combining polymer and low-molecular-weight gelators. AB - A simple approach to a patterned multidomain gel is reported, combining a pH responsive low-molecular-weight gelator (LMWG) and a photoinducible polymer gelator (PG). Using SEM (scanning electron microscopy), NMR spectroscopy, and CD, we demonstrate that self-assembly of the LMWG network occurs in the presence of the PG network, but that the PG has an influence on LMWG assembly kinetics and morphology. The application of a mask during photoirradiation allows patterning of the PG network; we define the resulting system as a "multidomain gel"-one domain consists of a LMWG, whereas the patterned region contains both LMWG and PG networks. The different domains have different properties with regard to diffusion of small molecules, and both gelator networks can control diffusion rates to give systems capable of controlled release. Such materials may have future applications in multikinetic control of drug release, or as patterned scaffolds for directed tissue engineering. PMID- 25146877 TI - Quantification and micron-scale imaging of spatial distribution of trace beryllium in shrapnel fragments and metallurgic samples with correlative fluorescence detection method and secondary ion mass spectrometry (SIMS). AB - Recently, a report raised the possibility of shrapnel-induced chronic beryllium disease from long-term exposure to the surface of retained aluminum shrapnel fragments in the body. Since the shrapnel fragments contained trace beryllium, methodological developments were needed for beryllium quantification and to study its spatial distribution in relation to other matrix elements, such as aluminum and iron, in metallurgic samples. In this work, we developed methodology for quantification of trace beryllium in samples of shrapnel fragments and other metallurgic sample-types with main matrix of aluminum (aluminum cans from soda, beer, carbonated water and aluminum foil). Sample preparation procedures were developed for dissolving beryllium for its quantification with the fluorescence detection method for homogenized measurements. The spatial distribution of trace beryllium on the sample surface and in 3D was imaged with a dynamic secondary ion mass spectrometry instrument, CAMECA IMS 3f secondary ion mass spectrometry ion microscope. The beryllium content of shrapnel (~100 ppb) was the same as the trace quantities of beryllium found in aluminum cans. The beryllium content of aluminum foil (~25 ppb) was significantly lower than cans. SIMS imaging analysis revealed beryllium to be distributed in the form of low micron-sized particles and clusters distributed randomly in X-Y- and Z dimensions, and often in association with iron, in the main aluminum matrix of cans. These observations indicate a plausible formation of Be-Fe or Al-Be alloy in the matrix of cans. Further observations were made on fluids (carbonated water) for understanding if trace beryllium in cans leached out and contaminated the food product. A direct comparison of carbonated water in aluminum cans and plastic bottles revealed that beryllium was below the detection limits of the fluorescence detection method (~0.01 ppb). These observations indicate that beryllium present in aluminum matrix was either present in an immobile form or its mobilization into the food product was prevented by a polymer coating on the inside of cans, a practice used in food industry to prevent contamination of food products. The lack of such coating in retained shrapnel fragments renders their surface a possible source of contamination for long-term exposure of tissues and fluids and induction of disease, as characterized in a recent study. Methodological developments reported here can be extended to studies of beryllium in electronics devices and components. PMID- 25146878 TI - Hemodynamic monitoring of Chlorin e6-mediated photodynamic therapy using diffuse optical measurements. AB - Tumor response during photodynamic therapy (PDT) is heavily dependent on treatment parameters such as light dose, photosensitizer concentration, and tissue oxygenation. Therefore, it is desirable to have a real-time hemodynamic monitoring device in order to fine-tune the parameters and improve PDT efficacy. In this paper, such a tumor response monitoring system was built incorporating both frequency domain diffuse optical spectroscopy (FD-DOS) and diffuse correlation spectroscopy (DCS), which enables concurrent monitoring of tissue oxygenation (StO2), total hemoglobin concentration (THC) and relative blood flow (rBF). The tumor metabolic rate of oxygen (TMRO2) was calculated by using the hemodynamic parameters. Mouse models bearing xenograft tumors were subjected to chlorin e6 (Ce6)-mediated PDT, and the four parameters were monitored with varying treatment conditions. The results show (1) At 3 h post-PDT, rStO2, rBF and rTMRO2 exhibited sharp PDT-induced decreases in responders (>40% reduction in tumor volume). Statistically significant difference between responders and non responders were observed in rStO2 and rBF, but not in rTMRO2. (2) Non-responders show gradual recovery of rStO2, rBF and rTMRO2 from ~24 h post-PDT, while responder group did not show recovery up until 48 h post-PDT. Long-term study results up to 2 weeks are also shown. It suggests the hybrid diffuse optical system is not only capable of real-time treatment monitoring, but also able to extract tumor metabolic rate of oxygen to provide more insights about therapy mechanism. Translation of this technique to the clinic will make a quick prognosis feasible and help with treatment optimization. PMID- 25146879 TI - Reactivity of Cl atom with triple-bonded molecules. An experimental and theoretical study with alcohols. AB - The reactivities of the Cl atom with triple-bonded molecules were examined by determining the rate coefficients of reactions of four triple-bonded alcohols (TA), namely, 2-propyn-1-ol, 3-butyn-1-ol, 3-butyn-2-ol, and 2-methyl-3-butyn-2 ol, using the relative rate method, at 298 K. The rate coefficients (k) of reaction of the four alcohols with Cl vary in the range (3.5-4.3) * 10(-10) cm(3) molecule(-1) s(-1). These values imply significant contribution of the Cl reaction in the tropospheric degradation of TAs in the conditions of the marine boundary layer. A striking difference is observed in the reactivity trend of Cl from that of OH/O3. Although the reactivity of OH/O3 is lower with triple-bonded molecules, as compared to the double-bonded analogues, the reactivity of the Cl atom is similar for both. For a deeper insight, the reactions of Cl and OH with the simplest TA, 2-propyn-1-ol, are investigated theoretically. Conventional transition state theory is applied to compute the values of k, using the calculated energies at QCISD and QCISD(T) levels of theory of the optimized geometries of the reactants, transition states (TS), and the product radicals of all the possible reaction pathways at the MP2/6-311++G(d,p) level. The k values calculated at the QCISD level for Cl and the QCISD(T) level for OH reactions are found to be very close to the experimental values at 298 K. In the case of the Cl reaction, the abstraction of alpha-H atoms as well as the addition at the terminal and middle carbon atoms have submerged TS and the contribution of the abstraction reaction is found to be significant at room temperature, at all levels of calculations. Addition at the terminal carbon atom is prominent compared to that at the middle carbon. In contrast to the Cl reaction, only addition at the middle carbon is associated with such low lying TS in the case of OH. The individual rate coefficients of addition and abstraction of OH are lower than that of Cl. The negative temperature dependence of the computed rate coefficients in the temperature range 200-400 K shows that the difference in the TS energy of Cl and OH affects the pre-exponential factor more than the activation energy. PMID- 25146880 TI - The identification of menstrual blood in forensic samples by logistic regression modeling of miRNA expression. AB - We report the identification of sensitive and specific miRNA biomarkers for menstrual blood, a tissue that might provide probative information in certain specialized instances. We incorporated these biomarkers into qPCR assays and developed a quantitative statistical model using logistic regression that permits the prediction of menstrual blood in a forensic sample with a high, and measurable, degree of accuracy. Using the developed model, we achieved 100% accuracy in determining the body fluid of interest for a set of test samples (i.e. samples not used in model development). The development, and details, of the logistic regression model are described. Testing and evaluation of the finalized logistic regression modeled assay using a small number of samples was carried out to preliminarily estimate the limit of detection (LOD), specificity in admixed samples and expression of the menstrual blood miRNA biomarkers throughout the menstrual cycle (25-28 days). The LOD was <1 ng of total RNA, the assay performed as expected with admixed samples and menstrual blood was identified only during the menses phase of the female reproductive cycle in two donors. PMID- 25146881 TI - Comparison of cancer stem cell antigen expression by tumor cell lines and by tumor biopsies from dogs with melanoma and osteosarcoma. AB - Cancer stem cells (CSCs) represent a small subpopulation of tumor cells that play a critical role in initiating and sustaining tumor growth. However, we currently have an incomplete understanding of the expression patterns of CSC antigens in tumors of dogs, nor do we understand how expression of these antigens vary between tumor cell lines and tumor biopsy specimens. Therefore, we used flow cytometry and commonly reported CSC surface and intracellular markers to evaluate the phenotype and overall frequency of CSC subpopulations in tumor cell lines and primary tumor biopsy samples from dogs with melanoma and osteosarcoma. We found that cells expressing common CSC antigens were rare in tumor cell lines, with the exception of tumor cells expressing CD44 and CD90. In contrast, tumor cells expressing conventional CSC antigens such as CD133, CD34, CD44, CD24 and Oct3/4 were much more common in tumor biopsy samples. Notably, the frequency and types of putative CSC subpopulations were very similar in biopsy samples from dogs with either melanoma or osteosarcoma. Our results suggest that the tumor microenvironment significantly influences CSC subpopulations within tumors and that tumor cell lines may not accurately reflect the actual frequency or types of CSC subpopulations present in tumor tissues in vivo. PMID- 25146882 TI - Comparison of flow cytometry, fluorescence microscopy and spectrofluorometry for analysis of gene electrotransfer efficiency. AB - In this study, we compared three different methods used for quantification of gene electrotransfer efficiency: fluorescence microscopy, flow cytometry and spectrofluorometry. We used CHO and B16 cells in a suspension and plasmid coding for GFP. The aim of this study was to compare and analyse the results obtained by fluorescence microscopy, flow cytometry and spectrofluorometry and in addition to analyse the applicability of spectrofluorometry for quantifying gene electrotransfer on cells in a suspension. Our results show that all the three methods detected similar critical electric field strength, around 0.55 kV/cm for both cell lines. Moreover, results obtained on CHO cells showed that the total fluorescence intensity and percentage of transfection exhibit similar increase in response to increase electric field strength for all the three methods. For B16 cells, there was a good correlation at low electric field strengths, but at high field strengths, flow cytometer results deviated from results obtained by fluorescence microscope and spectrofluorometer. Our study showed that all the three methods detected similar critical electric field strengths and high correlations of results were obtained except for B16 cells at high electric field strengths. The results also demonstrated that flow cytometry measures higher values of percentage transfection compared to microscopy. Furthermore, we have demonstrated that spectrofluorometry can be used as a simple and consistent method to determine gene electrotransfer efficiency on cells in a suspension. PMID- 25146883 TI - Gold nanoparticles confined in vertically aligned silica nanochannels and their electrocatalytic activity toward ascorbic acid. AB - A facile method of confining gold nanoparticles (AuNPs) in silica nanochannels aligned perpendicularly to an underlying electrode surface is reported. The nanochannel surface carrying a layer of (3-aminopropyl)triethoxy silane (APTS) displays a strong electrostatic interaction with AuCl4(-), eventually resulting in the confinement of AuNPs inside the nanochannels after chemical reduction. As prepared AuNPs in APTS-modified mesoporous silica film (APTS-MSF) are highly dispersed with a narrow size distribution. Furthermore, these AuNPs are free of protecting ligands and exhibit a good electrochemical catalytic activity toward the oxidation of ascorbic acid. PMID- 25146884 TI - Pepsin-modified chiral monolithic column for affinity capillary electrochromatography. AB - Pepsin-modified affinity monolithic capillary electrochromatography, a novel microanalysis system, was developed by the covalent bonding of pepsin on silica monolith. The column was successfully applied in the chiral separation of (+/-) nefopam. Furthermore, the electrochromatographic performance of the pepsin functionalized monolith for enantiomeric analysis was evaluated in terms of protein content, pH of running buffer, sample volume, buffer concentration, applied voltage, and capillary temperature. The relative standard deviation (%RSD) values of retention time (intraday <0.53, n = 10; interday <0.53, n = 10; column-to-column <0.70, n = 20; and batch-to-batch <0.80, n = 20) indicated satisfactory stability of these columns. No appreciable change was observed in retention and resolution for chiral recognition of (+/-)-nefopam in 50 days with 100 injections. The proteolytic activity of this stationary phase was further characterized with bovine serum albumin as substrate for online protein digestion. As for monolithic immobilized enzyme reactor, successive protein injections confirmed both the operational stability and ability to reuse the bioreactor for at least 20 digestions. It implied that the affinity monolith used in this research opens a new path of exploring particularly versatile class of enzymes to develop enzyme-modified affinity capillary monolith for enantioseparation. PMID- 25146885 TI - Relationship between universal health outcome priorities and willingness to take medication for primary prevention of myocardial infarction. AB - OBJECTIVES: To determine how well universal health outcome priorities represent individuals' preferences in specific clinical situations. DESIGN: Observational cohort study. SETTING: Community. PARTICIPANTS: Community-dwelling adults aged 65 and older (N = 357). MEASUREMENTS: Participants used three tools assessing universal health outcome priorities related to two common trade-offs: quality versus quantity of life and future health versus present inconveniences and burdens of treatment. The tools' ability to identify participants who were unwilling to take a medication that reduced the risk of myocardial infarction but caused dizziness and fatigue was analyzed. RESULTS: There were consistent and significant associations between unwillingness to take the medication and prioritizing quality of life or future health for all three tools in the expected direction (P < .05). Despite these associations, the positive (PPV) and negative predictive values for the tools were generally modest (0.49-0.83). The tool with the most specific statements resembling the medication scenario had the best specificity (0.97) and PPV (0.83). CONCLUSION: Universal health outcome priorities only modestly identified older persons who would be unwilling to take a medication for primary prevention of myocardial infarction that causes adverse effects. Although tools that are the most general in their assessment of priorities have the benefit of being applicable across the widest range of scenarios, tools with greater specificity may be necessary to inform individual treatment decisions. PMID- 25146886 TI - Altered expression of Aurora kinases in Arabidopsis results in aneu- and polyploidization. AB - Aurora is an evolutionary conserved protein kinase family involved in monitoring of chromosome segregation via phosphorylation of different substrates. In plants, however, the involvement of Aurora proteins in meiosis and in sensing microtubule attachment remains to be proven, although the downstream components leading to the targeting of spindle assembly checkpoint signals to anaphase-promoting complex have been described. To analyze the three members of Aurora family (AtAurora1, -2, and -3) of Arabidopsis we employed different combinations of T DNA insertion mutants and/or RNAi transformants. Meiotic defects and the formation of unreduced pollen were revealed including plants with an increased ploidy level. The effect of reduced expression of Aurora was mimicked by application of the ATP-competitive Aurora inhibitor II. In addition, strong overexpression of any member of the AtAurora family is not possible. Only tagged or truncated forms of Aurora kinases can be overexpressed. Expression of truncated AtAurora1 resulted in a high number of aneuploids in Arabidopsis, while expression of AtAurora1-TAPi construct in tobacco resulted in 4C (possible tetraploid) progeny. In conclusion, our data demonstrate an essential role of Aurora kinases in the monitoring of meiosis in plants. PMID- 25146887 TI - Triple-conducting layered perovskites as cathode materials for proton-conducting solid oxide fuel cells. AB - We report on an excellent anode-supported H(+) -SOFC material system using a triple conducting (H(+) /O(2-) /e(-) ) oxide (TCO) as a cathode material for H(+) -SOFCs. Generally, mixed ionic (O(2-) ) and electronic conductors (MIECs) have been selected as the cathode material of H(+) -SOFCs. In an H(+) -SOFC system, however, MIEC cathodes limit the electrochemically active sites to the interface between the proton conducting electrolyte and the cathode. New approaches to the tailoring of cathode materials for H(+) -SOFCs should therefore be considered. TCOs can effectively extend the electrochemically active sites from the interface between the cathode and the electrolyte to the entire surface of the cathode. The electrochemical performance of NBSCF/BZCYYb/BZCYYb-NiO shows excellent long term stability for 500 h at 1023 K with high power density of 1.61 W cm(-2) . PMID- 25146888 TI - Characteristics associated with physical activity among independently ambulant children and adolescents with unilateral cerebral palsy. AB - AIM: This study aimed to quantify the contribution of physical, personal and environmental characteristics to physical activity among independently ambulant children with unilateral cerebral palsy (CP). METHOD: One-hundred and two children with unilateral CP (52 males, 50 females; 52 right hemiplegia; mean age 11y 3mo, range 8-17y [SD 2y 4mo]) classified at Gross Motor Function Classification System (GMFCS) levels I = 44 and II = 58 participated. Physical activity was measured over 4 days using ActiGraph accelerometers recording as activity counts. GMFCS, functional strength, 6-minute walk test (6MWT), mobility limitations (MobQues28), age, sex, Assessment of Life-Habits recreation domain, Participation and Environment Measure for Children and Youth (PEM-CY) and environmental characteristics were considered for selection in a linear regression model. These served as independent variables which were determined using a backwards selection procedure. RESULTS: Younger age, male sex, increased performance on the 6MWT, and increased participation in the home and community measured using the PEM-CY were significantly associated with activity counts (p<0.001). However, the model fit was somewhat weak (R(2) =0.32), indicating that much of the variation was unexplained. Older age and reduced community participation were associated with high inactivity (p<0.001). INTERPRETATION: Physical activity interventions should primarily target adolescents and females. Walking endurance and participation in the home and community may represent modifiable characteristics to increase physical activity. PMID- 25146889 TI - Live imaging of calcium spikes during double fertilization in Arabidopsis. AB - Ca(2+) waves and oscillation are key signalling elements during the fertilization process of animals, and are involved, for example, in egg activation. In the unique double fertilization process in flowering plants, both the egg cell and the neighbouring central cell fuse with a sperm cell each. Here we succeeded in imaging cytosolic Ca(2+) in these two cells, and in the two synergid cells that accompany the gametes during semi-in vivo double fertilization. Following pollen tube discharge and plasmogamy, the egg and central cells displayed transient Ca(2+) spikes, but not oscillations. Only the events in the egg cell correlated with the plasmogamy. In contrast, the synergid cells displayed Ca(2+) oscillations on pollen tube arrival. The two synergid cells showed distinct Ca(2+) dynamics depending on their respective roles in tube reception. These Ca(2+) dynamics in the female gametophyte seem to represent highly specific signatures that coordinate successful double fertilization in the flowering plants. PMID- 25146890 TI - Jaw movements in patients with a history of pain: an exploratory study. AB - The aims were to determine whether individuals with a past history of pain exhibit (i) altered jaw movement (e.g. reduced amplitude, increased jaw movement variability) in comparison with matched asymptomatic controls, and (ii) correlations between psychological measures (e.g. catastrophising) and altered jaw movement variables. Sixteen participants with a history of trigeminal neuropathic pain (TNP) and 15 age- and gender-matched healthy controls had jaw movements recorded during open/close, free gum chewing and chewing at standardised rates. All completed the Pain Catastrophising Scale (PCS), the Pain Self-Efficacy Questionnaire (PSEQ), and the Depression, Anxiety and Stress Scales (DASS). Velocity and amplitude for open/close and chewing, as well as variability, bias and mean square error for open/close jaw movements were compared between groups. Spearman's rank correlation coefficient was used to relate kinematic variables with psychological variables. Statistical significance: P < 0.05. There were no significant differences in mean jaw velocity and amplitude between the TNP and control groups during the open/close jaw movements or free or standardised chewing. In comparison with control, the TNP participants exhibited significantly greater variability, bias and/or mean square error during slow and/or fast opening, and significantly greater variance in velocity and/or amplitude during free and standardised chewing. There were significant negative correlations between PCS scores and velocity and/or amplitude of free and/or standardised chewing. This exploratory study suggests that individuals with a history of pain have altered patterns of jaw movements in comparison with asymptomatic control participants and that catastrophising may play a role in the manifestation of these altered jaw movements. PMID- 25146891 TI - Maximum surface charge density for triboelectric nanogenerators achieved by ionized-air injection: methodology and theoretical understanding. AB - For the maximization of the surface charge density in triboelectric nanogenerators, a new method of injecting single-polarity ions onto surfaces is introduced for the generation of surface charges. The triboelectric nanogenerator's output power gets greatly enhanced and its maximum surface charge density is systematically studied, which shows a huge room for the improvement of the output of triboelectric nanogenerators by surface modification. PMID- 25146892 TI - Mannosylated lipoarabinomannan in serum as a biomarker candidate for subclinical bovine tuberculosis. AB - BACKGROUND: Early and unambiguous detection of bovine tuberculosis (bTB), a significant disease of cattle worldwide, is necessary to control the spread of infection to other animals and humans. Current testing strategies are laborious, time consuming and heavily reliant on host responses that do not distinguish bTB from other mycobacteria. We report the presence of a pathogen signature, liparabinomannan (LAM), as a potential biomarker for bTB infection. FINDINGS: Fifty-five animals (uninfected [n = 33], bTb [n = 10] and exposed cases [n = 12]) from a well characterized bovine serum repository were screened for the presence of LAM using a commercially available ELISA. Analysis showed that LAM had a sensitivity of 100% and a specificity of 91.7% for bTB detection (bTB positive versus bTB exposed animals). CONCLUSION: LAM detection easily separated bTB infected animals from bTB exposed and negative controls. We propose that pathogen related markers, such as LAM, should be included with current testing strategies as a battery diagnostic for bTB. PMID- 25146894 TI - Platinum-free binary Co-Ni alloy counter electrodes for efficient dye-sensitized solar cells. AB - Dye-sensitized solar cells (DSSCs) have attracted growing interest because of their application in renewable energy technologies in developing modern low carbon economies. However, the commercial application of DSSCs has been hindered by the high expenses of platinum (Pt) counter electrodes (CEs). Here we use Pt free binary Co-Ni alloys synthesized by a mild hydrothermal strategy as CE materials in efficient DSSCs. As a result of the rapid charge transfer, good electrical conduction, and reasonable electrocatalysis, the power conversion efficiencies of Co-Ni-based DSSCs are higher than those of Pt-only CEs, and the fabrication expense is markedly reduced. The DSSCs based on a CoNi0.25 alloy CE displays an impressive power conversion efficiency of 8.39%, fast start-up, multiple start/stop cycling, and good stability under extended irradiation. PMID- 25146895 TI - Latent variable analysis on Chinese medicine syndrome in patients with antituberculosis drug-induced liver injury. AB - OBJECTIVE: To explore the Chinese medicine (CM) syndrome discipline in patients with antituberculosis drug (ATBD)-induced liver injury to provide the basis of the standard Chinese medicine treatment for the disease with latent variable analysis. METHODS: Epidemiological investigation method was adopted. Two hundred and sixty-one patients with ATBD-induced liver injury were investigated using CM syndrome questionnaire. The syndrome types were determined with exploratory factor analysis (EFA), and the latent variables were analyzed by confirmatory factor analysis (CFA). RESULTS: Totally 26 indexes related to CM syndrome differentiation were obtained from the 261 eligible cases, among them, 5 were as the latent dependent variables, which corresponded to 5 common syndrome types, including dampness encumbering the Spleen (Pi), Liver (Gan)-qi stagnation, Spleen and Stomach (Wei) deficiency, stasis-toxin accumulation, and qi-yin deficiency. CFA indicated that the indexes with loading coefficient [Symbol: see text]0.6 exactly reflected the connotation of its corresponding syndrome type. CONCLUSIONS: Five CM syndrome types are the most common in patients with ATBD induced liver injury, which relate to their corresponding indexes for differentiation. It is feasible to apply combined EFA and CFA for explaination and measurement of the existence of CM syndrome under specific diseases. PMID- 25146893 TI - Identification of a novel pax8 gene sequence variant in four members of the same family: from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism. AB - BACKGROUND: Congenital hypothyroidism is often secondary to thyroid dysgenesis, including thyroid agenesis, hypoplasia, ectopic thyroid tissue or cysts. Loss of function mutations in TSHR, PAX8, NKX2.1, NKX2.5 and FOXE1 genes are responsible for some forms of inherited congenital hypothyroidism, with or without hypoplastic thyroid. The aim of this study was to analyse the PAX8 gene sequence in several members of the same family in order to understand whether the variable phenotypic expression, ranging from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism, could be associated to the genetic variant in the PAX8 gene, detected in the proband. METHODS: We screened a hypothyroid child with thyroid hypoplasia for mutations in PAX8, TSHR, NKX2.1, NKX2.5 and FOXE1 genes. We studied the inheritance of the new variant R133W detected in the PAX8 gene in the proband's family, and we looked for the same substitution in 115 Caucasian European subjects and in 26 hypothyroid children. Functional studies were performed to assess the in vitro effect of the newly identified PAX8 gene variant. RESULTS: A new heterozygous nucleotide substitution was detected in the PAX8 DNA-binding motif (c.397C/T, R133W) in the proband, affected by congenital hypothyroidism with thyroid hypoplasia, in his older sister, displaying a subclinical hypothyroidism associated with thyroid hypoplasia and thyroid nodules, in his father, affected by hypothyroidism with thyroid hypoplasia and thyroid nodules, and his first cousin as well, who revealed only a subclinical hypothyroidism. Functional studies of R133W-PAX8 in the HEK293 cells showed activation of the TG promoter comparable to the wild-type PAX8. CONCLUSIONS: In vitro data do not prove that R133W-PAX8 is directly involved in the development of the thyroid phenotypes reported for family members carrying the substitution. However, it is reasonable to conceive that, in the cases of transcriptions factors, such as Pax8, which establish several interactions in different protein complexes, genetic variants could have an impact in vivo. PMID- 25146896 TI - Kinematic effect of Chinese herbal fomentation on patients with chronic neck pain. AB - OBJECTIVE: To clarify the effectiveness of Chinese herbal fomentation in treating chronic neck pain by means of changes in cervical kinematics. METHODS: Seventy six patients with chronic neck pain were included in the study and were randomized into two groups based on the random number generator of the SPSS software: fomentation combined with Chinese herbal (Group 1) and fomentation without any medicine (Group 2). In both groups, the fomentation lasted for 60 min and heated to 35 degrees C, once a day for 28 consecutive days. Standard lateral radiographs of the cervical spine were obtained including the neutral, full flexion, and full extension positions. Before and after intervention, the following parameters were used to evaluate the changes in kinematics: range of motion (ROM), sagittal alignment and instantaneous center of rotation (ICR). RESULTS: After treatment, the ROM was signifcantly higher than that of before treatment in Group 1 (51.5, 95% CI: 49.8-55.9; P<0.05). There was no significant difference between before and after treatment in Group 2 (P>0.05). Although C2-C7 cervical alignment was increased in both groups after treatment, no significant difference was detected between before and after treatment (P>0.05). For Group 1, the significant X coordinate variation was only observed at C5/C6 level (38.1; 95% CI: 34.0, 42.1; P<0.05). There was a significant upward trend in the Y coordinate of the ICR at C5/C6 (-30.5; 95% CI: -34.3, -26.8; P<0.05) and C6/C7 after treatment (-6.1; 95% CI: -6.7, -5.4; P<0.05). For Group 2, the ICR location of each level was not statistically different between the pre- and post-treatment (P>0.05). CONCLUSIONS: Chinese herbal fomentation could improve abnormal mobility in terms of ROM and ICR. Chinese herbal fomentation might be an effective treatment for chronic neck pain. PMID- 25146897 TI - Mutation of Oryza sativa CORONATINE INSENSITIVE 1b (OsCOI1b) delays leaf senescence. AB - Jasmonic acid (JA) functions in plant development, including senescence and immunity. Arabidopsis thaliana CORONATINE INSENSITIVE 1 encodes a JA receptor and functions in the JA-responsive signaling pathway. The Arabidopsis genome harbors a single COI gene, but the rice (Oryza sativa) genome harbors three COI homologs, OsCOI1a, OsCOI1b, and OsCOI2. Thus, it remains unclear whether each OsCOI has distinct, additive, synergistic, or redundant functions in development. Here, we use the oscoi1b-1 knockout mutants to show that OsCOI1b mainly affects leaf senescence under senescence-promoting conditions. oscoi1b-1 mutants stayed green during dark-induced and natural senescence, with substantial retention of chlorophylls and photosynthetic capacity. Furthermore, several senescence associated genes were downregulated in oscoi1b-1 mutants, including homologs of Arabidopsis thaliana ETHYLENE INSENSITIVE 3 and ORESARA 1, important regulators of leaf senescence. These results suggest that crosstalk between JA signaling and ethylene signaling affects leaf senescence. The Arabidopsis coi1-1 plants containing 35S:OsCOI1a or 35S:OsCOI1b rescued the delayed leaf senescence during dark incubation, suggesting that both OsCOI1a and OsCOI1b are required for promoting leaf senescence in rice. oscoi1b-1 mutants showed significant decreases in spikelet fertility and grain weight, leading to severe reduction of grain yield, indicating that OsCOI1-mediated JA signaling affects spikelet fertility and grain filling. PMID- 25146898 TI - Glutamine flux imaging using genetically encoded sensors. AB - Genetically encoded sensors allow real-time monitoring of biological molecules at a subcellular resolution. A tremendous variety of such sensors for biological molecules became available in the past 15 years, some of which became indispensable tools that are used routinely in many laboratories. One of the exciting applications of genetically encoded sensors is the use of these sensors in investigating cellular transport processes. Properties of transporters such as kinetics and substrate specificities can be investigated at a cellular level, providing possibilities for cell-type specific analyses of transport activities. In this article, we will demonstrate how transporter dynamics can be observed using genetically encoded glutamine sensor as an example. Experimental design, technical details of the experimental settings, and considerations for post experimental analyses will be discussed. PMID- 25146899 TI - Intermittent hypoxia preconditioning-induced epileptic tolerance by upregulation of monocarboxylate transporter 4 expression in rat hippocampal astrocytes. AB - Noxious stimuli applied at doses close to but below the threshold of cell injury induce adaptive responses that provide a defense against additional stress. Epileptic preconditioning protects neurons against status epilepticus and ischemia; however, it is not known if the converse is true. During hypoxia/ischemia (H/I), lactate released from astrocytes is taken up by neurons and is stored for energy, a process mediated by monocarboxylate transporter 4 (MCT4) in astroglia. The present study investigated whether H/I preconditioning can provide protection to neurons against epilepsy through upregulation of MCT4 expression in astrocytes in vitro and in vivo. An oxygen/glucose deprivation protocol was used in primary astrocyte cultures, while rats were subjected to an intermittent hypoxia preconditioning (IHP) paradigm followed by lithium pilocarpine-induced epilepsy as well as lactate transportation inhibitor injection, with a subsequent evaluation of protein expression as well as behavior. H/I induced an upregulation of MCT4 expression, while an IHP time course of 5 days provided the greatest protection against epileptic seizures, which was most apparent by 3 days after IHP. However, lactate transport function disturbances can block the protective effect induced by IHP. These findings provide a potential basis for the clinical treatment of epilepsy. PMID- 25146901 TI - Effective suppression of acrylamide neurotoxicity by lithium in mouse. AB - The primary objective of this investigation was to assess the neuroprotective efficacy of lithium in an acrylamide (ACR)-induced neuropathy model in mice. In this study, Kunming male mice were administered ACR (25 mg/kg bw, i.p. once a day) with or without lithium (25 mg/kg bw, i.p. once a day) for 2 weeks. All ACR administered mice exhibited severe symptoms of neuropathy. We found that treatment with lithium effectively alleviated behavioral deficits in animals elicited by acrylamide. Interestingly, the reduction of hippocampal neurogenesis resulting from ACR injection was promoted by administration of lithium. Further, lithium treatment significantly offset ACR-induced depletion in p-GSK-3beta (Ser9) levels in hippocampus. Collectively our findings suggest the propensity of lithium to attenuate ACR-induced neuropathy. Further studies are necessary to understand the precise molecular mechanism by which the lithium attenuates neuropathy. Nevertheless, our data clearly demonstrate the beneficial effects of lithium on ACR-induced neuropathy in mice and suggest its possible therapeutic application as an adjuvant in the management of other forms of neuropathy in humans. PMID- 25146903 TI - Dying neurons in thalamus of asphyxiated term newborns and rats are autophagic. AB - OBJECTIVE: Neonatal hypoxic-ischemic encephalopathy (HIE) still carries a high burden by its mortality and long-term neurological morbidity in survivors. Apart from hypothermia, there is no acknowledged therapy for HIE, reflecting the lack of mechanistic understanding of its pathophysiology. (Macro)autophagy, a physiological intracellular process of lysosomal degradation, has been proposed to be excessively activated in excitotoxic conditions such as HIE. The present study examines whether neuronal autophagy in the thalamus of asphyxiated human newborns or P7 rats is enhanced and related to neuronal death processes. METHODS: Neuronal autophagy and cell death were evaluated in the thalamus (frequently injured in severe HIE) of both human newborns who died after severe HIE (n = 5) and P7 hypoxic-ischemic rats (Rice-Vannuci model). Autophagic (LC3, p62), lysosomal (LAMP1, cathepsins), and cell death (TUNEL, caspase-3) markers were studied by immunohistochemistry in human and rat brain sections, and by additional methods in rats (immunoblotting, histochemistry, and electron microscopy). RESULTS: Following severe perinatal asphyxia in both humans and rats, thalamic neurons displayed up to 10-fold (p < 0.001) higher numbers of autophagosomes and lysosomes, implying an enhanced autophagic flux. The highly autophagic neurons presented strong features of apoptosis. These findings were confirmed and elucidated in more detail in rats. INTERPRETATION: These results show for the first time that autophagy is enhanced in severe HIE in dying thalamic neurons of human newborns, as in rats. Experimental neuroprotective strategies targeting autophagy could thus be a promising lead to follow for the development of future therapeutic approaches. PMID- 25146902 TI - Inhibition of microbial adhesion to plastic surface and human buccal epithelial cells by Rhodomyrtus tomentosa leaf extract. AB - OBJECTIVE: The adherence of oral pathogenic microorganisms to host tissues is the initial step for successful process of oral diseases. This study aimed to determine the effect of the Rhodomyrtus tomentosa leaf extract and rhodomyrtone, an antibacterial compound from R. tomentosa leaf, on adhesion of some oral pathogens to polystyrene plastic surface and human buccal epithelial cells. METHODS: The minimum inhibitory concentration (MIC) was evaluated using broth microdilution method. The microbial adhesion to the plastic surface and buccal cells was determined using microtiter plate method and microscopy technique. RESULTS: The ethanol extract of leaf demonstrated antibacterial activity against oral microorganisms including Staphylococcus aureus ATCC 25923, Streptococcus mutans (clinical isolate), and Candida albicans ATCC 90028 with the MIC values of 31.25, 15.62, and 1000MUg/ml, respectively. Rhodomyrtone displayed activity with the MIC values of 0.78 and 0.39MUg/ml against S. aureus ATCC 25923 and S. mutans, respectively. The MIC value of the compound against C. albicans ATCC 90028 was more than 100MUg/ml which was the highest test concentration. All pathogenic microorganisms treated with the extract and rhodomyrtone at their subinhibitory concentrations resulted in a decrease in their adherence ability to both plastic surface and buccal cells. CONCLUSION: It is suggested that R. tomentosa extract and rhodomyrtone may be useful in therapy or as prophylaxis in infections involving oral pathogens. PMID- 25146900 TI - Group III metabotropic glutamate receptors: pharmacology, physiology and therapeutic potential. AB - Glutamate, the primary excitatory neurotransmitter in the central nervous system (CNS), exerts neuromodulatory actions via the activation of metabotropic glutamate (mGlu) receptors. There are eight known mGlu receptor subtypes (mGlu1 8), which are widely expressed throughout the brain, and are divided into three groups (I-III), based on signalling pathways and pharmacological profiles. Group III mGlu receptors (mGlu4/6/7/8) are primarily, although not exclusively, localised on presynaptic terminals, where they act as both auto- and hetero receptors, inhibiting the release of neurotransmitter. Until recently, our understanding of the role of individual group III mGlu receptor subtypes was hindered by a lack of subtype-selective pharmacological tools. Recent advances in the development of both orthosteric and allosteric group III-targeting compounds, however, have prompted detailed investigations into the possible functional role of these receptors within the CNS, and revealed their involvement in a number of pathological conditions, such as epilepsy, anxiety and Parkinson's disease. The heterogeneous expression of group III mGlu receptor subtypes throughout the brain, as well as their distinct distribution at glutamatergic and GABAergic synapses, makes them ideal targets for therapeutic intervention. This review summarises the advances in subtype-selective pharmacology, and discusses the individual roles of group III mGlu receptors in physiology, and their potential involvement in disease. PMID- 25146904 TI - Assessing the ecological status in the context of the European Water Framework Directive: where do we go now? AB - The Water Framework Directive (WFD) is now well established as the key management imperative in river basins across Europe. However, there remain significant concerns with the way WFD is implemented and there is now a need for water managers and scientists to communicate better in order to find solutions to these concerns. To address this, a Science-Policy Interface (SPI) activity was launched in 2010 led by Directorate-General for Research and Innovation and Onema (the French national agency for water and aquatic ecosystems), which provided an interactive forum to connect scientists and WFD end-users. One major aim of the SPI activity was to establish a list of the most crucial research and development needs for enhancing WFD implementation. This paper synthesises the recommendations from this event highlighting 10 priority issues relating to ecological status. For lakes, temporary streams and transitional and coastal waters, WFD implementation still suffers from a lack of WFD-compliant bioassessment methods. For rivers, special attention is required to assess the ecological impacts of hydromorphological alterations on biological communities, notably those affecting river continuity and riparian covering. Spatial extrapolation tools are needed in order to evaluate ecological status for water bodies for which no data are available. The need for more functional bioassessment tools as complements to usual WFD-compliant tools, and to connect clearly good ecological state, biodiversity and ecosystem services when implementing WFD were also identified as crucial issues. PMID- 25146905 TI - Determinants of manganese levels in house dust samples from the CHAMACOS cohort. AB - INTRODUCTION: Manganese (Mn) is an essential nutrient, but at high exposure levels Mn is a neurotoxicant. The fungicides maneb and mancozeb are approximately 21% Mn by weight and more than 150,000 kg are applied each year to crops in the Salinas Valley, California. It is not clear, however, whether agricultural use of these fungicides increases Mn levels in homes. MATERIALS AND METHODS: We collected house dust samples from 378 residences enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study with a second sample collected approximately nine months later from 90 of the residences. House dust samples were analyzed for Mn using inductively coupled plasma optical emission spectroscopy. Information from interviews, home inspections, and pesticide use reports was used to identify potential predictors of Mn dust concentrations and loadings. RESULTS: Mn was detectable in all dust samples. The median Mn concentration was 171 MUg/g and median Mn loading was 1,910 MUg/m(2) at first visit. In multivariable models, Mn dust concentrations and loadings increased with the number of farmworkers in the home and the amount of agricultural Mn fungicides applied within three kilometers of the residence during the month prior to dust sample collection. Dust concentrations of Mn and other metals (lead, cadmium and chromium) were higher in residences located in the southern Salinas Valley compared those located in other areas of the Salinas Valley. Dust loadings of Mn and other metals were also higher in residences located on Antioch Loam soil than other soil types, and in homes with poor or average housekeeping practices. CONCLUSIONS: Agricultural use of Mn containing fungicides was associated with Mn dust concentrations and loadings in nearby residences and farmworker homes. Housekeeping practices and soil type at residence were also important factors related to dust metal concentrations and loadings. PMID- 25146906 TI - Massive accumulation of highly polluted sedimentary deposits by river damming. AB - Uncontrolled dumping of anthropogenic waste in rivers regulated by dams has created contaminated deposits in reservoirs that have remained unidentified for decades. The Flix Reservoir is located in the Ebro River, the second largest river flowing into the NW Mediterranean, has been affected by residue dumping from a chlor-alkali electrochemical plant for decades. High-resolution seismic profiles, bathymetric data, surficial sediment samples and sediment cores were obtained in the Flix Reservoir to study the characteristics of the deposit accumulated by this dumping. These data were used to reconstruct the waste deposit history. Since the construction of the Flix Dam in 1948, more than 3.6*10(5) t of industrial waste has accumulated in the reservoir generating a delta-like deposit formed by three sediment lobes of fine-grained material highly contaminated by Hg, Cd, Zn and Cr (max: 640, 26, 420 and 750 mg kg(-1), respectively). This contamination was associated with the Hg that was used for the cathode in the electrochemical plant from 1949 and with the production of phosphorite derivatives from 1973. After the construction of two large dams only a few kilometres upstream during the 1960s, the solids discharged from the industrial complex became the main sediment source to the Flix Reservoir. The deposit has remained in the reservoir forming a delta that obstructs about 50% of the river water section. Its stability only depended on the flow retention by the Flix Dam. At present, this contaminated waste deposit is being removed from the water reservoir as it is a cause of concern for the environment and for human health downriver. PMID- 25146907 TI - A novel modeling tool with multi-stressor functionality for organic contaminant transport and fate in the Baltic Sea. AB - The coupled physical-biogeochemical model BALTSEM, previously used to assess nutrient/carbon cycles and eutrophication in the Baltic Sea, has been expanded to include algorithms for calculations of organic contaminant environmental transport and fate. This novel model version (BALTSEM-POP) is evaluated for polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) and hexachlorobenzene (HCB) in Baltic Sea surface water and sediment. Modeled dissolved concentrations are usually within a factor of 2-4 of observed concentrations, however with larger deviations for furans. Calculated concentrations in particulate organic matter are less accurate (within factors of 1-700), likely due to errors in estimated pelagic biomass, particulate matter water partitioning, and large natural variability in field data. Concentrations in sediments are usually predicted within a factor of 6. The good performance of the model illustrates its usefulness for exploration of contaminant fate in response to variations in nutrient input and climatic conditions in the Baltic Sea marine environment. PMID- 25146908 TI - Source apportionment of PM(2.5) in the harbour-industrial area of Brindisi (Italy): identification and estimation of the contribution of in-port ship emissions. AB - Harbours are important for economic and social development of coastal areas but they also represent an anthropogenic source of emissions often located near urban centres and industrial areas. This increases the difficulties in distinguishing the harbour contribution with respect to other sources. The aim of this work is the characterisation of main sources of PM2.5 acting on the Brindisi harbour industrial area, trying to pinpoint the contribution of in-port ship emissions to primary and secondary PM2.5. Brindisi is an important port-city of the Adriatic Sea considered a hot-spot for anthropogenic environmental pressures at National level. Measurements were performed collecting PM2.5 samples and characterising the concentrations of 23 chemical species (water soluble organic and inorganic carbon; major ions: SO4(2-), NO3(-), NH4(+), Cl(-), C2O4(2-), Na(+), K(+), Mg(2+), Ca(2+); and elements: Ni, Cu, V, Mn, As, Pb, Cr, Sb, Fe, Al, Zn, and Ti). These species represent, on average, 51.4% of PM2.5 and were used for source apportionment via PMF. The contributions of eight sources were estimated: crustal (16.4+/-0.9% of PM2.5), aged marine (2.6+/-0.5%), crustal carbonates (7.7+/ 0.3%), ammonium sulphate (27.3+/-0.8%), biomass burning-fires (11.7+/-0.7%), traffic (16.4+/-1.7 %), industrial (0.4+/-0.3%) and a mixed source oil combustion industrial including ship emissions in harbour (15.3+/-1.3%). The PMF did not separate the in-port ship emission contribution from industrial releases. The correlation of estimated contribution with meteorology showed directionality with an increase of oil combustion and sulphate contribution in the harbour direction with respect to the direction of the urban area and an increase of the V/Ni ratio. This allowed for the use of V as marker of primary ship contribution to PM2.5 (2.8%+/-1.1%). The secondary contribution of oil combustion to non-sea-salt sulphate, nssSO4(2-), was estimated to be 1.3 MUg/m(3) (about 40% of total nssSO4(2-) or 11% of PM2.5). PMID- 25146909 TI - The impact of mass transfer limitations on size distributions of particle associated SVOCs in outdoor and indoor environments. AB - Semi-volatile organic compounds (SVOCs) partition between the gas phase and airborne particles. The size distribution of particle-associated SVOCs impacts their fate in outdoor and indoor environments, as well as human exposure to these compounds and subsequent health risks. Allen et al. (1996) previously proposed that the rate of mass transfer can impact polycyclic aromatic hydrocarbon (PAH) partitioning among different sized particles, especially for time scales relevant to urban aerosols. The present study quantitatively builds on this idea, presenting a model that incorporates dynamic SVOC/particle interaction and applying this model to typical outdoor and indoor scenarios. The model indicates that the impact of mass transfer limitations on the size distribution of a particle-associated SVOC can be evaluated by the ratio of the time to achieve gas particle equilibrium relative to the residence time of particles. The higher this ratio, the greater the influence of mass transfer limitations on the size distribution of particle-associated SVOCs. The influence of such constraints is largest on the fraction of particle-associated SVOCs in the coarse mode (>2 MUm). Predictions from the model have been found to be in reasonable agreement with size distributions measured for PAHs at roadside and suburban locations in Japan. The model also quantitatively explains shifts in the size distributions of particle associated SVOCs compared to those for particle mass, and the manner in which these shifts vary with temperature and an SVOC's molecular weight. PMID- 25146910 TI - Interception and retention of wet-deposited radiocaesium and radiostrontium on a ley mixture of grass and clover. AB - The aims of this study were to assess the potential radioactive contamination of fodder in the case of accidental radionuclide fallout, and to analyse the relationship between interception and retention of radionuclides as a function of biomass and Leaf Area Index (LAI). The interception and the retention of wet deposited (134)Cs and (85)Sr in ley (a mixture of grass and clover) were measured after artificial wet deposition in a field trial in Uppsala (eastern central Sweden). The field trial had a randomised block design with three replicates. (134)Cs and (85)Sr were deposited at six different growth stages during two growing seasons (2010 and 2011) using a rainfall simulator. The biomass was sampled in the center of each parcel 2 to 3h after deposition and at later growth stages (1 to 5) during the growing season. The above ground biomass and LAI were measured as well. The interception of radionuclides by the ley was largest at the late growth stages; the spike and tassel/flowering (code 5:6) in the 1(st) year, and at flowering/initial flowering (code 6:5) in the 2(nd) year. There was a correlation between radionuclide interception and above ground plant biomass, as well as with LAI, for both radionuclides in both years. The highest activity concentrations of both radionuclides were measured after deposition at the late growth stages and were found to be higher in the 2(nd) year. The weathering half lives were shorter at the earlier growth stages than at the later growth stages for both radionuclides. For the magnitude of deposition chosen in our experiment, it can be concluded that the above ground biomass is a good predictor and the LAI a more uncertain predictor of the interception of radiocaesium and radiostrontium by ley grass and clover. PMID- 25146911 TI - Willingness to pay to avoid health risks from road-traffic-related air pollution and noise across five countries. AB - We conducted a multi-country study to estimate the perceived economic values of traffic-related air pollution and noise health risks within the framework of a large European project. We used contingent valuation as a method to assess the willingness-to-pay (WTP) for both types of pollutants simultaneously. We asked respondents how much they would be willing to pay annually to avoid certain health risks from specific pollutants. Three sets of vignettes with different levels of information were provided prior to the WTP questions. These vignettes described qualitative general health risks, a quantitative single health risk related to a pollutant, and a quantitative scenario of combined health risks related to a pollutant. The mean WTP estimates to avoid road-traffic air pollution effects for the three vignettes were: ?130 per person per year (pp/y) for general health risks, ?80 pp/y for a half year shorter in life expectancy, and ?330 pp/y to a 50% decrease in road-traffic air pollution. Their medians were ?40 pp/y, ?10 pp/y and ?50 pp/y, respectively. The mean WTP estimates to avoid road-traffic noise effects for the three vignettes were: ?90 pp/y for general health risks, ?100 pp/y for a 13% increase in severe annoyance, and ?320 pp/y for a combined-risk scenario related to an increase of a noise level from 50 dB to 65 dB. Their medians were ?20 pp/y, ?20 pp/y and ?50 pp/y, respectively. Risk perceptions and attitudes as well as environmental and pollutant concerns significantly affected WTP estimates. The observed differences in crude WTP estimates between countries changed considerably when perception-related variables were included in the WTP regression models. For this reason, great care should be taken when performing benefit transfer from studies in one country to another. PMID- 25146912 TI - Proton conductive watery channels constructed by Anderson polyanions and lanthanide coordination cations. AB - A 3D inorganic-organic hybrid proton conductor, [Sm(H2O)5(CO2CH2NH3)2][Al(OH)6Mo6O18].10H2O (), has been synthesized by using coordination cations, [Sm(H2O)5(gly)2](3+) (gly = (-)CO2CH2NH3(+)), and polyanions, [Al(OH)6Mo6O18](3-) ([AlMo6]). The polyanions ([AlMo6]) and the coordination cations ([Sm(H2O)5(gly)2](3+)) stack to form a 3D supramolecular network structure containing 1D channels along the c axis by electrostatic force and H-bonding. Significantly, the 1D channels are water-filled with a high water content (both Sm coordinated and in lattice). Dynamic adsorption measurements were implemented at 1 atm, and 95% relative humidity (RH). The water adsorption amount (6.51 wt% at 25 degrees C and 5.68 wt% at 80 degrees C) consistent with the number of lattice water molecules of suggests that the water chains were retained at elevated temperatures (80 degrees C) under 95% RH. Alternating current (AC) impedance measurements of reveal an outstanding conductivity for of 4.53 * 10(-3) S cm(-1) at 80 degrees C under 95% RH. The activation energy of calculated from the Arrhenius plots of the proton conductivity is 1.09 eV, which indicated that the protons transfer by a vehicle mechanism. PMID- 25146913 TI - Ovarian hyperstimulation syndrome and thrombotic events. AB - Ovarian hyperstimulation syndrome (OHSS) is one of the most important complications of ovarian stimulation with severe morbidity and is still a threat to every patient undergoing ovulation induction. This manuscript reviews the current evidence regarding the relationship between OHSS and thromboembolism in infertile patients undergoing ovarian stimulation published in the world literature. The PubMed Database was searched for publications on reported cases of OHSS and thromboembolic phenomenon published between 1965 and 2013. One hundred and forty cases of OHSS and thromboembolic phenomena were retrieved. The vascular accident had already occurred in the first cycle of treatment among 119 women (85%), at early stage of OHSS in 43% and late stage in 57% of cases. Venous thrombotic events were recorded mostly in unusual sites, jugular, and subclavian veins, with 69 and 38 thrombotic events, respectively. Coagulation status was found at 86 of the 140 cases (61%). Fifty-three of the pregnant patients (68%) delivered singleton births and 47% had preterm deliveries, and termination of pregnancy was indicated in 11 cases (14%). The most serious complication associated with OHSS is thrombotic phenomena as shown in the present review of 140 cases, world data, on both arterial and venous side. Thromboprophylaxis should be initiated in patients with thrombophilia and who develop moderate-to severe OHSS. PMID- 25146914 TI - An efficient pipeline for the generation and functional analysis of human BRCA2 variants of uncertain significance. AB - The implementation of next-generation sequence analysis of disease-related genes has resulted in an increasing number of genetic variants with an unknown clinical significance. The functional analysis of these so-called "variants of uncertain significance" (VUS) is hampered by the tedious and time-consuming procedures required to generate and test specific sequence variants in genomic DNA. Here, we describe an efficient pipeline for the generation of gene variants in a full length human gene, BRCA2, using a bacterial artificial chromosome. This method permits the rapid generation of intronic and exonic variants in a complete gene through the use of an exon-replacement strategy based on simple site-directed mutagenesis and an effective positive-negative selection system in E. coli. The functionality of variants can then be assessed through the use of functional assays, such as complementation of gene-deficient mouse-embryonic stem (mES) cells in the case of human BRCA2. Our methodology builds upon an earlier protocol and, through the introduction of a series of major innovations, now represents a practical proposition for the rapid analysis of BRCA2 variants and a blueprint for the analysis of other genes using similar approaches. This method enables rapid generation and reliable classification of VUS in disease-related genes, allowing informed clinical decision-making. PMID- 25146915 TI - Reply: 'Behr syndrome' with OPA1 compound heterozygote mutations. PMID- 25146916 TI - 'Behr syndrome' with OPA1 compound heterozygote mutations. PMID- 25146917 TI - Anisotropic cellular network formation in engineered muscle tissue through the self-organization of neurons and endothelial cells. AB - Tissue anisotropy directed by cell sheets: Aligned myoblasts can be harvested as an anisotropic cell sheet using a micropatterned thermoresponsive substrate. Neurons and endothelial cells sandwiched between multiple anisotropic cell sheets self-organize oriented cellular networks in the tissue construct. This simple tissue engineering technique is useful for the creation of biomimetic microstructures in complex tissue, required for future advances in regenerative medicine. PMID- 25146918 TI - Randomized clinical trial comparing self-gripping mesh with suture fixation of lightweight polypropylene mesh in open inguinal hernia repair. AB - BACKGROUND: Postoperative pain is an important adverse event following inguinal hernia repair. The aim of this trial was to compare postoperative pain within the first 3 months and 1 year after surgery in patients undergoing open mesh inguinal hernia repair using either a self-gripping lightweight polyester mesh or a polypropylene lightweight mesh fixed with sutures. METHODS: Adult men undergoing Lichtenstein repair for primary inguinal hernia were randomized to ProGripTM self gripping mesh or standard sutured lightweight polypropylene mesh. RESULTS: In total 557 men were included in the final analysis (self-gripping mesh 270, sutured mesh 287). Early postoperative pain scores were lower with self-gripping mesh than with sutured lightweight mesh: mean visual analogue pain score relative to baseline +1.3 and +8.6 respectively at discharge (P = 0.033), and mean surgical pain scale score relative to baseline +4.2 and +9.7 respectively on day 7 (P = 0.027). There was no significant difference in mid-term (1 month) and long term (3 months and 1 year) pain scores between the groups. Surgery was significantly quicker with self-gripping mesh (mean difference 7.6 min; P < 0.001). There were no significant differences in reported mesh handling, analgesic consumption, other wound complications, patient satisfaction or hernia recurrence between the groups. CONCLUSION: Self-gripping mesh for open inguinal hernia repair was well tolerated and reduced early postoperative pain (within the first week), without increasing the risk of early recurrence. It did not reduce chronic pain. REGISTRATION NUMBER: NCT00827944 (http://www.clinicaltrials.gov). PMID- 25146919 TI - Real-time imaging of endothelial cell-cell junctions during neutrophil transmigration under physiological flow. AB - During inflammation, leukocytes leave the circulation and cross the endothelium to fight invading pathogens in underlying tissues. This process is known as leukocyte transendothelial migration. Two routes for leukocytes to cross the endothelial monolayer have been described: the paracellular route, i.e., through the cell-cell junctions and the transcellular route, i.e., through the endothelial cell body. However, it has been technically difficult to discriminate between the para- and transcellular route. We developed a simple in vitro assay to study the distribution of endogenous VE-cadherin and PECAM-1 during neutrophil transendothelial migration under physiological flow conditions. Prior to neutrophil perfusion, endothelial cells were briefly treated with fluorescently labeled antibodies against VE-cadherin and PECAM-1. These antibodies did not interfere with the function of both proteins, as was determined by electrical cell-substrate impedance sensing and FRAP measurements. Using this assay, we were able to follow the distribution of endogenous VE-cadherin and PECAM-1 during transendothelial migration under flow conditions and discriminate between the para- and transcellular migration routes of the leukocytes across the endothelium. PMID- 25146920 TI - Imaging of the cerebellopontine angle. PMID- 25146922 TI - Sight-threatening pseudotumour cerebri associated with excess vitamin A supplementation. PMID- 25146923 TI - Genotoxic stress/p53-induced DNAJB9 inhibits the pro-apoptotic function of p53. AB - DNAJB9 is a recently isolated member of the molecular chaperone gene family, whose precise function is largely unknown. In the present study, we have identified DNAJB9 as an inducible gene of the tumor suppressor p53. DNAJB9 expression was induced by p53 or genotoxic stress in a p53-dependent manner, which was mediated by the Ras/Raf/ERK pathway. In addition, depletion of DNAJB9 by using siRNAs greatly increased genotoxic stress/p53-induced apoptosis, suggesting that DNAJB9 inhibits the pro-apoptotic function of p53. We also found that DNAJB9 physically interacts with p53 through its J domain, through which it inhibits the pro-apoptotic function of p53. Moreover, DNAJB9 colocalized with p53 in both cytoplasm and nucleus under genotoxic conditions. Together, these results demonstrate that DNAJB9 is a downstream target of p53 that belongs to the group of negative feedback regulators of p53. PMID- 25146925 TI - Bax targets mitochondria by distinct mechanisms before or during apoptotic cell death: a requirement for VDAC2 or Bak for efficient Bax apoptotic function. AB - In non-apoptotic cells, Bak constitutively resides in the mitochondrial outer membrane. In contrast, Bax is in a dynamic equilibrium between the cytosol and mitochondria, and is commonly predominant in the cytosol. In response to an apoptotic stimulus, Bax and Bak change conformation, leading to Bax accumulation at mitochondria and Bak/Bax oligomerization to form a pore in the mitochondrial outer membrane that is responsible for cell death. Using blue native-PAGE to investigate how Bax oligomerizes in the mitochondrial outer membrane, we observed that, like Bak, a proportion of Bax that constitutively resides at mitochondria associates with voltage-dependent anion channel (VDAC)2 prior to an apoptotic stimulus. During apoptosis, Bax dissociates from VDAC2 and homo-oligomerizes to form high molecular weight oligomers. In cells that lack VDAC2, constitutive mitochondrial localization of Bax and Bak was impaired, suggesting that VDAC2 has a role in Bax and Bak import to, or stability at, the mitochondrial outer membrane. However, following an apoptotic stimulus, Bak and Bax retained the ability to accumulate at VDAC2-deficient mitochondria and to mediate cell death. Silencing of Bak in VDAC2-deficient cells indicated that Bax required either VDAC2 or Bak in order to translocate to and oligomerize at the mitochondrial outer membrane to efficiently mediate apoptosis. In contrast, efficient Bak homo oligomerization at the mitochondrial outer membrane and its pro-apoptotic function required neither VDAC2 nor Bax. Even a C-terminal mutant of Bax (S184L) that localizes to mitochondria did not constitutively target mitochondria deficient in VDAC2, but was recruited to mitochondria following an apoptotic stimulus dependent on Bak or upon over-expression of Bcl-xL. Together, our data suggest that Bax localizes to the mitochondrial outer membrane via alternate mechanisms, either constitutively via an interaction with VDAC2 or after activation via interaction with Bcl-2 family proteins. PMID- 25146924 TI - TAK1 control of cell death. AB - Programmed cell death, a physiologic process for removing cells, is critically important in normal development and for elimination of damaged cells. Conversely, unattended cell death contributes to a variety of human disease pathogenesis. Thus, precise understanding of molecular mechanisms underlying control of cell death is important and relevant to public health. Recent studies emphasize that transforming growth factor-beta-activated kinase 1 (TAK1) is a central regulator of cell death and is activated through a diverse set of intra- and extracellular stimuli. The physiologic importance of TAK1 and TAK1-binding proteins in cell survival and death has been demonstrated using a number of genetically engineered mice. These studies uncover an indispensable role of TAK1 and its binding proteins for maintenance of cell viability and tissue homeostasis in a variety of organs. TAK1 is known to control cell viability and inflammation through activating downstream effectors such as NF-kappaB and mitogen-activated protein kinases (MAPKs). It is also emerging that TAK1 regulates cell survival not solely through NF-kappaB but also through NF-kappaB-independent pathways such as oxidative stress and receptor-interacting protein kinase 1 (RIPK1) kinase activity-dependent pathway. Moreover, recent studies have identified TAK1's seemingly paradoxical role to induce programmed necrosis, also referred to as necroptosis. This review summarizes the consequences of TAK1 deficiency in different cell and tissue types from the perspective of cell death and also focuses on the mechanism by which TAK1 complex inhibits or promotes programmed cell death. This review serves to synthesize our current understanding of TAK1 in cell survival and death to identify promising directions for future research and TAK1's potential relevance to human disease pathogenesis. PMID- 25146927 TI - E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis. AB - Tumor suppressor p53 has a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses, including apoptosis, cell cycle arrest and senescence. To ensure its proper levels and functions in cells, p53 is tightly regulated mainly through post translational modifications, such as ubiquitination. Here, we identified E3 ubiquitin ligase TRIM32 as a novel p53 target gene and negative regulator to regulate p53-mediated stress responses. In response to stress, such as DNA damage, p53 binds to the p53 responsive element in the promoter of the TRIM32 gene and transcriptionally induces the expression of TRIM32 in cells. In turn, TRIM32 interacts with p53 and promotes p53 degradation through ubiquitination. Thus, TRIM32 negatively regulates p53-mediated apoptosis, cell cycle arrest and senescence in response to stress. TRIM32 is frequently overexpressed in different types of human tumors. TRIM32 overexpression promotes cell oncogenic transformation and tumorigenesis in mice in a largely p53-dependent manner. Taken together, our results demonstrated that as a novel p53 target and a novel negative regulator for p53, TRIM32 has an important role in regulation of p53 and p53-mediated cellular stress responses. Furthermore, our results also revealed that impairing p53 function is a novel mechanism for TRIM32 in tumorigenesis. PMID- 25146926 TI - RIP kinases: key decision makers in cell death and innate immunity. AB - Innate immunity represents the first line of defence against invading pathogens. It consists of an initial inflammatory response that recruits white blood cells to the site of infection in an effort to destroy and eliminate the pathogen. Some pathogens replicate within host cells, and cell death by apoptosis is an important effector mechanism to remove the replication niche for such microbes. However, some microbes have evolved evasive strategies to block apoptosis, and in these cases host cells may employ further countermeasures, including an inflammatory form of cell death know as necroptosis. This review aims to highlight the importance of the RIP kinase family in controlling these various defence strategies. RIP1 is initially discussed as a key component of death receptor signalling and in the context of dictating whether a cell triggers a pathway of pro-inflammatory gene expression or cell death by apoptosis. The molecular and functional interplay of RIP1 and RIP3 is described, especially with respect to mediating necroptosis and as key mediators of inflammation. The function of RIP2, with particular emphasis on its role in NOD signalling, is also explored. Special attention is given to emphasizing the physiological and pathophysiological contexts for these various functions of RIP kinases. PMID- 25146928 TI - BRD4 regulates Nanog expression in mouse embryonic stem cells and preimplantation embryos. AB - Bromodomain-containing protein 4 (BRD4) is an important epigenetic reader implicated in the pathogenesis of a number of different cancers and other diseases. Brd4-null mouse embryos die shortly after implantation and are compromised in their ability to maintain the inner cell mass, which gives rise to embryonic stem cells (ESCs). Here we report that BRD4 regulates expression of the pluripotency factor Nanog in mouse ESCs and preimplantation embryos, as well as in human ESCs and embryonic cancer stem cells. Inhibition of BRD4 function using a chemical inhibitor, small interfering RNAs, or a dominant-negative approach suppresses Nanog expression, and abolishes the self-renewal ability of ESCs. We also find that BRD4 associates with BRG1 (brahma-related gene 1, aka Smarca4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4)), a key regulator of ESC self-renewal and pluripotency, in the Nanog regulatory regions to regulate Nanog expression. Our study identifies Nanog as a novel BRD4 target gene, providing new insights for the biological function of BRD4 in stem cells and mouse embryos. Knowledge gained from these non cancerous systems will facilitate future investigations of how Brd4 dysfunction leads to cancers. PMID- 25146929 TI - Perforin oligomers form arcs in cellular membranes: a locus for intracellular delivery of granzymes. AB - Perforin-mediated cytotoxicity is an essential host defense, in which defects contribute to tumor development and pathogenic disorders including autoimmunity and autoinflammation. How perforin (PFN) facilitates intracellular delivery of pro-apoptotic and inflammatory granzymes across the bilayer of targets remains unresolved. Here we show that cellular susceptibility to granzyme B (GzmB) correlates with rapid PFN-induced phosphatidylserine externalization, suggesting that pores are formed at a protein-lipid interface by incomplete membrane oligomers (or arcs). Supporting a role for these oligomers in protease delivery, an anti-PFN antibody (pf-80) suppresses necrosis but increases phosphatidylserine flip-flop and GzmB-induced apoptosis. As shown by atomic force microscopy on planar bilayers and deep-etch electron microscopy on mammalian cells, pf-80 increases the proportion of arcs which correlates with the presence of smaller electrical conductances, while large cylindrical pores decline. PFN appears to form arc structures on target membranes that serve as minimally disrupting conduits for GzmB translocation. The role of these arcs in PFN-mediated pathology warrants evaluation where they may serve as novel therapeutic targets. PMID- 25146931 TI - The utility of CT for predicting bile leaks in hepatic trauma. AB - The purpose of this study was to determine the efficacy of CT to predict the development of bile leaks in hepatic trauma. This HIPAA-compliant retrospective study was IRB approved and consent was waived. All patients who sustained hepatic trauma between January 1, 2006, and January 31, 2012, and who underwent CT and hepatobiliary scans during the same hospital admission were included. One hundred and thirty-two patients met the inclusion criteria. Comparison between the presence of biliary injury relative to American Association for the Surgery of Trauma (AAST) hepatic injury grade and mean distance of the hepatic laceration to the inferior vena cava (IVC) was made. The ability of free fluid to predict bile injury was analyzed. Forty-one (31 %) of the 132 patients had positive hepatobiliary scans. Of these 41 patients, seven (17 %) sustained low-grade and 34 (83 %) sustained high-grade hepatic injury compared with the 37 (41 %) low grade and 54 (59 %) high-grade hepatic injuries in the negative hepatobiliary scan group. The mean distance to the IVC was 2.4 cm (SD 2.9 cm) and 3.6 cm (SD 3.3 cm) in patients with and without bile leaks, respectively. A statistically significant difference in the proportion of high-grade injuries and the mean distance from the IVC between the two groups was identified. The presence of free fluid on CT is sensitive, but not specific, for detecting a bile leak. CT findings, including AAST liver injury grade and location of the liver laceration, are able to predict which patients are at risk for developing bile leaks as seen on hepatobiliary scintigraphy, whereas the presence of free fluid is not. PMID- 25146930 TI - Ubr3 E3 ligase regulates apoptosis by controlling the activity of DIAP1 in Drosophila. AB - Apoptosis has essential roles in a variety of cellular and developmental processes. Although the pathway is well studied, how the activities of individual components in the pathway are regulated is less understood. In Drosophila, a key component in apoptosis is Drosophila inhibitor of apoptosis protein 1 (DIAP1), which is required to prevent caspase activation. Here, we demonstrate that Drosophila CG42593 (ubr3), encoding the homolog of mammalian UBR3, has an essential role in regulating the apoptosis pathway. We show that loss of ubr3 activity causes caspase-dependent apoptosis in Drosophila eye and wing discs. Our genetic epistasis analyses show that the apoptosis induced by loss of ubr3 can be suppressed by loss of initiator caspase Drosophila Nedd2-like caspase (Dronc), or by ectopic expression of the apoptosis inhibitor p35, but cannot be rescued by overexpression of DIAP1. Importantly, we show that the activity of Ubr3 in the apoptosis pathway is not dependent on its Ring-domain, which is required for its E3 ligase activity. Furthermore, we find that through the UBR-box domain, Ubr3 physically interacts with the neo-epitope of DIAP1 that is exposed after caspase mediated cleavage. This interaction promotes the recruitment and ubiquitination of substrate caspases by DIAP1. Together, our data indicate that Ubr3 interacts with DIAP1 and positively regulates DIAP1 activity, possibly by maintaining its active conformation in the apoptosis pathway. PMID- 25146932 TI - Can rapid integrated polymerase chain reaction-based diagnostics for gastrointestinal pathogens improve routine hospital infection control practice? A diagnostic study. AB - BACKGROUND: Every year approximately 5000-9000 patients are admitted to a hospital with diarrhoea, which in up to 90% of cases has a non-infectious cause. As a result, single rooms are 'blocked' by patients with non-infectious diarrhoea, while patients with infectious diarrhoea are still in open bays because of a lack of free side rooms. A rapid test for differentiating infectious from non-infectious diarrhoea could be very beneficial for patients. OBJECTIVE: To evaluate MassCode multiplex polymerase chain reaction (PCR) for the simultaneous diagnosis of multiple enteropathogens directly from stool, in terms of sensitivity/specificity to detect four common important enteropathogens: Clostridium difficile, Campylobacter spp., Salmonella spp. and norovirus. DESIGN: A retrospective study of fixed numbers of samples positive for C. difficile (n = 200), Campylobacter spp. (n = 200), Salmonella spp. (n = 100) and norovirus (n = 200) plus samples negative for all these pathogens (n = 300). Samples were sourced from NHS microbiology laboratories in Oxford and Leeds where initial diagnostic testing was performed according to Public Health England methodology. Researchers carrying out MassCode assays were blind to this information. A questionnaire survey, examining current practice for infection control teams and microbiology laboratories managing infectious diarrhoea, was also carried out. SETTING: MassCode assays were carried out at Oxford University Hospitals NHS Trust. Further multiplex assays, carried out using Luminex, were run on the same set of samples at Leeds Teaching Hospitals NHS Trust. The questionnaire was completed by various NHS trusts. MAIN OUTCOME MEASURES: Sensitivity and specificity to detect C. difficile, Campylobacter spp., Salmonella spp., and norovirus. RESULTS: Nucleic acids were extracted from 948 clinical samples using an optimised protocol (200 Campylobacter spp., 199 C. difficile, 60 S. enterica, 199 norovirus and 295 negative samples; some samples contained more than one pathogen). Using the MassCode assay, sensitivities for each organism compared with standard microbiological testing ranged from 43% to 94% and specificities from 95% to 98%, with particularly poor performance for S. enterica. Relatively large numbers of unexpected positives not confirmed with quantitative PCR were also observed, particularly for S. enterica, Giardia lamblia and Cryptosporidium spp. As the results indicated that S. enterica detection might provide generic challenges to other multiplex assays for gastrointestinal pathogens, the Luminex xTag((r)) gastrointestinal assay was also run blinded on the same extracts (937/948 remaining) and on re-extracted samples (839/948 with sufficient material). For Campylobacter spp., C. difficile and norovirus, high sensitivities (> 92%) and specificities (> 96%) were observed. For S. enterica, on the original MassCode/Oxford extracts, Luminex sensitivity compared with standard microbiological testing was 84% [95% confidence interval (CI) 73% to 93%], but this dropped to 46% on a fresh extract, very similar to MassCode, with a corresponding increase in specificity from 92% to 99%. Overall agreement on the per-sample diagnosis compared with combined microbiology plus PCR for the main four/all pathogens was 85.6%/64.7%, 87.0%/82.9% and 89.8%/86.8% for the MassCode assay, Luminex assay/MassCode extract and Luminex assay/fresh extract, respectively. Luminex assay results from fresh extracts implied that 5% of samples did not represent infectious diarrhoea, even though enteropathogens were genuinely present. Managing infectious diarrhoea was a significant burden for infection control teams (taking 21% of their time) and better diagnostics were identified as having major potential benefits for patients. CONCLUSIONS: Overall, the Luminex xTag gastrointestinal panel showed similar or superior sensitivity and specificity to the MassCode assay. However, on fresh extracts, this test had low sensitivity to detect a key enteric pathogen, S. enterica; making it an unrealistic option for most microbiology laboratories. Extraction efficiency appears to be a major obstacle for nucleic acid-based tests for this organism, and possibly the whole Enterobacteriaceae family. To improve workflows in service microbiology laboratories, to reduce workload for infection control practitioners, and to improve outcomes for NHS patients, further research on deoxyribonucleic acid-based multiplex gastrointestinal diagnostics is urgently needed. FUNDING: The Health Technology Assessment programme of the National Institute for Health Research. PMID- 25146934 TI - The 5-choice serial reaction time task: a task of attention and impulse control for rodents. AB - This protocol describes the 5-choice serial reaction time task, which is an operant based task used to study attention and impulse control in rodents. Test day challenges, modifications to the standard task, can be used to systematically tax the neural systems controlling either attention or impulse control. Importantly, these challenges have consistent effects on behavior across laboratories in intact animals and can reveal either enhancements or deficits in cognitive function that are not apparent when rats are only tested on the standard task. The variety of behavioral measures that are collected can be used to determine if other factors (i.e., sedation, motivation deficits, locomotor impairments) are contributing to changes in performance. The versatility of the 5CSRTT is further enhanced because it is amenable to combination with pharmacological, molecular, and genetic techniques. PMID- 25146933 TI - Serotonin concentrations in platelets, plasma, mitral valve leaflet, and left ventricular myocardial tissue in dogs with myxomatous mitral valve disease. AB - HYPOTHESIS/OBJECTIVES: Altered serotonin (5-hydroxytryptamine, 5HT) signaling is postulated in development and progression of canine myxomatous mitral valve disease (MMVD). Little is known regarding platelet, plasma, valvular, or myocardial 5HT concentration ([5HT]) in affected dogs. We quantified [5HT] in platelet-rich plasma (PRP), platelet-poor plasma (PPP), mitral valve leaflets (MV), and left ventricular myocardium (LV). ANIMALS: Forty-five dogs comprised 4 plasma groups of Cavalier King Charles Spaniels (CKCS) or non-CKCS, either healthy (CON) or MMVD affected: CKCS CON (n = 12); non-CKCS CON (n = 8); CKCS MMVD (n = 14); non-CKCS MMVD (n = 11). Twenty-four dogs comprised 3 tissue groups: MMVD (n = 8); other-HD (heart disease) (n = 7); non-HD, extracardiac disease (n = 9). METHODS: High-performance liquid chromatography measured PRP, PPP, MV, and LV [5HT]. RESULTS: Platelet-rich plasma platelet [5HT] was greater in CKCS CON (1.83 femtograms/platelet [fg/plt]; range, 0.20-4.76; P = .002), CKCS MMVD (1.58 fg/plt; range, 0.70-4.03; P = .005), and non-CKCS MMVD (1.72 fg/plt; range, 0.85-4.44; P = .003) versus non-CKCS CON (0.92 fg/plt; range, 0.63-1.30). There was no group difference in PPP [5HT]. MV [5HT] was significantly higher in MMVD (32.4 ng/mg; range, 8.4-106.7) versus non-HD (3.6 ng/mg; range, 0-28.3; P = .01) and LV [5HT] was significantly higher in MMVD (11.9 ng/mg; range, 4.0-104.8) versus other-HD (0.9 ng/mg; range, 0-10.1; P = .011) and non-HD (2.5 ng/mg; range, 0-6.9; P = .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Platelet [5HT] was highest in healthy CKCS and both MMVD groups, but plasma [5HT] showed no group differences. Tissue [5HT] was highest in MV and LV of MMVD-affected dogs, suggesting altered 5HT signaling as a potential feature of MMVD. Interactions of platelet, valvular, and myocardial 5HT signaling warrant further investigation. PMID- 25146935 TI - Prevalence of antibiotic resistant bacteria in healthy adults, foods, food animals, and the environment in selected areas in Thailand. AB - OBJECTIVES: The aim of this study was to determine the prevalence of antibiotic resistant bacteria, especially extended-spectrum beta-lactamase (ESBL) producing Escherichia coli, in samples from healthy adults, foods, food animals, and the environment in selected areas of Thailand. METHODS: Samples were collected from stool specimens from adult food factory and food animal farm workers, fresh and cooked foods sold at markets, rectal swabs of healthy pigs and chickens, fresh pork meat from slaughterhouses, water samples from canals as well as fish and shrimp farm ponds, and stagnant water sources on pig farms. Antibiotic susceptibility was determined using the disk diffusion or agar dilution methods. Extended-spectrum beta-lactamase production was assayed using a double disk diffusion method. RESULTS: Among 544 healthy adult food factory workers, 75.5% were positive for ESBL producing E. coli, while 77.3% of E. coli isolated from 30 healthy animal farm workers were positive. Amongst healthy food animals, ESBL producing status among E. coli isolates were more commonly detected in pigs (76.7%) than broilers (40%). Extended-spectrum beta-lactamase producing E. coli seemed to be more prevalent in fresh meat samples than in fresh vegetables, in fresh foods than in cooked foods, and in water samples collected from the animal farms than those from canals and fish and shrimp ponds. CONCLUSIONS: Extended spectrum beta-lactamase producing E. coli isolates are prevalent amongst healthy individuals, foods along the food production chain from farms to consumers, and in the environment in selected areas in Thailand. PMID- 25146936 TI - The QQS orphan gene of Arabidopsis modulates carbon and nitrogen allocation in soybean. AB - The genome of each species contains as high as 8% of genes that are uniquely present in that species. Little is known about the functional significance of these so-called species specific or orphan genes. The Arabidopsis thaliana gene Qua-Quine Starch (QQS) is species specific. Here, we show that altering QQS expression in Arabidopsis affects carbon partitioning to both starch and protein. We hypothesized QQS may be conserved in a feature other than primary sequence, and as such could function to impact composition in another species. To test the potential of QQS in affecting composition in an ectopic species, we introduced QQS into soybean. Soybean T1 lines expressing QQS have up to 80% decreased leaf starch and up to 60% increased leaf protein; T4 generation seeds from field-grown plants contain up to 13% less oil, while protein is increased by up to 18%. These data broaden the concept of QQS as a modulator of carbon and nitrogen allocation, and demonstrate that this species-specific gene can affect the seed composition of an agronomic species thought to have diverged from Arabidopsis 100 million years ago. PMID- 25146937 TI - Human lysyl oxidase-like 2. AB - Lysyl oxidase like-2 (LOXL2) belongs to the lysyl oxidase (LOX) family, which comprises Cu(2+)- and lysine tyrosylquinone (LTQ)-dependent amine oxidases. LOXL2 is proposed to function similarly to LOX in the extracellular matrix (ECM) by promoting crosslinking of collagen and elastin. LOXL2 has also been proposed to regulate extracellular and intracellular cell signaling pathways. Dysregulation of LOXL2 has been linked to many diseases, including cancer, pro-oncogenic angiogenesis, fibrosis and heart diseases. In this review, we will give an overview of the current understandings and hypotheses regarding the molecular functions of LOXL2. PMID- 25146938 TI - Epidermal growth factor receptor (EGFR) exon 20 mutations in non-small-cell lung cancer and resistance to EGFR-tyrosine kinase inhibitors. AB - INTRODUCTION: In patients with non-small cell lung cancer (NSCLC), the predictive value of rare epidermal growth factor receptor (EGFR) exon 20 mutations in determining a patient's response to EGFR tyrosine kinase inhibitor (TKI) treatment is unclear. PATIENTS AND METHODS: We reviewed data for NSCLC patients harboring EGFR exon 20 mutations from two hospitals in Korea. EGFR mutations were analyzed using directional sequencing. RESULTS: We identified eight patients carrying EGFR exon 20 mutations, seven of whom had insertional mutations. Three patients carried previously unreported insertional mutations. Among six patients who were treated with EGFR TKI, one showed stable disease and three showed primary resistance. Response evaluations were not performed for the other two patients because of their clinical deterioration. CONCLUSIONS: EGFR exon 20 insertional mutations, including three that were previously unreported, were associated with the poor response of patients to TKI treatment. PMID- 25146939 TI - Estimating the prevalence and burden of major disorders of the brain in Nepal: methodology of a nationwide population-based study. AB - BACKGROUND: The major disorders of the brain (MDBs), in terms of their prevalence and the burdens of ill health, disability and financial cost that they impose on individuals and society, are headache, depression and anxiety. No population based studies have been conducted in Nepal. AIM: Our purpose was to assess the prevalence and burden attributable to MDBs in Nepal in order to inform health policy. Here we report the methodology. METHODS: The unusual sociocultural diversity and extreme geographical variation of the country required adaptation of standard methodology. We ran pre-pilot and pilot studies before embarking on the main study. The study design was cross-sectional. The population of interest were adults aged 18-65 years who were Nepali speaking and living in Nepal. We selected, employed and trained groups of interviewers to visit randomly selected households by cold-calling. Households were selected from 15 representative districts out of 75 in the country through multistage cluster sampling. One participant was selected randomly from each household. We used structured questionnaires (the HARDSHIP questionnaire, Hospital Anxiety and Depression Scale, and Eysenck Personality Questionnaire -Neuroticism), culturally adapted and translated into Nepali. We recorded blood pressure, weight, height and waist circumference, and altitude of each household. We implemented various quality assurances measures. RESULTS: We completed the survey in one month, prior to onset of the monsoon. Among 2,210 selected households, all were contacted, 2,109 were eligible for the study and, from these, 2,100 adults participated. The participation rate was 99.6%. CONCLUSION: Standard methodology was successfully applied in Nepal, with some adaptations. The sociocultural and extraordinary geographic diversity were challenging, but did not require us to compromise the scientific quality of the study. PMID- 25146940 TI - Compatible quantum theory. AB - Formulations of quantum mechanics (QM) can be characterized as realistic, operationalist, or a combination of the two. In this paper a realistic theory is defined as describing a closed system entirely by means of entities and concepts pertaining to the system. An operationalist theory, on the other hand, requires in addition entities external to the system. A realistic formulation comprises an ontology, the set of (mathematical) entities that describe the system, and assertions, the set of correct statements (predictions) the theory makes about the objects in the ontology. Classical mechanics is the prime example of a realistic physical theory. A straightforward generalization of classical mechanics to QM is hampered by the inconsistency of quantum properties with classical logic, a circumstance that was noted many years ago by Birkhoff and von Neumann. The present realistic formulation of the histories approach originally introduced by Griffiths, which we call 'compatible quantum theory (CQT)', consists of a 'microscopic' part (MIQM), which applies to a closed quantum system of any size, and a 'macroscopic' part (MAQM), which requires the participation of a large (ideally, an infinite) system. The first (MIQM) can be fully formulated based solely on the assumption of a Hilbert space ontology and the noncontextuality of probability values, relying in an essential way on Gleason's theorem and on an application to dynamics due in large part to Nistico. Thus, the present formulation, in contrast to earlier ones, derives the Born probability formulas and the consistency (decoherence) conditions for frameworks. The microscopic theory does not, however, possess a unique corpus of assertions, but rather a multiplicity of contextual truths ('c-truths'), each one associated with a different framework. This circumstance leads us to consider the microscopic theory to be physically indeterminate and therefore incomplete, though logically coherent. The completion of the theory requires a macroscopic mechanism for selecting a physical framework, which is part of the macroscopic theory (MAQM). The selection of a physical framework involves the breaking of the microscopic 'framework symmetry', which can proceed either phenomenologically as in the standard quantum measurement theory, or more fundamentally by considering the quantum system under study to be a subsystem of a macroscopic quantum system. The decoherent histories formulation of Gell-Mann and Hartle, as well as that of Omnes, are theories of this fundamental type, where the physical framework is selected by a coarse-graining procedure in which the physical phenomenon of decoherence plays an essential role. Various well-known interpretations of QM are described from the perspective of CQT. Detailed definitions and proofs are presented in the appendices. PMID- 25146941 TI - [Cancer: early detection of neurologic complications of the illness and therapy to avoid long-term damage]. PMID- 25146942 TI - [Systemic glucocorticoids: diagnosis, prophylaxis and treatment of side effects]. PMID- 25146944 TI - [Common infections of the ear, nose, and throat]. AB - Infectious diseases of the ear, nose and throat are common reasons why patients visit their family physician. Therefore, the aim of this mini-review is to give an overview of the most important and frequent infectious diseases of the ear, nose and throat, the appropriate diagnostic measurements and therapy with relevance for the family physician. Most of these infectious diseases can be treated by the family physician and do not necessarily need to be seen by an ENT specialist. PMID- 25146945 TI - [Neurological complications in cancer patients]. AB - Neurological symptoms in cancer patients have a great impact on quality of life and need an interdisciplinary approach. They lead to significant impairment in activities of daily living (gait disorders, dizziness), a loss of patients independency (vegetative disturbances, wheel-chair dependency) and interfere with social activities (ban of driving in case of epilepsy). In this article we describe three main and serious neurological problems in the context of oncological patients. These are chemotherapy-induced polyneuropathy, malignant spinal cord compression and epileptic seizures. Our aim is to increase the awareness of neurological complications in cancer patients to improve patients care. PMID- 25146946 TI - [Work stress in the second half of adult life]. AB - Stress at work is a risk factor for common mental and somatic diseases. As we get past 50 and enter the second half of adult life, our body reminds us relentlessly of our advancing age. In a society dominated by ideals of youth and success, employees in the second half of their lives, experience special forms of stress. Based upon contemporary concepts of stress, solutions for the particular stressful challenges met by older people at work are discussed. PMID- 25146949 TI - [New oral anticoagulants are as safe in elderly patients as conventional drugs]. PMID- 25146950 TI - [Physical therapy of hip arthrosis, compared with placebo therapy, is ineffective]. PMID- 25146947 TI - [A very slow growing ankle swelling in a healthy male]. AB - We describe the case report of a 66-year-old man with a very slow growing ankle tumour caused by a subcutaneous fungal abscess. Phaeoacremonium inflatipes, a member of the Dematiaceae family, was identified by needle puncture and culture of the non-odorous creamy yellow brown fluid. The fungal pseudocyst was surgically removed in toto and no further fungicidal drug therapy was required. Human infections by dematiaceous fungi causes subcutaneous phaeohyphomycosis, a rare, deep fungal infection of the skin and subcutaneous tissues usually acquired through traumatic skin lesions. In addition, systemic infections are reported, predominantly in immunosuppressed individuals. PMID- 25146952 TI - [CME ultrasound diagnosis 59. Fever and pain the left kidney region. An extremely severe infection of the left autosome dominant polycystic kidney]. PMID- 25146954 TI - [Personalities in the history of medicine. Wladimir Michailowitsch Bechterew]. PMID- 25146955 TI - VEGF: a potential target for hydrocephalus. AB - Growth factors are primarily responsible for the genesis, differentiation and proliferation of cells and maintenance of tissues. Given the central role of growth factors in signaling between cells in health and in disease, it is understandable that disruption of growth factor-mediated molecular signaling can cause diverse phenotypic consequences including cancer and neurological conditions. This review will focus on the specific questions of enlarged cerebral ventricles and hydrocephalus. It is also well known that angiogenic factors, such as vascular endothelial growth factor (VEGF), affect tissue permeability through activation of receptors and adhesion molecules; hence, recent studies showing elevations of this factor in pediatric hydrocephalus led to the demonstration that VEGF can induce ventriculomegaly and altered ependyma when infused in animals. In this review, we discuss recent findings implicating the involvement of biochemical and biophysical factors that can induce a VEGF-mimicking effect in communicating hydrocephalus and pay particular attention to the role of the VEGF system as a potential pharmacological target in the treatment of some cases of hydrocephalus. The source of VEGF secretion in the cerebral ventricles, in periventricular regions and during pathologic events including hydrocephalus following hypoxia and hemorrhage is sought. The review is concluded with a summary of potential non-surgical treatments in preclinical studies suggesting several molecular targets including VEGF for hydrocephalus and related neurological disorders. PMID- 25146956 TI - Tissue-specific mechanical and geometrical control of cell viability and actin cytoskeleton alignment. AB - Different tissues have specific mechanical properties and cells of different geometries, such as elongated muscle cells and polygonal endothelial cells, which are precisely regulated during embryo development. However, the mechanisms that underlie these processes are not clear. Here, we built an in vitro model to mimic the cellular microenvironment of muscle by combining both mechanical stretch and geometrical control. We found that mechanical stretch was a key factor that determined the optimal geometry of myoblast C2C12 cells under stretch, whereas vascular endothelial cells and fibroblasts had no such dependency. We presented the first experimental evidence that can explain why myoblasts are destined to take the elongated geometry so as to survive and maintain parallel actin filaments along the stretching direction. The study is not only meaningful for the research on myogenesis but also has potential application in regenerative medicine. PMID- 25146957 TI - PNPLA3 I148M variant is associated with metabolic stress-response phenotype in patients with nonalcoholic fatty liver disease. PMID- 25146958 TI - Initial velocity distribution of MALDI/LDI ions measured by internal MALDI source Fourier-transform ion cyclotron resonance mass spectrometry. AB - A new method for measuring the ion velocity distribution using an internal matrix assisted laser desorption/ionization (MALDI) source Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometer is described. The method provides the possibility of studying ion velocities without any influence of electric fields in the direction of the instrument axis until the ions reach the ICR cell. It also allows to simultaneously account for and to estimate not only the velocity distribution but the angular distribution as well. The method was demonstrated using several types of compounds in laser desorption/ionization (LDI) mode. PMID- 25146959 TI - Design and synthesis of aminostilbene-arylpropenones as tubulin polymerization inhibitors. AB - A series of aminostilbene-arylpropenones were designed and synthesized by Michael addition and were investigated for their cytotoxic activity against various human cancer cell lines. Some of the investigated compounds exhibited significant antiproliferative activity against a panel of 60 human cancer cell lines of the US National Cancer Institute, with 50 % growth inhibition (GI50) values in the range from < 0.01 to 19.9 MUM. One of the compounds showed a broad spectrum of antiproliferative efficacy on most of the cell lines, with a GI50 value of < 0.01 MUM. All of the synthesized compounds displayed cytotoxicity against A549 (non small-cell lung cancer), HeLa (cervical carcinoma), MCF-7 (breast cancer), and HCT116 (colon carcinoma) with 50 % inhibitory concentration (IC50) values ranging from 0.011 to 8.56 MUM. A cell cycle assay revealed that these compounds arrested the G2/M phase of the cell cycle. Two compounds exhibited strong inhibitory effects on tubulin assembly with IC50 values of 0.71 and 0.79 MUM. Moreover, dot blot analysis of cyclin B1 demonstrated that some of the congeners strongly induced cyclin B1 protein levels. Molecular docking studies indicated that these compounds occupy the colchicine binding site of tubulin. PMID- 25146960 TI - Correlates of quality of life in rural patients with heart failure. AB - BACKGROUND: There is abundant research indicating poor physical, psychological, and social functioning of patients with chronic heart failure (HF), a reality that can lead to poor health-related quality of life (QoL). Little is known about the experience of rural patients with HF. METHODS AND RESULTS: This study was part of a randomized clinical trial titled Rural Education to Improve Outcomes in Heart Failure (REMOTE-HF) designed to test an education and counseling intervention to improve self-care in patients with HF. We evaluated 612 rural patients. Multiple validated questionnaires were administered to assess patient perceptions of health and health literacy. Baseline factors were collected and compared with baseline QoL measures only. Patients' health-related QoL was assessed using the Minnesota Living with Heart Failure scale. The data were analyzed using a general linear model to test the association of various patient characteristics with QoL in rural patients with HF. Patients were 65.8 (+12.9) years of age. The majority were men (58.7%), married (56.4%), and had completed a high-school education (80.9%). Factors associated with reduced QoL among this population include geographic location, younger age, male sex, higher New York Heart Association class, worse HF knowledge, poorer perceived control, and symptoms of depression or anxiety. The data provided no evidence of an association between left ventricular ejection fraction and QoL. CONCLUSIONS: This study of rural patients with HF confirms previously identified factors associated with perceptions of QoL. However, further study is warranted with an urban control group. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00415545. PMID- 25146961 TI - Brain activation induced by voluntary alcohol and saccharin drinking in rats assessed with manganese-enhanced magnetic resonance imaging. AB - The neuroanatomical and neurochemical basis of alcohol reward has been studied extensively, but global alterations of neural activity in reward circuits during chronic alcohol use remain poorly described. Here, we measured brain activity changes produced by long-term voluntary alcohol drinking in the alcohol preferring AA (Alko alcohol) rats using manganese-enhanced magnetic resonance imaging (MEMRI). MEMRI is based on the ability of paramagnetic manganese ions to accumulate in excitable neurons and thereby enhance the T1-weighted signal in activated brain areas. Following 6 weeks of voluntary alcohol drinking, AA rats were allowed to drink alcohol for an additional week, during which they were administered manganese chloride (MnCl2 ) with subcutaneous osmotic minipumps before MEMRI. A second group with an identical alcohol drinking history received MnCl2 during the abstinence week following alcohol drinking. For comparing alcohol with a natural reinforcer, MEMRI was also performed in saccharin-drinking rats. A water-drinking group receiving MnCl2 served as a control. We found that alcohol drinking increased brain activity extensively in cortical and subcortical areas, including the mesocorticolimbic and nigrostriatal dopamine pathways and their afferents. Remarkably similar activation maps were seen after saccharin ingestion. Particularly in the prelimbic cortex, ventral hippocampus and subthalamic nucleus, activation persisted into early abstinence. These data show that voluntary alcohol recruits an extensive network that includes the ascending dopamine systems and their afferent connections, and that this network is largely shared with saccharin reward. The regions displaying persistent alterations after alcohol drinking could participate in brain networks underlying alcohol seeking and relapse. PMID- 25146962 TI - Relationship between cigarette format and mouth-level exposure to tar and nicotine in smokers of Russian king-size cigarettes. AB - Differences in length and circumference of cigarettes may influence smoker behaviour and exposure to smoke constituents. Superslim king-size (KSSS) cigarettes (17mm circumference versus 25mm circumference of conventional king size [KS] cigarettes), have gained popularity in several countries, including Russia. Some smoke constituents are lower in machine-smoked KSSS versus KS cigarettes, but few data exist on actual exposure in smokers. We investigated mouth-level exposure (MLE) to tar and nicotine in Russian smokers of KSSS versus KS cigarettes and measured smoke constituents under machine-smoking conditions. MLE to tar was similar for smokers of 1mg ISO tar yield products, but lower for smokers of 4mg and 7mg KSSS versus KS cigarettes. MLE to nicotine was lower in smokers of 4mg KSSS versus KS cigarettes, but not for other tar bands. No gender differences were observed for nicotine or tar MLE. Under International Organization for Standardization, Health Canada Intense and Massachusetts regimes, KSSS cigarettes tended to yield less carbon monoxide, acetaldehyde, nitric oxide, acrylonitrile, benzene, 1,3-butadiene and tobacco-specific nitrosamines, but more formaldehyde, than KS cigarettes. In summary, differences in MLE were observed between cigarette formats, but not systematically across pack tar bands. PMID- 25146963 TI - HIV-1 Tat C modulates NOX2 and NOX4 expressions through miR-17 in a human microglial cell line. AB - HIV-1 invades CNS in the early course of infection, which can lead to the cascade of neuroinflammation. NADPH oxidases (NOXs) are the major producers of reactive oxygen species (ROS), which play important roles during pathogenic insults. The molecular mechanism of ROS generation via microRNA-mediated pathway in human microglial cells in response to HIV-1 Tat protein has been demonstrated in this study. Over-expression and knockdown of microRNAs, luciferase reporter assay, and site-directed mutagenesis are main molecular techniques used in this study. A significant reduction in miR-17 levels and increased NOX2, NOX4 expression levels along with ROS production were observed in human microglial cells upon HIV-1 Tat C exposure. The validation of NOX2 and NOX4 as direct targets of miR-17 was done by luciferase reporter assay. The over-expression and knockdown of miR-17 in human microglial cells showed the direct role of miR-17 in regulation of NOX2, NOX4 expression and intracellular ROS generation. We demonstrated the regulatory role of cellular miR-17 in ROS generation through over-expression and knockdown of miR-17 in human microglial cells exposed to HIV-1 Tat C protein. Activated microglial cells mediated neuroinflammatory events are observed in HIV-associated neurological disorders. The reduction in miR-17 levels was observed in microglial cells exposed to HIV-1 Tat C protein. miR-17 regulated the expression of NOX2 and NOX4, which in turn regulated the reactive oxygen species (ROS) production in microglial cells. Increased ROS production led to the activation of microglial cells and increased cytokine production. This study thus demonstrated a novel miR 17-mediated regulatory pathway of ROS production in microglial cells. HMC3 = human microglia clone 3 cell lines. PMID- 25146964 TI - Synthesis, biological evaluation, and molecular docking studies of xanthone sulfonamides as ACAT inhibitors. AB - Three series of xanthone sulfonamides were synthesized, and their inhibitory activities against acyl-CoA: cholesterol acyltransferase (ACAT) were evaluated. Results showed that most of the title compounds exhibited strong inhibitory activity against ACAT, of which compounds 1c, 1e, 1f, 2d, 2e, and 3d were proved to be more active than the positive control Sandoz 58-035. Computational docking experiments indicated that the interaction between inhibitors and ACAT contained the H-bond interaction, the hydrophobic interaction, and the narrow hydrophobic cleft. PMID- 25146965 TI - Recent patents survey on self emulsifying drug delivery system. AB - Self-Emulsifying Drug Delivery System is a unique feasible approach to overcome low oral bioavailability problem which is associated with the hydrophobic drugs due to their unparalleled potential as a drug delivery with the broad range of application. The estimated 40% of active pharmaceuticals are poorly water soluble. Now recently, formulation containing oral SEDDS has received much interest as it solve problems related to oral bioavailability, intra and inter subject variability and lack of dose proportionality of hydrophobic drugs. Now a days, it is the first way to investigate the development of any kind of innovative dosage forms. Many important in-vitro characteristics such as surfactant concentration, oil/surfactant ratio, emulsion polarity, droplet size and zeta potential play an important role in oral absorption of drug from SEEDS. It can be orally administered in the form of SGC or HGC and also enhances bioavailability of drugs to increase solubility and minimizes the gastric irritation. After administration the drug remains entrapped in the oily droplets (inside the droplet or in the surfactant's film at the interface) of the emulsion that are formed in the GIT upon self-emulsification process. It is also a bit problematic to say that the drug is being released from SMEDDS, it would be more precise to say that it diffuses out of oily droplets into the GIT media resulting in the formation of an equilibrium between the drug dissolved in oily droplets and the outer dispersed media (e.g. GIT fluids). Many of the application and preparation methods of SEDDS are reported by research articles and patents in different countries. We present an exhaustive and updated account of numerous literature reports and more than 150 patents published on SEDDS in the recent period. This current patent review is useful in knowledge of SEDDS for its preparations and patents in different countries with emphasis on their formulation, characterization and systematic optimization strategies, thus paving the way for accelerated progress into the SEDDS application in pharmaceutical research as well as patents on SEDDS methods. PMID- 25146966 TI - Large hyperconjugation in strained systems. AB - Carbocations can appear as transient species, for instance, in elimination reactions and various rearrangements. Hyperconjugation (or conjugation) can then stabilize the cationic character and form a partial pi bond. The effect of the electronic delocalization from strained substituents to a carbocation part was calculated. Very large hyperconjugation was found, sometimes more than 80 kcal mol(-1) , which is much larger than typical conjugation effects (56 kcal mol(-1) for the allyl cation). PMID- 25146967 TI - IPX066 , a mixed immediate/sustained-release levodopa preparation for Parkinson's disease. AB - INTRODUCTION: L-DOPA has long been the 'gold standard' treatment for Parkinson's disease (PD), but suffers from poor oral bioavailability and rapid pharmacokinetic elimination. A longer acting preparation has long been sought. AREAS COVERED: We conducted PubMed search for IPX066 and reviewed abstracts from meetings that included the topic of PD. IPX066 is a novel mixed immediate release (IR) and sustained-release levodopa preparation designed to prolong the clinical effect of a single dose. Pharmacokinetic studies demonstrate similar time to peak dose as regular IR L-DOPA, but a longer duration of time with > 50% of peak dose. This contrasts with available controlled release preparations that have a delay to onset. Clinic trials in fluctuating PD patients show that IPX066 provided more 'on' time despite fewer daily doses, compared to IR L-DOPA. As expected, it was also superior to placebo in early PD. However, it is not known whether it can achieve l-DOPA levels that are continuous enough to delay the onset of fluctuations when given early in the disease. EXPERT OPINION: Although not a radical advance in L-DOPA therapy, the drug will clearly have a role in more advanced patients taking multiple L-DOPA doses and may have a role as first-line therapy when starting l-DOPA. PMID- 25146968 TI - High sensitivity and specificity of elevated cerebrospinal fluid kappa free light chains in suspected multiple sclerosis. AB - Cerebrospinal fluid (CSF) analysis is routinely used in the diagnostic work-up of multiple sclerosis (MS), by detecting CSF-specific oligoclonal bands (OCB). More recently, several studies have reported CSF free light chains (FLC) as an alternative. We show that absolute CSF kappaFLC concentrations were highly sensitive - more than OCB testing - and specific for clinically isolated syndrome, relapsing remitting and primary progressive MS. Measurement of kappaFLC alone was sufficient. Our results suggest that CSF kappaFLC levels measured by nephelometry, if validated in a larger series, are a preferred test to OCB analysis in the diagnostic work-up of patients suspected of having MS. PMID- 25146969 TI - Tautomerism in neutral histidine. AB - Histidine is an important natural amino acid, involved in many relevant biological processes, which, because of its physical properties, proved difficult to characterize experimentally in its neutral form. In this work, neutral histidine has been generated in the gas phase by laser ablation of solid samples and its N(epsilon)H tautomeric form unraveled through its rotational spectrum. The quadrupole hyperfine structure, arising from the existing three (14)N nuclei, constituted a site-specifically probe for revealing the tautomeric form as well as the side chain configuration of this proteogenic amino acid. PMID- 25146970 TI - Competence for chemical reprogramming of sexual fate correlates with an intersexual molecular signature in Caenorhabditis elegans. AB - In multicellular organisms, genetic programs guide cells to adopt cell fates as tissues are formed during development, maintained in adults, and repaired after injury. Here we explore how a small molecule in the environment can switch a genetic program from one fate to another. Wild-type Caenorhabditis elegans XX adult hermaphrodites make oocytes continuously, but certain mutant XX adults make sperm instead in an otherwise hermaphrodite soma. Thus, puf-8; lip-1 XX adults make only sperm, but they can be switched from sperm to oocyte production by treatment with a small-molecule MEK inhibitor. To ask whether this chemical reprogramming is common, we tested six XX sperm-only mutants, but found only one other capable of cell fate switching, fbf-1; lip-1. Therefore, reprogramming competence relies on genotype, with only certain mutants capable of responding to the MEK inhibitor with a cell fate change. To gain insight into the molecular basis of competence for chemical reprogramming, we compared polyadenylated transcriptomes of competent and noncompetent XX sperm-only mutants in the absence of the MEK inhibitor and hence in the absence of cell fate reprogramming. Despite their cellular production of sperm, competent mutants were enriched for oogenic messenger RNAs relative to mutants lacking competence for chemical reprogramming. In addition, competent mutants expressed the oocyte-specific protein RME-2, whereas those lacking competence did not. Therefore, mutants competent for reprogramming possess an intersexual molecular profile at both RNA and protein levels. We suggest that this intersexual molecular signature is diagnostic of an intermediate network state that poises the germline tissue for changing its cellular fate in response to environmental cues. PMID- 25146971 TI - Efficient detection of unpaired DNA requires a member of the rad54-like family of homologous recombination proteins. AB - Meiotic silencing by unpaired DNA (MSUD) is a process that detects unpaired regions between homologous chromosomes and silences them for the duration of sexual development. While the phenomenon of MSUD is well recognized, the process that detects unpaired DNA is poorly understood. In this report, we provide two lines of evidence linking unpaired DNA detection to a physical search for DNA homology. First, we have found that a putative SNF2-family protein (SAD-6) is required for efficient MSUD in Neurospora crassa. SAD-6 is closely related to Rad54, a protein known to facilitate key steps in the repair of double-strand breaks by homologous recombination. Second, we have successfully masked unpaired DNA by placing identical transgenes at slightly different locations on homologous chromosomes. This masking falls apart when the distance between the transgenes is increased. We propose a model where unpaired DNA detection during MSUD is achieved through a spatially constrained search for DNA homology. The identity of SAD-6 as a Rad54 paralog suggests that this process may be similar to the searching mechanism used during homologous recombination. PMID- 25146972 TI - Prevalence and Risk Factors for Overweight and Obesity among HIV-Infected Adults in Dar es Salaam, Tanzania. AB - BACKGROUND: Overweight and obesity are increasingly prevalent among HIV-infected populations. We describe their prevalence and associated risk factors among HIV infected adults in Dar es Salaam, Tanzania. METHODS: A cross-sectional study was conducted to determine the proportion of patients who were overweight or obese at enrollment to care and treatment centres from 2004 to 2011. Multivariate relative risk regression models were fit to identify risk factors. RESULTS: A total of 53 825 patients were included in the analysis. In all, 16% of women and 8% of men were overweight, while 7% and 2% were obese, respectively. In multivariate analyses, older age, higher CD4 count, higher hemoglobin levels, female sex, and being married were associated with obesity and overweight. World Health Organization HIV disease stage, tuberculosis history, and previous antiretroviral therapy were inversely associated with obesity and overweight. CONCLUSION: Overweight and obesity were highly prevalent among HIV-infected patients. Screening for overweight and obesity and focused interventions should be integrated into HIV care. PMID- 25146973 TI - JIAPAC Mourns the Loss of Joep M. A. Lange, MD, PHD. PMID- 25146975 TI - Intramolecular charge transfer of push-pull pyridinium salts in the triplet manifold. AB - The solvent effect on the triplet state properties of the iodides of three trans (E) isomers of 2-D-vinyl-1-methylpyridinium, where D is a donor group (4 (dimethylamino)phenyl, 3,4,5-trimethoxyphenyl, and 1-pyrenyl), was studied by nanosecond transient absorption techniques. The results obtained allowed us to complete a previous study on the negative solvatochromism and the role of the solvent-controlled intramolecular charge transfer (ICT) relaxation pathways in the excited singlet state, carried out by ultrafast absorption techniques and DFT calculations (J. Phys. Chem. A 2014, 118, 3580-3592 ). The solvent effect on the intersystem crossing to the triplet manifold gave information on the competition of the relaxation processes in the singlet and triplet states and the extent and mechanism of the photoreactive deactivation, particularly operative for the pyrenyl derivative. For the latter the results showed that the ICT process also occurs in the triplet manifold. In fact, the formation of two triplet states with different nature and affected differently by oxygen was observed for the pyrenyl derivative in water and assigned to the (3)LE* and (3)ICT* states. The related structure and solvent effects on the trans -> cis photoisomerization are briefly discussed. PMID- 25146974 TI - Global proteome analysis identifies active immunoproteasome subunits in human platelets. AB - The discovery of new functions for platelets, particularly in inflammation and immunity, has expanded the role of these anucleate cell fragments beyond their primary hemostatic function. Here, four in-depth human platelet proteomic data sets were generated to explore potential new functions for platelets based on their protein content and this led to the identification of 2559 high confidence proteins. During a more detailed analysis, consistently high expression of the proteasome was discovered, and the composition and function of this complex, whose role in platelets has not been thoroughly investigated, was examined. Data set mining resulted in identification of nearly all members of the 26S proteasome in one or more data sets, except the beta5 subunit. However, beta5i, a component of the immunoproteasome, was identified. Biochemical analyses confirmed the presence of all catalytically active subunits of the standard 20S proteasome and immunoproteasome in human platelets, including beta5, which was predominantly found in its precursor form. It was demonstrated that these components were assembled into the proteasome complex and that standard proteasome as well as immunoproteasome subunits were constitutively active in platelets. These findings suggest potential new roles for platelets in the immune system. For example, the immunoproteasome may be involved in major histocompatibility complex I (MHC I) peptide generation, as the MHC I machinery was also identified in our data sets. PMID- 25146976 TI - Boron-centered soft ligands based on tetrazole units and their complexes with sodium, potassium and bismuth ions. AB - The syntheses of Na(Ttt(Me)) (), K(Ttt(Me)) (), K(Btt(Me)) (), and Na(Btt(Ph)) () are reported, where (Ttt(Me))(-) and (Btt(R))(-) (R = Me, Ph) are tri- and di substituted boron-centered soft ligands; they were produced by the reaction of NaBH4 and KBH4 with the corresponding tetrazole heterocycles: 1-methyl-5 thiotetrazole (L(1)H) and 1-phenyl-5-thiotetrazole (L(2)H). The syntheses of Na(Ttt(Me)) () and K(Ttt(Me)) () were carried out following Trofimenko's protocol. The anion (Ttt(Me))(-) is a typical Janus scorpionate ligand. Na(Ttt(Me)) () and Na(Btt(Ph)) () were reacted with Bi(CH3COO)3 to observe the coordination pattern of these ligands towards bismuth ions. These reactions afforded the complexes [Bi(Ttt(Me))2(CH3COO)] (), [Bi(L(2))2]2 (, ) and [Bi(L(2))3] (). The products were characterized by NMR spectroscopy, elemental analyses and mass spectrometry. Solid state structures were determined by X-ray diffraction of single crystals of , , , , , , and . M(Ttt(Me)) (M = Na (), K ()) and K(Btt(Me)) () exhibit sheet-like structures. The alkali metal complexes dissociate in solution as observed in (1)H, (13)C NMR and (1)H diffusion NMR experiments. Negative mode ESI-MS data also indicate the presence of monomers. Both the sodium salts of (Ttt(Me))(-) and (Btt(Ph))(-) as well as the Bi complexes and were investigated by absorption and emission spectroscopy. PMID- 25146977 TI - The gibberellin biosynthetic genes AtKAO1 and AtKAO2 have overlapping roles throughout Arabidopsis development. AB - Ent-kaurenoic acid oxidase (KAO), a class of cytochrome P450 monooxygenases of the subfamily CYP88A, catalyzes the conversion of ent-kaurenoic acid (KA) to gibberellin (GA) GA12 , the precursor of all GAs, thereby playing an important role in determining GA concentration in plants. Past work has demonstrated the importance of KAO activity for growth in various plant species. In Arabidopsis, this enzyme is encoded by two genes designated KAO1 and KAO2. In this study, we used various approaches to determine the physiological roles of KAO1 and KAO2 throughout plant development. Analysis of gene expression pattern reveals that both genes are mainly expressed in germinating seeds and young developing organs, thus suggesting functional redundancy. Consistent with this, kao1 and kao2 single mutants are indistinguishable from wild-type plants. By contrast, the kao1 kao2 double mutant exhibits typical non-germinating GA-dwarf phenotypes, similar to those observed in the severely GA-deficient ga1-3 mutant. Phenotypic characterization and quantitative analysis of endogenous GA contents of single and double kao mutants further confirm an overlapping role of KAO1 and KAO2 throughout Arabidopsis development. PMID- 25146978 TI - The effect of serum origin on tissue engineered skeletal muscle function. AB - Skeletal muscle phenotype is regulated by a complex interaction between genetic, hormonal, and electrical inputs. However, because of the interrelatedness of these factors in vivo it is difficult to determine the importance of one over the other. Over the last 5 years, we have engineered skeletal muscles in the European Union (EU) and the United States (US) using the same clone of C2C12 cells. Strikingly, the dynamics of contraction of the muscles was dramatically different. Therefore, in this study we sought to determine whether the hormonal milieu (source of fetal bovine serum (FBS)) could alter engineered muscle phenotype. In muscles engineered in serum of US origin time-to-peak tension (2.2 fold), half relaxation (2.6-fold), and fatigue resistance (improved 25%) all showed indications of a shift towards a slower phenotype. Even though there was a dramatic shift in the rate of contraction, myosin heavy chain expression was the same. The contraction speed was instead related to a shift in calcium release/sensitivity proteins (DHPR = 3.1-fold lower, slow CSQ = 3.4-fold higher, and slow TnT = 2.4-fold higher) and calcium uptake proteins (slow SERCA = 1.7 fold higher and parvalbumin = 41-fold lower). These shifts in calcium dynamics were accompanied by a partial shift in metabolic enzymes, but could not be explained by purported regulators of muscle phenotype. These data suggest that hormonal differences in serum of USDA and EU origin cause a shift in calcium handling resulting in a dramatic change in engineered muscle function. PMID- 25146979 TI - A forensic perspective on the genetic identification of grapevine (Vitis vinifera L.) varieties using STR markers. AB - The grapevine (Vitis vinifera subsp. vinifera) is one of the most important agricultural crops worldwide. A long interest in the historical origins of ancient and cultivated current grapevines, as well as the need to establish phylogenetic relationships and parentage, solve homonymies and synonymies, fingerprint cultivars and clones, and assess the authenticity of plants and wines has encouraged the development of genetic identification methods. STR analysis is currently the most commonly used method for these purposes. A large dataset of grapevines genotypes for many cultivars worldwide has been produced in the last decade using a common set of recommended dinucleotide nuclear STRs. This type of marker has been replaced by long core-repeat loci in standardized state-of-the art human forensic genotyping. The first steps toward harmonized grapevine genotyping have already been taken to bring the genetic identification methods closer to human forensic STR standards by previous authors. In this context, we bring forward a set of basic suggestions that reinforce the need to (i) guarantee trueness-to-type of the sample; (ii) use the long core-repeat markers; (iii) verify the specificity and amplification consistency of PCR primers; (iv) sequence frequent alleles and use these standardized allele ladders; (v) consider mutation rates when evaluating results of STR-based parentage and pedigree analysis; (vi) genotype large and representative samples in order to obtain allele frequency databases; (vii) standardize genotype data by establishing allele nomenclature based on repeat number to facilitate information exchange and data compilation. PMID- 25146980 TI - Exciton-stimulated molecular transformation in organic light-emitting diodes. AB - An exciton-stimulated molecular transformation in an organic light-emitting diode (OLED) on a time scale of a few seconds under electrical bias is shown to reach nearly 100% under standard operating conditions, leading to color switching. It is reversible in both a thin film and an OLED when sufficient thermal energy is supplied. Such an exciton-stimulated molecular transformation suggests a new process which may be exploited for applications such as electrochromic and memory devices. PMID- 25146981 TI - The demethylating agent 5-Aza reduces the growth, invasiveness, and clonogenicity of uveal and cutaneous melanoma. AB - PURPOSE: Uveal melanoma is the most common primary intraocular malignancy in adults. Although local disease can be controlled with radiation therapy or enucleation, many cases are complicated by metastases, which account for the significant mortality from this disease. To date, no chemotherapeutic regimens effectively treat local or metastatic disease. Epigenetic silencing of tumor suppressor genes has been shown to be an important factor in the growth and metastasis of many cancers. One form of epigenetic alteration is DNA methylation, which often occurs at promoter elements resulting in the silencing of target gene transcription. METHODS: We used 5-aza-2'-deoxycytidine (5-Aza), a well characterized demethylating agent that is US Food and Drug Administration approved to decrease DNA methylation in multiple uveal and cutaneous melanoma cell lines. RESULTS: Demethylation of melanoma cell lines using 5-Aza causes significant decreases in growth, invasion, and clonogenicity. Treatment of melanoma cells with combined 5-Aza therapy and irradiation showed an even more pronounced effect on cell viability. In addition, treatment with 5-Aza decreased the number of metastases from the eye to the lung in a murine cutaneous melanoma xenograft model. CONCLUSIONS: We demonstrate in vitro and in vivo that demethylating agents such as 5-Aza may be promising chemotherapeutic agents for treating melanoma and decreasing progression to metastatic disease. These results provide proof of concept for an exciting potential therapy to reduce mortality from this disease. Future work will focus on identifying pathways that mediate these changes. PMID- 25146983 TI - Comparison of aqueous levels of inflammatory mediators between toxic anterior segment syndrome and endotoxin-induced uveitis animal models. AB - PURPOSE: To compare clinical findings and the aqueous levels of inflammatory mediators between toxic anterior segment syndrome (TASS) and endotoxin-induced uveitis (EIU) animal models and to evaluate the efficacy of systemic steroid pretreatment in both animal models. METHODS: Rats were used in this study. Ortho phthalaldehyde solution was injected into the anterior chamber to produce TASS (n=30), and lipopolysaccharide was injected into one hind footpad to produce EIU (n=30). Clinical findings were evaluated under slit-lamp examination, and the aqueous levels of prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF alpha) were measured 24 hours after these procedures. Twelve of the rats in each animal model were pretreated with intraperitoneal injection of dexamethasone for 4 days before the development of TASS and EIU. RESULTS: Corneal haze scores were significantly higher for TASS than EIU, but clinical scores for anterior uveitis were not different between the two animal models. Although aqueous levels of PGE2 were markedly increased in both animal models, PGE2 levels were significantly higher for TASS than for EIU. However, an increase in aqueous levels of TNF-alpha was observed only in EIU. Dexamethasone pretreatment reduced the corneal haze score and clinical score for anterior uveitis in both animal models and inhibited the increase in aqueous levels of PGE2 and TNF-alpha. CONCLUSIONS: Prostaglandin E2 and TNF-alpha in aqueous humor seem to be regulated differently in animal models of TASS and EIU. However, dexamethasone pretreatment improved the clinical findings and inhibited the increases in PGE2 and TNF-alpha in both animal models. PMID- 25146982 TI - The resolvin D1 analogue controls maturation of dendritic cells and suppresses alloimmunity in corneal transplantation. AB - PURPOSE: To analyze the effect of a resolvin D1 (RvD1) analogue (RvD1a) on dendritic cell maturation, T-cell sensitization, and allograft rejection in corneal allotransplantation. METHODS: The receptor expression of RvD1 (ALX/FPR2) on bone marrow-derived dendritic cells (BMDC) was measured using quantitative real-time PCR. We determined BMDC maturation after treatment with RvD1a using ELISA to measure interleukin (IL)-12 protein expression and flow cytometry to assess the expression of CD40, major histocompatibility complex (MHC) II, CD80, and CD86. After corneal transplantation in BALB/c mice, we analyzed T-cell infiltration in the cornea and the draining lymph nodes using flow cytometry. The enzyme-linked immunospot (ELISPOT) assay was used to measure T-cell sensitization via the direct and indirect pathway. Angiogenesis and lymphangiogenesis in the cornea after transplantation were measured using immunohistochemistry. Graft opacity and survival were evaluated by slit lamp biomicroscopy. RESULTS: The receptor for RvD1, lipoxin A4/formyl peptide receptor 2 (ALX/FPR2), was expressed at a significantly lower level on immature than mature dendritic cells (DCs), and RvD1a reduced DC expression of MHC II, CD40, and IL-12 following lipopolysaccharide (LPS) stimulation. Using a murine model of corneal transplantation, RvD1a-treated hosts exhibited significantly reduced allosensitization as demonstrated by decreased frequencies of interferon-gamma secreting T cells in the draining lymph nodes, and reduced T-cell infiltration into the grafts. Graft survival was significantly enhanced and angiogenesis at the graft site was suppressed in RvD1a-treated hosts compared with vehicle treated hosts. CONCLUSIONS: These results suggest that RvD1 inhibits DC maturation and reduces alloimmune sensitization following transplantation, thereby establishing a novel connection between resolvin D1 and the regulation of DC-mediated, antigen-specific immunity. PMID- 25146984 TI - Prognostic value of multifocal electroretinography and optical coherence tomography in eyes undergoing panretinal photocoagulation for diabetic retinopathy. AB - PURPOSE: To investigate the prognostic utility on visual acuity of multifocal electroretinography (mfERG) and optical coherence tomography (OCT) in diabetic eyes receiving panretinal photocoagulation (PRP). METHODS: Patients with severe nonproliferative diabetic retinopathy (NPDR) or early proliferative diabetic retinopathy (PDR) who needed PRP were included in this study. The mfERG and OCT data were recorded before PRP, and the final best-corrected visual acuity (BCVA) was recorded at 6 months after PRP. The correlation between pre-PRP data and post PRP BCVA was analyzed using Pearson's correlation analysis and multivariate linear regression analysis. RESULTS: Among the 42 eyes included, 31 eyes (73.8%) had improvement or remained stable in visual acuity, and 11 eyes (26.2%) had deterioration in BCVA. The final BCVA was significantly correlated with the amplitude and latency of mfERG in all nine sectors, and the amplitude had a stronger correlation than latency. The foveal ellipsoid zone of the photoreceptors and external limiting membrane (ELM) status, as well as the retinal thickness in most sectors, were also correlated with the final BCVA. In a multivariate linear regression model, age, pre-PRP BCVA, amplitude of mfERG in the central sector, and foveal ellipsoid zone status were significantly correlated with the final BCVA. The retinal thickness was correlated with the amplitude or latency of mfERG in some sectors, and the correlation was tighter in temporal and inferior sectors. CONCLUSIONS: A lower amplitude of mfERG and disrupted foveal ellipsoid zone status were significantly correlated with a worse visual prognosis in diabetic eyes after PRP. PMID- 25146985 TI - Native American ancestry is associated with severe diabetic retinopathy in Latinos. AB - PURPOSE: Diabetic retinopathy (DR) is a leading cause of blindness in working age adults. Studies have observed that Latinos have a higher prevalence of DR than whites. The purpose of this study is to test the association between genetic admixture and severe DR in Latinos with type 2 diabetes mellitus (T2DM). METHODS: We conducted a case-control study using 944 T2DM subjects from the Los Angeles Latino Eye Study. Cases (n = 135) were defined as proliferative or severe nonproliferative DR subjects. Controls (n = 809) were other diabetic subjects in the cohort. Genotyping was performed on the Illumina OmniExpress BeadChip. We estimated genetic ancestry in Latinos using STRUCTURE with the HapMap reference panels. Univariate and multivariate logistic regression analyses were used to test the relationship between the proportions of genetic ancestry and severe DR. RESULTS: Native American ancestry (NAA) in Latino T2DM subjects is associated significantly with severe DR (P = 0.002). The association remained significant (P = 0.005) after adjusting for age, sex, duration of diabetes, hemoglobin A1c, body mass index, systolic blood pressure, education, and income. We also validated the NAA estimates in Latinos using ADMIXTURE with the 1000 Genomes Project reference panels and obtained consistent results. CONCLUSIONS: Our results demonstrate for the first time to our knowledge that NAA is a significant risk factor for severe DR in Latinos. PMID- 25146986 TI - Direct-to-consumer personal genome testing for age-related macular degeneration. AB - PURPOSE: Genetic testing may be the next step in clinical medicine for a more personalized approach in determining risk of disease. Direct-to-consumer (DTC) personal genome tests may fulfill this role. We explored the practicability and predictive value of DTC tests from four companies (23andMe, deCODEme, Easy DNA, Genetic Testing Laboratories) for AMD. METHODS: Body specimens of three individuals were collected and sent to four companies for DNA genotyping and disease risk estimation. In addition, DNA was also genotyped using Illumina HumanOmniExpress 12v1 array in the Rotterdam Study laboratory, and risk estimates of AMD were calculated using the validated prediction model from the population based Three Continent AMD Consortium. RESULTS: Genotyped results of the four DTC tests matched genotyping performed by the Rotterdam Study laboratory. The estimated risks provided by the companies varied considerably in the tested individuals, from a 1.6-fold difference for overall relative risk to an up to 12 fold difference for lifetime risk. The lifetime risks for the individuals ranged from 1.4% to 16.1% in the DTC tests, while they varied from 0.5% to 4.2% in the validated prediction model. Most important reasons for the differences in risks were the testing of only a limited set of genetic markers, the choice of the reference population, and the methodology applied for risk calculation. CONCLUSIONS: Direct-to-consumer personal genome tests are not suitable for clinical application as yet. More comprehensive genetic testing and inclusion of environmental risk factors may improve risk prediction of AMD. PMID- 25146987 TI - Systemic administration of the antioxidant/iron chelator alpha-lipoic acid protects against light-induced photoreceptor degeneration in the mouse retina. AB - PURPOSE: Oxidative stress and inflammation have key roles in the light damage (LD) model of retinal degeneration as well as in age-related macular degeneration (AMD). We sought to determine if lipoic acid (LA), an antioxidant and iron chelator, protects the retina against LD. METHODS: Balb/c mice were treated with LA or control saline via intraperitoneal injection, and then were placed in constant cool white light-emitting diode (LED) light (10,000 lux) for 4 hours. Retinas were evaluated at several time points after LD. Photoreceptor apoptosis was assessed using the TUNEL assay. Retinal function was analyzed via electroretinography (ERG). Retinal degeneration was assessed after LD by optical coherence tomography (OCT), TUNEL analysis, and histology. The mRNAs of several oxidative stress, inflammation, and iron-related genes were quantified by quantitative PCR (qPCR). RESULTS: The LD resulted in substantial photoreceptor specific cell death. Dosing with LA protected photoreceptors, decreasing the numbers of TUNEL-positive photoreceptors and increasing the number of surviving photoreceptors. The retinal mRNA levels of genes indicating oxidative stress, inflammation, and iron accumulation were lower following LD in mice treated with LA than in control mice. The ERG analysis demonstrated functional protection by LA. CONCLUSIONS: Systemic LA is protective against light-induced retinal degeneration. Since this agent already has proven protective in other retinal degeneration models, and is safe and protective against diabetic neuropathy in patients, it is worthy of consideration for a human clinical trial against retinal degeneration or AMD. PMID- 25146988 TI - Molecular mechanism of formation of cortical opacity in CRYAAN101D transgenic mice. AB - PURPOSE: The CRYAAN101D transgenic mouse model expressing deamidated alphaA crystallin (deamidation at N101 position to D) develops cortical cataract at the age of 7 to 9 months. The present study was carried out to explore the molecular mechanism that leads to the development of cortical opacity in CRYAAN101D lenses. METHODS: RNA sequence analysis was carried out on 2- and 4-month-old alphaA-N101D and wild type (WT) lenses. To understand the biologic relevance and function of significantly altered genes, Ingenuity Pathway Analysis (IPA) was done. To elucidate terminal differentiation defects, immunohistochemical, and Western blot analyses were carried out. RESULTS: RNA sequence and IPA data suggested that the genes belonging to gene expression, cellular assembly and organization, and cell cycle and apoptosis networks were altered in N101D lenses. In addition, the tight junction signaling and Rho A signaling were among the top three canonical pathways that were affected in N101D mutant. Immunohistochemical analysis identified a series of terminal differentiation defects in N101D lenses, specifically, increased proliferation and decreased differentiation of lens epithelial cells (LEC) and decreased denucleation of lens fiber cells (LFC). The expression of Rho A was reduced in different-aged N101D lenses, and, conversely, Cdc42 and Rac1 expressions were increased in the N101D mutants. Moreover, earlier in development, the expression of major membrane-bound molecular transporter Na,K ATPase was drastically reduced in N101D lenses. CONCLUSIONS: The results suggest that the terminal differentiation defects, specifically, increased proliferation and decreased denucleation are responsible for the development of lens opacity in N101D lenses. PMID- 25146989 TI - Longitudinal structure/function analysis in reticular pseudodrusen. AB - PURPOSE: To describe longitudinal structure/function correlations in eyes with progressive reticular pseudodrusen (RPD). METHODS: Thirteen eyes of 12 patients with exclusively RPD in the posterior pole were included (75.1 +/- 5.7 years). All patients underwent spectral-domain optical coherence tomography (SD-OCT), confocal scanning laser ophthalmoscopy (cSLO), and multifocal electroretinography (mfERG) at baseline and 12-month follow-up. Size of retinal area affected by RPD, number and stages of RPD lesions, and choroidal thickness (CT) were quantified at baseline and at follow-up visit. Amplitudes obtained by mfERG in RPD eyes at baseline and follow-up were analyzed and correlated to morphologic changes. Eyes were compared to those of age-matched healthy controls. RESULTS: The total number of RPD lesions increased from 540 at baseline to 667 at 12-month follow-up. Mean CT was 198.5 +/- 69.3 MUm at baseline (control group 263.5 +/- 42.6 MUm; P = 0.005) and 189.2 +/- 65.3 MUm at follow-up (P < 0.001) (control group 265 +/- 47.8 MUm; P = 0.74). A mean growth of RPD-affected area of 3.3 mm(2) was measured. Multifocal ERG amplitudes decreased in both the study and control groups to a similar extent. Amplitudes differed significantly at the follow-up time point when compared between RPD-affected and nonaffected areas within the same eye. No correlations between changes of morphologic parameters and mfERG amplitude changes were found. CONCLUSIONS: Multifocal ERG allows for detecting a decline of function over time in eyes with progressive RPD. Yet functional decline could not be correlated to changes in individual morphologic parameters. PMID- 25146990 TI - High-resolution imaging of photoreceptors in macular microholes. AB - PURPOSE: To assess photoreceptor structure in macular microholes by using adaptive optics scanning laser ophthalmoscopy (AO-SLO) and spectral-domain optical coherence tomography (SD-OCT) and compare with visual acuity. METHODS: Fourteen eyes from 12 patients with macular microholes underwent a full ophthalmologic examination and imaging with a fundus camera, SD-OCT, and an original prototype AO-SLO system at each visit. RESULTS: All eyes had a cone outer segment tip line disruption and a normal retinal pigment epithelium line on SD-OCT images. Adaptive optics scanning laser ophthalmoscopy revealed foveal cone disruption (13 eyes, round or oval; 1 eye, T-shaped) in all eyes. Cone disruption area (mean = 14,805 +/- 9120 MUm(2); range, 3495-35,901 MUm(2)) positively correlated with logMAR visual acuity at the first visit (P = 0.015, rs = 0.679). During the follow-up period, cone disruption area increased in two eyes, was stable in seven eyes, and decreased in five eyes. At the last visit, cone disruption area (mean = 8717 +/- 7432 MUm(2); range, 0-25,746 MUm(2)) also positively correlated with logMAR visual acuity (P = 0.035, rs = 0.610). In one patient with bilateral microholes and no apparent vitreous traction, lesion size gradually increased. Cone disruption area decreased and visual acuity improved following oral prednisone therapy. CONCLUSIONS: Cone disruption occurs in eyes with macular microholes and a larger cone disruption area translates into a poorer visual acuity. Macular microholes, which are commonly observed as foveal cone inner and outer segment disruptions, may occur in eyes with or without vitreofoveal traction. PMID- 25146991 TI - In vivo adaptive optics imaging of the temporal raphe and its relationship to the optic disc and fovea in the human retina. AB - PURPOSE: To investigate the anatomy of the temporal raphe and its angular relationship to the optic disc and fovea in the human retina in vivo. METHODS: Adaptive optics scanning laser ophthalmoscope (AOSLO) was used to image the temporal raphe in 11 young subjects. The raphe's angle relative to a horizontal line and the raphe-fovea-disc angle (angle between the raphe and the line connecting the disc and fovea center) were determined. In addition, to investigate the impact of aging on the raphe, we imaged the raphe at 9 degrees eccentricity in 10 additional older healthy subjects and compared the raphe's anatomy between the two age groups. RESULTS: The raphe's in vivo appearance was generally in agreement with major findings of ex vivo studies. The raphe angle was -1.67 degrees +/- 4.8 degrees , with the ranges from -9 degrees to 6 degrees . It was related to the angle of the foveal depression relative to the disc. The raphe-fovea-disc angle was 170.3 degrees +/- 3.6 degrees . The raphe gap, defined as the averaged distance between superior and inferior bundles, was significantly larger in the older subjects than in younger subjects (230.83 +/- 113.22 MUm vs. 1.93 +/- 68.73 MUm, P < 0.0001). CONCLUSIONS: The angle of the raphe in the study was not consistent with classic raphe models. While the angle showed relatively large individual variability, there seems to be a systematic relation between the disc, fovea, and raphe. It may be useful for individualizing retinal measurement strategies with regard to perimetry. PMID- 25146992 TI - Tear menisci after laser in situ keratomileusis with mechanical microkeratome and femtosecond laser. AB - PURPOSE: To investigate the effect on tear menisci after laser in situ keratomileusis (LASIK) with flap creation by either microkeratome or femtosecond laser. METHODS: Sixty eyes of 30 myopes were analyzed. Fifteen patients underwent LASIK with Moria II microkeratome, and the other 15 patients with 60-KHz IntraLase femtosecond laser. Upper and lower tear meniscus parameters of height (UTMH, LTMH) and area (UTMA, LTMA) were measured by SD-OCT preoperatively and 1 week, 1 month, and 3 months postoperatively. RESULTS: Compared with the baseline values, all tear meniscus parameters decreased significantly at each postoperative time point (all P < 0.01) in both groups. LTMH increased significantly between 1 week and 1 month and between 1 and 3 months after surgery in the microkeratome (both P < 0.01) and femtosecond laser groups (P < 0.01, P = 0.012, respectively). There were significant increases in LTMA between 1 week and 1 month after surgery in the microkeratome group (P < 0.01) and in the femtosecond laser group (P = 0.028). There were no significant differences in UTMH, UTMA, LTMH, or LTMA between two groups. The depth of ablation was negatively correlated with the LTMA at 1 week after surgery (R = -0.256, P = 0.049) for all patients. CONCLUSIONS: There were no significant differences in the tear meniscus parameters between the microkeratome and femtosecond laser groups. The depth of ablation was significantly correlated with the LTMA only at 1 week after surgery. PMID- 25146993 TI - Ocular surface injury induces inflammation in the brain: in vivo and ex vivo evidence of a corneal-trigeminal axis. AB - PURPOSE: To test whether a corneal injury can stimulate inflammation in the trigeminal ganglion (TG), a structure located in the brain. METHODS: At 4 and 8 days after alkali burn induced in the right eyes of mice, in vivo magnetic resonance imaging (MRI) of the brain was done before and after ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) contrast to track macrophages. Trigeminal ganglia were stained for Prussian Blue and inflammatory cell markers. Interleukin-1beta, TNF-alpha, and VEGF-A transcripts were quantified on days 1, 4, and 8, and 4 days after corneal topical anti-inflammatory treatment with 0.2% dexamethasone. The expression of Substance P and its receptor NK-1R was also measured in the TG on day 4. RESULTS: Corneal alkali burn induced leukocyte infiltration, including T cells, in the right TG at 4 and 8 days. In vivo MRI showed an increased contrast uptake in the right TG, which peaked at day 8. Prussian Blue(+) USPIO(+) macrophages were observed in the right TG and exhibited an M2 phenotype. The M2-macrophage infiltration was preponderant in the TG after damage. The proinflammatory cytokines Substance P and NK-1R were significantly increased in both the TGs. The expression of IL-1beta and VEGF-A was significantly reduced in the right TG with dexamethasone treatment. CONCLUSIONS: We suggest, for the first time, inflammatory involvement of brain structures following ocular surface damage. Our findings support the hypothesis that the neuropeptide Substance P may be involved in the propagation of inflammation from the cornea to the TG through corneal nerves. PMID- 25146994 TI - Imaging brain effects of APOE4 in cognitively normal individuals across the lifespan. AB - The epsilon4 allele of the apolipoprotein E (APOE4) is associated with an increased risk of developing Alzheimer's disease (AD). Hence, several studies have compared the brain characteristics of APOE4 carriers versus non-carriers in presymptomatic stages to determine early AD biomarkers. The present review provides an overview on APOE4-related brain changes in cognitively normal individuals, focusing on the main neuroimaging biomarkers for AD, i.e. cortical beta-amyloid (Abeta) deposition, hypometabolism and atrophy. The most consistent findings are observed with Abeta deposition as most studies report significantly higher cortical Abeta load in APOE4 carriers compared with non-carriers. Fluorodeoxyglucose-positron emission tomography studies are rare and tend to show hypometabolism in brain regions typically impaired in AD. Structural magnetic resonance imaging findings are the most numerous and also the most discrepant, showing atrophy in AD-sensitive regions in some studies but contradicting results as well. Altogether, this suggests a graded effect of APOE4, with a predominant effect on Abeta over brain structure and metabolism. Multimodal studies confirm this view and also suggest that APOE4 effects on brain structure and function are mediated by both Abeta-dependent and Abeta-independent pathological processes. Neuroimaging studies on asymptomatic APOE4 carriers offer relevant information to the understanding of early pathological mechanisms of the disease, although caution is needed as to whether APOE4 effects reflect AD pathological processes, and are representative of these effects in non-carriers. PMID- 25146996 TI - Neuroimaging of the aging brain: introduction to the special issue of neuropsychology review. PMID- 25146995 TI - Structural imaging measures of brain aging. AB - During the course of normal aging, biological changes occur in the brain that are associated with changes in cognitive ability. This review presents data from neuroimaging studies of primarily "normal" or healthy brain aging. As such, we focus on research in unimpaired or nondemented older adults, but also include findings from lifespan studies that include younger and middle aged individuals as well as from populations with prodromal or clinically symptomatic disease such as cerebrovascular or Alzheimer's disease. This review predominantly addresses structural MRI biomarkers, such as volumetric or thickness measures from anatomical images, and measures of white matter injury and integrity respectively from FLAIR or DTI, and includes complementary data from PET and cognitive or clinical testing as appropriate. The findings reveal highly consistent age related differences in brain structure, particularly frontal lobe and medial temporal regions that are also accompanied by age-related differences in frontal and medial temporal lobe mediated cognitive abilities. Newer findings also suggest that degeneration of specific white matter tracts such as those passing through the genu and splenium of the corpus callosum may also be related to age related differences in cognitive performance. Interpretation of these findings, however, must be tempered by the fact that comorbid diseases such as cerebrovascular and Alzheimer's disease also increase in prevalence with advancing age. As such, this review discusses challenges related to interpretation of current theories of cognitive aging in light of the common occurrence of these later-life diseases. Understanding the differences between "Normal" and "Healthy" brain aging and identifying potential modifiable risk factors for brain aging is critical to inform potential treatments to stall or reverse the effects of brain aging and possibly extend cognitive health for our aging society. PMID- 25146997 TI - Peptidyl succinimidyl peptides as taspase 1 inhibitors. AB - Taspase 1 is an N-terminal threonine protease implicated in leukemia and other cancers. Despite intensive efforts in recent years, only a limited number of Taspase 1 inhibitors are currently available, and they lack general applicability. Here we present a novel class of Taspase 1 inhibitors based on a peptidyl succinimidyl peptide motif. These inhibitors were obtained from the substrate cleavage sequence and mechanistic considerations involving the previously proposed asparaginase-type cleavage mechanism. We anticipate that this class of Taspase 1 inhibitor will find wide application in further biochemical and structural studies, for example for better investigating the molecular details of the unusual enzymatic cleavage mechanism of Taspase 1. PMID- 25146998 TI - Vestibular paroxysmia in children: a treatable cause of short vertigo attacks. AB - Vestibular paroxysmia due to neurovascular compression is a syndrome consisting of frequent short episodes of vertigo in adults that can be easily treated. Here we describe the initial presentation and follow-up of three children (one female, 12y; two males, 8y and 9y) who experienced typical, brief, vertiginous attacks several times a day. Nystagmus was observed during the episodes. Cranial magnetic resonance imaging revealed arterial compression of the eighth cranial nerve. The attacks ceased after administration of low-dose carbamazepine (2-4mg/kg daily). Vestibular paroxysmia must be considered in the differential diagnosis of children with brief vertiginous episodes. PMID- 25146999 TI - Oral health-related quality of life of removable partial denture wearers and related factors. AB - This study aims to investigate the oral health-related quality of life (OHRQoL) in a group of removable partial denture (RPD) wearers in Shiraz (Iran), using the Persian version of the Oral Health Impact Profile (OHIP-14). Two hundred removable partial denture wearers had completed a questionnaire regarding patients' demographic characteristics and denture-related factors. In addition, the OHIP-14 questionnaire was filled out by interviewing the patients. Two measures of interpreting the OHIP-14 scales were utilised: OHIP-14 sum and OHIP 14 prevalence. The relationship of the patients' demographic characteristics and denture-related factors, with their OHRQoL was investigated. The mean OHIP-14 sum and OHIP-14 prevalence of RPD wearers were 13.80 (+/-10.08) and 44.5%, respectively. The most problematic aspects of OHIP-14 were physical disability and physical pain. Twenty-seven percentage and 24% of participants had reported meal interruption and eating discomfort, respectively. OHIP-14 prevalence and OHIP-14 sum were found to be significantly associated with factors representing RPD wearer's oral health such as self-reported oral health and frequency of denture cleaning. Furthermore, OHIP-14 prevalence and OHIP-14 sum were significantly associated with factors related to frequency of denture use such as hours of wearing the denture during the day and wearing the denture while eating and sleeping. Therefore, it can be concluded that the OHRQoL of the patients of the study was generally not optimal and found to be strongly associated with oral health. PMID- 25147000 TI - Effect of Aloe vera application on the content and molecular arrangement of glycosaminoglycans during calcaneal tendon healing. AB - Although several treatments for tendon lesions have been proposed, successful tendon repair remains a great challenge for orthopedics, especially considering the high incidence of re-rupture of injured tendons. Our aim was to evaluate the pharmacological potential of Aloe vera on the content and arrangement of glycosaminoglycans (GAGs) during tendon healing, which was based on the effectiveness of A. vera on collagen organization previously observed by our group. In rats, a partial calcaneal tendon transection was performed with subsequent topical A. vera application at the injury site. The tendons were treated with A. vera ointment for 7 days and excised on the 7(th) , 14(th) , or 21(st) day post-surgery. Control rats received ointment without A. vera. A higher content of GAGs and a lower amount of dermatan sulfate were detected in the A. vera-treated group on the 14(th) day compared with the control. Also at 14 days post-surgery, a lower dichroic ratio in toluidine blue stained sections was observed in A. vera-treated tendons compared with the control. No differences were observed in the chondroitin-6-sulfate and TGF-beta1 levels between the groups, and higher amount of non-collagenous proteins was detected in the A. vera treated group on the 21(st) day, compared with the control group. No differences were observed in the number of fibroblasts, inflammatory cells and blood vessels between the groups. The application of A. vera during tendon healing modified the arrangement of GAGs and increased the content of GAGs and non-collagenous proteins. PMID- 25147001 TI - Identifying functional co-activation patterns in neuroimaging studies via poisson graphical models. AB - Studying the interactions between different brain regions is essential to achieve a more complete understanding of brain function. In this article, we focus on identifying functional co-activation patterns and undirected functional networks in neuroimaging studies. We build a functional brain network, using a sparse covariance matrix, with elements representing associations between region-level peak activations. We adopt a penalized likelihood approach to impose sparsity on the covariance matrix based on an extended multivariate Poisson model. We obtain penalized maximum likelihood estimates via the expectation-maximization (EM) algorithm and optimize an associated tuning parameter by maximizing the predictive log-likelihood. Permutation tests on the brain co-activation patterns provide region pair and network-level inference. Simulations suggest that the proposed approach has minimal biases and provides a coverage rate close to 95% of covariance estimations. Conducting a meta-analysis of 162 functional neuroimaging studies on emotions, our model identifies a functional network that consists of connected regions within the basal ganglia, limbic system, and other emotion related brain regions. We characterize this network through statistical inference on region-pair connections as well as by graph measures. PMID- 25147002 TI - A field study to unravel factors that are significantly associated with the secretory activity of the corpus luteum during the first three postpartum cycles in high yielding dairy cows, based on the amount of steroidogenic and endothelial cells present in the luteal tissue. AB - Fourteen multi- and eight primiparous high-yielding dairy cows were followed from the first till the fourth ovulation postpartum. Cows were randomly divided into two groups and supplemented with soybean (group I; n = 11) or rapeseed meal (group II; n = 11). Both groups were subjected to a biopsy sampling of the corpus luteum (CL) at cycle day 9. The luteal capillary network (visualized by Bandeiraea simplicifolia) was denser in cycles 2 and 3 (p = 0.0005). The same was seen for the surface occupied by steroidogenic cells (visualized by 3beta hydroxysteroiddehydrogenase) (p = 0.0001). The peripheral blood progesterone concentration showed an increasing trend with increasing cycle number and was higher in primiparous cows (p = 0.013), which had also larger glands on cycle day 9. The area occupied by endothelial cells was positively correlated with the area occupied by steroidogenic cells (r = 0.59; p < 0.0001). Both the areas occupied by endothelial and by steroidogenic cells were negatively correlated with the blood concentration of nonesterified fatty acids (NEFAs) (respectively, r = 0.377; p = 0.004 and r = -0.355; p = 0.007). We can conclude that primiparous cows generally have higher peripheral progesterone levels during the first three cycles after calving which is associated with a larger CL. In comparison with those of the first post-partum cycle, corpora lutea of cycles 2 and 3 have a denser capillary network and a larger area of steroidogenic cells, while these are only associated with a trend of higher peripheral progesterone concentrations. PMID- 25147003 TI - Balancing authority, deference and trust across the public-private divide in health care: tuberculosis health visitors in western Maharashtra, India. AB - While concepts such as 'partnership' are central to the terminology of private public mix (PPM), little attention has been paid to how social relations are negotiated among the diverse actors responsible for implementing these inter sectoral arrangements. India's Revised National Tuberculosis Control Programme (RNTCP) has used intermediary agents to facilitate the involvement of private providers in the expansion of Directly Observed Therapy, Short-Course (DOTS). We examine the roles of tuberculosis health visitors (TB HVs) in mediating working relationships among private providers, programme staff and patients that underpin a PPM-DOTS launched by the RNTCP in western Maharashtra. In addition to observations and informal interactions with the programme and participating health providers, researchers conducted in-depth interviews with senior programme officers and eight TB HVs. Framed by a political discourse of clinical governance, working relationships within the PPM are structured by the pluralistic context, social and professional hierarchies and paternalism of health care in India. TB HVs are at the nexus of these relationships, yet remain undervalued partly because accountability is measured through technical rather than social outcomes of the 'partnership'. Close attention to the dynamics of power relations in working practices within the health system can improve accountability and sustainability of partnerships. PMID- 25147004 TI - PFAS concentrations in plasma samples from Danish school children and their mothers. AB - Perfluoroalkyl substances (PFASs) are accumulating in our environment and human exposure to these potentially harmful chemicals are of growing concern. In the present study, 116 children aged 6-11 and 143 mothers in two locations in Denmark donated blood samples as a supplement to their participation in the large European human biomonitoring project, DEMOCOPHES (Demonstration of a study to COordinate and Perform Human Biomonitoring on a European Scale). The blood samples were analyzed by LC-MS/MS for the concentration of six PFASs: PFOA, PFHxS, PFNA, PFDA, br-PFOS and n-PFOS. All measured compounds were above the detection limit in both mothers and children except for PFHxS in one child. There was a significant correlation between the levels in children and their mothers, indicating a family-related exposure pattern. However, we also found that the levels of PFOA, PFNA, PFDA, br-PFOS and total-PFOS were significantly higher in children compared to their mothers. This may be due to higher exposure in children through for example dust and soil, and due to the fact that children are smaller in body size and blood volume and hence have a lower storage capacity. Furthermore, we found an association between plasma levels and the age of the mothers and higher levels of plasma PFASs in mothers with low parity. There were no associations between PFAS concentrations and residential area, dietary habits of the participants or with respect to the birth order of the children. The levels are comparable to concentrations found in other Western countries. PMID- 25147005 TI - Transplantation of tail skin to study allogeneic CD4 T cell responses in mice. AB - The study of T cell responses and their consequences during allo-antigen recognition requires a model that enables one to distinguish between donor and host T cells, to easily monitor the graft, and to adapt the system in order to answer different immunological questions. Medawar and colleagues established allogeneic tail-skin transplantation in mice in 1955. Since then, the skin transplantation model has been continuously modified and adapted to answer specific questions. The use of tail-skin renders this model easy to score for graft rejection, requires neither extensive preparation nor deep anesthesia, is applicable to animals of all genetic background, discourages ischemic necrosis, and permits chemical and biological intervention. In general, both CD4(+) and CD8(+) allogeneic T cells are responsible for the rejection of allografts since they recognize mismatched major histocompatibility antigens from different mouse strains. Several models have been described for activating allogeneic T cells in skin-transplanted mice. The identification of major histocompatibility complex (MHC) class I and II molecules in different mouse strains including C57BL/6 mice was an important step toward understanding and studying T cell-mediated alloresponses. In the tail-skin transplantation model described here, a three point mutation (I-A(bm12)) in the antigen-presenting groove of the MHC-class II (I-A(b)) molecule is sufficient to induce strong allogeneic CD4(+) T cell activation in C57BL/6 mice. Skin grafts from I-A(bm12) mice on C57BL/6 mice are rejected within 12-15 days, while syngeneic grafts are accepted for up to 100 days. The absence of T cells (CD3(-/-) and Rag2(-/-) mice) allows skin graft acceptance up to 100 days, which can be overcome by transferring 2 x 10(4) wild type or transgenic T cells. Adoptively transferred T cells proliferate and produce IFN-gamma in I-A(bm12)-transplanted Rag2(-/-) mice. PMID- 25147006 TI - Prognostic value of preoperative D-dimer and carcinoembryonic antigen levels in patients undergoing intended curative resection for colorectal cancer: a prospective cohort study. AB - PURPOSE: Carcinoembryonic antigen (CEA) has limited value as an isolated predictor for survival among colorectal cancer (CRC) patients. D-dimer (DD) is a strong predictor of survival among metastatic CRC patients, but the prognostic value in non-metastatic CRC patients remains controversial. We examined the prognostic value of preoperative DD levels in relation to CEA levels in non metastatic, resectable CRC patients. METHODS: Between October 2003 and November 2005, 166 patients were included. We used the Kaplan-Meier method to compute 5 year mortality rates, stratified by preoperative DD and CEA levels. Adjusted Cox regression analysis was used to compute mortality rate ratios (MRRs) during postoperative years 0-1 and 1-5 based on the preoperative CEA and DD levels. RESULTS: The cumulative 5-year mortality rate was 15 % (95 % confidence interval [CI], 9-25 %) in patients with normal DD and CEA levels, 30 % (CI, 16-53 %) in patients with isolated elevated CEA levels, 37 % (CI, 25-53 %) in patients with isolated elevated DD levels, and 60 % (CI, 37-83 %) in patients with elevated CEA and DD levels. Elevated CEA was associated with an approximately ten-fold increase in mortality within the first postoperative year (adjusted MRR 9.8, CI 2.5-38.3); this association was lost during postoperative years 1-5 (adjusted MRR 1.1, CI 0.5-2.7). Elevated DD was associated with a greater than two-fold increase in mortality during postoperative years 0-1 (adjusted MRR 2.8, CI 0.7 11.0) and 1-5 (adjusted MRR 2.2, CI 1.1-4.8). CONCLUSION: DD is a strong predictor of survival among non-metastatic curatively resected CRC patients, particularly in combination with CEA. PMID- 25147007 TI - Compression therapy for deep vein thrombosis. PMID- 25147008 TI - Asymptomatic peripheral artery disease and antiplatelet management. AB - Peripheral arterial disease (PAD) is a hallmark of generalized atherosclerosis. Depending on the specific diagnostic criteria that are being used, the prevalence of PAD may be as high as 30 % in the population of people 70 or more years old. Unfortunately, although PAD is prevalent and has many important consequences for patients, it is often under-detected and under-treated by primary care physicians. The aim of this review is to provide an overview of the available literature on epidemiology and antiplatelets management of PAD patients. In particular, we focus on the "hidden" side of PAD burden, the asymptomatic patients, who are at high risk of negative cardiovascular outcomes. Identification of such PAD patients is therefore an important clinical goal to reduce mortality and morbidity and reduce the social cost of atherosclerotic disease. Early screening of PAD and an evidence-based antithrombotic approach are also discussed as potential strategies to counteract the negative impact of such condition in general population, as well as, in patients with other cardiovascular diseases. PMID- 25147009 TI - Lower extremity vasculitis in giant cell arteritis: important differential diagnosis in patients with lower limb claudication. AB - Most patients with peripheral arterial disease suffer from arteriosclerosis, the prevalence of which increases with age. In some of these patients, however, the ischemic symptoms are not caused by stenotic arteriosclerosis, but by large vessel giant cell arteritis (LV-GCA), a disease also predominantly affecting patients of the older generation. Identifying large vessel vasculitis is a challenge for all physicians caring for patients with peripheral artery disease. The results of invasive treatment such as bypass surgery and angioplasty of inflammatory vascular lesions differ fundamentally from those of patients with atherosclerosis. Duplex ultrasound is a widely available diagnostic method for examining patients with lower limb claudication and pathological ankle-/toe- brachial index or pulse volume recording with or without exercise. Knowledge of characteristic sonographic findings suspicious about large vessel vasculitis is essential for a differential diagnosis of vasculitis versus atherosclerosis. In addition to clinical and laboratory findings, further imaging techniques, e.g. contrast-enhanced computed tomography, magnetic resonance imaging or a combination of positron emission tomography and computed tomography (PET-CT) can provide information on further vessel involvement and inflammatory activity. The present study focuses on diagnostic imaging of LV-GCA in patients presenting with claudication, illustrated by a series of cases. PMID- 25147010 TI - Thromboangiitis obliterans (Buerger's disease). AB - Thromboangiitis obliterans (TAO, Buerger's disease) is an inflammatory vascular disease affecting small and medium sized arteries and veins. It is characterized by segmental thrombotic occlusions by highly mononuclear cellular thrombi. Its occurrence and re-occurrence is closely related to tobacco use. Immunohistological examinations and the detections of various autoantibodies led to the new paradigm of an immunopathogenesis of TAO. Clinically it is characterized by distal ischemia syndromes in young people and high amputation rates. This article summarizes the disease characteristics, clinical features, and diagnostic and therapeutic approaches and focuses on new therapeutic options, i.e. stem cell derived therapies, immunoadsorption, and the endothelin-receptor blocking agent bosentan. PMID- 25147011 TI - G-protein coupled receptor auto-antibodies in thromboangiitis obliterans (Buerger's disease) and their removal by immunoadsorption. AB - BACKGROUND: Immunhistopathological and serological data favors an immunopathogenesis of thromboangiitis onliterans (TAO, Buerger's disease). Auto antbodies seem to play a major role. Immunoadsorption (IA) proved to be therapeutically effective. We focused on agonistic autoantibodies (agAAB) directed against G-protein coupled receptors (GPCR) and proved the hypothesis, that these agAAB might be present in TAO and that a five day course of IA might be able to eliminate these agAAB effectively. PATIENTS AND METHODS: Between December 2012 and May 2014 11 TAO-patients were treated by IA in a five day course. AgAAB-analysis was performed using specific ELISA techniques. RESULTS: AgAAB were detected in 9 out of 11 patients (81.8 %).Multiple agAAB were present in 7 patients (63.6 %). A clustering of agAAB directed against loop1 of the adrenergic alpha1-receptor and the endothelin-A-(ETA)receptor was identified, representing 72.7 % resp. 54.5 % of the patients. AgAAB directed against the angiotensin-1 (AT-1) epitope 1 or 2 were detected in 3 patients and agAAB directed against protease-activated receptor (PAR) loop1/2 were seen in 2 patients. AgAAB directed against ETA-receptor loop1 never appeared without agAAB directed against alpha1-receptor loop1. Immediately after a five day-course of IA agAAB were absent in 81.8 % of the total study group and in 77.8 % of all cases tested positive for agAAB before IA. CONCLUSIONS: AgAAB directed against GPCR were identified in TAO patients with a clustering of agAAB directed against alpha 1-adrenergic receptor loop1 and ETA-receptor loop1. AgAA were eliminated by IA in the majority of cases. We suggest that these agAA play an important role in the pathogenesis of TAO and that their elimination might be responsible for the positive therapeutic effects reported in patients treated with IA. PMID- 25147012 TI - New oral anticoagulants in the treatment of acute venous thromboembolism - a systematic review with indirect comparisons. AB - BACKGROUND: For decades, heparins and vitamin K antagonists (VKAs) have been the gold standards in therapy of venous thromboembolism (VTE). The advent of factor IIa and Xa inhibitors provides new therapeutic options. The aim of this analysis is to compare the currently available new oral anticoagulants (NOACs) with VKAs and also indirectly the NOACs with each other, as it is unlikely that a head-to head comparison will ever be available. PATIENTS AND METHODS: In total, 27,024 patients were included in the RE-COVER, RE-COVER II, EINSTEIN DVT and PE, AMPLIFY and HOKUSAI studies with 13,511 in the VKA arm and 13,513 in the NOAC arm. Efficacy and safety endpoints were assessed by relative risks (RR) and absolute risk reductions (ARR) relative to VKA. The indirect comparison between the NOACs was performed according to ISPOR guidelines. RESULTS: No differences between NOACs and VKA were found regarding recurrent VTE and death. Bleeding was significantly reduced by NOACs: major bleeding by rivaroxaban (RR 0.55; 0.38 - 0.81) and apixaban (RR 0.31; 0.17 - 0.55); major and clinically relevant non major bleeding by dabigatran (RR 0.63; 0.51 - 0.77), apixaban (RR 0.44; 0.36 - 0.55) and edoxaban (RR 0.81; 0.71 - 0.93). The ARR for major bleeding was 1 % for rivaroxaban and apixaban; and for the composite bleeding endpoint 3.2 % for dabigatran, 5.4 % for apixaban, and 1.9 % for edoxaban. Regarding efficacy, no differences were found between NOACs. Apixaban reduced incidence of major bleeding more than dabigatran and edoxaban. Regarding occurrence of the composite bleeding endpoint, apixaban performed better than all other NOACs and dabigatran better than rivaroxaban and edoxaban. CONCLUSIONS: NOACs are as efficient in the treatment of VTE as VKA but with reduced risk of bleeding complications. Indirect comparisons indicate differences in the risk of clinically relevant bleeding events. Important issues such as monitoring and reversal of anticoagulation are still unresolved, but introduction of NOACs increased the therapeutic spectrum and thereby the potential for individualized therapy. PMID- 25147013 TI - Balneohydrotherapy in the treatment of chronic venous insufficiency. AB - BACKGROUND: Physical therapy has not been evaluated much for the treatment of chronic venous insufficiency before. The question is whether balneohydrotherapy and usual care combined is superior to usual care alone. PATIENTS AND METHODS: In a randomized trial comparing spa therapy versus waiting list patients were treated on an out-patient basis in a private spa center. Patients had to be between 18 and 80 years old, with chronic venous insufficiency (stage 3 or 4 according to the CEAP classification). The balneohydrotherapy group received 18 days of treatment in Aix-Les-Bains spa center continuing their usual care. The control group continued their usual care as well during the study. The balneohydrotherapy program consisted of Kneipp therapy (10 minutes), walking 10 minutes in a special mineral water pool with underwater jets at 23 degrees C, massage and bathing in a mineral water tub at 34 degrees C. The main outcome criterion was the number of patients with 20 % self assessed improvement on the Chronic Venous Insufficiency Questionnaire at three months after therapy. RESULTS: 192 patients were assessed for eligibility, 99 were randomized 5 retired drew back their consent and were not included in the intention to treat analysis. None were lost to follow up. After three months 32 (66 %) patients improved in the balneohydrotherapy group and 13 (28 %) in the control group. The difference between groups was significant (odd ratio 5.08 [1.94 - 13.55], relative risk reduction 2.33 [1.42 - 3.84]).There were no serious side effects. CONCLUSIONS: Balneohydrotherapy seems to improve quality of life of patients with chronic venous insufficiency. PMID- 25147014 TI - Validation of the disease-specific quality of life Wuerzburg Wound Score in patients with chronic leg ulcer. AB - BACKGROUND: Aim of the study was to validate a newly developed disease-specific quality of life questionnaire (Wuerzburg Wound Score, WWS) in patients with chronic arterial or venous leg ulcers. PATIENTS AND METHODS: In this prospective study 115 patients with vascular disease associated leg ulcer (54 arterial ulcer, 61 venous ulcer) were studied (mean age 66 +/- 11 years, 51 % male). All patients completed the WWS at baseline, and after four and 12 weeks. To assess construct validity additionally all patients completed the generic QoL-questionnaires Short Form-36 (SF-36) and Nottingham Health Profile (NHP). Construct validity and responsiveness of the WWS were tested. RESULTS: WWS showed acceptable construct validity versus SF-36 (r = 0.5 - 0.78; P < 0.001) and NHP (r = 0.36 - 0.68; P < 0.001). Responsiveness of the WWS was superior to SF-36 (P < 0.05) and NHP (P = 0.01). Generic as well as disease-specific QoL were more impaired in patients with arterial ulcer. CONCLUSIONS: The WWS is a valid measure of disease-specific QoL in patients with leg ulcers and it is more sensitive than the generic instruments in detecting changes of wound healing over time. Further assessment of the psychometric properties of the WWS with larger patient samples is required before the test can be recommended for use in clinical practice. PMID- 25147015 TI - Isolated true aneurysm of the superficial temporal artery: a truly enigmatic lesion. PMID- 25147016 TI - IgG4-related disease and isolated thoracic aortic aneurysm. PMID- 25147017 TI - Surgically challenging pulmonary and hepatic vascular malformations treated with Onyx application. PMID- 25147018 TI - Intraabdominal textiloma with aortic pseudoaneurysm. PMID- 25147020 TI - Lack of body positional effects on paresthesias when stimulating the dorsal root ganglion (DRG) in the treatment of chronic pain. AB - OBJECTIVES: One prominent side effect from neurostimulation techniques, and in particular spinal cord stimulation (SCS), is the change in intensity of stimulation when moving from an upright (vertical) to a recumbent or supine (horizontal) position and vice versa. It is well understood that the effects of gravity combined with highly conductive cerebrospinal fluid provide the mechanism by which changes in body position can alter the intensity of stimulation-induced paresthesias. While these effects are well established for leads that are placed within the more medial aspects of the spinal canal, little is known about these potential effects in leads placed in the lateral epidural space and in particular within the neural foramina near the dorsal root ganglion (DRG). MATERIALS AND METHODS: We prospectively validated a newly developed paresthesia intensity rating scale and compared perceived paresthesia intensities when subjects assumed upright vs. supine bodily positions during neuromodulation of the DRG. RESULTS: On average, the correlation coefficient between stimulation intensity (pulse amplitude) and perceived paresthesia intensity was 0.83, demonstrating a strong linear relationship. No significant differences in paresthesia intensities were reported within subjects when moving from an upright (4.5 +/- 0.14) to supine position 4.5 (+/- 0.12) (p > 0.05). This effect persisted through 12 months following implant. CONCLUSIONS: Neuromodulation of the DRG produces paresthesias that remain consistent across body positions, suggesting that this paradigm may be less susceptible to positional effects than dorsal column stimulation. PMID- 25147021 TI - Potential migration of buoyant LNAPL from intermediate level waste (ILW) emplaced in a geological disposal facility (GDF) for U.K. radioactive waste. AB - A safety case for the disposal of Intermediate Level (radioactive) Waste (ILW) in a deep geological disposal facility (GDF) requires consideration of the potential for waste-derived light non-aqueous phase liquid (LNAPL) to migrate under positive buoyancy from disposed waste packages. Were entrainment of waste-derived radionuclides in LNAPL to occur, such migration could result in a shorter overall travel time to environmental or human receptors than radionuclide migration solely associated with the movement of groundwater. This paper provides a contribution to the assessment of this issue through multiphase-flow numerical modelling underpinned by a review of the UK's ILW inventory and literature to define the nature of the associated ILW LNAPL source term. Examination has been at the waste package-local GDF environment scale to determine whether proposed disposal of ILW would lead to significant likelihood of LNAPL migration, both from waste packages and from a GDF vault into the local host rock. Our review and numerical modelling support the proposition that the release of a discrete free phase LNAPL from ILW would not present a significant challenge to the safety case even with conservative approximations. 'As-disposed' LNAPL emplaced with the waste is not expected to pose a significant issue. 'Secondary LNAPL' generated in situ within the disposed ILW, arising from the decomposition of plastics, in particular PVC (polyvinyl chloride), could form the predominant LNAPL source term. Released high molecular weight phthalate plasticizers are judged to be the primary LNAPL potentially generated. These are expected to have low buoyancy based mobility due to their very low density contrast with water and high viscosity. Due to the inherent uncertainties, significant conservatisms were adopted within the numerical modelling approach, including: the simulation of a deliberately high organic material--PVC content wastestream (2D03) within an annular grouted waste package vulnerable to LNAPL release; upper bound inventory estimates of LNAPLs; incorporating the lack of any hydraulic resistance of the package vent; the lack of any degradation of dissolved LNAPL; and, significantly, the small threshold displacement pressure assumed at which LNAPL is able to enter initially water-saturated pores. Initial scoping calculations on the latter suggested that the rate at which LNAPL is able to migrate from a waste package is likely to be very small and insignificant for likely representative displacement pressure data: this represents a key result. Adopting a conservative displacement pressure, however, allowed the effect of other features and processes in the system to be assessed. High LNAPL viscosity together with low density contrast with water reduces LNAPL migration potential. Migration to the host rock is less likely if waste package vent fluxes are small, solubility limits are high and path lengths through the backfill are short. The capacity of the system to dissolve all of the free LNAPL will, however, depend on groundwater availability. Even with the conservatisms invoked, the overall conclusion of model simulations of intact and compromised (cracked or corroded) waste packages, for a range of realistic ILW LNAPL scenarios, is that it is unlikely that significant LNAPL would be able to migrate from the waste packages and even more unlikely it would be sufficiently persistent to reach the host rock immediately beyond the GDF. PMID- 25147022 TI - Identification and characterization of more than 4 million intervarietal SNPs across the group 7 chromosomes of bread wheat. AB - Despite being a major international crop, our understanding of the wheat genome is relatively poor due to its large size and complexity. To gain a greater understanding of wheat genome diversity, we have identified single nucleotide polymorphisms between 16 Australian bread wheat varieties. Whole-genome shotgun Illumina paired read sequence data were mapped to the draft assemblies of chromosomes 7A, 7B and 7D to identify more than 4 million intervarietal SNPs. SNP density varied between the three genomes, with much greater density observed on the A and B genomes than the D genome. This variation may be a result of substantial gene flow from the tetraploid Triticum turgidum, which possesses A and B genomes, during early co-cultivation of tetraploid and hexaploid wheat. In addition, we examined SNP density variation along the chromosome syntenic builds and identified genes in low-density regions which may have been selected during domestication and breeding. This study highlights the impact of evolution and breeding on the bread wheat genome and provides a substantial resource for trait association and crop improvement. All SNP data are publically available on a generic genome browser GBrowse at www.wheatgenome.info. PMID- 25147023 TI - Basic helix-loop-helix transcription factor BcbHLHpol functions as a positive regulator of pollen development in non-heading Chinese cabbage. AB - Cytoplasmic male sterility (CMS) is a common trait in higher plants, and several transcription factors regulate pollen development. Previously, we obtained a basic helix-loop-helix transcription factor, BcbHLHpol, via suppression subtractive hybridization in non-heading Chinese cabbage. However, the regulatory function of BcbHLHpol during anther and pollen development remains unclear. In this study, BcbHLHpol was cloned, and its tissue-specific expression profile was analyzed. The results of real-time polymerase chain reaction showed that BcbHLHpol was highly expressed in maintainer buds and that the transcripts of BcbHLHpol significantly decreased in the buds of pol CMS. A virus-induced gene silencing vector that targets BcbHLHpol was constructed and transformed into Brassica campestris plants to further explore the function of BcbHLHpol. Male sterility and short stature were observed in BcbHLHpol-silenced plants. The degradation of tapetal cells was inhibited in BcbHLHpol-silenced plants, and nutrients were insufficiently supplied to the microspore. These phenomena resulted in pollen abortion. This result indicates that BcbHLHpol functions as a positive regulator in pollen development. Yeast two-hybrid and bimolecular fluorescence complementation assays revealed that BcbHLHpol interacted with BcSKP1 in the nucleus. This finding suggests that BcbHLHpol and BcSKP1 are positive coordinating regulators of pollen development. Quantitative real-time PCR indicated that BcbHLHpol and BcSKP1 can be induced at low temperatures. Thus, we propose that BcbHLHpol is necessary for meiosis. This study provides insights into the regulatory functions of the BcbHLHpol network during anther development. PMID- 25147024 TI - A high-throughput SNP array in the amphidiploid species Brassica napus shows diversity in resistance genes. AB - Single-nucleotide polymorphisms (SNPs)are molecular markers based on nucleotide variation and can be used for genotyping assays across populations and to track genomic inheritance. SNPs offer a comprehensive genotyping alternative to whole genome sequencing for both agricultural and research purposes including molecular breeding and diagnostics, genome evolution and genetic diversity analyses, genetic mapping, and trait association studies. Here genomic SNPs were discovered between four cultivars of the important amphidiploid oilseed species Brassica napus and used to develop a B. napus InfiniumTM array containing 5,306 SNPs randomly dispersed across the genome. Assay success was high, with >94 % of these producing a reproducible, polymorphic genotype in the 1,070 samples screened. Although the assay was designed to B. napus, successful SNP amplification was achieved in the B. napus progenitor species, Brassica rapa and Brassica oleracea, and to a lesser extent in the related species Brassica nigra. Phylogenetic analysis was consistent with the expected relationships between B. napus individuals. This study presents an efficient custom SNP assay development pipeline in the complex polyploid Brassica genome and demonstrates the utility of the array for high-throughput genotyping in a number of related Brassica species. It also demonstrates the utility of this assay in genotyping resistance genes on chromosome A7, which segregate amongst the 1,070 samples. PMID- 25147025 TI - Quantum non-Markovianity: characterization, quantification and detection. AB - We present a comprehensive and up-to-date review of the concept of quantum non Markovianity, a central theme in the theory of open quantum systems. We introduce the concept of a quantum Markovian process as a generalization of the classical definition of Markovianity via the so-called divisibility property and relate this notion to the intuitive idea that links non-Markovianity with the persistence of memory effects. A detailed comparison with other definitions presented in the literature is provided. We then discuss several existing proposals to quantify the degree of non-Markovianity of quantum dynamics and to witness non-Markovian behavior, the latter providing sufficient conditions to detect deviations from strict Markovianity. Finally, we conclude by enumerating some timely open problems in the field and provide an outlook on possible research directions. PMID- 25147026 TI - Impact of variance components on reliability of absolute quantification using digital PCR. AB - BACKGROUND: Digital polymerase chain reaction (dPCR) is an increasingly popular technology for detecting and quantifying target nucleic acids. Its advertised strength is high precision absolute quantification without needing reference curves. The standard data analytic approach follows a seemingly straightforward theoretical framework but ignores sources of variation in the data generating process. These stem from both technical and biological factors, where we distinguish features that are 1) hard-wired in the equipment, 2) user-dependent and 3) provided by manufacturers but may be adapted by the user. The impact of the corresponding variance components on the accuracy and precision of target concentration estimators presented in the literature is studied through simulation. RESULTS: We reveal how system-specific technical factors influence accuracy as well as precision of concentration estimates. We find that a well chosen sample dilution level and modifiable settings such as the fluorescence cut off for target copy detection have a substantial impact on reliability and can be adapted to the sample analysed in ways that matter. User-dependent technical variation, including pipette inaccuracy and specific sources of sample heterogeneity, leads to a steep increase in uncertainty of estimated concentrations. Users can discover this through replicate experiments and derived variance estimation. Finally, the detection performance can be improved by optimizing the fluorescence intensity cut point as suboptimal thresholds reduce the accuracy of concentration estimates considerably. CONCLUSIONS: Like any other technology, dPCR is subject to variation induced by natural perturbations, systematic settings as well as user-dependent protocols. Corresponding uncertainty may be controlled with an adapted experimental design. Our findings point to modifiable key sources of uncertainty that form an important starting point for the development of guidelines on dPCR design and data analysis with correct precision bounds. Besides clever choices of sample dilution levels, experiment-specific tuning of machine settings can greatly improve results. Well chosen data-driven fluorescence intensity thresholds in particular result in major improvements in target presence detection. We call on manufacturers to provide sufficiently detailed output data that allows users to maximize the potential of the method in their setting and obtain high precision and accuracy for their experiments. PMID- 25147027 TI - Explaining individual differences in cognitive processes underlying hindsight bias. AB - After learning an event's outcome, people's recollection of their former prediction of that event typically shifts toward the actual outcome. Erdfelder and Buchner (Journal of Experimental Psychology: Learning, Memory, and Cognition, 24, 387-414, 1998) developed a multinomial processing tree (MPT) model to identify the underlying processes contributing to this hindsight bias (HB) phenomenon. More recent applications of this model have revealed that, in comparison to younger adults, older adults are more susceptible to two underlying HB processes: recollection bias and reconstruction bias. However, the impact of cognitive functioning on these processes remains unclear. In this article, we extend the MPT model for HB by incorporating individual variation in cognitive functioning into the estimation of the model's core parameters in older and younger adults. In older adults, our findings revealed that (1) better episodic memory was associated with higher recollection ability in the absence of outcome knowledge, (2) better episodic memory and inhibitory control and higher working memory capacity were associated with higher recollection ability in the presence of outcome knowledge, and (3) better inhibitory control was associated with less reconstruction bias. Although the pattern of effects was similar in younger adults, the cognitive covariates did not significantly predict the underlying HB processes in this age group. In sum, we present a novel approach to modeling individual variability in MPT models. We applied this approach to the HB paradigm to identify the cognitive mechanisms contributing to the underlying HB processes. Our results show that working memory capacity and inhibitory control, respectively, drive individual differences in recollection bias and reconstruction bias, particularly in older adults. PMID- 25147028 TI - Drug delivering technology for endovascular management of infrainguinal peripheral artery disease. AB - Endovascular intervention has become a well-recognized treatment modality for peripheral artery disease; however, mid- and long-term outcomes have been plagued by limited durability. Plain balloon angioplasty and bare-metal stents have historically suffered from high restenosis rates leading to the need for frequent repeat revascularization procedures. The innovation of locally administered, drug delivering balloons and stents has been a direct result of technological innovations directed toward prevention and treatment of this limitation. Over the last 5 years, numerous clinical trials investigating the use of drug-coated stents and drug-coated balloons indicate a significant improvement in endovascular treatment durability and outcomes. This review provides an up-to date assessment of the current evidence for the use of drug-coated stents and drug-coated balloons in the treatment of femoropopliteal and infrapopliteal peripheral artery disease. Additionally, it provides an overview of the development of this technology, highlights landmark ongoing and completed clinical trials, examines evidence to support the use of drug-coated technologies in combination with other modalities, and examines promising new technological developments. Last, it summarizes the challenges and safety concerns that have delayed U.S. Food and Drug Administration approval of these devices. PMID- 25147029 TI - Randomized comparison of everolimus-eluting stents and sirolimus-eluting stents in patients with ST elevation myocardial infarction: RACES-MI trial. AB - OBJECTIVES: The aim of the current study was to compare everolimus-eluting stents (EES) with sirolimus-eluting stents (SES) in patients undergoing primary angioplasty. BACKGROUND: Drug-eluting stents may offer benefits in terms of repeat revascularization. However, as shown for first-generation drug-eluting stents, they may be counterbalanced by a potential higher risk of stent thrombosis, especially among patients with ST-segment elevation myocardial infarction (STEMI). No data have been reported so far on the long-term benefits and safety of the new generation of drug-eluting stents in STEMI. METHODS: Consecutive STEMI patients admitted within 12 h of symptom onset and undergoing primary angioplasty and stent implantation at a tertiary center with 24-h primary percutaneous coronary intervention capability were randomly assigned to SES or EES. The primary endpoint was a major adverse cardiac event at 3-year follow-up. The secondary endpoints were death, reinfarction, definite or probable stent thrombosis, and target vessel revascularization at 3-year follow-up. No patient was lost to follow-up. RESULTS: From April 2007 to May 2009, 500 patients with STEMI were randomized to EES (n = 250) or SES (n = 250). No difference was observed in terms of baseline demographic and clinical characteristics between the groups. No difference was observed between the groups in terms of number of implanted stents per patient or total stent length. However, a larger reference diameter was observed with SES (3.35 +/- 0.51 mm vs. 3.25 +/- 0.51 mm, p = 0.001), whereas patients randomized to EES more often received glycoprotein IIb/IIIa inhibitors (54.4% vs. 42.4%, p = 0.006). Follow-up data were available in all patients (1,095 +/- 159 days). No significant difference was observed between EES and SES in major adverse cardiac events (16% vs. 20.8%, adjusted hazard ratio [HR]: 0.75 [95% confidence interval (CI): 0.5 to 1.13], p = 0.17), cardiac death (4.4% vs. 5.6%, adjusted HR: 0.77 [95% CI: 0.35 to 1.71], p = 0.53), recurrent MI (6.4% vs. 10%, adjusted HR: 0.62 [95% CI: 0.33 to 1.16], p = 0.13), and target vessel revascularization (4.8% vs. 4.8%, adjusted HR: 1.00 [95% CI: 0.45 to 2.32], p = 0.99). However, EES was associated with a significant reduction in stent thrombosis (1.6% vs. 5.2%, adjusted HR: 0.3 [95% CI: 0.1 to 0.92], p = 0.035). CONCLUSIONS: This study shows that among STEMI patients undergoing primary angioplasty, EES has similar efficacy as SES, but is associated with a significant reduction in stent thrombosis. (Randomized Comparison of Everolimus Eluting Stents and Sirolimus Eluting Stent in Patients With ST Elevation Myocardial Infarction [RACES-MI]; NCT01684982). PMID- 25147030 TI - A registry-based randomized trial comparing radial and femoral approaches in women undergoing percutaneous coronary intervention: the SAFE-PCI for Women (Study of Access Site for Enhancement of PCI for Women) trial. AB - OBJECTIVES: This study sought to determine the effect of radial access on outcomes in women undergoing percutaneous coronary intervention (PCI) using a registry-based randomized trial. BACKGROUND: Women are at increased risk of bleeding and vascular complications after PCI. The role of radial access in women is unclear. METHODS: Women undergoing cardiac catheterization or PCI were randomized to radial or femoral arterial access. Data from the CathPCI Registry and trial-specific data were merged into a final study database. The primary efficacy endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding or vascular complications requiring intervention. The primary feasibility endpoint was access site crossover. The primary analysis cohort was the subgroup undergoing PCI; sensitivity analyses were conducted in the total randomized population. RESULTS: The trial was stopped early for a lower than expected event rate. A total of 1,787 women (691 undergoing PCI) were randomized at 60 sites. There was no significant difference in the primary efficacy endpoint between radial or femoral access among women undergoing PCI (radial 1.2% vs. 2.9% femoral, odds ratio [OR]: 0.39; 95% confidence interval [CI]: 0.12 to 1.27); among women undergoing cardiac catheterization or PCI, radial access significantly reduced bleeding and vascular complications (0.6% vs. 1.7%; OR: 0.32; 95% CI: 0.12 to 0.90). Access site crossover was significantly higher among women assigned to radial access (PCI cohort: 6.1% vs. 1.7%; OR: 3.65; 95% CI: 1.45 to 9.17); total randomized cohort: (6.7% vs. 1.9%; OR: 3.70; 95% CI: 2.14 to 6.40). More women preferred radial access. CONCLUSIONS: In this pragmatic trial, which was terminated early, the radial approach did not significantly reduce bleeding or vascular complications in women undergoing PCI. Access site crossover occurred more often in women assigned to radial access. (SAFE-PCI for Women; NCT01406236). PMID- 25147031 TI - Intravascular ultrasound-derived minimal lumen area criteria for functionally significant left main coronary artery stenosis. AB - OBJECTIVES: This study sought to evaluate the intravascular ultrasound (IVUS) minimal lumen area (MLA) for functionally significant left main coronary artery (LMCA) stenosis using fractional flow reserve (FFR) as the standard. BACKGROUND: The evaluation of significant LMCA stenosis remains challenging. METHODS: We identified 112 patients with isolated ostial and shaft intermediate LMCA stenosis (angiographic diameter stenosis of 30% to 80%) who underwent IVUS and FFR measurement. RESULTS: The FFR was <=0.80 in 66 LMCA lesions (59%); these exhibited smaller reference vessels, smaller minimal lumen diameter, greater diameter of stenosis, longer lesion length, smaller MLA, larger plaque burden, and more frequent plaque rupture. The independent factors of an FFR of <=0.80 were plaque rupture (odds ratio [OR]: 4.47; 95% Confidence Interval (CI): 1.35 to 14.8; p = 0.014); body mass index (OR: 1.19; 95% CI: 1.00 to 1.41; p = 0.05), age (OR: 0.95; 95% CI: 0.90 to 1.00; p = 0.031), and IVUS MLA (OR: 0.37; 95% CI: 0.25 to 0.56; p < 0.001). The optimal IVUS MLA cutoff value for an FFR of <=0.80 was 4.5 mm(2) (77% sensitivity, 82% specificity, 84% positive predictive value, 75% negative predictive value, area under the curve: 0.83, 95% CI: 0.76 to 0.96; p < 0.001) overall and 4.1 to 4.5 mm(2) in various subgroups. Adjustment for the body surface area, body mass index, and left ventricular mass did not improve the diagnostic accuracy of the IVUS MLA. CONCLUSIONS: In patients with isolated ostial and shaft intermediate LMCA stenosis, an IVUS-derived MLA of <=4.5 mm(2) is a useful index of an FFR of <=0.80. PMID- 25147032 TI - Survival of transcatheter mitral valve repair compared with surgical and conservative treatment in high-surgical-risk patients. AB - OBJECTIVES: The goal of this study was to compare survival between transcatheter mitral valve (MV) repair using MitraClip system (Abbott Vascular, Santa Clara, California), MV-surgery, and conservative treatment in high-surgical-risk patients symptomatic with severe mitral valve regurgitation (MR). BACKGROUND: Up to 50% of patients with symptomatic severe MR are denied for surgery due to high perioperative risk. Transcatheter MV repair might be an alternative. METHODS: Consecutive patients (n = 139) treated with transcatheter MV repair were included. Comparator surgically (n = 53) and conservatively (n = 59) treated patients were identified retrospectively. Surgical risk was based on the logistic European System for Cardiac Operative Risk Evaluation (log EuroSCORE) or the presence of relevant risk factors, as judged by the heart team. RESULTS: The log EuroSCORE was higher in the transcatheter MV repair group (23.9 +/- 16.1%) than in the surgically (14.2 +/- 8.9%) and conservatively (18.7 +/- 13.2%, p < 0.0001) treated patients. Left ventricular ejection fraction was higher in surgical patients (43.9 +/- 14.4%, p = 0.003), with similar values for the transcatheter MV repair (36.8 +/- 15.3%) and conservatively treated (34.5 +/- 16.5%) groups. After 1 year of follow-up, the transcatheter MV repair and surgery groups showed similar survival rates (85.8% and 85.2%, respectively), whereas 67.7% of conservatively treated patients survived. The same trend was observed after the second and third years. After weighting for propensity score and controlling for risk factors, both the transcatheter MV repair (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: 0.22 to 0.78, p = 0.006) and surgical (HR: 0.52, 95% CI: 0.30 to 0.88, p = 0.014) groups showed better survival than the conservatively treated group. The transcatheter MV repair and surgical groups did not differ (HR: 1.25, 95% CI: 0.72 to 2.16, p = 0.430). CONCLUSIONS: Despite a higher log EuroSCORE, high-surgical-risk patients with symptomatic severe MR treated with transcatheter MV repair show similar survival rates compared with surgically treated patients, with both displaying survival benefit compared with conservative treatment. PMID- 25147033 TI - The saga continues: does mitral valve repair improve survival in secondary mitral regurgitation? PMID- 25147034 TI - Quantity and location of aortic valve complex calcification predicts severity and location of paravalvular regurgitation and frequency of post-dilation after balloon-expandable transcatheter aortic valve replacement. AB - OBJECTIVES: This study sought to determine the impact of quantity and location of aortic valve calcification (AVC) on paravalvular regurgitation (PVR) and rates of post-dilation (PD) immediately after transcatheter aortic valve replacement (TAVR). BACKGROUND: The impact of AVC in different locations within the aortic valve complex is incompletely understood. METHODS: This study analyzed 150 patients with severe, symptomatic aortic stenosis who underwent TAVR. Total AVC volume scores were calculated from contrast-enhanced multidetector row computed tomography imaging. AVC was divided by leaflet sector and region (Leaflet, Annulus, left ventricular outflow tract [LVOT]), and a combination of LVOT and Annulus (AnnulusLVOT). Asymmetry was assessed. Receiver-operating characteristic analysis was performed with greater than or equal to mild PVR and PD as classification variables. Logistic regression was performed. RESULTS: Quantity of and asymmetry of AVC for all regions of the aortic valve complex predicted greater than or equal to mild PVR by receiver-operating characteristic analysis (area under the curve = 0.635 to 0.689), except Leaflet asymmetry. Receiver operating characteristic analysis for PD was significant for quantity and asymmetry of AVC in all regions, with higher area under the curve values than for PVR (area under the curve = 0.648 to 0.741). On multivariable analysis, Leaflet and AnnulusLVOT calcification were independent predictors of both PVR and PD regardless of multidetector row computed tomography area cover index. CONCLUSIONS: Quantity and asymmetry of AVC in all regions of the aortic valve complex predict greater than or equal to mild PVR and performance of PD, with the exception of Leaflet asymmetry. Quantity of AnnulusLVOT and Leaflet calcification independently predict PVR and PD when taking into account multidetector row computed tomography area cover index. PMID- 25147035 TI - Paravalvular regurgitation and post-deployment balloon dilation after transcatheter aortic valve replacement: can we predict and prevent? PMID- 25147036 TI - Results of the U.S. Food and Drug Administration continued access clinical trial of the GORE HELEX septal occluder for secundum atrial septal defect. AB - OBJECTIVES: This report describes the immediate, 1-, and 5-year follow-up results of the U.S. Food and Drug Administration Continued Access clinical trial of the GORE HELEX Septal Occluder (W. L. Gore & Associates, Inc., Flagstaff, Arizona) for closure of secundum atrial septal defect. BACKGROUND: The trial was conducted between May 2003 and August 2006 to allow continued enrollment in a trial of the investigational device during review of data from the Pivotal Trial. Devices with hydrophilic coating on the expanded polytetrafluoroethylene to improve echocardiographic visualization were first used in this trial. METHODS: A total of 137 devices were implanted in 137 patients at 13 US institutions. Evaluations were scheduled at 1, 6, and 12 months for the initial trial and at 36 and 60 months for a later extension of the trial in those who consented to longer term evaluations. RESULTS: Twelve-month follow-up was completed on 122 of 126 patients with implantations, and 5-year follow-up on 83 of 95 patients who agreed to the trial extension. The overall clinical success rate was 96.7%, and the major adverse event rate 3.6%. Wire frame fractures were seen in 11.7% of patients with no clinical symptoms. A trivial, clinically insignificant leak was seen, or could not be ruled out, in 26.6% of patients at the 5-year evaluation, but no clinically significant leaks were seen. No patient experienced an erosion or sudden catastrophic event. CONCLUSIONS: The immediate, 1-, and 5-year follow-up outcomes of the Continued Access clinical trial continue to demonstrate that the GORE HELEX Septal Occluder is a safe and effective transcatheter occluder for repair of ostium secundum atrial septal defect. PMID- 25147037 TI - Predictors of recurrent events in patients with cryptogenic stroke and patent foramen ovale within the CLOSURE I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale) trial. AB - OBJECTIVES: This study sought to identify predictors of recurrent ischemic neurologic events within the CLOSURE I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale) trial. BACKGROUND: The CLOSURE I trial found that transcatheter patent foramen ovale (PFO) closure using the STARFlex device was not superior to medical therapy in patients with cryptogenic stroke or transient ischemic attack (TIA) and PFO. METHODS: The CLOSURE I trial is a multicenter, randomized trial of transcatheter PFO closure compared with medical therapy in patients who presented with cryptogenic stroke or TIA and had a PFO. We identified clinical predictors of recurrent ischemic stroke or TIA during 2 years of follow-up using Cox proportional hazards regression within the pooled intention-to-treat cohort. RESULTS: In 909 patients, the incidence of recurrent events was 5.7% with 25 patients suffering a recurrent stroke and 30 a TIA. Patients who had a recurrent event had higher body mass index (30.2 +/- 6.2 vs. 28.3 +/- 5.8%; p = 0.03) and more frequently had diabetes (19.2% vs. 7.1%; p = 0.0016), hypertension (46.2% vs. 30.1%; p = 0.015), and ischemic heart disease (3.8% vs. 0.9%; p = 0.05). Diabetes (hazard ratio [HR]: 3.39; 95% confidence interval [CI]: 1.69 to 6.84; p = 0.0007), index TIA (HR vs. stroke: 2.13; 95% CI: 1.20 to 3.80; p = 0.01), and the detection of atrial fibrillation after study enrollment (HR: 4.85; 95% CI: 2.05 to 11.47; p = 0.0003) independently predicted recurrent ischemic neurologic events. Recurrent neurologic events were more frequent in subjects with RoPE (Risk of Paradoxical Embolism) score <=5 than those with >5 (14.5% vs. 4.2%; p < 0.0001). CONCLUSIONS: These findings suggest an alternative etiology to paradoxical embolism was frequently responsible for recurrent events within the CLOSURE I trial. (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke or TIA Due to the Possible Passage of a Clot of Unknown Origin Through a Patent Foramen Ovale (PFO) [CLOSURE I]; NCT00201461). PMID- 25147038 TI - The paradox of paradoxical embolism and recurrent stroke. PMID- 25147039 TI - Lower extremity revascularization using directional atherectomy: 12-month prospective results of the DEFINITIVE LE study. AB - OBJECTIVES: The aim of this study was to assess the safety and effectiveness of directional atherectomy (DA) for endovascular treatment of peripheral arterial disease (PAD) in infrainguinal arteries in patients with claudication or critical limb ischemia. BACKGROUND: To date, no prospective, multicenter, independently adjudicated study has evaluated the effectiveness and durability of DA in the treatment of PAD. Previous DA studies have not been prospectively powered to evaluate any differences in outcomes in patients with and without diabetes. METHODS: DEFINITIVE LE (Determination of EFfectiveness of the SilverHawk((r)) PerIpheral Plaque ExcisioN System (SIlverHawk Device) for the Treatment of Infrainguinal VEssels / Lower Extremities) prospectively enrolled subjects at 47 multinational centers with an infrainguinal lesion length up to 20 cm. Primary endpoints were defined as primary patency at 12 months for claudicants and freedom from major unplanned amputation for critical limb ischemia (CLI) subjects. A pre-specified statistical hypothesis evaluated noninferiority of primary patency in diabetic versus nondiabetic claudicants. Independent angiographic and sonographic core laboratories assessed outcomes, and events were adjudicated by a clinical events committee. RESULTS: A total of 800 subjects were enrolled. The 12-month primary patency was 78% (95% confidence interval: 74.0% to 80.6%) in claudicants, with a 77% rate in the diabetic subgroup versus 78% in the nondiabetic subgroup (noninferior, p < 0.001). The rate of freedom from major unplanned amputation of the target limb at 12 months in CLI subjects was 95% (95% confidence interval: 90.7% to 97.4%). Periprocedural adverse events included embolization (3.8%), perforation (5.3%), and abrupt closure (2.0%). The bail-out stent rate was 3.2%. CONCLUSIONS: The DEFINITIVE LE study demonstrated that DA is a safe and effective treatment modality at 12 months for a diverse patient population with either claudication or CLI. Furthermore, DA was shown to be noninferior for treating PAD in patients with diabetes compared with those without diabetes. (Study of SilverHawk/TurboHawk in Lower Extremity Vessels [DEFINITIVE LE]; NCT00883246). PMID- 25147040 TI - The DEFINITIVE LE: atherectomy's ability to leave no trace or need for more DEFINITIVE data? PMID- 25147041 TI - Different findings in a calcified nodule between histology and intravascular imaging such as intravascular ultrasound, optical coherence tomography, and coronary angioscopy. PMID- 25147042 TI - Left atrial appendage occlusion devices versus pharmacological agents for stroke prevention in atrial fibrillation: testing the noninferiority margins. PMID- 25147043 TI - Reply: Left atrial appendage occlusion devices versus pharmacological agents for stroke prevention in atrial fibrillation: testing the noninferiority margins. PMID- 25147044 TI - A day at the beach. PMID- 25147045 TI - Tardive coronary obstruction by a native leaflet after transcatheter aortic valve replacement in a patient with heavily calcified aortic valve stenosis. PMID- 25147046 TI - Endovascular stenting of suture line supravalvular pulmonic stenosis after orthotopic heart transplantation using rapid pacing stabilization. PMID- 25147047 TI - HCV reinfection among HIV-positive men who have sex with men: a pragmatic approach. PMID- 25147048 TI - Scavenging of rodent carcasses following simulated mortality due to field applications of anticoagulant rodenticide. AB - Worldwide, agricultural uses of anticoagulant rodenticides (ARs) cause poisonings of non-target wildlife as observed in France where bromadiolone is used to control water vole outbreaks. Following bromadiolone field application, a part of the vole population may die aboveground of the treated plots and thus, can represent an important risk of secondary poisoning for scavengers. In this study, water voles were trapped in a non-treated area and their carcasses were placed aboveground in plots located in an area where a vole outbreak occurred. Then, the environmental persistence, the diurnal and nocturnal scavenging rates of water vole carcasses were assessed in autumn 2011 and in spring 2012. The diurnal scavenger species were also identified. The environmental persistence of the carcasses to reach at least a scavenging rate of 87.5 % was 0.5-1.5 day. The average rates of diurnal and nocturnal scavenging ranged from 67 to 100 % and 5 to 100 %, respectively. They depended on the composition of the scavenger community present near the monitored plots; diurnal scavenging rates being higher with corvids than with raptors. In autumn, the red kite and the common buzzard were the main scavengers in one of the plots, what suggests a high risk of poisoning for these raptors during post-nuptial migration. So, the collection of vole carcasses after treatments and the limitations of bromadiolone applications when high densities of predators/scavengers are observed could be implemented to mitigate the risks of secondary poisoning. PMID- 25147049 TI - Biocompatible reactive oxygen species (ROS)-responsive nanoparticles as superior drug delivery vehicles. AB - A novel reactive oxygen species (ROS)-responsive nanoplatform can be successfully manufactured from a ROS-triggerable beta-cyclodextrin material. Extensive in vitro and in vivo studies validate that this nanoscaled system may serve as a new drug delivery vehicle with well-defined ROS-sensitivity and superior biocompatibility. This nanocarrier can be used for ROS-triggered transport of diverse therapeutics and imaging agents. PMID- 25147050 TI - NMR characterization of the conformational fluctuations of the human lymphocyte function-associated antigen-1 I-domain. AB - Lymphocyte function-associated antigen-1 (LFA-1) is an integrin protein that transmits information across the plasma membrane through the so-called inside-out and outside-in signaling mechanisms. To investigate these mechanisms, we carried out an NMR analysis of the dynamics of the LFA-1 I-domain, which has enabled us to characterize the motions of this domain on a broad range of timescales. We studied first the internal motions on the nanosecond timescale by spin relaxation measurements and model-free analysis. We then extended this analysis to the millisecond timescale motions by measuring (15) N-(1) H residual dipolar couplings of the backbone amide groups. We analyzed these results in the context of the three major conformational states of the I-domain using their corresponding X-ray crystallographic structures. Our results highlight the importance of the low-frequency motions of the LFA-1 I-domain in the inactive apo state. We found in particular that alpha-helix 7 is in a position in the apo closed state that cannot be fully described by any of the existing X-ray structures, as it appears to be in dynamic exchange between different conformations. This type of motion seems to represent an inherent property of the LFA-1 I-domain and might be relevant for controlling the access to the allosteric binding pocket, as well as for the downward displacement of alpha-helix 7 that is required for the activation of LFA-1. PMID- 25147051 TI - Dimers and trimers of diphosphenes: a wealth of cyclo-phosphanes. AB - Various new P-based ring systems were synthesised by transferring established reaction routes from NP chemistry to the analogous PP compounds. Due to the different electronic situations of phosphorus and nitrogen with respect to s and p character of the lone pair, different reactivity of the phosphorus compounds was observed, especially with regard to the specificity of the reactions and the stability of the products. Whereas Mes*N?PCl (Mes*=2,4,6-tri-tert-butylphenyl) is stable in the solid state and in solution, the formal phosphorus congener Mes*P?PCl is highly reactive and could not be observed. Instead, several formal dimers and trimers of Mes*P?PCl could be isolated, which constitute an intriguing variety of three- and four-membered ring systems. PMID- 25147053 TI - Fertilizer addition lessens the flux of microbial carbon to higher trophic levels in soil food webs of grassland. AB - Roots and root-derived C compounds are increasingly recognised as important resources for soil animal food webs. We used (13)C-labelled glucose as a model C compound representing root exudates to follow the incorporation of root-derived C into the soil animal food web of a temperate grassland over a period of 52 weeks. We investigated variations in glucose C incorporation with fertilizer addition and sward composition, i.e. variations in plant functional groups. The approach allowed the differentiation of trophic chains based on primary decomposers feeding on litter and phytophagous species feeding on roots (i.e. not incorporating glucose C) from those based on secondary decomposers feeding on microorganisms (thereby assimilating glucose C). Each of the studied soil animal species incorporated glucose C, indicating that the majority of grassland soil animal species rely on microorganisms as food resources with microorganisms being fuelled by root exudates. However, incorporation of glucose C into soil animal species varied markedly with species identity, suggesting that detritivorous microarthropods complement each other in channelling microbial C through soil food webs. Fertilizer addition markedly reduced the concentration of glucose C in most soil animal species as well as the absolute transfer of glucose C into oribatid mites as major secondary decomposers. The results suggest that fertilizer addition shifts the basis of the decomposer food web towards the use of unlabelled resources, presumably roots, i.e. towards a herbivore system, thereby lessening the link between microorganisms and microbial grazers and hampering the propagation of microbial C to higher trophic levels. PMID- 25147052 TI - Epidermal fatty acid-binding protein protects nerve growth factor-differentiated PC12 cells from lipotoxic injury. AB - Epidermal fatty acid-binding protein (E-FABP/FABP5/DA11) binds and transport long chain fatty acids in the cytoplasm and may play a protecting role during neuronal injury. We examined whether E-FABP protects nerve growth factor-differentiated PC12 cells (NGFDPC12 cells) from lipotoxic injury observed after palmitic acid (C16:0; PAM) overload. NGFDPC12 cells cultures treated with PAM/bovine serum albumin at 0.3 mM/0.15 mM show PAM-induced lipotoxicity (PAM-LTx) and apoptosis. The apoptosis was preceded by a cellular accumulation of reactive oxygen species (ROS) and higher levels of E-FABP. Antioxidants MCI-186 and N-acetyl cysteine prevented E-FABP's induction in expression by PAM-LTx, while tert-butyl hydroperoxide increased ROS and E-FABP expression. Non-metabolized methyl ester of PAM, methyl palmitic acid (mPAM), failed to increase cellular ROS, E-FABP gene expression, or trigger apoptosis. Treatment of NGFDPC12 cultures with siE-FABP showed reduced E-FABP levels correlating with higher accumulation of ROS and cell death after exposure to PAM. In contrast, increasing E-FABP cellular levels by pre-loading the cells with recombinant E-FABP diminished the PAM-induced ROS and cell death. Finally, agonists for PPARbeta (GW0742) or PPARgamma (GW1929) increased E-FABP expression and enhanced the resistance of NGFDPC12 cells to PAM LTx. We conclude that E-FABP protects NGFDPC12 cells from lipotoxic injury through mechanisms that involve reduction of ROS. Epidermal fatty acid-binding protein (E-FABP) may protect nerve cells from the damaging exposure to high levels of free fatty acids (FA). We show that E-FABP can neutralize the effects of reactive oxygen species (ROS) generated by the high levels of FA in the cell and protect PC12 cells from lipotoxic injuries common in Type 2 diabetes neuropathy. Potentially, E-FABP gene up-regulation may be mediated through the NFkB pathway and future studies are needed to further evaluate this proposition. PMID- 25147054 TI - Genotypic and technological diversity of Brevibacterium linens strains for use as adjunct starter cultures in 'Pecorino di Filiano' cheese ripened in two different environments. AB - Twenty-two Brevibacterium linens strains isolated from 'Pecorino di Filiano' cheese ripened in two different environments (natural cave and storeroom) were characterized and differentiated for features of technological interest and by genotypic methods, in order to select strains with specific features to be used as surface starter cultures. Results showed significant differences among strains on the basis of physiological and technological features, indicating heterogeneity within the species. A middle-low level of proteolytic activity was observed in 27.3 % of strains, while a small group (9.1 %) showed a high ability. Lipolytic activity was observed at three different temperatures and the highest value was detected at 20 degrees C with 13.6 % of strains, while an increase in temperature produced a slightly lower lipolysis in all strains. The evaluation of diacetyl production revealed that only 22.8 % of strains showed this ability, and most of them were isolated from product ripened in the natural cave. All strains exhibited only leu-aminopeptidase activity, with values more elevated in strains coming from the natural cave product. The combined analysis of genotypic results with the data obtained by the features of technological interest study established that the random amplified polymorphic DNA (RAPD) clusters obtained were composed not only of different genotypes but of different profiles based on technological properties too. This study demonstrated the importance of the ripening environment that affects the typical features of the artisanal product, leading to the selection of a specific surface microflora. Characterized strains could be associated within surface starters to standardize the production process of cheese, but preserving its typical organoleptic and sensory characteristics and improving the quality of the final product. PMID- 25147056 TI - Engaging civil society through deliberative dialogue to create the first Mental Health Strategy for Canada: Changing Directions, Changing Lives. AB - Citizen engagement through deliberative dialogue is increasingly being used to address 'wicked problems' in policy-making, such as the development of national mental health policy. In 2012, the Mental Health Commission of Canada (MHCC), a national organization funded by and operating at arm's length from the federal government, released the first Mental Health Strategy for Canada: Changing Directions, Changing Lives (Mental Health Commission of Canada, 2012). Despite much-needed reform, Canada, unlike most other industrialized countries, had never previously developed a national Mental Health Strategy (the Strategy). This was due to a mix of policy factors, including a federalist system of government where primary responsibility for healthcare resides with provincial and territorial governments and a highly diverse set of stakeholder groups with diverging core ideas for mental health reform that were rooted in deeply held value differences. In this case study, we review the essential role that engagement of civil society played in the creation of the Strategy, beginning with the efforts to create a national body to shine the light on the need for mental health reform in Canada, followed by the development of a framework of specific goals based on core principles to guide the development of the Strategy, and ultimately, the creation of the Strategy itself. We discuss the various approaches to civil society engagement in each step of this process and focus in particular on how deliberative approaches helped build trust and common ground amongst stakeholders around complex, and often contentious, issues. The nature and outcomes of the deliberative processes including the key tensions between different stakeholder perspectives and values are described. We close by highlighting the lessons learned in a process that culminated with a Strategy that received strong endorsement from stakeholders across Canada. Mental Health Commission of Canada (2012). Changing Directions Changing Lives, The Mental Health Strategy for Canada. Calgary, AB: MHCC. PMID- 25147057 TI - The impact of health insurance for children under age 6 in Vietnam: A regression discontinuity approach. AB - Accessing health services at an early age is important to future health and life outcomes. Yet, little is currently known on the role of health insurance in facilitating access to care for children. Exploiting a regression discontinuity design made possible through a policy to provide health insurance to pre-school aged children in Vietnam, this paper evaluates the impact of health insurance on the health care utilization outcomes of children at the eligibility threshold of six years. Using three rounds of the Vietnam Household Living Standards Survey, the study finds a positive impact on inpatient and outpatient visits and no significant impact on expenditures per visit at public facilities. We find moderately high use of private outpatient services and no evidence of a switch from private to covered public facilities under insurance. Results suggest that adopting public health insurance programs for children under age 6 may be an important vehicle to improving service utilization in a low- and middle-income country context. Challenges remain in providing adequate protections from the costs and other barriers to care. PMID- 25147055 TI - The oral microbiome diversity and its relation to human diseases. AB - As one of the most clinically relevant human habitats, the human mouth is colonized by a set of microorganisms, including bacteria, archaea, fungi, and viruses. Increasing evidence has supported that these microbiota contribute to the two commonest oral diseases of man (dental caries and periodontal diseases), presenting significant risk factors to human health conditions, such as tumor, diabetes mellitus, cardiovascular diseases, bacteremia, preterm birth, and low birth weight in infants. It is widely accepted that oral microorganisms cause diseases mainly by a synergistic or cooperative way, and the interspecies interactions within the oral community play a crucial role in determining whether oral microbiota elicit diseases or not. Since a comprehensive understanding of the complex interspecies interactions within a community needs the knowledge of its endogenous residents, a plenty of research have been carried out to explore the oral microbial diversity. In this review, we focus on the recent progress in this field, including the oral microbiome composition and its association with human diseases. PMID- 25147058 TI - Structure-activity relationship, biological, and pharmacological characterization of the proline sulfonamide ACT-462206: a potent, brain-penetrant dual orexin 1/orexin 2 receptor antagonist. AB - The orexin system consists of two G-protein-coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB-649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT-462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non-rapid eye movement (non-REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT-462206 shows anxiolytic-like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia. PMID- 25147059 TI - Structural and binding studies of SAP-1 protein with heparin. AB - SAP-1 is a low molecular weight cysteine protease inhibitor (CPI) which belongs to type-2 cystatins family. SAP-1 protein purified from human seminal plasma (HuSP) has been shown to inhibit cysteine and serine proteases and exhibit interesting biological properties, including high temperature and pH stability. Heparin is a naturally occurring glycosaminoglycan (with varied chain length) which interacts with a number of proteins and regulates multiple steps in different biological processes. As an anticoagulant, heparin enhances inhibition of thrombin by the serpin antithrombin III. Therefore, we have employed surface plasmon resonance (SPR) to improve our understanding of the binding interaction between heparin and SAP-1 (protease inhibitor). SPR data suggest that SAP-1 binds to heparin with a significant affinity (KD = 158 nm). SPR solution competition studies using heparin oligosaccharides showed that the binding of SAP-1 to heparin is dependent on chain length. Large oligosaccharides show strong binding affinity for SAP-1. Further to get insight into the structural aspect of interactions between SAP-1 and heparin, we used modelled structure of the SAP-1 and docked with heparin and heparin-derived polysaccharides. The results suggest that a positively charged residue lysine plays important role in these interactions. Such information should improve our understanding of how heparin, present in the reproductive tract, regulates cystatins activity. PMID- 25147060 TI - Takotsubo-like cardiomyopathy in a giant pheochromocytoma. PMID- 25147061 TI - Dynamic assessment of the changing geometry of the mitral apparatus in 3D could stratify abnormalities in functional mitral regurgitation and potentially guide therapy. AB - INTRODUCTION: In functional mitral regurgitation (FMR), effective regurgitant orifice area (EROA) displays a dynamic pattern. The impact of dynamic changes of annulus dysfunction and leaflets tenting on phasic EROA was explored with real time three-dimensional transesophageal echocardiography (RT3D-TEE). METHODS: RT3D TEE was performed in 52 FMR patients and 30 controls. Mitral annulus dimensions and leaflets tenting were measured throughout systole (TomTec, Germany). Phasic EROA was measured by proximal isovelocity surface area (PISA) method. RESULTS: Mitral annulus had the minimal area and an oval shape with saddle configuration during early systole in controls, which enlarged and became round and flattened towards mid and late systole (P<0.05). In contrast, annulus in FMR was significantly larger, rounder and flatter (P<0.001), which further dilated and became more flattened at late systole (P<0.05 vs control). Leaflet tenting height in FMR decreased in mid systole and remains unchanged towards late systole. The leaflet tenting volume peaked at early and late systole with a mid-systolic trough in both FMR and controls. But tenting volume of patients with FMR was significantly larger than that of controls (all P<0.001 vs control in whole systole). Further analysis demonstrated that early tenting volume (beta value=0.053, P<0.05) was a predictor of early EROA, whereas late tenting volume (beta value=0.031, P<0.05) and late annular displacement velocity were predictors of late EROA. CONCLUSIONS: The early and late peak EROAs of FMR was primarily contributed by tenting volume at early systole and late systole respectively. These findings would be of value to consider in interventions aimed at reducing the severity of FMR. PMID- 25147062 TI - Demographic parameters related to 30-day readmission of patients with congestive heart failure: analysis of 2,536,439 hospitalizations. PMID- 25147063 TI - Prosthetic thrombosis and pregnancy on warfarin: debate on mechanical mitral valve replacement in sub-Saharan Africa based on a case report. PMID- 25147064 TI - Rare cardiac tumor simulating ST elevated acute myocardial infarction. PMID- 25147065 TI - Atrial fibrillation may be prevalent in individuals who report late-night dinner eating and concomitant breakfast skipping, a complex abnormal eating behavior around sleep. PMID- 25147066 TI - Establishment of an experimental angiographic slow coronary flow model by microsphere embolism in swines. PMID- 25147067 TI - Heart-type fatty acid-binding protein is a novel prognostic marker in patients with essential hypertension. PMID- 25147068 TI - Modulation of phasic left atrial function and left ventricular filling in patients with extrinsic left atrial compression by hiatal hernia. PMID- 25147069 TI - Successful recanalization of a blind stumpless aorto-ostial left main chronic total occlusion. PMID- 25147070 TI - Omega-3 fatty acid therapy dose-dependently and significantly decreased triglycerides and improved flow-mediated dilation, however, did not significantly improve insulin sensitivity in patients with hypertriglyceridemia. AB - BACKGROUND: Experimental studies demonstrate that higher intake of omega-3 fatty acids (n-3 FA) improves insulin sensitivity, however, we reported that n-3 FA 2g therapy, most commonly used dosage did not significantly improve insulin sensitivity despite reducing triglycerides by 21% in patients. Therefore, we investigated the effects of different dosages of n-3 FA in patients with hypertriglyceridemia. METHODS: This was a randomized, single-blind, placebo controlled, parallel study. Age, sex, and body mass index were matched among groups. All patients were recommended to maintain a low fat diet. Forty-four patients (about 18 had metabolic syndrome/type 2 diabetes mellitus) in each group were given placebo, n-3 FA 1 (O1), 2 (O2), or 4 g (O4), respectively daily for 2 months. RESULTS: n-3 FA therapy dose-dependently and significantly decreased triglycerides and triglycerides/HDL cholesterol and improved flow-mediated dilation, compared with placebo (by ANOVA). However, each n-3 FA therapy did not significantly decrease high-sensitivity C-reactive protein and fibrinogen, compared with placebo. O1 significantly increased insulin levels and decreased insulin sensitivity (determined by QUICKI) and O2 significantly decreased plasma adiponectin levels relative to baseline measurements. Of note, when compared with placebo, each n-3 FA therapy did not significantly change insulin, glucose, adiponectin, glycated hemoglobin levels and insulin sensitivity (by ANOVA). We observed similar results in a subgroup of patients with the metabolic syndrome. CONCLUSIONS: n-3 FA therapy dose-dependently and significantly decreased triglycerides and improved flow-mediated dilation. Nonetheless, n-3 FA therapy did not significantly improve acute-phase reactants and insulin sensitivity in patients with hypertriglyceridemia, regardless of dosages. PMID- 25147071 TI - Determinants and outcomes of atrial fibrillation complicating myocardial infarction: the EURHOBOP study in Portugal. PMID- 25147072 TI - Early levosimendan administration may improve outcome in patients with subarachnoid hemorrhage complicated by acute heart failure. PMID- 25147073 TI - Chronic total occlusion in a non-infarct-related coronary artery exacerbates prognosis in acute myocardial infarction: a Japanese single-center retrospective study. PMID- 25147074 TI - The effect of percutaneous renal denervation on muscle sympathetic nerve activity in hypertensive patients: more questions than answers. PMID- 25147075 TI - Catheter interventional creation of a "double aortic arch" for treatment of a complex residual coarctation of the aorta. PMID- 25147076 TI - Depth of valve implantation, conduction disturbances and pacemaker implantation with CoreValve and CoreValve Accutrak system for Transcatheter Aortic Valve Implantation, a multi-center study. AB - BACKGROUND: Transcatheter Aortic Valve Implantation (TAVI) is now considered an indispensable treatment strategy in high operative risk patients with severe, symptomatic aortic stenosis. However, conduction disturbances and the need for Permanent Pacemaker (PPM) implantation after TAVI with the CoreValve prosthesis still remain frequent. METHODS AND RESULTS: We aimed to evaluate the implantation depth, the incidence and predictors of new conduction disturbances, and the need for PPM implantation within the first month after TAVI, using the new Accutrak CoreValve delivery system (ACV), compared to the previous generation CoreValve (non-ACV). In 5 experienced TAVI-centers, a total of 120 consecutive non-ACV and 112 consecutive ACV patients were included (n=232). The mean depth of valve implantation (DVI) was 8.4+/-4.0 mm in the non-ACV group and 7.1+/-4.0 mm in the ACV group (p=0.034). The combined incidence of new PPM implantation and new LBBB was 71.2% in the non-ACV group compared to 50.5% in the ACV group (p=0.014). DVI (p=0.002), first degree AV block (p=0.018) and RBBB (p<0.001) were independent predictors of PPM implantation. DVI (p<0.001) and pre-existing first degree AV block (p=0.021) were identified as significant predictors of new LBBB. CONCLUSION: DVI is an independent predictor of TAVI-related conduction disturbances and can be reduced by using the newer CoreValve Accutrak delivery system, resulting in a significantly lower incidence of new LBBB and new PPM implantation. PMID- 25147077 TI - Regioselective dihalohydration reactions of propargylic alcohols: gold-catalyzed and noncatalyzed reactions. AB - The regioselective conversion of propargylic alcohols into previously unreported alpha,alpha-diiodo-beta-hydroxyketones was achieved by treatment with N iodosuccinimide in the presence of a gold catalyst. The corresponding alpha,alpha dichloro-beta-hydroxyketones were obtained by treatment with trichloroisocyanuric acid in the absence of a catalyst. The latter reaction can be extended to other alkynols. These transformations can be used to prepare potentially useful halogenated building blocks. Preliminary mechanistic studies suggest that the reaction involves participation of the acetonitrile solvent in the formation of a 5-halo-1,3-oxazine intermediate. PMID- 25147078 TI - Cytoskeletal regulation of mitochondrial movements in myoblasts. AB - Mitochondria are distributed in the cell to match the energy demands, and it is their interaction with the cytoskeleton that controls their movement and displacement. Our purpose was to determine which cytoskeletal components are primarily responsible for mitochondrial movement in muscle cells. Live-cell imaging was used to visualize mitochondrial dynamics in myoblasts. Destabilization of microtubules (MT) reduced the total path length and average speed traveled by mitochondria by 64-74%, whereas actin disruption only reduced these variables by 37-40%. Downregulation of the microtubule motor proteins, Kif5B and dynein, by siRNA resulted in decreases in the average speed of mitochondrial movements, by 30 to 40%. We observed a reduction in the average speed of mitochondrial movements (by 22 to 48%) under high calcium conditions. This attenuation in the presence of calcium was negated in cells pre-treated with siRNA targeted to the microtubule motor protein adaptor, Milton, suggesting that Milton is involved in mediating mitochondrial arrest in the presence of high calcium within muscle cells. Thus, we have demonstrated that, in myoblasts, mitochondria primarily move along microtubules tracks with the aid of the motor proteins Kif5B and dynein, in a manner which is inhibited by calcium. These observations will eventually help us understand organelle movements in more complex muscle systems, such as mature myotubes subjected to elevated calcium levels and contractile activity. PMID- 25147079 TI - Central sympathetic inhibition to reduce postablation atrial fibrillation recurrences in hypertensive patients: a randomized, controlled study. AB - BACKGROUND: The autonomic system is an important determinant of atrial arrhythmogenesis. Current evidence indicates that a combined sympathovagal drive is most commonly responsible for eliciting atrial fibrillation (AF) episodes. The purpose of this study was to test whether moxonidine, a centrally acting sympathoinhibitory agent, can lead to a reduction in postablation AF recurrence. METHODS AND RESULTS: This was a prospective, double-blinded, randomized study of 291 hypertensive patients with symptomatic paroxysmal AF who were scheduled to undergo pulmonary vein isolation. Patients were randomly assigned to receive either moxonidine (0.2-0.4 mg daily) or placebo, along with standard antihypertensive treatment. No significant differences in blood pressure levels were observed between the 2 groups. In the primary outcome analysis, mean recurrence-free survival was 467 days (95% CI, 445-489 days) in the moxonidine group as compared with 409 days (95% CI, 381-437 days) in control subjects (log rank test, P=0.006). The calculated 12-month recurrence rate estimates were 36.9% in the control group and 20.0% in the moxonidine group (P=0.007). Moxonidine treatment was associated with lower recurrence risk after adjustment for age, body mass index, number of AF episodes in the previous year, and left atrial diameter (adjusted hazard ratio, 0.35 [95% CI, 0.22-0.55]; P<0.001). CONCLUSIONS: Treatment with moxonidine is associated with less AF recurrences after ablation treatment for drug-refractory AF in patients with hypertension. The observed effect does not appear to depend on the antihypertensive action of this agent. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01791699. PMID- 25147080 TI - Perceptual hysteresis as a marker of perceptual inflexibility in schizophrenia. AB - People with schizophrenia are known to exhibit difficulties in the updating of their current belief states even in the light of disconfirmatory evidence. In the present study we tested the hypothesis that people with schizophrenia could also manifest perceptual inflexibility, or difficulties in the updating of their current sensory states. The presence of perceptual inflexibility might contribute both to the patients' altered perception of reality and the formation of some delusions as well as to their social cognition deficits. Here, we addressed this issue with a protocol of auditory hysteresis, a direct measure of sensory persistence, on a population of stabilized antipsychotic-treated schizophrenia patients and a sample of control subjects. Trials consisted of emotional signals (i.e., screams) and neutral signals (i.e., spectrally-rotated versions of the emotional stimuli) progressively emerging from white noise - Ascending Sequences or progressively fading away in white noise - Descending Sequences. Results showed that patients presented significantly stronger hysteresis effects than control subjects, as evidenced by a higher rate of perceptual reports in Descending Sequences. The present study thus provides direct evidence of perceptual inflexibility in schizophrenia. PMID- 25147081 TI - Metabolic and behavior changes in surubim acutely exposed to a glyphosate-based herbicide. AB - This study examined the effect of glyphosate-based herbicide (Roundup Original), the major herbicide used in soybean crops in Mato Grosso state, at concentrations of 0, 2.25, 4.5, 7.5, and 15 mg L(-1) on metabolic and behavior parameters of the hybrid fish surubim in an acute exposure lasting 96 h. Glycogen content, glucose, lactate, and protein levels were measured in different tissues. Plasma levels of cholesterol, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were also determined. Ventilatory frequency (VF) and swimming activity (SA) were considered behavior parameters. Results showed that herbicide exposure decreased plasma glucose levels and increased it in surubim liver. Lactate increased in both plasma and liver but decreased in muscle. Protein levels decreased in plasma and muscle but increased in liver. After herbicide exposure, liver and muscle glycogen was decreased. Cholesterol levels decreased in plasma at all concentrations tested. Plasma ALT increased, and no alterations were recorded for AST levels. VF increased after glyphosate exposure (5 min) and decreased after 96 h. SA showed differences among all groups (5 min). At the end of 96 h, SA was altered by the 7.5 mg L(-1) concentration. Fish used anaerobic glycolysis as indicated by generally decreased glycogen levels and decreased lactate levels in muscle but increased ones in plasma and liver. We suggest that the studied parameters could be used as indicators of herbicide toxicity in surubim and may provide extremely important information for understanding the biology of the animal and its responsiveness to external stimuli (stressors). PMID- 25147082 TI - Role of Runx2 in crosstalk between Mek/Erk and PI3K/Akt signaling in MCF-10A cells. AB - Crosstalk among mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3' kinase (PI3K) signaling pathways integrates extracellular cues to regulate mammary epithelial cell growth, proliferation, differentiation, and survival. The runt-related transcription factor, Runx2, is expressed in normal mammary epithelium and promotes differentiation, however, its function in regulation of the MAPK and PI3K signaling crosstalk is not known. We determined the function of Runx2 expression in growth factor-mediated phosphorylation of Erk1/2 and Akt, key downstream kinases in MAPK and PI3K pathway crosstalk in MCF-10A mammary epithelial cells. The Runx2-mediated alterations in cell signaling and associated changes in phenotype were determined by real-time quantitative PCR, Western blotting, immunofluorescence, and flow cytometry approaches. The results revealed that ectopic Runx2 expression differentially downregulates the growth factor (EGF vs. IGF or insulin)-induced pErk1/2 and pAkt levels. Additionally, the ectopic Runx2 expression increases FOXO1 levels, cell cycle G1 stage and promotes survival of MCF-10A cells. Furthermore, we demonstrate that Runx2 expression increases EGF-induced phosphorylation of epidermal growth factor receptor (pEGFR) and relieves Mek/Erk-mediated negative regulation of pEGFR and pAkt levels. Altogether, our results identify functions of Runx2 in MAPK and PI3K signaling crosstalk in MCF-10A cells that could be critical in understanding the mammary epithelial cell growth and survival. PMID- 25147083 TI - Modeling forward stutter: toward increased objectivity in forensic DNA interpretation. AB - Forward stutter, or over stutter, one repeat unit length larger than the parent allele (N + 1 stutter), is a relatively rare product of the PCR amplification of STRs used in forensic DNA analysis. We have investigated possible explanatory variables for the occurrence and size of forward stutter for four different autosomal multiplexes. In addition, we have investigated models used to predict the expected heights of forward stutter. For all tetra and penta-nucleotide repeats we can find no correlation between allelic peak height, marker, or longest uninterrupted sequence in the allele. The data fit a gamma distribution with no explanatory variables. For the single trinucleotide repeat present in two of the four multiplexes (D22S1045) forward stutter is much more common and the best explanatory variable appears to be back stutter height. This suggests some fundamental cocausation of high backward and forward stutter for this locus. PMID- 25147084 TI - Amphiphilic star copolymer-based bimodal fluorogenic/magnetic resonance probes for concomitant bacteria detection and inhibition. AB - Four-arm star-shaped copolymers, TPE-star-P(DMA-co-BMA-co-Gd), containing TPE cores with an aggregation-induced emission (AIE) feature, a T 1 -type magnetic resonance (MR) contrast agent, and amphiphilic cationic arms, are synthesized. By taking advantage of non-covalent interactions between star copolymers and bacteria surfaces, bimodal fluorometric/MR detection and concomitant inhibition of both Gram-positive and Gram-negative bacteria strains in aqueous media are explored. PMID- 25147085 TI - Subcutaneous phaeohyphomycosis in a patient with IgG4-related sclerosing disease caused by a novel ascomycete, Hongkongmyces pedis gen. et sp. nov.: first report of human infection associated with the family Lindgomycetaceae. AB - No members of the freshwater ascomycetes family Lindgomycetaceae have been associated with human infections. We isolated a mould (HKU35(T)) from the biopsy specimen of a patient with invasive foot infection and underlying immunoglobulin G4-related sclerosing disease. Histology showed florid, suppurative, granulomatous inflammation in the dermis, with central microabscess formation surrounded by epithelioid histiocytes, scattered giant cells, and a small number of lymphocytes. A Grocott stain revealed fungal elements in the center of the lesion. On Sabouraud glucose agar, HKU35(T) grew as gray and velvety colonies. Among the members of the family Lindgomycetaceae, HKU35(T) was the only strain that grew at 37 degrees C. Microscopically, only sterile mycelia, but no fruiting bodies, were observed. HKU35(T) was susceptible to itrazonazole, voriconazole, and posaconazole, which was in line with the patient's clinical response to itraconazole treatment. Internal transcribed spacer and partial 18S nuclear rDNA (nrDNA), 28S nrDNA, beta-tubulin gene, and EF1alpha gene sequencing showed that HKU35(T) occupied a unique phylogenetic position, most closely related to but distinct from members of the genera Clohesyomyces and Lindgomyces. We propose a new genus and species, Hongkongmyces pedis gen. et sp. nov., to describe this fungus, which belongs to the family Lindgomycetaceae in the orderPleosporales of class Dothideomycetes. This case also represents the first report of human infection associated with the family Lindgomycetaceae. PMID- 25147086 TI - Moderate-intensity physical activity, hippocampal volume, and memory in older adults with mild cognitive impairment. AB - BACKGROUND: Greater physical activity (PA) is associated with better memory performance and greater hippocampal volume in older adults. However, most studies to date assessed PA via questionnaires and thereby lacked objective characterization of PA (eg, intensity, duration, etc.). Thus, we currently do not have a comprehensive understanding of PA characteristics that are important for neuroprotection, especially among older adults with mild cognitive impairment (MCI). Thus, using triaxial accelerometers, we examined the association between light- and moderate-intensity PA, total duration of PA, hippocampal volume, and memory in older adults with MCI. METHODS: This cross-sectional study involved 310 older adults with MCI who completed neuropsychological tests of memory, and structural magnetic resonance imaging. Participants were instructed to wear the accelerometer on an elastic band on their hip at all times for 2 weeks. Average daily duration of light, moderate, and total PA (min/day) was calculated. RESULTS: Moderate PA was associated with hippocampal volume (beta = .167, p = .003) after controlling for age, but light PA (beta = -.021, p = .713) and total PA (beta = .011, p = .844) were not. Both light and moderate PAs were not associated with memory performance. Structural equation modeling demonstrated that moderate PA was not directly associated with memory but significantly contributed to hippocampal volume; hippocampal volume loss was significantly and directly associated with poor memory performance. CONCLUSIONS: Our results suggest that the benefits of moderate PA on memory among older adults with MCI are mediated by hippocampal volume. Furthermore, light PA may not reduce dementia risk among older adults with MCI. PMID- 25147087 TI - Heterologous production of glidobactins/luminmycins in Escherichia coli Nissle containing the glidobactin biosynthetic gene cluster from Burkholderia DSM7029. AB - Natural product peptide-based proteasome inhibitors show great potential as anticancer drugs. Here we have cloned the biosynthetic gene cluster of a potent proteasome inhibitor-glidobactin from Burkholderia DSM7029-and successfully detected glidobactins/luminmycins in E. coli Nissle. We have also improved the yield of glidobactin A tenfold by promoter change in a heterologous host. In addition, two new biosynthetic intermediates were identified by comparative MS/MS fragmentation analysis. Identification of acyclic luminmycin E implies substrate specificity of the TE domain for cyclization. The establishment of a heterologous expression system for syrbactins provided the basis for the generation of new syrbactins as proteasome inhibitors by molecular engineering, but the TE domain's specificity cannot be ignored. PMID- 25147088 TI - What needs to happen before an International Classification of Function, Disability and Health Core Set is ready for clinical use? PMID- 25147089 TI - Letter to the editor. PMID- 25147090 TI - Response to Tucker. PMID- 25147091 TI - JPEN Journal Club 7. Subgroup analyses. PMID- 25147092 TI - A randomized trial of chewing gum to prevent postoperative ileus after laparotomy for benign gynecologic surgery. AB - OBJECTIVE: To assess whether chewing gum prevents postoperative ileus after laparotomy for benign gynecologic surgery. METHODS: A randomized study was conducted from December 1, 2010, to February 29, 2012. Patients scheduled to undergo laparotomy were randomly assigned to receive chewing gum or routine care after surgery. A chart review was performed to establish incidence of nausea and vomiting, use of antiemetics, cases of postoperative ileus (>=2 episodes of emesis of 100 mL or more, with abdominal distention and absence of bowel sounds), and time to discharge. Inpatient surveys recorded the time to specific events. RESULTS: A total of 109 patients were randomly assigned to receive chewing gum (n=51) or routine postoperative care (n=58). Fewer participants assigned to receive chewing gum than routine care experienced postoperative nausea (16 [31.4%] versus 29 [50.0%]; P=0.049) and postoperative ileus (0 vs. 5 [8.6%]; P=0.032). There were no differences in the need for postoperative antiemetics, episodes of postoperative vomiting, readmissions, repeat surgeries, time to first hunger, time to toleration of clear liquids, time to regular diet, time to first flatus, or time to discharge. CONCLUSION: Chewing gum after laparotomy for gynecologic surgery is safe and lowers the incidence of postoperative ileus and nausea. ClinicalTrials.gov:NCT01579175. PMID- 25147093 TI - Diphtheria toxin-based recombinant murine IL-2 fusion toxin for depleting murine regulatory T cells in vivo. AB - Regulatory T cells (Tregs) are a subpopulation of CD4(+) T cells which suppress immune responses of effector cells and are known to play a very important role in protection against autoimmune disease development, induction of transplantation tolerance and suppression of effective immune response against tumor cells. An effective in vivo Treg depletion agent would facilitate Treg-associated studies across many research areas. In this study, we have developed diphtheria toxin based monovalent and bivalent murine IL-2 fusion toxins for depleting murine IL-2 receptor positive cells including CD25(+) Treg in vivo. Their potencies were assessed by in vitro protein synthesis inhibition and cell proliferation inhibition assays using a murine CD25(+) CTLL-2 cell line. Surprisingly, in contrast to our previously developed recombinant fusion toxins, the monovalent isoform (DT390-mIL-2) was approximately 4-fold more potent than its bivalent counterpart (DT390-bi-mIL-2). Binding analysis by flow cytometry demonstrated that the monovalent isoform bound stronger than the bivalent version. In vivo Treg depletion with the monovalent murine IL-2 fusion toxin was performed using C57BL/6J (B6) mice. Spleen Treg were significantly depleted with a maximum reduction of ~70% and detectable as early as 12 h after the last injection. The spleen Treg numbers were reduced until Day 3 and returned to control levels by Day 7. We believe that this monovalent murine IL-2 fusion toxin will be an effective in vivo murine Treg depleter. PMID- 25147094 TI - Change in Identity Diffusion and Psychopathology in a Specialized Inpatient Treatment for Borderline Personality Disorder. AB - OBJECTIVES: Patients with borderline personality disorder (BPD) show various psychopathological symptoms and suffer especially from disturbance in their identity. The purpose of the study was to investigate changes-particularly in affective BPD symptoms and identity diffusion-during a structured, disorder specific inpatient treatment (DST) that combined a psychodynamic transference focused psychotherapy approach with modules of dialectical behavioural skills training. METHOD: In a prospective, two-group comparison trial, 44 patients with BPD were assessed with questionnaires addressing identity diffusion and state, as well as trait affective psychopathology, before and after 12 weeks of inpatient treatment. Thirty-two patients received DST, whereas 12 patients were given inpatient treatment-as-usual (TAU). The patients were allocated in a non-random procedure for two groups, in order of admission and availability of treatment options in the DST unit. RESULTS: In the pre-post-comparison, the DST group showed a significant decrease in identity diffusion (p < 0.001) and improvements in instability of the image of self and others (p < 0.008), as well as in pathological (trait and state) symptoms. However, there was no significant improvement in the TAU group. CONCLUSIONS: After a 12-week inpatient treatment, the findings indicate significant improvements in the DST group in typical affective borderline symptomatology and in the personality structure feature of identity diffusion. This highlights the significance of a short-term specific inpatient therapy for BPD. KEY PRACTITIONER MESSAGE: A structured, disorder specific inpatient treatment of patients diagnosed with borderline personality disorder (BPD) combined a psychodynamic transference-focused psychotherapy treatment approach (focusing on pathological features in personality organization, particularly on non-integrated images of self and others) with modules of dialectical behavioural skills training. This treatment is associated with a decrease in identity diffusion of these patients after 12 weeks of treatment. The treatment is also related to a significant decrease in borderline typical psychopathological symptoms such as depressive symptoms, as well as an improvement in state anger. The outcomes of this structured, disorder-specific inpatient treatment of severely ill BPD patients indicated the relevance of intensive short-term inpatient psychotherapy in terms of psychopathological improvements as well as initial changes in structural personality organization. PMID- 25147095 TI - CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations. AB - BACKGROUND: Nevirapine, an NNRTI used in HIV treatment, can cause hypersensitivity reactions in 6%-10% of patients. In the most serious cases (1.3%) this can manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). METHODS: DNA samples were obtained and analysed from a total of 209 adult patients with nevirapine hypersensitivity (57 from a prospective cohort and 152 routine clinic patients) and compared with 463 control patients on nevirapine without any hypersensitivity. The case group included 70 patients with SJS/TEN. All individuals were genotyped for two SNPs in the CYP2B6 gene [c.516G>T (CYP2B6*9) and c.983T>C (CYP2B6*18)] using the TaqMan real-time genotyping platform. The replication cohort comprised 29 controls and 55 nevirapine hypersensitive patients, including 8 SJS/TEN cases. RESULTS: An association between the CYP2B6 c.983T>C polymorphism and nevirapine-induced SJS/TEN was observed. In the SJS/TEN group, 30% of individuals possessed at least one c.983T>C versus 16% in the tolerant group [P = 0.006; OR (95% CI) 2.24 (1.27 3.94)]. This association was not significant in the replication cohort [P = 0.075; OR (95% CI) 4.33 (0.80-23.57)]. Combined analysis resulted in an OR of 2.52 (95% CI 1.48-4.20; P = 0.0005) for the association of c.983T>C with SJS/TEN. No association was observed for c.983T>C with other hypersensitivity phenotypes and for CYP2B6 c.516G>T with any hypersensitivity phenotypes. CONCLUSIONS: Our data show an association between the c.983T>C polymorphism and nevirapine-induced SJS/TEN. CYP2B6 c.983T>C has a frequency of 5%-10% in a variety of African populations, but is not observed in Caucasians, thus representing an ethnic specific predisposing factor. PMID- 25147096 TI - Parenting Needs of Urban, African American Fathers. AB - Fathers play a critical role in children's development; similarly, fatherhood positively affects men's health. Among the larger population of fathers relatively little is known about the parenting knowledge of urban, African American fathers. Focusing on urban, African American fathers, the objectives of this study were to (1) understand the primary sources from which fathers learn about parenting, (2) determine where and how fathers prefer to receive future parenting education, and (3) explore the information perceived as most valuable to fathers and how this compares with the recommended anticipatory guidance (Bright Futures-based) delivered during well visits. Five focus groups, with a total of 21 participants, were conducted with urban fathers at a community-based organization. Study eligibility included being more than 18 years old, English speaking, and having at least one child 0 to 5 years old. During the focus groups, fathers were asked where they received parenting information, how and where they preferred to receive parenting information, and what they thought about Bright Futures parenting guidelines. Fathers most commonly described receiving parenting information from their own relatives rather than from their child's health care provider. Most fathers preferred to learn parenting from a person rather than a technology-based source and expressed interest in learning more about parenting at community-based locations. Although fathers viewed health care providers' role as primarily teaching about physical health, they valued Bright Futures anticipatory guidance about parenting. Fathers valued learning about child rearing, health, and development. Augmenting physician counseling about Bright Futures with community-based parenting education may be beneficial for fathers. PMID- 25147097 TI - Prevalence of Cannabis Lifetime Use in Iranian High School and College Students: A Systematic Review, Meta-Analyses, and Meta-Regression. AB - Cannabis is the most widely used substance in the world. This study aimed to estimate the prevalence of cannabis lifetime use (CLU) in high school and college students of Iran and also to determine factors related to changes in prevalence. A systematic review of literature on cannabis use in Iran was conducted according to MOOSE guideline. Domestic scientific databases, PubMed/Medline, ISI Web of Knowledge, and Google Scholar, relevant reference lists, and relevant journals were searched up to April, 2014. Prevalences were calculated using the variance stabilizing double arcsine transformation and confidence intervals (CIs) estimated using the Wilson method. Heterogeneity was assessed by Cochran's Q statistic and I(2) index and causes of heterogeneity were evaluated using meta regression model. In electronic database search, 4,000 citations were retrieved, producing a total of 33 studies. CLU was reported with a random effects pooled prevalence of 4.0% (95% CI = 3.0% to 5.0%). In subgroups of high school and college students, prevalences were 5.0% (95% CI = 3.0% to -7.0%) and 2.0% (95% CI = 2.0% to -3.0%), respectively. Meta-regression model indicated that prevalence is higher in college students (beta = 0.089, p < .001), male gender (beta = 0.017, p < .001), and is lower in studies with sampling versus census studies (beta = -0.096, p < .001). This study reported that prevalence of CLU in Iranian students are lower than industrialized countries. In addition, gender, level of education, and methods of sampling are highly associated with changes in the prevalence of CLU across provinces. PMID- 25147098 TI - Liver histology of acute brucellosis caused by Brucella melitensis. AB - As a major organ of the mononuclear phagocytic system, the liver is probably involved in all cases of brucellosis. In this prospective study, liver slides prepared from percutaneous liver biopsy samples of 20 patients with clinical and laboratory evidence of acute brucellosis due to Brucella melitensis were examined for the presence or absence of granulomas by pathologists in Iran and the United States. Nineteen men and one woman ranging in age from 14 to 62 years were studied. All patients had clinical signs and symptoms compatible with acute brucellosis, and all had significantly elevated titers of antibodies to Brucella in their serum. Liver function tests were mildly elevated in 11 (55%) cases, and C-reactive protein was positive in 15 (65%) patients. Thirteen (65%) patients had blood cultures positive for B melitensis. Iranian and American pathologists reported granulomas in 3 (15%) and in 4 (20%) cases, respectively. There was agreement between Iranian and American pathologists in 17 (85%) cases. The most prevalent findings were mild portal or lobular lymphocytic inflammation (16 cases). Two cases revealed noncaseating epithelioid granulomas, and 2 had microgranulomas. The results show that all patients had microscopic evidence of liver involvement. The predominant histologic finding was mild portal or lobular inflammation with lymphocytes. Granulomas were present in only 4 cases. PMID- 25147099 TI - Synthesis and photophysical properties of multichromophoric carbonyl-bridged triarylamines. AB - The synthesis and photophysical properties of two novel multichromophoric compounds is presented. Their molecular design comprises a carbonyl-bridged triarylamine core and either naphthalimides or 4-(5-hexyl-2,2' bithiophene)naphthalimides as second chromophore in the periphery. The lateral chromophores are attached to the core via an amide linkage and a short alkyl spacer. The synthetic approach demonstrates a straightforward functionalization strategy for carbonyl-bridged triarylamines. Steady-state and time-resolved spectroscopic investigations of these compounds, in combination with three reference compounds, provide clear evidence for energy transfer in both multichromophoric compounds. The direction of the energy transfer depends on the lateral chromophore used. Furthermore, the compound bearing the lateral 4 (bithiophene)naphthaimides is capable of forming fluorescent gels at very low concentrations in the sub-millimolar regime whilst retaining its energy transfer properties. PMID- 25147100 TI - Formation and influence of the dynamic adsorption layer on kinetics of the rising bubble collisions with solution/gas and solution/solid interfaces. AB - BACKGROUND: The DAL (dynamic adsorption layer) formation, that is, the establishment of uneven distribution of adsorption coverage over the rising bubble surface, with significantly diminished coverage at the upstream pole, is the factor of crucial importance for the bubble motion parameters and kinetic of the bubble collisions with various interfaces. The DAL presence can influence the stability of the thin liquid films formed by the colliding bubble at solution/gas and solution solid interfaces. AIM: The purpose of this paper is to critically review the existing state of art regarding the influence of the DAL formation and existence on the bubble motion parameters as well as kinetics of coalescence at free solution surface and three phase contact (TPC) formation at solid/liquid interfaces of different hydrophilic/hydrophobic properties. CONCLUSIONS: Despite the fact that up to now there is no direct experimental evidence showing DAL existence, it is documented by experimental data showing clear correlation between bubble local velocity variations and shape pulsations as well as lifetimes of the liquid film formed by the colliding bubble at gas/liquid and gas/solid interfaces. PMID- 25147101 TI - How feedback biases give ineffective medical treatments a good reputation. AB - BACKGROUND: Medical treatments with no direct effect (like homeopathy) or that cause harm (like bloodletting) are common across cultures and throughout history. How do such treatments spread and persist? Most medical treatments result in a range of outcomes: some people improve while others deteriorate. If the people who improve are more inclined to tell others about their experiences than the people who deteriorate, ineffective or even harmful treatments can maintain a good reputation. OBJECTIVE: The intent of this study was to test the hypothesis that positive outcomes are overrepresented in online medical product reviews, to examine if this reputational distortion is large enough to bias people's decisions, and to explore the implications of this bias for the cultural evolution of medical treatments. METHODS: We compared outcomes of weight loss treatments and fertility treatments in clinical trials to outcomes reported in 1901 reviews on Amazon. Then, in a series of experiments, we evaluated people's choice of weight loss diet after reading different reviews. Finally, a mathematical model was used to examine if this bias could result in less effective treatments having a better reputation than more effective treatments. RESULTS: Data are consistent with the hypothesis that people with better outcomes are more inclined to write reviews. After 6 months on the diet, 93% (64/69) of online reviewers reported a weight loss of 10 kg or more while just 27% (19/71) of clinical trial participants experienced this level of weight change. A similar positive distortion was found in fertility treatment reviews. In a series of experiments, we show that people are more inclined to begin a diet with many positive reviews, than a diet with reviews that are representative of the diet's true effect. A mathematical model of medical cultural evolution shows that the size of the positive distortion critically depends on the shape of the outcome distribution. CONCLUSIONS: Online reviews overestimate the benefits of medical treatments, probably because people with negative outcomes are less inclined to tell others about their experiences. This bias can enable ineffective medical treatments to maintain a good reputation. PMID- 25147102 TI - Challenge of representing entropy at different levels of resolution in molecular simulation. AB - The role of entropic contributions in processes involving biomolecules is illustrated using the process of vaporization or condensation of the solvents water and methanol and the process of polypeptide folding in solution using molecular models at different levels of resolution: subatomic, atomic, supra atomic, and supramolecular. For the folding process, a beta-hexapeptide that adopts, as inferred from NMR experiments, both a right-handed 2.710/12-helical fold and a left-handed 314-helical fold in methanol, is used to illustrate the challenge of modeling thermodynamically driven processes at different levels of resolution. PMID- 25147103 TI - Do patients with Alzheimer's disease draw like young children? An exploratory study. AB - BACKGROUND: Previous studies have shown that AD patients present a stepwise regression to their cognitive functioning from a mature adult to that of an infant. OBJECTIVES: The present study aimed to compare Alzheimer's disease (AD) patients' and 4-10 year old children's drawing performance, taking into account that drawing is currently considered as a cognitive process and that AD manifests a severe cognitive impairment. METHODS: The sample consisted of 10 AD patients and 10 adult controls, as well as of 40 children, divided into 4 age groups (4-, 6-, 8-, and 10-years old). Participants were asked to draw from memory (a) six simple objects, (b) a man, and (c) a tree behind a house. RESULTS: Analysis showed an improvement with age in children's drawing performance, while controls' drawing scores were similar to those obtained by older children. On the contrary, drawing performance of AD patients significantly decreased into levels under that of the 4-year old children in drawing errors, or under that of the 8-year old children in drawing a man task and partial occlusion task. CONCLUSIONS: The observed regression in AD patients' drawing performance is discussed in relation to the cognitive deficits accompanying the disease. PMID- 25147104 TI - A theta-band EEG based index for early diagnosis of Alzheimer's disease. AB - Despite recent advances, early diagnosis of Alzheimer's disease (AD) from electroencephalography (EEG) remains a difficult task. In this paper, we offer an added measure through which such early diagnoses can potentially be improved. One feature that has been used for discriminative classification is changes in EEG synchrony. So far, only the decrease of synchrony in the higher frequencies has been deeply analyzed. In this paper, we investigate the increase of synchrony found in narrow frequency ranges within the theta band. This particular increase of synchrony is used with the well-known decrease of synchrony in the alpha band to enhance detectable differences between AD patients and healthy subjects. We propose a new synchrony ratio that maximizes the differences between two populations. The ratio is tested using two different data sets, one of them containing mild cognitive impairment patients and healthy subjects, and another one, containing mild AD patients and healthy subjects. The results presented in this paper show that classification rate is improved, and the statistical difference between AD patients and healthy subjects is increased using the proposed ratio. PMID- 25147105 TI - Identifying cost-effective predictive rules of amyloid-beta level by integrating neuropsychological tests and plasma-based markers. AB - BACKGROUND: Detecting participants who are positive for amyloid-beta (Abeta) pathology is germane in designing prevention trials by enriching for those cases that are more likely to be amyloid positive. Existing brain amyloid measurement techniques, such as the Pittsburgh Compound B-positron emission tomography and cerebrospinal fluid, are not reasonable first-line approaches limited by either feasibility or cost. OBJECTIVE: We aimed to identify simple and cost-effective rules that can predict brain Abeta level by integrating both neuropsychological measurements and blood-based markers. METHOD: Several decision tree models were built for extracting the predictive rules based on the Alzheimer's Disease Neuroimaging Initiative cohort. RESULTS: We successfully extracted predictive rules of Abeta level. For cognitive function variables, cases above the 45th percentile in total cognitive score (TOTALMOD), above the 52nd percentile of delayed word recall, and above the 70th percentile in orientation resulted in a group that was highly enriched for amyloid negative cases. Conversely scoring below the 15th percentile of TOTALMOD resulted in a group highly enriched for amyloid positive cases. For blood protein markers, scoring below the 57th percentile for apolipoprotein E (ApoE) levels (irrespective of genotype) enriched two fold for the risk of being amyloid positive. In the high ApoE cases, scoring above the 60th percentile for transthyretin resulted in a group that was >90% amyloid negative. A third decision tree using both cognitive and blood-marker data slightly improved the classification of cases. CONCLUSION: Our study demonstrated that the integration of the neuropsychological measurements and blood-based markers significantly improved prediction accuracy. The prediction model has led to several simple rules, which have a great potential of being naturally translated into clinical settings such as enrichment screening for AD prevention trials of anti-amyloid treatments. PMID- 25147106 TI - N-terminal truncation of microtubule associated protein tau dysregulates its cellular localization. AB - Tau protein is a member of microtubule-associated protein family. Under pathological conditions, tau undergoes multiple modifications that lead to the formation of insoluble deposits in neurons, resulting in neuronal dysfunction in several neurodegenerative disorders collectively called tauopathies, with Alzheimer's disease being the most frequent example. This typical cytosolic protein has been shown to translocate into the nucleus and participate in DNA protection upon stress conditions. In our study, we demonstrate that truncated Tau151-391/4R changes its usual behavior and gains constitutive access into the nucleus of both primary rat neurons and human neuroblastoma cells. Our results show that partial/dysregulated nuclear localization of tau results from the removal of the N-terminal (1-150) residues of the protein. Data obtained by cell fractionation data were supported by confocal microscopy analysis of GFP-fused tau proteins. Furthermore, neither addition of the fusion protein, nor increased tau phosphorylation had any effect on the intracellular distribution of truncated tau. Our data further suggest that differential tau phospho-status between cytosolic and nuclear fractions is rather a consequence than a cause of truncated tau nuclear localization. Finally, truncated tau in the nucleus is engaged in interactions with subnuclear structure(s), since it exhibits reduced mobility. We conclude that N-terminal truncation of tau proteins leads to their nonphysiological subcellular distribution as a result of modified tau conformation. PMID- 25147107 TI - Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer's disease dementia. AB - BACKGROUND: The cerebral metabolic rate of glucose (CMRg) is lower in specific brain regions in Alzheimer's disease (AD). The ketones, acetoacetate and beta hydroxybutyrate, are the brain's main alternative energy substrates to glucose. OBJECTIVE: To gain insight into brain fuel metabolism in mild AD dementia by determining whether the regional CMR and the rate constant of acetoacetate (CMRa and Ka, respectively) reflect the same metabolic deficit reported for cerebral glucose uptake (CMRg and Kg). METHODS: Mild AD dementia (Mild AD; n = 10, age 76 y) patients were compared with gender- and age-matched cognitively normal older adults (Controls; n = 29, age 75 y) using a PET/MRI protocol and analyzed with both ROI- and voxel-based methods. RESULTS: ROI-based analysis showed 13% lower global CMRg in the gray matter of mild AD dementia versus Controls (34.2 +/- 5.0 versus 38.3 +/- 4.7 MUmol/100 g/min, respectively; p = 0.015), with CMRg and Kg in the parietal cortex, posterior cingulate, and thalamus being the most affected (p <= 0.022). Neither global nor regional CMRa or Ka differed between the two groups (all p >= 0.188). Voxel-based analysis showed a similar metabolic pattern to ROI-based analysis with seven clusters of significantly lower CMRg in the mild AD dementia group (uncorrected p <= 0.005) but with no difference in CMRa. CONCLUSION: Regional brain energy substrate hypometabolism in mild AD dementia may be specific to impaired glucose uptake and/or utilization. This suggests a potential avenue for compensating brain energy deficit in AD dementia with ketones. PMID- 25147108 TI - Brain changes in Alzheimer's disease patients with implanted encapsulated cells releasing nerve growth factor. AB - New therapies with disease-modifying effects are urgently needed for treating Alzheimer's disease (AD). Nerve growth factor (NGF) protein has demonstrated regenerative and neuroprotective effects on basal forebrain cholinergic neurons in animal studies. In addition, AD patients treated with NGF have previously shown improved cognition, EEG activity, nicotinic binding, and glucose metabolism. However, no study to date has analyzed brain atrophy in patients treated with NGF producing cells. In this study we present MRI results of the first clinical trial in patients with AD using encapsulated NGF biodelivery to the basal forebrain. Six AD patients received the treatment during twelve months. Patients were grouped as responders and non-responders according to their twelve months change in MMSE. Normative values were created from 131 AD patients from ADNI, selecting 36 age- and MMSE-matched patients for interpreting the longitudinal changes in MMSE and brain atrophy. Results at baseline indicated that responders showed better clinical status and less pathological levels of cerebrospinal fluid (CSF) Abeta1-42. However, they showed more brain atrophy, and neuronal degeneration as evidenced by higher CSF levels of T-tau and neurofilaments. At follow-up, responders showed less brain shrinkage and better progression in the clinical variables and CSF biomarkers. Noteworthy, two responders showed less brain shrinkage than the normative ADNI group. These results together with previous evidence supports the idea that encapsulated biodelivery of NGF might have the potential to become a new treatment strategy for AD with both symptomatic and disease-modifying effects. PMID- 25147109 TI - Air pollution and children: neural and tight junction antibodies and combustion metals, the role of barrier breakdown and brain immunity in neurodegeneration. AB - Millions of children are exposed to concentrations of air pollutants, including fine particulate matter (PM2.5), above safety standards. In the Mexico City Metropolitan Area (MCMA) megacity, children show an early brain imbalance in oxidative stress, inflammation, innate and adaptive immune response-associated genes, and blood-brain barrier breakdown. We investigated serum and cerebrospinal fluid (CSF) antibodies to neural and tight junction proteins and environmental pollutants in 139 children ages 11.91 +/- 4.2 y with high versus low air pollution exposures. We also measured metals in serum and CSF. MCMA children showed significantly higher serum actin IgG, occludin/zonulin 1 IgA, IgG, myelin oligodendrocyte glycoprotein IgG and IgM (p < 0.01), myelin basic protein IgA and IgG, S-100 IgG and IgM, and cerebellar IgG (p < 0.001). Serum IgG antibodies to formaldehyde, benzene, and bisphenol A, and concentrations of Ni and Cd were significantly higher in exposed children (p < 0.001). CSF MBP antibodies and nickel concentrations were higher in MCMA children (p = 0.03). Air pollution exposure damages epithelial and endothelial barriers and is a robust trigger of tight junction and neural antibodies. Cryptic 'self' tight junction antigens can trigger an autoimmune response potentially contributing to the neuroinflammatory and Alzheimer and Parkinson's pathology hallmarks present in megacity children. The major factor determining the impact of neural antibodies is the integrity of the blood-brain barrier. Defining the air pollution linkage of the brain/immune system interactions and damage to physical and immunological barriers with short and long term neural detrimental effects to children's brains ought to be of pressing importance for public health. PMID- 25147110 TI - Stress-induced activation of the sympathoadrenal system is determined by genetic background in rat models of tauopathy. AB - Stress may accelerate onset of neurodegenerative diseases in vulnerable subjects and, vice versa, neurodegeneration affects the responsiveness to stressors. We investigated the neuroendocrine response to immobilization stress in normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and transgenic rats of respective WKY and SHR strains overexpressing human truncated tau protein. Plasma levels of epinephrine, norepinephrine, and corticosterone were determined. An immobilization-induced elevation of epinephrine and norepinephrine was significantly reduced in WKY transgenic rats compared to WKY wild-type rats, while no differences were seen between SHR transgenic and SHR wild-type animals. Our data have shown that sympathoadrenal system response to stress strongly depends on both tau protein-induced neurodegeneration and genetic background of experimental animals. PMID- 25147111 TI - 2003-2013: a decade of body mass index, Alzheimer's disease, and dementia. AB - The occurrence of obesity, commonly estimated using body mass index (BMI), and the most common late-onset dementia, Alzheimer's disease (AD), are increasing globally. The year 2013 marked a decade of epidemiologic observational reports on the association between BMI and late-onset dementias. In this review, we highlight epidemiological studies that measured both mid- and late-life BMI in association with dementia. Studies investigating the association between midlife BMI and risk for dementia demonstrated generally an increased risk among overweight and obese adults. When measured in late-life, elevated BMI has been associated with lower risk. In addition, being underweight and/or having a decrease in BMI in late-life are associated with higher dementia risk compared to BMI in the normal range or stable BMI. In this review, a decade (2003-2013) of epidemiologic observational studies on associations between BMI and AD is highlighted. These observations provide a strong base for addressing biological mechanisms underlying this complex association. PMID- 25147112 TI - Biophysical alterations in lipid rafts from human cerebral cortex associate with increased BACE1/AbetaPP interaction in early stages of Alzheimer's disease. AB - In the present study, we have assessed the biophysical properties of lipid rafts from different brain areas in subjects exhibiting early neuropathological stages of Alzheimer's disease (AD). By means of steady-state fluorescence polarization analyses using two environment-sensitive fluorescent probes, we demonstrate that lipid rafts from cerebellum, and frontal and entorhinal cortices, exhibit different biophysical behaviors depending on the stage of the disease. Thus, while membrane anisotropies were similar in the cerebellum along stages, lipid rafts from frontal and entorhinal cortices at AD stages I/II and AD III were significantly more liquid-ordered than in control subjects, both at the aqueous interface and hydrophobic core of the raft membrane. Thermotropic analyses demonstrated the presence of Arrhenius breakpoints between 28.3-32.0 degrees C, which were not influenced by the disease stage. However, analyses of membrane microviscosity (etaapp) demonstrate that frontal and entorhinal lipid rafts are notably more viscous and liquid-ordered all across the membrane from early stages of the disease. These physicochemical alterations in lipid rafts do not correlate with changes in cholesterol or sphingomyelin levels, but to reduced unsaturation index and increased saturate/polyunsaturated ratios in phospholipid acyl chains. Moreover, we demonstrate that beta-secretase/AbetaPP (amyloid-beta protein precursor) interaction and lipid raft microviscosity are strongly, and positively, correlated in AD frontal and entorhinal cortices. These observations strengthens the hypothesis that physical properties of these microdomains modulate the convergence of amyloidogenic machinery toward lipid rafts, and also points to a critical role of polyunsaturated fatty acids in amyloidogenic processing of AbetaPP. PMID- 25147113 TI - Optimal cutoff scores for dementia and mild cognitive impairment of the Montreal Cognitive Assessment among elderly and oldest-old Chinese population. AB - BACKGROUND: All versions of the Montreal Cognitive Assessment (MoCA) lack population-based data of 80-plus individuals. The norms and cut-off scores for mild cognitive impairment (MCI) and dementia of the MoCA are different among five Chinese versions. OBJECTIVE: To provide the cut-off scores in detecting MCI and dementia of the Peking Medical Union College Hospital version of the MoCA (MoCA P). METHODS: In a cross-sectional survey, Chinese veterans aged >=60 years completed the MoCA-P and the Mini-Mental State Examination (MMSE). RESULTS: Among 7,445 elderly veterans, 5,085 (68.30%) were aged >=80 years old, 2,621 (35.20%) had 6 years of education or less, 6,847 (91.97%) were male, and 2,311 (31.04%) and 984 (13.22%) veterans were diagnosed as having MCI and dementia, respectively. Adding two points and one point to the MoCA scores for the primary and middle school groups, respectively, can fully adjust for the notable impact of education but cannot compensate for the effect of age. In the three age groups (60-79, 80-89, and >=90 years old), the optimal MoCA-P cut-off scores for detecting MCI were <=25, <=24, and <=23, respectively, and for detecting dementia were <=24, <=21, and <=19, respectively, which demonstrated relatively high sensitivities and specificities. The areas under the curves for the MoCA-P for detecting MCI and dementia (0.937 and 0.908, respectively) were greater than those for the MMSE (0.848 and 0.892, respectively). CONCLUSION: Compared with the MMSE, the MoCA-P is significantly better for detecting MCI in the elderly, particularly in the oldest old population, and it also displays more effectiveness in detecting dementia. PMID- 25147114 TI - Differential regulation of resolution in inflammation induced by amyloid-beta42 and lipopolysaccharides in human microglia. AB - Resolution of inflammation terminates the inflammatory response in physiological conditions and promotes restoration and healing of the tissue; however, failure in resolution results in chronic inflammation that may lead to disease. Chronic inflammation mediated by microglia is a feature of Alzheimer's disease (AD) and can be a pathogenic factor in which both treatment targets and diagnostic markers may be found. In addition, there is evidence that the resolution pathway is altered in AD. It is therefore relevant to investigate whether amyloid-beta (Abeta) peptide, the major component of senile plaque in AD brain, may have a negative influence on components of the resolution cascade. In this pursuit, we exposed microglia to Abeta42, and with bacterial lipopolysaccharides (LPS) for comparison with a general infectious stimulus. Differential effects were observed: LPS upregulated components of the resolution pathway including the LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2) and phosphorylated 5-lipoxygenase (p-5-LOX), as well as cholinergic alpha 7 nicotinic receptor (alpha7nAChR) and peroxisome proliferator-activated receptor (PPAR)-delta whereas Abeta42 had an opposite or insignificant effect. Our results indicate that LPS-induced changes in the microglia were conducive for resolution of inflammation, whereas these responses were absent or suppressed in microglia treated with Abeta42. Further studies may prove if Abeta42-induced dysfunction of resolution in microglia contributes to the impaired resolution in the AD brain, and if stimulation of microglial resolution constitutes a treatment strategy for AD. PMID- 25147115 TI - The pathophysiology of axonal transport in Alzheimer's disease. AB - Neurons communicate in the nervous system by carrying out information along the length of their axons to finally transmit it at the synapse. Proper function of axons and axon terminals relies on the transport of proteins, organelles, vesicles, and other elements from the site of synthesis in the cell body. Conversely, neurotrophins secreted from axonal targets and other components at nerve terminals need to travel toward the cell body for clearance. Molecular motors, namely kinesins and dyneins, are responsible for the movement of these elements along cytoskeletal tracks. Given the challenging structure of neurons, axonal transport machinery plays a crucial role in maintaining neuronal viability and function, allowing the proper neurotransmitter release at the presynaptic ending. On this basis, failure of axonal transport has been proposed as a key player in the development and/or progression of neurodegenerative disorders such as Alzheimer's disease (AD). Increasing evidence suggests that amyloid-beta peptide, a hallmark of AD, may disrupt axonal transport and in so doing, contribute to AD pathophysiology. Here we discuss the molecular mechanisms of axonal transport with specific emphasis on the possible relationship between defective axonal transport and AD. PMID- 25147116 TI - Development and psychometric properties of a neuropsychological battery for mild cognitive impairment with small vessel disease: the VMCI-Tuscany Study. AB - BACKGROUND AND OBJECTIVE: Vascular cognitive impairment may have a selective neuropsychological profile. We developed a battery for assessing mild cognitive impairment (MCI) in patients with small vessel disease (SVD), its applicability, and psychometric properties. METHODS: Among those proposed by the 2006 NINDS-CSN Consensus Conference, we selected tests for which norms based on healthy Italians and equivalent scores methodology were available. Confirmatory factor analysis was applied to ascertain the fit of the theoretically assumed dimensions to empirical data and to derive each cognitive dimension compound measures. RESULTS: The entire battery was applied to 146 out of a cohort of 201 patients with MCI and SVD. Most tests showed good applicability. Fifty-five patients, who were older and cognitively more impaired, proved unable to complete the Trail Making Test part B, the Rey-Osterrieth Complex Figure, and the Stroop test, and were excluded from the analysis. Among the remaining patients, Mini-Mental State Examination proved largely normal, while Rey-Osterrieth Complex Figure, Symbol digit modalities test, and Trail Making Test part B were most frequently abnormal. Confirmatory factor analysis showed a good fit of the 4-factor theoretical model to empirical data. Praxis domain resulted in the highest percentage of abnormal performance (65%), followed by Memory and Attention/EF domains (19% and 15%), and Language (8%). CONCLUSIONS: Our battery proved to be comprehensive, robust, and applicable. Attention-executive dysfunction and impaired memory and visuo-constructional abilities, were the prominent features. The assessment of the Consensus Conference, that included Trial Making Test, looks poorly applicable to older and cognitively impaired patients. PMID- 25147117 TI - Antipsychotic drug treatment in ambulatory dementia care: prevalence and correlates. AB - BACKGROUND: The present study is the first to analyze primary data about the use of antipsychotic drugs among community dwelling people with dementia in German primary care. OBJECTIVES: To determine (1) prevalence of antipsychotic drug treatment in German primary care patients who screened positive for dementia and (2) factors associated with antipsychotic drug treatment. METHODS: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is an ongoing general practitioner-based, randomized, controlled intervention trial. A total of 4,064 community dwelling patients (>=70 years) recruited from 108 participating practices were screened for dementia (DemTect <9). Of 692 eligible patients (17%), a total of 406 patients provided informed consent (59%). Present analyses are based on data of 243 patients who completed baseline assessment before January 2014 (preliminary data). RESULTS: Of the 243 patients who screened positive for dementia, a total of 25 patients (10%) received at least one antipsychotic drug. Atypical antipsychotic drugs (64%) were prescribed more often than typical antipsychotic drugs (36%). The results of the multivariate analysis showed that treatment by a specialist (neurologist/psychiatrist) was the only factor significantly associated with antipsychotic drug treatment (odds ratio, 12.86; p < 0.05; 95% confidence interval, 1.04-158.71). CONCLUSIONS: Compared to the antipsychotic drug treatment rate among people with dementia living in nursing homes (>50%), the rate we found for community dwelling primary care patients who screened positive for dementia was low. Further research is needed to evaluate if these patients are adequately treated or if the antipsychotic drug treatment should and could be further reduced. PMID- 25147119 TI - Auraptene increases the production of amyloid-beta via c-Jun N-terminal kinase dependent activation of gamma-secretase. AB - Amyloid-beta (Abeta) peptide plays a major role in the pathogenesis of Alzheimer's disease (AD), and is generated by beta- and gamma-secretase-mediated proteolytic processing of amyloid-beta protein precursor (AbetaPP). In the present study, we investigated the effect of 118 natural compounds on Abeta production in the medium of HEK293 cells stably expressing human AbetaPP695 (HEK293-AbetaPP) using Abeta42 sandwich ELISA to find natural compounds that can modulate Abeta production. We found that a coumarin derivative of citrus fruits, auraptene, increased Abeta production. Treatment of HEK293-AbetaPP cells and rat primary cortical neurons with auraptene significantly increased the secretion of Abeta40, Abeta42, and the Abeta42/40 ratio. However, auraptene did not change the protein levels of the AbetaPP processing enzymes, a disintegrin and metalloproteinases 10 (ADAM10, alpha-secretase), beta-site AbetaPP cleaving enzyme-1 (BACE-1, beta-secretase), and presenilin 1 (PS1, gamma-secretase component). Auraptene increased the activity of gamma-secretase but not that of alpha- and beta-secretase. Furthermore, auraptene enhanced gamma-secretase mediated production of Abeta from AbetaPP or AbetaPP-C99, but not through alpha- and beta-secretase. Auraptene also phosphorylated c-Jun N-terminal kinase (JNK), and pretreatment with the JNK inhibitor, SP600125, reduced auraptene-induced gamma-secretase activity. Overall, our results suggest that auraptene-mediated activation of JNK may contribute to the production of Abeta by promoting gamma secretase activity. PMID- 25147118 TI - Synaptic change in the posterior cingulate gyrus in the progression of Alzheimer's disease. AB - Mild cognitive impairment (MCI) is considered to be an early stage in the progression of Alzheimer's disease (AD) providing an opportunity to investigate brain pathogenesis prior to the onset of dementia. Neuroimaging studies have identified the posterior cingulate gyrus (PostC) as a cortical region affected early in the onset of AD. This association cortex is involved in a variety of different cognitive tasks and is intimately connected with the hippocampal/entorhinal cortex region, a component of the medial temporal memory circuit that displays early AD pathology. We quantified the total number of synapses in lamina 3 of the PostC using unbiased stereology coupled with electron microscopy from short postmortem autopsy tissue harvested from cases at different stage of AD progression. Individuals in the early stages of AD showed a significant decline in synaptic numbers compared to individuals with no cognitive impairment (NCI). Subjects with MCI exhibited synaptic numbers that were between the AD and NCI cohorts. Adjacent tissue was evaluated for changes in both pre and postsynaptic proteins levels. Individuals with MCI demonstrated a significant loss in presynaptic markers synapsin-1 and synaptophysin and postsynaptic markers PSD-95 and SAP-97. Levels of [3H]PiB binding was significantly increased in MCI and AD and correlated strongly with levels of synaptic proteins. All synaptic markers showed a significant association with Mini-Mental Status Examination scores. These results support the idea that the PostC synaptic function is affected during the prodromal stage of the disease and may underlie some of the early clinical sequelae associated with AD. PMID- 25147120 TI - The role of endocannabinoid signaling in the molecular mechanisms of neurodegeneration in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of progressive neurodegenerative disease characterized by cognitive impairment and mental disorders. The actual cause and cascade of events in the progression of this pathology is not fully determined. AD is multifaceted in nature and is linked to different multiple mechanisms in the brain. This aspect is related to the lack of efficacious therapies that could slow down or hinder the disease onset/progression. The ideal treatment for AD should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway. Recently, the endocannabinoid system emerged as a novel potential therapeutic target to treat AD. In fact, exogenous and endogenous cannabinoids seem to be able to modulate multiple processes in AD, although the mechanisms that are involved are not fully elucidated. This review provides an update of this area. In this review, we recapitulate the role of endocannabinoid signaling in AD and the probable mechanisms through which modulators of the endocannabinoid system provide their effects, thus highlighting how this target might provide more advantages over other therapeutic targets. PMID- 25147121 TI - Reply: To PMID 24797101. PMID- 25147122 TI - [History of aesthetic rhinoplasty]. AB - One of the first surgical procedures described in the history of medicine is reconstructive surgery of the nose. Over the centuries, surgeons have developed techniques aimed at reconstructing noses amputated or traumatized by disease. The concept of aesthetic rhinoplasty was only introduced at the end of the 19th century. Since then, techniques have evolved toward constant ameliorations. Nowadays, this surgery is one of the most performed aesthetic procedures. Current technical sophistication is the result of over a century of history marked by many surgeons. All of these techniques derive from a detailed understanding of the anatomical nose from the surgical and artistic point of view. PMID- 25147123 TI - [Lactation after breast plastic surgery: literature review]. AB - The occurrence of lactation is a rare complication of breast plastic surgery. During the course of his practice, the plastic surgeon will probably encounter this complication. The goal of this article is to carry out a literature review of all published galactorrhea and/or galactocele cases following a breast reduction or a breast-augmentation, representing a total of 34 cases reported in 21 articles. The physiopathology of this complication is linked to an inappropriate secretion of prolactin in a surgical context. The factors favoring this complication would be the number of pregnancies, a history of recent and extensive nursing, and the intake of certain medicines such as an oestro progestative pill. The main symptom of this complication is the occurrence of a uni- or bilateral galactorrhea, on average 12.6 days after the surgery. The main differential diagnosis is a postoperative infection. The explorations presented a hyperprolactinemia in 69% of cases. No biological inflammatory syndrome was reported. A fluid collection evoking a galactocele was visible on the ultrasound in 65% of cases. One case of prolactin-secreting pituitary adenoma was reported. Depending on the case, the treatment varied from a simple surveillance to the association of a dopamine agonist, an antibiotic therapy, and a surgical revision. A diagnostic and therapeutic management strategy is proposed. PMID- 25147124 TI - Acetylcholinesterase biosensor based on multi-walled carbon nanotubes-SnO2 chitosan nanocomposite. AB - A sensitive amperometric acetylcholinesterase (AChE) biosensor was developed based on the nanocomposite of multi-walled carbon nanotubes (MWCNTs), tin oxide (SnO2) nanoparticles and chitosan (CHIT). Acetylcholinesterase (AChE) and Nafion were immobilized onto the nanocomposite film to prepare AChE biosensor for pesticide residues detection. The morphologies and electrochemistry properties of the surface modification were investigated using cyclic voltammetry, differential pulse voltammetry, and scanning electron microscopy, respectively. Compared with individual MWCNTs-CHIT, SnO2-CHIT and bare gold electrode, this nanocomposite showed the most obvious electrochemical signal in the presence of [Fe(CN)6](3-/4 ) as a redox couple. Incorporating MWCNTs and SnO2 into 0.2% CHIT solution can promote electron transfer, enhance the electrochemical response, and improve the microarchitecture of the electrode surface. All variables involved in the preparation process and analytical performance of the biosensor were optimized. Under optimized conditions, the AChE biosensor exhibited a wide linear range from 0.05 to 1.0 * 10(5 )MUg/L and with a detection limit for chlorpyrifos was 0.05 MUg/L. Based on the inhibition of pesticides on the AChE activity, using chlorpyrifos as model pesticide, the proposed biosensor exhibited a wide range, low detection limit, good reproducibility, and high stability. Using cabbages, lettuces, leeks, and pakchois as model samples, acceptable recovery of 98.7 105.2% was obtained. The proposed method was proven to be a feasible quantitative method for chlorpyrifos analysis, which may open a new door ultrasensitive detection of chlorpyrifos residues in vegetables and fruits. PMID- 25147125 TI - Water with food intake does not influence caloric intake after gastric bypass (GBP): a cross-over trial. AB - BACKGROUND: Bariatric patients seeking information meet very different recommendations on postoperative diet and eating behaviour. A reason for variability may be lack of hard evidence. A national survey on current dietary advice was conducted to serve as background for the present study on how drinking during a meal influenced caloric consumption. METHODS: A standardised questionnaire was sent to all units in the Scandinavian Obesity surgery registry (SOReg) in order to obtain information regarding current diet advice after gastric bypass. Twenty-eight patients, 14 in each group, were studied either 2 months or 1 year after a standard gastric bypass (GBP). A standardised lunch was served on two separate days with or without water in randomised order. Meal and water weights were measured before and after. Hunger/satiety scores were obtained using visual analogue scales. RESULTS: Response rate for surgeons was low, for dieticians 75 %. No clear consensus for liquid intake during meals was found; few surgeons advised patients whether or not to drink with meals. All patients ate to full satiety. Two months post-GBP, 7/14 patients consumed more solid food when allowed drinking water; the increase in caloric consumption was not significant. One year post-GBP, 5/14 patients consumed more solid food when allowed drinking water, the difference not reaching statistical significance. CONCLUSION: Our study does not indicate that patients should refrain from drinking during meals the first year after a GBP, at least not from a caloric intake point of view. PMID- 25147126 TI - Biosecurity on Finnish cattle, pig and sheep farms - results from a questionnaire. AB - Biosecurity is important in order to prevent disease transmission between animals on farms as well as from farm to farm. Personal biosecurity routines such as hand washing and the use of protective clothing and footwear are measures that should be used at all farms. Other measures are for example related to purchasing new animals to the farm. A questionnaire-based survey was undertaken to study the frequency of use of different biosecurity measures on cattle, pig and sheep farms in Finland. Information about which biosecurity measures are in use is needed for contingency planning of emerging diseases or when combating endemic diseases. Knowledge about the level of biosecurity of a farm is also needed in order to assess if and where improvement is needed. Information regarding biosecurity levels may benefit future animal disease risk assessments. A total of 2242 farmers responded to the questionnaire resulting in a response rate of 45%. The implementation frequencies of different biosecurity measures are reported. The results revealed differences between species: large pig farms had a better biosecurity level than small cattle farms. There were also differences between production types such as dairy farming versus beef cattle farming, but these were not as remarkable. Sheep farming in Finland is sparse and the large number of hobby farmers keeps the biosecurity level low on sheep farms. This might represent a risk for the entire sheep farming industry. The Finnish farmers were satisfied with their on-farm biosecurity. Eighty percent of the farmers report that they were satisfied even though the biosecurity level was not particularly high. The implementation of biosecurity measures could be further improved. Even though the disease situation in Finland is good today, one must be prepared for possible epidemics of threatening diseases. PMID- 25147129 TI - Wanting to Get More or Protecting One's Assets: Age-Differential Effects of Gain Versus Loss Perceptions on the Willingness to Engage in Collective Action. AB - OBJECTIVES: The present research examined motivational differences across adulthood that might contribute to age-related differences in the willingness to engage in collective action. Two experiments addressed the role of gain and loss orientation for age-related differences in the willingness to engage in collective action across adulthood. METHOD: In Experiment 1, N = 169 adults (20 85 years) were confronted with a hypothetical scenario that involved either an impending increase or decrease of health insurance costs for their respective age group. In Experiment 2, N = 231 adults (18-83 years) were asked to list an advantage or disadvantage they perceived in being a member of their age group. Subsequently, participants indicated their willingness to engage in collective action on behalf of their age group. RESULTS: Both experiments suggest that, with increasing age, people are more willing to engage in collective action when they are confronted with the prospect of loss or a disadvantage. DISCUSSION: The findings highlight the role of motivational processes for involvement in collective action across adulthood. With increasing age, (anticipated) loss or perceived disadvantages become more important for the willingness to participate in collective action. PMID- 25147130 TI - Anonymization of DICOM electronic medical records for radiation therapy. AB - Electronic medical records (EMR) and treatment plans are used in research on patient outcomes and radiation effects. In many situations researchers must remove protected health information (PHI) from EMRs. The literature contains several studies describing the anonymization of generic Digital Imaging and Communication in Medicine (DICOM) files and DICOM image sets but no publications were found that discuss the anonymization of DICOM radiation therapy plans, a key component of an EMR in a cancer clinic. In addition to this we were unable to find a commercial software tool that met the minimum requirements for anonymization and preservation of data integrity for radiation therapy research. The purpose of this study was to develop a prototype software code to meet the requirements for the anonymization of radiation therapy treatment plans and to develop a way to validate that code and demonstrate that it properly anonymized treatment plans and preserved data integrity. We extended an open-source code to process all relevant PHI and to allow for the automatic anonymization of multiple EMRs. The prototype code successfully anonymized multiple treatment plans in less than 1min/patient. We also tested commercial optical character recognition (OCR) algorithms for the detection of burned-in text on the images, but they were unable to reliably recognize text. In addition, we developed and tested an image filtering algorithm that allowed us to isolate and redact alpha-numeric text from a test radiograph. Validation tests verified that PHI was anonymized and data integrity, such as the relationship between DICOM unique identifiers (UID) was preserved. PMID- 25147131 TI - An in silico case study of idiopathic dilated cardiomyopathy via a multi-scale model of the cardiovascular system. AB - Mathematical modelling has been used to comprehend the pathology and the assessment of different treatment techniques such as heart failure and left ventricular assist device therapy in the cardiovascular field. In this study, an in-silico model of the heart is developed to understand the effects of idiopathic dilated cardiomyopathy (IDC) as a pathological scenario, with mechanisms described at the cellular, protein and organ levels. This model includes the right and left atria and ventricles, as well as the systemic and pulmonary arteries and veins. First, a multi-scale model of the whole heart is simulated for healthy conditions. Subsequently, the model is modified at its microscopic and macroscopic spatial scale to obtain the characteristics of IDC. The extracellular calcium concentration, the binding affinity of calcium binding proteins and the maximum and minimum elastances have been identified as key parameters across all relevant scales. The modified parameters cause a change in (a) intracellular calcium concentration characterising cellular properties, such as calcium channel currents or the action potential, (b) the proteins being involved in the sliding filament mechanism and the proportion of the attached crossbridges at the protein level, as well as (c) the pressure and volume values at the organ level. This model allows to obtain insight and understanding of the effects of the treatment techniques, from a physiological and biological point of view. PMID- 25147132 TI - A multitasking vanadium-dependent chloroperoxidase as an inspiration for the chemical synthesis of the merochlorins. AB - The vanadium-dependent chloroperoxidase Mcl24 was discovered to mediate a complex series of unprecedented transformations in the biosynthesis of the merochlorin meroterpenoid antibiotics. In particular, a site-selective naphthol chlorination is followed by an oxidative dearomatization/terpene cyclization sequence to build up the stereochemically complex carbon framework of the merochlorins in one step. Inspired by the enzyme reactivity, a chemical chlorination protocol paralleling the biocatalytic process was developed. These chemical studies led to the identification of previously overlooked merochlorin natural products. PMID- 25147133 TI - A method for monitoring enamel erosion using laser irradiated surfaces and optical coherence tomography. AB - INTRODUCTION: Since optical coherence tomography (OCT) is well suited for measuring small dimensional changes on tooth surfaces, OCT has great potential for monitoring tooth erosion. Previous studies have shown that enamel areas ablated by a carbon dioxide laser manifested lower rates of erosion compared to the non-ablated areas. The purpose of this study was to develop a model to monitor erosion in vitro that could potentially be used in vivo. METHODS: Thirteen bovine enamel blocks were used in this in vitro study. Each 10 mm * 2 mm block was partitioned into five regions, the central region was unprotected, the adjacent windows were irradiated by a CO2 laser operating at 9.3 um with a fluence of 2.4 J/cm(2) , and the outermost windows were coated with acid resistant varnish. The samples were exposed to a pH cycling regimen that caused both erosion and subsurface demineralization for 2, 4 and 6 days. The surfaces were scanned using a time-domain polarization sensitive optical coherence tomography (PS-OCT) system and the degree of surface loss (erosion) and the integrated reflectivity with lesion depth was calculated for each window. RESULTS: There was a large and significant reduction in the depth of surface loss (erosion) and the severity of demineralization in the areas irradiated by the laser. CONCLUSION: Irradiation of the enamel surface with a pulsed carbon dioxide laser at sub-ablative intensities results in significant inhibition of erosion and demineralization under the acid challenge employed in this study. In addition, these results suggest that it may be feasible to modify regions of the enamel surface using the laser to serve as reference marks to monitor the rate of erosion in vivo. PMID- 25147134 TI - Biofilm-eradicating properties of quaternary ammonium amphiphiles: simple mimics of antimicrobial peptides. AB - Bacterial biofilms are difficult to eradicate because of reduced antibiotic sensitivity and altered metabolic processes; thus, the development of new approaches to biofilm eradication is urgently needed. Antimicrobial peptides (AMPs) and quaternary ammonium cations (QACs) are distinct, yet well-known, classes of antibacterial compounds. By mapping the general regions of charge and hydrophobicity of QACs onto AMP structures, we designed a small library of QACs to serve as simple AMP mimics. In order to explore the role that cationic charge plays in biofilm eradication, structures were varied with respect to cationic character, distribution of charge, and alkyl side chain. The reported compounds possess minimum biofilm eradication concentrations (MBEC) as low as 25 MUM against Gram-positive biofilms, making them the most active anti-biofilm structures reported to date. These potent AMP mimics were synthesized in 1-2 steps and hint at the minimal structural requirements for biofilm destruction. PMID- 25147135 TI - FoodSwitch: A Mobile Phone App to Enable Consumers to Make Healthier Food Choices and Crowdsourcing of National Food Composition Data. AB - BACKGROUND: Front-of-pack nutrition labeling (FoPL) schemes can help consumers understand the nutritional content of foods and may aid healthier food choices. However, most packaged foods in Australia carry no easily interpretable FoPL, and no standard FoPL system has yet been mandated. About two thirds of Australians now own a smartphone. OBJECTIVE: We sought to develop a mobile phone app that would provide consumers with easy-to-understand nutrition information and support the selection of healthier choices when shopping for food. METHODS: An existing branded food database including 17,000 Australian packaged foods underpinned the project. An iterative process of development, review, and testing was undertaken to define a user interface that could deliver nutritional information. A parallel process identified the best approach to rank foods based on nutritional content, so that healthier alternative products could be recommended. RESULTS: Barcode scanning technology was identified as the optimal mechanism for interaction of the mobile phone with the food database. Traffic light labels were chosen as the preferred format for presenting nutritional information, and the Food Standards Australia New Zealand nutrient profiling method as the best strategy for identifying healthier products. The resulting FoodSwitch mobile phone app was launched in Australia in January 2012 and was downloaded by about 400,000 users in the first 18 months. FoodSwitch has maintained a 4-plus star rating, and more than 2000 users have provided feedback about the functionality. Nutritional information for more than 30,000 additional products has been obtained from users through a crowdsourcing function integrated within the app. CONCLUSIONS: FoodSwitch has empowered Australian consumers seeking to make better food choices. In parallel, the huge volume of crowdsourced data has provided a novel means for low-cost, real-time tracking of the nutritional composition of Australian foods. There appears to be significant opportunity for this approach in many other countries. PMID- 25147136 TI - Effect of low estrogen on neurons in the preoptic area of hypothalamus of ovariectomized rats. AB - The purpose of this study was to investigate the difference in neuronal activity in the preoptic area of the hypothalamus (POAH) under low estrogen condition induced by ovariectomy. One hundred and twenty sham-operated (SHAM) and ovariectomized (OVX) rats were placed in different temperatures for 2h. Twelve rats from each group were stimulated by 4 degrees C, 10 degrees C, 25 degrees C, 33 degrees C and 38 degrees C, respectively. c-Fos expression in the POAH was detected by immunohistochemistry. Following exposure to warm and cold stimuli, there were markedly lower c-Fos-positive cell densities in the OVX group compared with the SHAM group in the median preoptic nucleus (MnPO) at 4 degrees C, 10 degrees C, 33 degrees C and 38 degrees C, in the medial preoptic area (MPA) at 25 degrees C and 38 degrees C, in the ventromedial preoptic nucleus (VMPO) at 4 degrees C, 10 degrees C and 38 degrees C and in the ventrolateral preoptic nucleus (VLPO) at 4 degrees C and 38 degrees C. Both temperature and surgery had an impact on c-Fos expression by two-way ANOVA method except in the lateral preoptic area (LPO). c-Fos expression differed within different nuclei of the two groups in the same and different temperature stimuli. This indicated that the temperature-sensitive nuclei in the POAH exhibited lower and different activities during temperature stimuli following ovariectomy, which possibly resulted in abnormal thermoregulation and menopausal symptoms. PMID- 25147137 TI - The relationship between perceived emotional intelligence and depressive symptomatology: the mediating role of perceived stress. AB - This study investigated the mediating role of perceived stress in the relationship between perceived emotional intelligence and depressive symptoms in adolescence. A total of 661 high school Spanish students participated in the study. The analyses indicated that the effects of each of the perceived emotional intelligence sub-scales (namely, Attention, Clarity and Repair) on depressive symptomatology were partially mediated by perceived stress. Specifically, the mediating effect was negative for Clarity and Repair, but positive for attention. The analysis also showed that the direct effects were positive for all sub scales. These results suggest that the promotion of stress management skills may be core in the development of prevention and treatment programs for depression in adolescents, and possibly more beneficial than the promotion of emotion regulation skills. Our findings, along with previous evidence, suggest that emotional attention, as measured in the present study, may be targeting a pathological type of attention. PMID- 25147138 TI - Emotion regulation in first episode adolescent non-suicidal self-injury: what difference does a year make? AB - We examined the roles of cognitive reappraisal, expressive suppression, and rumination in first episode non-suicidal self-injury (NSSI) among adolescents, and the impact of age-related differences in emotion regulation use. Adverse life events and psychological distress played a significant role in NSSI onset. Being male and less use of cognitive reappraisal contributed to NSSI risk but only in regard to 12-month incidence; this effect was not observed when predicting 24 month incidence. Neither expressive suppression nor rumination was related to NSSI onset in our sample. Age-related differences in emotion regulation were found, but did not modify the above relationships. Findings hint at the possible impact of developmental changes in adolescents' cognitive-emotional processing and their subsequent risk of NSSI. Results support further investigation into prevention and early intervention initiatives aimed at assisting adolescents cope with acute life stressors to prevent/delay first episode NSSI. PMID- 25147139 TI - Mild cognitive impairment and Parkinson's disease--something to remember. AB - Cognitive impairment is common in Parkinson's disease (PD), and many patients will eventually develop a dementia, which has a devastating impact on the patient and their family. As such, there has been much interest in identifying a prodromal state to inform prognosis and facilitate earlier management, similar to the concept of 'MCI' in the Alzheimer's field. However, grouping the early cognitive deficits of PD together as 'PD-MCI' may not be the best way forward as it implies a single aetiological basis with one clinical consequence. In this review, we argue that cognitive deficits in PD arise from a number of different pathological pathways, only some of which herald a dementing process. This has important implications both for treatment of individual patients, and for the design of future disease-modifying therapy trials. PMID- 25147140 TI - The significance of walking from the perspective of people with Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is associated with progressive mobility and walking difficulties. Although these aspects have been found to be central from a patient perspective, the perceived significance of walking is less well understood. OBJECTIVE: To explore the significance of walking as perceived and experienced by individuals with PD. METHODS: Eleven persons with PD (seven men; median age, 71 years; median PD duration, 7 years) participated. Data were collected through semi-structured interviews, which were recorded and transcribed verbatim. Data were qualitatively analysed by systematic text condensation. RESULTS: The ability to walk had a complex and multifaceted impact on the participants, including physical, psychological and emotional aspects as well as on the ability to be active in daily life and to participate in society. The central role of coping strategies was prominent in filtering emotional reactions to physical changes, and when managing the activities and participation in everyday situations. The sense of unpredictability, uncertainty and loss of control were underlying phenomena in all categories. Furthermore, inability to manage walking difficulties had a negative impact on the participants' self concept. CONCLUSIONS: The central meaning of being able to walk appears to be intimately linked to an individual's social identity, emotional well-being and integrity. Consequently, being able to walk independently was a prerequisite to an autonomous life and participation in society. This implies that rehabilitation and other mobility interventions also need to consider individual emotional, psychological, and social implications, and to facilitate appropriate compensatory and coping strategies. PMID- 25147141 TI - Synthesis and biological evaluation of hydroxycinnamic acid hydrazide derivatives as inducer of caspase-3. AB - In order to generate compounds with superior antitumor activity and reduced toxicity, twelve new hydroxycinnamic acid hydrazide derivatives were synthesized and evaluated for their antiproliferative activities against two cancer cell lines (H1299 lung carcinoma cells and MCF-7 breast cancer cells), and compared to two normal counterparts (NL-20 lung epithelial cells and H184B5F5/M10 breast cells) by MTT method. The results demonstrated that some of these compounds possessed good antiproliferative activity against the two cancer cell lines. Among them, compound 2c was active against the growth of H1299 lung carcinoma cells with IC50 values of 1.50 MUM, which was more active than the positive topotecan (IC50 = 4.18 MUM). Simultaneously, it showed lower cytotoxic effects on normal NL-20 lung epithelial cells (IC50 > 10 MUM). Mechanism studies indicated that it induced cell cycle arrest at G2/M phase followed by activation of caspase 3, and consequently caused the cell death. Further studies on the structure optimization are ongoing. PMID- 25147143 TI - Waiting for Merlot: anticipatory consumption of experiential and material purchases. AB - Experiential purchases (money spent on doing) tend to provide more enduring happiness than material purchases (money spent on having). Although most research comparing these two types of purchases has focused on their downstream hedonic consequences, the present research investigated hedonic differences that occur before consumption. We argue that waiting for experiences tends to be more positive than waiting for possessions. Four studies demonstrate that people derive more happiness from the anticipation of experiential purchases and that waiting for an experience tends to be more pleasurable and exciting than waiting to receive a material good. We found these effects in studies using questionnaires involving a variety of actual planned purchases, in a large-scale experience-sampling study, and in an archival analysis of news stories about people waiting in line to make a purchase. Consumers derive value from anticipation, and that value tends to be greater for experiential than for material purchases. PMID- 25147142 TI - Biological activities of green silver nanoparticles synthesized with Acorous calamus rhizome extract. AB - Nanomedicine utilize biocompatible nanomaterials for diagnostic and therapeutic purposes. This study reports the synthesis of silver nanoparticles using aqueous rhizome extract of Acorus calamus (ACRE) and evaluation of antioxidant, antibacterial as well as anticancer effects of synthesized A. calamus silver nanoparticles (ACAgNPs). The formation of ACAgNPs was confirmed by UV-visible spectroscopy and their average size was found to be 31.83 nm by DLS particle size analyzer. Scanning electron micrograph (SEM) revealed spherical shape of ACAgNPs and energy dispersive spectroscopy (EDX) data showed the presence of metallic silver. Fourier transform infrared spectroscopy (FTIR) analysis indicated the presence of phenol/alcohol, aromatic amine and carbonyl groups in ACRE that were involved in reduction and capping of nanoparticles. ACRE and ACAgNPs exhibited substantial free radical quenching ability in various in vitro antioxidant assays performed in this study. ACAgNPs also displayed appreciable antibacterial activity against three different pathogenic bacteria and the growth kinetic study with Escherichia coli designated the inhibition of bacterial growth at the log phase. The cytotoxic effect of ACAgNPs was assessed by MTT assay in HeLa and A549 cells. The IC50 value of ACAgNPs respectively after 24 and 48 h was found to be 92.48 and 69.44 MUg/ml in HeLa cells and in A549 cells it was 53.2 and 32.1 MUg/ml. Apoptotic cell death in ACAgNPs treated cells was indicated by acridine orange/ethidium bromide (AO/EB) and annexinV-Cy3 staining techniques. Staining with propidium iodide (PI) and 4', 6-diamidino-2-phenylindole, dihydrochloride (DAPI) also confirmed nuclear changes such as condensation and fragmentation. Further, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed distribution of ACAgNPs treated cells in the late apoptotic stage. These findings emphasize that such biocompatible green nanoparticles with multifaceted biological activities may find their applications in the field of nanomedicine. PMID- 25147144 TI - Gerontology in Five Images. AB - In his Kent Award lecture, Scott Bass called for a greater coherence of gerontology. This article proposes that the teaching of gerontology is one way to address the centrifugal tendencies of the field and economize its disciplinary sprawl. The instructional strategy is to concentrate attention to a limited number of focal visuals from which the exposition of gerontological knowledge can radiate out and to which it can circle back. The 5 images selected here synthesize numerous ideas about life course; senescence, development, and interventions in these processes; the long gestation of relative health and illness; the succession of cohorts and social change; and the question of preparing for and managing the uncertainties of adult life. The 5 pictures and charts show some common features, such as lifelong flows of time and a recurring arc-like shape that is used to depict them. A sixth image is suggested in order to counter the impression that aging is a process of diminishment. Most knowledge about aging is rooted in a core discipline, but the teaching of that knowledge beyond the discipline can integrate content in fruitful ways. PMID- 25147145 TI - Synthesis and anticancer activity of (E)-2-benzothiazole hydrazones. AB - Benzothiazole hydrazones have been synthesized and evaluated for their in vitro antiproliferative activity against three human cancer cell lines: HL-60 (leukemia), MDAMB-435 (breast) and HCT-8 (colon). The good cytotoxicity for the three cancer cell lines and theoretical profile of compounds 3o and 3p pointed them as promising lead molecules for anticancer drug design. PMID- 25147146 TI - 2-Pyridyl thiazoles as novel anti-Trypanosoma cruzi agents: structural design, synthesis and pharmacological evaluation. AB - The present work reports on the synthesis, anti-Trypanosoma cruzi activities and docking studies of a novel series of 2-(pyridin-2-yl)-1,3-thiazoles derived from 2-pyridine thiosemicarbazone. The majority of these compounds are potent cruzain inhibitors and showed excellent inhibition on the trypomastigote form of the parasite, and the resulting structure-activity relationships are discussed. Together, these data present a novel series of thiazolyl hydrazones with potential effects against Chagas disease and they could be important leads in continuing development against Chagas disease. PMID- 25147147 TI - Identification and pharmacological characterization of 3,6 diazabicyclo[3.1.1]heptane-3-carboxamides as novel ligands for the alpha4beta2 and alpha6/alpha3beta2beta3 nicotinic acetylcholine receptors (nAChRs). AB - We have synthesized a novel series of compounds, 3,6-diazabicyclo[3.1.1]heptane-3 carboxamides, targeting both the alpha4beta2 and alpha6/alpha3beta2beta3 nAChRs. Members of the obtained chemical library are partial or full agonists at both the high sensitivity (alpha4)2(beta2)3 and alpha6/alpha3beta2beta3 nAChRs. 3 (Cyclopropylcarbonyl)-3,6-diazabicyclo[3.1.1]heptane (TC-8831 or compound 7 herein) demonstrated a safe in vitro pharmacological profile and the potential for reducing or preventing L-dopa-induced dyskinesias (LID) in several in vivo animal models [1-4]. In vivo metabolism studies in rat and in vitro metabolism studies in liver microsomes from human, rat, dog and monkey showed TC-8831 to be relatively stable. In vivo pharmacokinetic analysis in the rat confirmed brain penetration, with an average brain:plasma ratio of approximately 0.3 across time points from 0.5 to 4 h. Docking into homology models predicted alternative binding modes for TC-8831 and highlighted the importance of the cationic center, hydrogen-bond acceptor, and hydrophobic aliphatic features in promoting binding affinity to both nAChRs. Pharmacophore elucidation confirmed the importance of these key interactions. QSAR modeling suggested that binding affinity is primarily driven by ligand shape, relative positive charge distribution onto the molecular surface, and molecular flexibility. Of the two subtypes, ligand binding to alpha6beta2beta3 appears to be more sensitive to bulkiness and flexibility. PMID- 25147148 TI - Synthesis of novel 1,2,4-triazoles, triazolothiadiazines and triazolothiadiazoles as potential anticancer agents. AB - A series of new N-substituted-3-mercapto-1,2,4-triazoles (3a,b and 7a-d), triazolo[1,3,4]thiadiazines (5a,b) and triazolo[1,3,4]thiadiazoles (4a-d, 6 and 8a-d) have been synthesized starting from isonicotinic acid hydrazide. The structure of the newly synthesized compounds was confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against 6 human cancer cell lines and normal fibroblasts. Seven of the tested compounds (3a,b, 4c, 5a and 8b-d) exhibited significant cytotoxicity against most cell lines. Among these derivatives compound 4c exhibited equivalent cytotoxic effect to the standard CHS 828 against gastric cancer cell line (IC50 = 25 nM). Normal fibroblast cells (WI38) were affected to a much lesser extent (IC50 > 10,000 nM). PMID- 25147149 TI - Highly potent anti-proliferative effects of a gallium(III) complex with 7 chloroquinoline thiosemicarbazone as a ligand: synthesis, cytotoxic and antimalarial evaluation. AB - A gallium(III) complex with 7-chloroquinoline thiosemicarbazone was synthesized and characterized. The complex proved to be thirty-one times more potent on colon cancer cell line, HCT-116, with considerably less cytotoxicity on non-cancerous colon fibroblast, CCD-18Co, when compared to etoposide. Its anti-malarial potential on 3D7 isolate of Plasmodium falciparum was better than lumefantrine. PMID- 25147150 TI - Design, synthesis, and fungicidal evaluation of a series of novel 5-methyl-1H 1,2,3-trizole-4-carboxyl amide and ester analogues. AB - Succinate dehydrogenase inhibitors (SDHIs) are efficient fungicides that are widely used to control plant diseases caused by phytopathogenic fungi, although their effectiveness is undermined by the development of resistance across a range of different fungi. One of the most common structural features of SDHIs is their amide bond. The introduction of greater structural diversity to SDHIs is a promising strategy to delay the onset of resistance. A series of novel SDHIs containing a bioactive 1,2,3-triazole moiety have been designed and synthesized and their fungicidal and insecticidal activities evaluated. The results of these analyses show that most of the newly synthesized 1,2,3-trizole-4-carboxyl amide (ester) analogues exhibit good fungicidal activities, especially towards Sclerotinia sclerotiorum, and a structure-activity relationship study confirmed that the replacement of the amide group with an ester group had little effect on fungicidal activity, which could be provideous in terms of issues and metabolism. 1,6-Dimethyl phenyl was confirmed as the most efficient substituent of the current study when it was placed on both the amide and ester compounds. Interestingly, some of the newly synthesized compounds displayed good insecticidal activities against Culex pipiens pallens. The results of the current study show that these 1,2,3-triazole-4-carboxyl amide and ester analogues represent a new type of SDHI that could be used for the development of novel pesticides. PMID- 25147151 TI - Sulfamates of methyl triterpenoates are effective and competitive inhibitors of carbonic anhydrase II. AB - Carbonic anhydrase II, belonging to one of the most important enzyme groups of the human body, is a well-studied isozyme from the family of the carbonic anhydrases. Since it is involved in several physiological processes, it has been a pharmaceutical target for many years. In this study we synthesized a number of sulfamates derived from pentacyclic methyl triterpenoates, and we demonstrate their potential as carbonic anhydrase II inhibitors using the well-established photometric 4-nitrophenyl acetate assay. Inhibition constants, as an indicator of their inhibition strength, were in the micromolar range; one compound (10, methyl (3beta) 3-(aminosulfonyloxy)-oleanoate) showed a Ki value as low as 0.3 MUM. This Ki value is comparable to that of acetazolamide which is a potent carbonic anhydrase inhibitor and a drug for the treatment of glaucoma. PMID- 25147152 TI - Kaempferol, a potential cytostatic and cure for inflammatory disorders. AB - Kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a flavonoid found in many edible plants (e.g., tea, broccoli, cabbage, kale, beans, endive, leek, tomato, strawberries, and grapes) and in plants or botanical products commonly used in traditional medicine (e.g., Ginkgo biloba, Tilia spp, Equisetum spp, Moringa oleifera, Sophora japonica and propolis). Its anti oxidant/anti-inflammatory effects have been demonstrated in various disease models, including those for encephalomyelitis, diabetes, asthma, and carcinogenesis. Moreover, kaempferol act as a scavenger of free radicals and superoxide radicals as well as preserve the activity of various anti-oxidant enzymes such as catalase, glutathione peroxidase, and glutathione-S-transferase. The anticancer effect of this flavonoid is mediated through different modes of action, including anti-proliferation, apoptosis induction, cell-cycle arrest, generation of reactive oxygen species (ROS), and anti-metastasis/anti angiogenesis activities. In addition, kaempferol was found to exhibit its anticancer activity through the modulation of multiple molecular targets including p53 and STAT3, through the activation of caspases, and through the generation of ROS. The anti-tumor effects of kaempferol have also been investigated in tumor-bearing mice. The combination of kaempferol and conventional chemotherapeutic drugs produces a greater therapeutic effect than the latter, as well as reduces the toxicity of the latter. In this review, we summarize the anti-oxidant/anti-inflammatory and anticancer effects of kaempferol with a focus on its molecular targets and the possible use of this flavonoid for the treatment of inflammatory diseases and cancer. PMID- 25147153 TI - 1H-1,2,3-triazole tethered mono- and bis-ferrocenylchalcone-beta-lactam conjugates: synthesis and antimalarial evaluation. AB - A series of ferrocenylchalcone-beta-lactam conjugates were synthesized and evaluated against 3D7 (CQ-Sensitive) and W2 (CQ-Resistant) strains of Plasmodium falciparum. The SAR studies revealed the dependence of activities at N-1 substituent of beta-lactam ring with compounds being more potent on resistant strain. The compound 9f and 9l with N-cyclohexyl substituent proved to be the most potent and non-cytotoxic among the series exhibiting IC50 values of 2.36 and 2.43 MUM respectively, against W2 strain of P. falciparum. PMID- 25147154 TI - Design, synthesis and molecular docking study of novel quinoxalin-2(1H)-ones as anti-tumor active agents with inhibition of tyrosine kinase receptor and studying their cyclooxygenase-2 activity. AB - On continuation to our work, new quinoxalin-2(1H)-ones were synthesized to study their cytotoxic effect against HepG-2 and MCF-7 with their effect on the human tyrosine kinase (TRK). Compounds 12, 18, 15, 13, 11a, 20 and 16, respectively, were found to be more potent than cisplatin against HepG2 and selective to TRK. Also, compounds 12, 18, 20, 13, 14, and 22, respectively, exhibited decidedly activity against MCF-7 and selectivity against human TRK compared to cisplatin. A molecular docking study was also performed to gain comprehensive understanding into plausible binding modes and to conclude the structure activity relationships of the synthesized compounds. Moreover, anti-inflammatory activity was studied. Compounds 12, 15, 18 and 22 were found to be potent and selective against COX-2. PMID- 25147155 TI - Effect of increasing dietary fiber on plasma levels of colon-derived solutes in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Numerous uremic solutes are derived from the action of colon microbes. Two such solutes, indoxyl sulfate and p-cresol sulfate, have been associated with adverse outcomes in renal failure. This study tested whether increasing dietary fiber in the form of resistant starch would lower the plasma levels of these solutes in patients on hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fifty-six patients on maintenance hemodialysis were randomly assigned to receive supplements containing resistant starch (n=28) or control starch (n=28) daily for 6 weeks in a study conducted between October 2010 and May 2013. Of these, 40 patients (20 in each group) completed the study and were included in the final analysis. Plasma indoxyl sulfate and p-cresol sulfate levels were measured at baseline and week 6. RESULTS: Increasing dietary fiber for 6 weeks significantly reduced the unbound, free plasma level of indoxyl sulfate (median -29% [25th percentile, 75th percentile, -56, -12] for fiber versus -0.4% [-20, 34] for control, P=0.02). The reduction in free plasma levels of indoxyl sulfate was accompanied by a reduction in free plasma levels of p cresol sulfate (r=0.81, P<0.001). However, the reduction of p-cresol sulfate levels was of lesser magnitude and did not achieve significance (median -28% [ 46, 5] for fiber versus 4% [-28, 36] for control, P=0.05). CONCLUSIONS: Increasing dietary fiber in hemodialysis patients may reduce the plasma levels of the colon-derived solutes indoxyl sulfate and possibly p-cresol sulfate without the need to intensify dialysis treatments. Further studies are required to determine whether such reduction provides clinical benefits. PMID- 25147156 TI - Can oral therapy reduce uremic toxins? PMID- 25147157 TI - The new histopathologic classification of ANCA-associated GN and its association with renal outcomes in childhood. AB - BACKGROUND AND OBJECTIVES: A proposed histopathologic classification for ANCA associated GN is predictive of long-term renal outcome in adult populations. This study sought to validate this system in a pediatric cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective, single-center, cohort study of 40 children diagnosed and followed until their transition to adult care at one institution between 1987 and 2012. Renal biopsy specimens were reviewed by a pathologist blinded to patient outcome and were classified using the new histopathologic classification system of focal, crescentic, mixed, and sclerotic groups. Time to the composite outcome of CKD stages 3 and 4 (determined by eGFR with repeated creatinine measures using the Schwartz equation) or ESRD (defined as dialysis dependence or transplantation) were ascertained. RESULTS: The study population consisted of 40 children (70% female), followed for a median of 2.4 years. The biopsy specimens were categorized as focal in 13 patients (32.5%), crescentic in 20 (50%), mixed in two (5%), and sclerotic in five (12.5%). Mixed and crescentic were combined for analyses. Survival analysis of time to the composite renal endpoint of at least 3 months of eGFR<60 ml/min per 1.73 m(2) or ESRD differed significantly among the three biopsy groups log-rank P<0.001), with an adjusted hazard ratio of 3.14 (95% confidence interval, 0.68 to 14.4) in the crescentic/mixed group and 23.6 (95% confidence interval, 3.9 to 144.2) in the sclerotic category compared with the focal category. The probability of having an eGFR>60 ml/min per 1.73 m(2) at 2 years was 100% for the focal, 56.5% for the crescentic/mixed, and 0% for the sclerotic biopsy categories. CONCLUSIONS: This study showed the clinical utility of this histopathologic classification system and its ability to discriminate renal outcomes among children with ANCA GN. PMID- 25147158 TI - Antineoplastic agents and the associated myelosuppressive effects: a review. AB - Bone marrow is a complex organ responsible for the regulation of hematopoietic cell distribution throughout the human body. Patients receiving antineoplastic agents as a therapeutic intervention for hematologic malignancy often experience varying degrees of myelotoxicity. Antineoplastic agents cause hypocellularity in marrow resulting in a reduction in hematopoietic tissue activity and a corresponding decline in cell production. Quantifying the adverse effects on hematopoiesis is based on the properties of a single agent, the use of individual drugs within a combination chemotherapy regimen, and the course, or courses, of chemotherapy designed to treat cancer. The direct or indirect suppression of erythrocytes, granulocytes, and megakaryocytes has potential for multiple negative clinical consequences ranging from increased monitoring of blood counts to life-threatening infection and death. This review will provide an overview of the structure and function of competent adult bone marrow, describe the process of hematopoiesis, and characterize the myelotoxicities associated with common antineoplastic agents currently used in the treatment of cancer. PMID- 25147159 TI - Evaluating Patients' Understanding of Printed Warfarin Medication Information. AB - OBJECTIVE: Warfarin is a high-risk medication whose safe use may be greatly improved by patient education. This study evaluate evaluated patients' understanding of warfarin instructions, medication management, the Food and Drug Administration's (FDA) warfarin medication guide content, and patient information recommendations. METHODS: Interviews conducted at 2 hospital-based outpatient primary care sites with patients initiated on warfarin therapy within the last year. RESULTS: Interviews were conducted with 49 patients. Seventy percent were between 36 and 64 years old and reported taking between 1 and 18 different medications daily. Many (76%) received information about warfarin when first prescribed to them, 65% written and 60% verbal (answers reflect more than one response). Patients found content in the medication guide difficult to understand; 18% were unable to identify information about diet and 21% were unable to locate information about when to call their provider. Analysis showed that 19% had trouble with numeracy issues related to warfarin. Patients' suggestions of ways to convey warfarin information included more graphics, in person counseling, and multilingual translations. CONCLUSION: This study demonstrates gaps in patients' understanding of warfarin therapy. Relying solely on the information in the FDA medication guide is insufficient to guarantee adequate understanding. Utilizing the suggestions from patients' feedback on other ways to deliver information should help future patients with different learning abilities and styles. PMID- 25147160 TI - Use of DEAD-box polypeptide-4 (Ddx4) gene promoter-driven fluorescent reporter mice to identify mitotically active germ cells in post-natal mouse ovaries. AB - Several laboratories have independently isolated mitotically active germ cells, termed female germline stem cells or oogonial stem cells (OSCs), from adult mouse ovaries. However, a recent study using Ddx4-Cre;Rosa26 reporter mice concluded that such germ cells do not exist. Given the disparity in conclusions drawn in this study compared with others, we felt it was important to re-assess the utility of Ddx4-Cre;Rosa26 reporter mice for identification of OSCs in adult mouse ovaries. Transgenic Ddx4-Cre mice were crossed with Rosa26(tdTm/tdTm) mice to drive restricted tomato red (tdTm) gene expression in cells in which the Ddx4 gene promoter has been activated. Crude dispersion of ovaries from recombined offspring generated cell fractions containing tdTm-positive immature oocytes, which are incapable of proliferation and thus probably represent the uncharacterized reporter-positive ovarian cells identified in the paper Zhang et al. (2012) as being mitotically inactive. Dispersed ovaries further subjected to fluorescence-activated cell sorting yielded a large population of non-germline tdTm-positive cells, indicative of promoter 'leakiness' in the Ddx4-Cre mouse line. Nonetheless, a small percentage of these tdTm-positive cells exhibited externalized (extracellular, ec) expression of Ddx4 protein (ecDdx4-positive), expressed markers of primitive germ cells but not of oocytes, and actively proliferated in culture, all of which are characteristic features of OSCs. Thus, crude dispersion of ovaries collected from Ddx4 gene promoter-driven reporter mice is not, by itself, a reliable approach to identify OSCs, whereas the same ovarian dispersates further subjected to cell sorting strategies yield purified OSCs that can be expanded in culture. PMID- 25147161 TI - Idelalisib approved for three blood cancers. PMID- 25147162 TI - Rosiglitazone REMS restrictions removed. PMID- 25147163 TI - Vaccine safety signal from spontaneous system not supported by active surveillance. PMID- 25147164 TI - Supporting research efforts of residents through annual Resident Research Day. PMID- 25147165 TI - Incompatibility of undiluted busulfan injection with a needle-free valve. PMID- 25147166 TI - Residents' perspectives: weighing your options in pursuing a postgraduate year 2 pharmacy residency. PMID- 25147167 TI - Pomalidomide for the management of refractory multiple myeloma. AB - PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, dosage and administration, and place in therapy of pomalidomide for the management of refractory multiple myeloma are reviewed. SUMMARY: Pomalidomide is a second generation immunomodulatory agent that has been approved by the Food and Drug Administration (FDA) for the management of multiple myeloma refractory to both lenalidomide and bortezomib, with or without the addition of dexamethasone. The overarching mechanism of action is thought to be antiproliferative and directly cytotoxic to malignant plasma cells in the bone marrow. Clinical trials have demonstrated both safety and efficacy with the 4-mg dose given orally on days 1 21 of a 28-day cycle with the possible addition of dexamethasone 40 mg weekly. The most common nonhematologic toxicities found in clinical trials were fatigue, pneumonia, and deep vein thrombosis. The most common hematologic toxicity was neutropenia, which was the only dose-limiting factor of pomalidomide. In order to be able to prescribe and dispense pomalidomide, physicians, patients, and pharmacies must enroll in an FDA-mandated risk evaluation and mitigation strategy program due to the drug's teratogenic effects. Future studies will evaluate the use of pomalidomide with other oncolytic agents, as well as combination regimens with proteasome inhibitors, such as bortezomib, for the management of multiple myeloma. CONCLUSION: Pomalidomide when administered with weekly low-dose dexamethasone appears to be both safe and effective for the treatment of relapsed or refractory multiple myeloma in patients who have had disease progression after completing treatment with bortezomib, lenalidomide, or both. PMID- 25147168 TI - Off-label uses of alvimopan and methylnaltrexone. AB - PURPOSE: Off-label uses of the peripheral MU-opioid receptor antagonists alvimopan and methylnaltrexone are reviewed. SUMMARY: Alvimopan is approved by the Food and Drug Administration (FDA) for postoperative ileus after surgeries that include partial bowel resection with primary anastomosis, while methylnaltrexone is approved for the treatment of opioid-induced constipation (OIC) in patients with advanced illness who are receiving palliative care. Literature describing the off-label use of alvimopan in the treatment of OIC and of methylnaltrexone in postoperative ileus was reviewed and included retrospective studies and prospective Phase II-IV trials. Randomized controlled trials did not demonstrate consistent benefit of alvimopan in OIC nor of methylnaltrexone in postoperative ileus. A greater proportion of patients receiving alvimopan for OIC experienced severe adverse cardiovascular events, leading to a risk evaluation and mitigation strategy and discontinuation of its study in this condition. Data are limited and unreplicated for the off-label use of alvimopan for postoperative ileus in patients undergoing abdominal hysterectomy. Individual studies suggest benefit with methylnaltrexone for OIC in unlabeled populations, including patients with non-cancer-related pain, opioid dependence, opioid sedation, and opioid use after orthopedic surgery; however, confirmatory evaluations have not been performed. CONCLUSION: Trials of alvimopan in the FDA-approved use of methylnaltrexone (OIC) indicate potentially serious cardiovascular safety concerns and conflicting findings of efficacy. Similarly, trials of methylnaltrexone in the FDA-approved use of alvimopan (postoperative ileus) consistently showed no benefit. Evaluations of both drugs in their labeled conditions in populations not endorsed in their product labeling have been limited and largely unreplicated. PMID- 25147169 TI - A case of profound neutropenia and agranulocytosis associated with off-label use of ceftaroline. AB - PURPOSE: A case of profound neutropenia and agranulocytosis associated with the off-label use of ceftaroline is reported. SUMMARY: A 67-year-old Caucasian man arrived at the emergency room with right shoulder pain and weakness that radiated to his right chest, back, and right arm. A review of symptoms was notable for two days of burning with urination associated with decreased urinary output and decreased appetite. Multiple tests revealed the presence of methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis, which was treated with an off label dosage of ceftaroline (600 mg intravenously every eight hours). At the start of ceftaroline therapy, the patient's baseline absolute neutrophil count (ANC) was 6640 cells/MUL and decreased to 816 cells/MUL by day 19, eventually falling to 0 cells/MUL on day 21 of therapy. Ceftaroline was then discontinued due to the suspicion that the neutropenia was secondary to maturation arrest of the bone marrow. The patient was switched to i.v. daptomycin to finish a six-week course of antibiotics. Interventional radiology placed a drain in the patient's right shoulder during the hospital stay, with symptom improvement. His white blood cell count continued to increase after ceftaroline discontinuation, reaching 6.5*10(3) cells/MUL with a differential of 56.6% segmented neutrophils and 28.4% lymphocytes after nine days off of ceftaroline. CONCLUSION: A 67-year old man developed profound neutropenia and agranulocytosis after three weeks of high-dose ceftaroline therapy for the treatment of MRSA septic arthritis. His neutropenia resolved after ceftaroline discontinuation and treatment with an alternative antibiotic. PMID- 25147170 TI - Pseudohyperphosphatemia in children treated with liposomal amphotericin B. AB - PURPOSE: The results of a study to determine the frequency of pseudohyperphosphatemia in a sample of pediatric patients treated with i.v. liposomal amphotericin B are reported. METHODS: A single-site retrospective study was conducted to identify evidence of pseudohyperphosphatemia in the medical records of patients 18 years of age or younger who received at least five doses of amphotericin B liposome; the maximum dose was calculated for each regimen and categorized as either <=5 or >5 mg/kg/day. The primary objective was to ascertain the rate of pseudohyperphosphatemia (i.e., abnormally high serum phosphate without elevated serum calcium). The secondary objective was to compare rates of pseudohyperphosphatemia at the higher and lower amphotericin B dosage levels. A multivariate generalized estimating equation (GEE) regression model was used to identify potential predictors of pseudohyperphosphatemia. RESULTS: Data were collected on 72 courses of amphotericin B liposome administered during a 13-month period to 47 patients; based on a review of chart notations and clinical data, it was determined that 36 regimens (50%) involved pseudohyperphosphatemia. The GEE model revealed no significant association between pseudohyperphosphatemia and any evaluated variable, including age, weight, duration of therapy, and concurrent use of medications known to alter serum phosphorus. CONCLUSION: In children receiving amphotericin B liposome, half of the regimens were associated with pseudohyperphosphatemia. Although no factors were found to predict pseudohyperphosphatemia, on average, patients who developed the abnormality were significantly older and heavier and received a significantly higher absolute initial dosage of amphotericin B liposome than those who did not develop the condition. PMID- 25147171 TI - Effects of a hospitalwide pharmacy practice model change on readmission and return to emergency department rates. AB - PURPOSE: The impact of an innovative medication reconciliation and discharge education program on 30-day readmissions and emergency department (ED) visits was evaluated. METHODS: An observational pre-post analysis was conducted at an academic medical center to compare rates of hospital readmissions and return to ED visits during three-month periods before and after implementation of a restructured pharmacy practice model including (1) medication reconciliation at transitions of care for every patient and discharge education for a high-risk subgroup, (2) new or expanded services in the preanesthesia testing clinic and ED, (3) a medication reconciliation technician team, and (4) pharmacist-to patient ratios of 1:30 on acute care floors and 1:18 on critical care units. The primary outcome was the composite of rates of readmissions and return to ED visits within 30 days of discharge. RESULTS: A total of 3,316 patients were included in the study. Pharmacy teams completed medication reconciliation in 95.8% of cases at admission and 69.7% of cases at discharge. Discharge education was provided to 73.5% of high-risk patients (defined as those receiving anticoagulation therapy or treatment for acute myocardial infarction, chronic obstructive pulmonary disease, congestive heart failure, or pneumonia). No significant difference was observed between the preimplementation and postimplementation groups with regard to the primary outcome. In the high-risk subgroup, there was a significant reduction in the 30-day rate of hospital readmissions, which declined from 17.8% to 12.3% (p=0.042); cost projections indicated that this reduction in readmissions could yield annual direct cost savings of more than $780,000. CONCLUSION: Implementation of a team-based pharmacy practice model resulted in a significant decrease in the rate of 30-day readmissions for high-risk patients. PMID- 25147172 TI - Stability of ertapenem 100 mg/mL in polypropylene syringes stored at 25, 4, and 20 degrees C. AB - PURPOSE: The stability of ertapenem solution in syringes at room, refrigerator, and freezer temperatures was determined to establish options for extended storage. METHODS: Six replicate solutions of ertapenem (100 mg/mL) in 0.9% sodium chloride injection were prepared in 20-mL polypropylene syringes and stored at 25, 4, or -20 degrees C. Syringe samples were collected immediately after preparation and at preselected time points and assayed by a validated high performance liquid chromatography (HPLC) method. The ertapenem solution was considered stable if at least 90% of the mean initial concentration remained at the time of HPLC analysis. RESULTS: The mean+/-S.D. baseline ertapenem concentration across all stability studies was 109.9+/-9.2 mg/mL. One hour after preparation, the mean+/-S.D. ertapenem concentration of samples kept at room temperature was 87.8+/-4.6% of the initial concentration. After 24 and 48 hours of refrigeration, mean+/-S.D. drug concentrations had declined to 93.6+/-5.9% and 86.2+/-4.3% of the respective baseline concentrations. Frozen syringes required 1 hour to thaw at room temperature; after 14 and 28 days of frozen storage, the mean+/-S.D. ertapenem concentrations of these samples 4 hours after thawing were 93.4+/-3.5% and 86.4+/-2.6% of the respective baseline values. CONCLUSION: Ertapenem 100 mg/mL prepared in 20-mL polypropylene syringes was stable at room temperature for approximately 30 minutes. Room-temperature stability was extended to 4 hours after 24 hours of refrigeration. After being frozen for 14 or 28 days, ertapenem was stable for 3-5 hours after removal from the freezer. PMID- 25147173 TI - Economic impact of converting from 10-mL insulin vials to 3-mL vials and pens in a hospital setting. AB - PURPOSE: The economic impact associated with the conversion from 10-mL vials of insulin to 3-mL vials and pens at a community hospital was assessed. METHODS: Pharmacy purchasing and administrative data from Providence St. Vincent Hospital in Portland, Oregon, were used in this analysis. The hospital converted floor stock 10-mL vials of insulin in October 2010 to individual patient supply (IPS) 3 mL vials and pens. Insulin acquisition costs from the nine-month preconversion period were compared with those during the nine-month postconversion period. RESULTS: Before the conversion, total acquisition costs were $168,783 for 5,086,500 units of insulin. After the conversion, total acquisition costs were reduced by 8.6% (to $154,303) and units purchased were reduced by 33.1% (to 3,404,900 units of insulin). The analyses also examined the results of converting to 3-mL vials of rapid-, short-, or intermediate-acting insulin to 3-mL pens of long-acting insulin analog. Conversion from 10- to 3-mL vials was associated with a 37.6% reduction in units of insulin and a 23.5% reduction in acquisition costs. In contrast, switching from 10-mL vials to 3-mL pens was associated with a 10.1% increase in costs, despite the fact that there was a 11.5% reduction in units purchased. CONCLUSION: Conversion from floor-stock 10-mL insulin vials to IPS 3 mL insulin vials or pens reduced the number of units of insulin purchased and expenditures for insulin. The overall cost savings was driven by the conversion from 10- to 3-mL vials, whereas cost increased for the conversion of 10-mL vials to 3-mL pens for long-acting insulin analogs. PMID- 25147174 TI - Using lean methodology to improve productivity in a hospital oncology pharmacy. AB - PURPOSE: Quality improvements achieved by a hospital pharmacy through the use of lean methodology to guide i.v. compounding workflow changes are described. SUMMARY: The outpatient oncology pharmacy of Yale-New Haven Hospital conducted a quality-improvement initiative to identify and implement workflow changes to support a major expansion of chemotherapy services. Applying concepts of lean methodology (i.e., elimination of non-value-added steps and waste in the production process), the pharmacy team performed a failure mode and effects analysis, workflow mapping, and impact analysis; staff pharmacists and pharmacy technicians identified 38 opportunities to decrease waste and increase efficiency. Three workflow processes (order verification, compounding, and delivery) accounted for 24 of 38 recommendations and were targeted for lean process improvements. The workflow was decreased to 14 steps, eliminating 6 non value-added steps, and pharmacy staff resources and schedules were realigned with the streamlined workflow. The time required for pharmacist verification of patient-specific oncology orders was decreased by 33%; the time required for product verification was decreased by 52%. The average medication delivery time was decreased by 47%. The results of baseline and postimplementation time trials indicated a decrease in overall turnaround time to about 70 minutes, compared with a baseline time of about 90 minutes. CONCLUSION: The use of lean methodology to identify non-value-added steps in oncology order processing and the implementation of staff-recommended workflow changes resulted in an overall reduction in the turnaround time per dose. PMID- 25147175 TI - Implementation of standardized pediatric i.v. medication concentrations. AB - PURPOSE: The development and implementation of a comprehensive and standardized list of pediatric i.v. medication concentrations across a large healthcare system are described. SUMMARY: In accordance with National Patient Safety Goals, facilities affiliated with the Hospital Corporation of America system had independently standardized and limited the number of drug concentrations in use. This resulted in variation among facilities, which prevented the systemwide standardization of drug dictionaries within the computerized pharmacy and prescriber-order-entry systems, complicated the movement of providers among facilities, and contributed to inconsistency in medication prescribing. A team of experts collaborated to create a comprehensive standard list that included 119 medications and 372 concentrations for pediatric i.v. medications. Implementation of this standard list was driven through a financial incentive from the malpractice insurance provider; facilities that completed the required activities for this optional program could apply for a credit of a portion of their malpractice insurance cost. For the standardization of pediatric i.v. medications, required activities included approval of the standard medication list, incorporation of this list into facility pharmacy dictionaries, and update of all smart pump software to include only the new standard medications and concentrations. Of the 145 facilities that were eligible for the implementation of standard pediatric i.v. medication concentrations, 141 (97%) completed all requirements and received the 2% malpractice insurance cost credit. CONCLUSION: The use of a financial incentive strategy, in the form of a malpractice insurance credit, successfully motivated the implementation of standardized pediatric medication concentrations across a large healthcare system. PMID- 25147176 TI - A genomic view of the peopling and population structure of India. AB - Recent advances in molecular and statistical genetics have enabled the reconstruction of human history by studying living humans. The ability to sequence and study DNA by calibrating the rate of accumulation of changes with evolutionary time has enabled robust inferences about how humans have evolved. These data indicate that modern humans evolved in Africa about 150,000 years ago and, consistent with paleontological evidence, migrated out of Africa. And through a series of settlements, demographic expansions, and further migrations, they populated the entire world. One of the first waves of migration from Africa was into India. Subsequent, more recent, waves of migration from other parts of the world have resulted in India being a genetic melting pot. Contemporary India has a rich tapestry of cultures and ecologies. There are about 400 tribal groups and more than 4000 groups of castes and subcastes, speaking dialects of 22 recognized languages belonging to four major language families. The contemporary social structure of Indian populations is characterized by endogamy with different degrees of porosity. The social structure, possibly coupled with large ecological heterogeneity, has resulted in considerable genetic diversity and local genetic differences within India. In this essay, we provide genetic evidence of how India may have been peopled, the nature and extent of its genetic diversity, and genetic structure among the extant populations of India. PMID- 25147177 TI - The sexual cascade and the rise of pre-ejaculatory (Darwinian) sexual selection, sex roles, and sexual conflict. AB - After brief historic overviews of sexual selection and sexual conflict, I argue that pre-ejaculatory sexual selection (the form of sexual selection discussed by Darwin) arose at a late stage in an inevitable succession of transitions flowing from the early evolution of syngamy to the evolution of copulation and sex roles. If certain conditions were met, this "sexual cascade" progressed inevitably, if not, sexual strategy remained fixed at a given stage. Prolonged evolutionary history of intense sperm competition/selection under external fertilization preceded the rise of advanced mobility, which generated pre-ejaculatory sexual selection, followed on land by internal fertilization and reduced sperm competition in the form of postcopulatory sexual selection. I develop a prospective model of the early evolution of mobility, which, as Darwin realized, was the catalyst for pre-ejaculatory sexual selection. Stages in the cascade should be regarded as consequential rather than separate phenomena and, as such, invalidate much current opposition to Darwin-Bateman sex roles. Potential for sexual conflict occurs throughout, greatly increasing later in the cascade, reaching its peak under precopulatory sexual selection when sex roles become highly differentiated. PMID- 25147178 TI - A meta-analysis of the use of electronic reminders for patient adherence to medication in chronic disease care. AB - We conducted a meta-analysis of randomized controlled trials (RCTs) up to January 2014 which evaluated the effects of electronic reminders on patient adherence to medication in chronic disease care. A random-effects model was used to pool the outcome data. Subgroup analyses were performed to examine a set of moderators. Data from 20 studies, representing 22 RCTs, were synthesized. Thirteen trials utilized short message service (SMS) reminders, three used pager reminders and six employed electronic alarm device-triggered reminders. The meta-analysis showed that the use of electronic reminders was associated with a significant, yet small, improvement in patient adherence to medication (pooled Cohen's d=0.29, 95% confidence interval 0.18, 0.41). The effect was sensitive to sample size, type of disease and intervention duration. The frequency and type of electronic reminders appeared to have no moderating effect on medication adherence. The use of electronic reminders seems to be a simple and potentially effective way of improving patient adherence to chronic medication. Future research should concern the optimum strategies for the design and implementation of electronic reminders, with which the effectiveness of the reminders is likely to be augmented. PMID- 25147179 TI - The translation initiation factor eIF3i up-regulates vascular endothelial growth factor A, accelerates cell proliferation, and promotes angiogenesis in embryonic development and tumorigenesis. AB - Vascular endothelial growth factor A (VEGFA) is a critical proangiogenic factor that is activated by hypoxia at both the transcriptional and post-transcriptional levels. In hypoxia conditions, stabilized hypoxia-inducible factor 1alpha (HIF1A) is the key regulator for transcriptional activation of VEGFA. However, the post transcriptional control of VEGFA expression remains poorly understood. Here, we report that the eukaryotic translation initiation factor 3i (eIF3i) is required for VEGFA protein expression in both normal embryonic and tumorigenic angiogenesis. eIF3i is dynamically expressed in the early stages of zebrafish embryogenesis and in human hepatocellular carcinoma tissues. eIF3i homozygous mutant zebrafish embryos show severe angiogenesis defects and human hepatocellular cancer cells with depletion of eIF3i to induce less angiogenesis in tumor models. Under hypoxia, the HIF1A protein can interact with its binding sequence in the eIF3i promoter and activate eIF3i transcription. The expression of VEGFA, which should rise in hypoxia, is significantly inhibited by eIF3i siRNA treatment. Moreover, eIF3i knockdown did not cause a general translation repression but specifically reduced the translation efficiency of the VEGFA mRNAs. Taken together, our results suggest that eIF3i is induced by HIF1A under hypoxia and controls normal and tumorigenic angiogenesis through regulating VEGFA protein translation. PMID- 25147181 TI - Cooperative DNA binding and protein/DNA fiber formation increases the activity of the Dnmt3a DNA methyltransferase. AB - The Dnmt3a DNA methyltransferase has been shown to bind cooperatively to DNA and to form large multimeric protein/DNA fibers. However, it has also been reported to methylate DNA in a processive manner, a property that is incompatible with protein/DNA fiber formation. We show here that the DNA methylation rate of Dnmt3a increases more than linearly with increasing enzyme concentration on a long DNA substrate, but not on a short 30-mer oligonucleotide substrate. We also show that addition of a catalytically inactive Dnmt3a mutant, which carries an amino acid exchange in the catalytic center, increases the DNA methylation rate by wild type Dnmt3a on the long substrate but not on the short one. In agreement with this finding, preincubation experiments indicate that stable protein/DNA fibers are formed on the long, but not on the short substrate. In addition, methylation experiments with substrates containing one or two CpG sites did not provide evidence for a processive mechanism over a wide range of enzyme concentrations. These data clearly indicate that Dnmt3a binds to DNA in a cooperative reaction and that the formation of stable protein/DNA fibers increases the DNA methylation rate. Fiber formation occurs at low MUm concentrations of Dnmt3a, which are in the range of Dnmt3a concentrations in the nucleus of embryonic stem cells. Understanding the mechanism of Dnmt3a is of vital importance because Dnmt3a is a hotspot of somatic cancer mutations one of which has been implicated in changing Dnmt3a processivity. PMID- 25147180 TI - Fucosylated chondroitin sulfates from the body wall of the sea cucumber Holothuria forskali: conformation, selectin binding, and biological activity. AB - Fucosylated chondroitin sulfate (fCS) extracted from the sea cucumber Holothuria forskali is composed of the following repeating trisaccharide unit: -> 3)GalNAcbeta4,6S(1 -> 4) [FucalphaX(1 -> 3)]GlcAbeta(1 ->, where X stands for different sulfation patterns of fucose (X = 3,4S (46%), 2,4S (39%), and 4S (15%)). As revealed by NMR and molecular dynamics simulations, the fCS repeating unit adopts a conformation similar to that of the Le(x) blood group determinant, bringing several sulfate groups into close proximity and creating large negative patches distributed along the helical skeleton of the CS backbone. This may explain the high affinity of fCS oligosaccharides for L- and P-selectins as determined by microarray binding of fCS oligosaccharides prepared by Cu(2+) catalyzed Fenton-type and photochemical depolymerization. No binding to E selectin was observed. fCS poly- and oligosaccharides display low cytotoxicity in vitro, inhibit human neutrophil elastase activity, and inhibit the migration of neutrophils through an endothelial cell layer in vitro. Although the polysaccharide showed some anti-coagulant activity, small oligosaccharide fCS fragments had much reduced anticoagulant properties, with activity mainly via heparin cofactor II. The fCS polysaccharides showed prekallikrein activation comparable with dextran sulfate, whereas the fCS oligosaccharides caused almost no effect. The H. forskali fCS oligosaccharides were also tested in a mouse peritoneal inflammation model, where they caused a reduction in neutrophil infiltration. Overall, the data presented support the action of fCS as an inhibitor of selectin interactions, which play vital roles in inflammation and metastasis progression. Future studies of fCS-selectin interaction using fCS fragments or their mimetics may open new avenues for therapeutic intervention. PMID- 25147182 TI - Quantitative Lys-epsilon-Gly-Gly (diGly) proteomics coupled with inducible RNAi reveals ubiquitin-mediated proteolysis of DNA damage-inducible transcript 4 (DDIT4) by the E3 ligase HUWE1. AB - Targeted degradation of proteins through the ubiquitin-proteasome system (UPS) via the activities of E3 ubiquitin ligases regulates diverse cellular processes, and misregulation of these enzymes contributes to the pathogenesis of human diseases. One of the challenges facing the UPS field is to delineate the complete cohort of substrates for a particular E3 ligase. Advances in mass spectrometry and the development of antibodies recognizing the Lys-epsilon-Gly-Gly (diGly) remnant from ubiquitinated proteins following trypsinolysis have provided a tool to address this question. We implemented an inducible loss of function approach in combination with quantitative diGly proteomics to find novel substrates of HUWE1 (HECT, UBA, and WWE domain containing 1, E3 ubiquitin protein ligase), an E3 ligase implicated in cancer and intellectual disabilities. diGly proteomics results led to the identification of DNA damage-inducible transcript 4 (DDIT4) as a putative HUWE1 substrate. Cell-based assays demonstrated that HUWE1 interacts with and regulates ubiquitination and stability of DDIT4. Together these data suggest a model in which HUWE1 mediates DDIT4 proteasomal degradation. Our results demonstrate proof of concept that inducible knockdown of an E3 ligase in combination with diGly proteomics provides a potentially advantageous method for identifying novel E3 substrates that may help to identify candidates for therapeutic modulation in the UPS. PMID- 25147184 TI - Do maternal interactive behaviors correlate with developmental outcomes and mastery motivation in toddlers with and without motor delay? AB - BACKGROUND: Maternal interactive behaviors theoretically affect developmental outcomes and mastery motivation in young children. However, these associations are inconsistent in the literature. OBJECTIVE: The purposes of this study were: (1) to examine the differences in maternal behaviors between toddlers with motor delay (MD) and those with typical development (TD), (2) to investigate the correlation of maternal behaviors and developmental quotients (DQs) in toddlers with MD and TD, and (3) to examine the correlation of maternal behaviors and mastery motivation in toddlers with MD and TD. DESIGN: This was a sex- and mental age-matched case-control study. METHODS: Twenty-two mother-child dyads of toddlers with MD (ages 23-47 months) and 22 dyads of sex- and mental age-matched toddlers with TD (ages 15-29 months) were recruited. Maternal scores from the Nursing Child Assessment Teaching Scale, 2 indicators of motivation (persistence and mastery pleasure) from individualized mastery tasks and the Dimensions of Mastery Questionnaire, and DQs from the Comprehensive Developmental Inventory for Infants and Children were assessed. RESULTS: Mothers of children in the MD group showed significantly lower cognitive growth fostering scores than mothers of children in the TD group. Maternal total scores were significantly correlated with whole DQs in both groups. In the MD group, maternal total scores correlated significantly with DMQ mastery pleasure but not with mastery task motivation. LIMITATIONS: The study design makes it impossible to know the causal relationships between maternal behaviors and children's DQs and motivation. CONCLUSIONS: Mothers of toddlers with MD exhibited less adequate interactive behaviors than mothers of toddlers with TD. Because higher-quality maternal behaviors correlated with higher DQs in the MD group, clinicians should encourage parents to participate in early intervention programs and model high-quality parenting behavior to enhance parents' and children's outcomes. PMID- 25147183 TI - Self-association of an insect beta-1,3-glucan recognition protein upon binding laminarin stimulates prophenoloxidase activation as an innate immune response. AB - Insect beta-glucan recognition protein (betaGRP), a pathogen recognition receptor for innate immune responses, detects beta-1,3-glucan on fungal surfaces via its N terminal carbohydrate-binding domain (N-betaGRP) and triggers serine protease cascades for the activation of prophenoloxidase (pro-PO) or Toll pathways. Using biophysical and biochemical methods, we characterized the interaction of the N terminal domain from Manduca sexta betaGRP2 (N-betaGRP2) with laminarin, a soluble form of beta-1,3-glucan. We found that carbohydrate binding by N-betaGRP2 induces the formation of two types of protein-carbohydrate complexes, depending on the molar ratio of carbohydrate to protein ([C]/[P]). Precipitation, analytical ultracentrifugation, and chemical cross-linking experiments have shown that an insoluble aggregate forms when the molar ratio of carbohydrate to protein is low ([C]/[P] ~ 1). In contrast, a soluble complex, containing at least five N betaGRP2 molecules forms at a higher molar ratio of carbohydrate/protein ([C]/[P] >5). A hypothesis that this complex is assembled partly due to protein-protein interactions was supported by chemical cross-linking experiments combined with LC MS/MS spectrometry analysis, which permitted identification of a specific intermolecular cross-link site between N-betaGRP molecules in the soluble complex. The pro-PO activation in naive plasma was strongly stimulated by addition of the insoluble aggregates of N-betaGRP2. The soluble complex with laminarin formed in the plasma also stimulated pro-PO activation, but at a lower level. Taken together, these results provide experimental evidence for novel mechanisms in which associations of betaGRP with microbial polysaccharide promotes assembly of betaGRP oligomers, which may form a platform needed to trigger the pro-PO pathway activation cascade. PMID- 25147185 TI - Reproducibility and validity of the physical activity scale for the elderly (PASE) questionnaire in patients after total hip arthroplasty. AB - BACKGROUND: The assessment of physical activity is of concern in patients after total hip arthroplasty (THA). However, so far, no questionnaire has demonstrated adequate reproducibility and validity for assessing physical activity in these patients. OBJECTIVE: The aim of this study was to evaluate the reproducibility and validity of the Physical Activity Scale for the Elderly (PASE) questionnaire in patients after THA. DESIGN: This was a measurement study. METHODS: Fifty patients who had undergone THA (25 women, 25 men), with an average age of 68 years, were evaluated. Of these patients, 25 were assessed between 2 and 7 months after surgery (THAearly), and another 25 were assessed between 7 and 12 months after surgery (THAlate). Reproducibility of the PASE questionnaire was evaluated by administering the questionnaire on 2 different occasions. Construct validity of the PASE questionnaire was assessed by comparing the physical activity level reported by patients with that objectively recorded by a body-mounted accelerometer. Reproducibility was investigated with intraclass correlation coefficients (ICC [2,1]) for reliability and standard errors of measurement (SEM) for agreement. Validity was investigated with Pearson correlation coefficients (r). RESULTS: The ICC (2,1) for the PASE total score was .77 (95% confidence interval [95% CI]=.63, .86); the SEM was 23.0% (95% CI=19.2, 28.7). Validity correlation for the PASE total score was .38 (95% CI=.12, .60). No significant differences were found between THAearly and THAlate groups for reliability, agreement, and validity outcomes. LIMITATIONS: Reproducibility of the PASE questionnaire may have been underestimated because the physical activity of patients was compared between 2 consecutive but different weeks. Reliability and validity analyses were underpowered. CONCLUSIONS: Further study with a larger sample size is necessary to obtain precise reliability and validity estimates. Nevertheless, inadequate agreement calls into question the PASE questionnaire's ability to assess the physical activity level of patients after THA surgery. PMID- 25147186 TI - Dual tasking with the timed "up & go" test improves detection of risk of falls in people with Parkinson disease. AB - BACKGROUND: Falls are a common and disabling feature of Parkinson disease (PD). Early identification of patients at greatest risk of falling is a key goal of physical therapy assessment. The Timed "Up & Go" Test (TUG), a frequently used mobility assessment tool, has moderate sensitivity and specificity for identifying fall risk. OBJECTIVE: The study objective was to investigate whether adding a task (cognitive or manual) to the TUG (TUG-cognitive or TUG-manual, respectively) increases the utility of the test for identifying fall risk in people with PD. DESIGN: This was a retrospective cohort study of people with PD (N=36). METHODS: Participants were compared on the basis of self-reported fall exposure in the preceding 6 months (those who had experienced falls ["fallers"] versus those who had not ["nonfallers"]). The time taken to complete the TUG, TUG cognitive, and TUG-manual was measured for both groups. Between-group differences were calculated with the Mann-Whitney U test. The discriminative performance of the test at various cutoff values was examined, and estimates of sensitivity and specificity were based on receiver operating characteristic curve plots. RESULTS: Fallers took significantly longer than nonfallers (n=19) to complete the TUG under all 3 conditions. The TUG-cognitive showed optimal discriminative performance (receiver operating characteristic area under the curve=0.82; 95% confidence interval [CI]=0.64, 0.92) at a cutoff of 14.7 seconds. The TUG cognitive was more likely to correctly classify participants with a low risk of falling (positive likelihood ratio=2.9) (<14.7 seconds) and had higher estimates of sensitivity (0.76; 95% CI=0.52, 0.90) than of specificity (0.73; 95% CI=0.51, 0.88) at this threshold (negative likelihood ratio=0.32). LIMITATIONS: Retrospective classification of fallers and nonfallers was used. CONCLUSIONS: The addition of a cognitive task to the TUG enhanced the identification of fall risk in people with PD. The TUG-cognitive should be considered a component of a multifaceted fall risk assessment in people with PD. PMID- 25147187 TI - Curing color blindness--mice and nonhuman primates. AB - It has been possible to use viral-mediated gene therapy to transform dichromatic (red-green color-blind) primates to trichromatic. Even though the third cone type was added after the end of developmental critical periods, treated animals acquired red-green color vision. What happened in the treated animals may represent a recapitulation of the evolution of trichromacy, which seems to have evolved with the acquisition of a third cone type without the need for subsequent modification to the circuitry. Some transgenic mice in which a third cone type was added also acquired trichromacy. However, compared with treated primates, red green color vision in mice is poor, indicating large differences between mice and monkeys in their ability to take advantage of the new input. These results have implications for understanding the limits and opportunities for using gene therapy to treat vision disorders caused by defects in cone function. PMID- 25147188 TI - Manipulation of the mononuclear phagocyte system by Mycobacterium tuberculosis. AB - Over the past 20 years, there has been an emerging appreciation about the role of the mononuclear phagocyte system (MPS) to control and eradicate pathogens. Likewise, there have been significant advances in dissecting the mechanisms involved in the microbial subversion of MPS cells, mainly affecting their differentiation and effector functions. Mycobacterium tuberculosis is a chronic bacterial pathogen that represents an enigma to the field because of its remarkable ability to thrive in humans. One reason is that M. tuberculosis renders a defective MPS compartment, which is perhaps the most ingenious strategy for survival in the host given the prominence of these cells to modulate microenvironments, their function as sentinels and orchestrators of the immune response, and their pathogenic role as reservoirs for microbial persistence. In this article, the principal strategies used by M. tuberculosis to subvert the MPS compartment are presented along with emerging concepts. PMID- 25147190 TI - Crossability of Triticum urartu and Triticum monococcum wheats, homoeologous recombination, and description of a panel of interspecific introgression lines. AB - Triticum monococcum (genome A(m)) and T. urartu (genome A(u)) are diploid wheats, with the first having been domesticated in the Neolithic Era and the second being a wild species. In a germplasm collection, rare wild T. urartu lines with the presence of T. monococcum alleles were found. This stimulated our interest to develop interspecific introgression lines of T. urartu in T. monococcum, a breeding tool currently implemented in several crop species. Moreover, the experiments reported were designed to reveal the existence in nature of A(m)/A(u) intermediate forms and to clarify whether the two species are at least marginally sexually compatible. From hand-made interspecific crosses, almost-sterile F1 plants were obtained when the seed-bearing parent was T. monococcum. A high degree of fertility was, however, evident in some advanced generations, particularly when T. urartu donors were molecularly more related to T. monococcum. Analysis of the marker populations demonstrated chromosome pairing and recombination in F1 hybrid plants. Forty-six introgression lines were developed using a line of T. monococcum with several positive agronomic traits as a recurrent parent. Microsatellite markers were tested on A(u) and A(m) genomes, ordered in a T. monococcum molecular map, and used to characterize the exotic DNA fragments present in each introgression line. In a test based on 28 interspecific introgression lines, the existence of genetic variation associated with T. urartu chromosome fragments was proven for the seed content of carotenoids, lutein, beta cryptoxanthin, and zinc. The molecular state of available introgression lines is summarized. PMID- 25147189 TI - Small RNA expression from the human macrosatellite DXZ4. AB - Small noncoding RNAs play several roles in regulating gene expression. In the nucleus, small RNA-Argonaute complexes recruit epigenetic modifying activities to genomic sites. This pathway has been described in mammals primarily for the germline; however, its role in somatic cells is less characterized. Here, we describe in human somatic cells a potential link between the expression of small RNAs from the macrosatellite DXZ4 and Argonaute-dependent DNA methylation of this locus. DXZ4 was found to express a wide range of small RNAs potentially representing several classes of small RNAs. A subpopulation of these RNAs is bound by Argonaute. Moreover, we show AGO association with DXZ4 and that the Argonaute proteins AGO-1 and PIWIL4 may play a role in DNA methylation of DXZ4. We hypothesize that the RNAs are involved in Argonaute-dependent methylation of DXZ4 DNA. PMID- 25147191 TI - The alternative oxidase AOX does not rescue the phenotype of tko25t mutant flies. AB - A point mutation [technical knockout(25t) (tko(25t))] in the Drosophila gene coding for mitoribosomal protein S12 generates a phenotype of developmental delay and bang sensitivity. tko(25t) has been intensively studied as an animal model for human mitochondrial diseases associated with deficiency of mitochondrial protein synthesis and consequent multiple respiratory chain defects. Transgenic expression in Drosophila of the alternative oxidase (AOX) derived from Ciona intestinalis has previously been shown to mitigate the toxicity of respiratory chain inhibitors and to rescue mutant and knockdown phenotypes associated with cytochrome oxidase deficiency. We therefore tested whether AOX expression could compensate the mutant phenotype of tko(25t) using the GeneSwitch system to activate expression at different times in development. The developmental delay of tko(25t) was not mitigated by expression of AOX throughout development. AOX expression for 1 d after eclosion, or continuously throughout development, had no effect on the bang sensitivity of tko(25t) adults, and continued expression in adults older than 30 d also produced no amelioration of the phenotype. In contrast, transgenic expression of the yeast alternative NADH dehydrogenase Ndi1 was synthetically semi-lethal with tko(25t) and was lethal when combined with both AOX and tko(25t). We conclude that AOX does not rescue tko(25t) and that the mutant phenotype is not solely due to limitations on electron flow in the respiratory chain, but rather to a more complex metabolic defect. The future therapeutic use of AOX in disorders of mitochondrial translation may thus be of limited value. PMID- 25147192 TI - A saturated genetic linkage map of autotetraploid alfalfa (Medicago sativa L.) developed using genotyping-by-sequencing is highly syntenous with the Medicago truncatula genome. AB - A genetic linkage map is a valuable tool for quantitative trait locus mapping, map-based gene cloning, comparative mapping, and whole-genome assembly. Alfalfa, one of the most important forage crops in the world, is autotetraploid, allogamous, and highly heterozygous, characteristics that have impeded the construction of a high-density linkage map using traditional genetic marker systems. Using genotyping-by-sequencing (GBS), we constructed low-cost, reasonably high-density linkage maps for both maternal and paternal parental genomes of an autotetraploid alfalfa F1 population. The resulting maps contain 3591 single-nucleotide polymorphism markers on 64 linkage groups across both parents, with an average density of one marker per 1.5 and 1.0 cM for the maternal and paternal haplotype maps, respectively. Chromosome assignments were made based on homology of markers to the M. truncatula genome. Four linkage groups representing the four haplotypes of each alfalfa chromosome were assigned to each of the eight Medicago chromosomes in both the maternal and paternal parents. The alfalfa linkage groups were highly syntenous with M. truncatula, and clearly identified the known translocation between Chromosomes 4 and 8. In addition, a small inversion on Chromosome 1 was identified between M. truncatula and M. sativa. GBS enabled us to develop a saturated linkage map for alfalfa that greatly improved genome coverage relative to previous maps and that will facilitate investigation of genome structure. GBS could be used in breeding populations to accelerate molecular breeding in alfalfa. PMID- 25147193 TI - Conformational stability, reversibility and heat-induced aggregation of alpha-1 acid glycoprotein. AB - To investigate the relationship between conformational stability, reversibility of denaturation and aggregation of protein, we determined the conformation, melting temperature (Tm), and reversibility of heat-induced denaturation of alpha 1-acid glycoprotein (AGP) in aqueous solutions at various pH values using circular dichroism (CD) and differential scanning microcalorimetry. To quantitate and characterize heat-induced AGP aggregation under the same pH conditions, solutions of AGP were incubated at 50 degrees C and then analysed by size exclusion chromatography (SEC), sodium dodecyl sulfate-polyacrylamide gel electrophoresis, CD and SEC in the presence of 4,4'-dianilino-1,1'-binaphthyl 5,5'-disulfonic acid. The conformational stability of AGP was reduced at lower pH, whereas the reversibility of protein denaturation was reduced at higher pH. AGP formed some large non-covalent aggregates during incubation at lower pH, whereas incubation at higher pH tended to cause the formation of dimer species without the formation of large aggregates. These results indicated that lower conformational stability was related to the formation of non-covalent large aggregates, whereas reduced reversibility was related to dimer formation. Thus, evaluating both conformational stability and reversibility is necessary for developing optimal formulations and to predict the kinds of aggregates that will be induced during protein storage. PMID- 25147194 TI - Molecular characterization of acidic peptide:N-glycanase from the dimorphic yeast Yarrowia lipolytica. AB - Peptide:N-glycanase (PNGase) A is used preferentially to cleave the glycans from plant and insect glycopeptides. Although many putative PNGase A homologous genes have been found in the plant and fungus kingdoms through sequence similarity analyses, only several PNGases from plants and one from a filamentous fungus have been characterized. In this study, we identified and characterized a PNGase A like enzyme, PNGase Yl, in the dimorphic yeast Yarrowia lipolytica. The corresponding gene was cloned and recombinantly expressed in Pichia pastoris. The purified enzyme cleaved glycans from glycopeptides with the maximum activity at pH 5. No metal ions were required for full activity, and rather it was repressed by three metal ions (Fe(3+), Cu(2+) and Zn(2+)). Using glycopeptide substrates, PNGase Yl was shown to release various types of N-glycans including high-mannose and complex-type glycans as well as glycans containing core-linked alpha(1,3) fucose that are frequently found in plants and insects. Moreover, in comparison with PNGase A, PNGase Yl was able to cleave with higher efficiency the glycans from some denatured glycoproteins. Taken together, our results suggest that PNGase Yl, the first biochemically characterized yeast PNGase A homologue, can be developed through protein engineering as a useful deglycosylation tool for N glycosylation study. PMID- 25147195 TI - Visualization of human inner ear anatomy with high-resolution MR imaging at 7T: initial clinical assessment. AB - BACKGROUND AND PURPOSE: In many centers, MR imaging of the inner ear and auditory pathway performed on 1.5T or 3T systems is part of the preoperative work-up of cochlear implants. We investigated the applicability of clinical inner ear MR imaging at 7T and compared the visibility of inner ear structures and nerves within the internal auditory canal with images acquired at 3T. MATERIALS AND METHODS: Thirteen patients with sensorineural hearing loss eligible for cochlear implantation underwent examinations on 3T and 7T scanners. Two experienced head and neck radiologists evaluated the 52 inner ear datasets. Twenty-four anatomic structures of the inner ear and 1 overall score for image quality were assessed by using a 4-point grading scale for the degree of visibility. RESULTS: The visibility of 11 of the 24 anatomic structures was rated higher on the 7T images. There was no significant difference in the visibility of 13 anatomic structures and the overall quality rating. A higher incidence of artifacts was observed in the 7T images. CONCLUSIONS: The gain in SNR at 7T yielded a more detailed visualization of many anatomic structures, especially delicate ones, despite the challenges accompanying MR imaging at a high magnetic field. PMID- 25147196 TI - Susceptibility-weighted MR imaging: a better technique in the detection of capillary telangiectasia compared with T2* gradient-echo. AB - BACKGROUND AND PURPOSE: Enhancing lesions on brain MR imaging can present a diagnostic quandary as both benign lesions such as brain capillary telangiectasia and pathologic lesions such as demyelination may appear similar. Stagnation of blood in low-flow venous channels of brain capillary telangiectasias results in susceptibility effect secondary to the increased local deoxyhemoglobin. Both T2* gradient-echo imaging and SWI were demonstrated as valuable in the diagnosis of brain capillary telangiectasia. Because SWI is more sensitive to susceptibility changes than gradient-echo, we aim to demonstrate increased diagnostic value of SWI compared with gradient-echo in making the diagnosis of brain capillary telangiectasia. MATERIALS AND METHODS: We retrospectively reviewed the MR images of 17 patients with a presumed diagnosis of brain capillary telangiectasia and who were examined from June 2010 to September 2012. All patients underwent MR imaging at 1.5T with T1, T2, FLAIR, gradient-echo, SWI, and gadolinium-enhanced T1 sequences. Lesions were evaluated for the presence or absence of signal abnormality on each particular sequence. RESULTS: All 17 brain capillary telangiectasias demonstrated distinct signal-intensity loss on SWI compared with 7 of 17 (41%) who showed signal-intensity loss on gradient-echo. The increased frequency of detection using SWI versus gradient-echo is statistically significant (z = 2.85, P < .01; chi(2) = 8.10, P < .01). Six of the lesions showed signal-intensity changes on T1 and/or T2 whereas the remaining lesions were isointense to normal brain. CONCLUSIONS: Brain capillary telangiectasias are more conspicuous on SWI than gradient-echo imaging and other precontrast MR imaging. SWI is a valuable tool in diagnosing these benign lesions and should serve to increase diagnostic confidence. PMID- 25147197 TI - Radiology reports for incidental thyroid nodules on CT and MRI: high variability across subspecialties. AB - BACKGROUND AND PURPOSE: Variability in radiologists' reporting styles and recommendations for incidental thyroid nodules can lead to confusion among clinicians and may contribute to inconsistent patient care. Our aim was to describe reporting practices of radiologists for incidental thyroid nodules seen on CT and MR imaging and to determine factors that influence reporting styles. MATERIALS AND METHODS: This is a retrospective study of patients with incidental thyroid nodules reported on CT and MR imaging between January and December 2011, identified by text search for "thyroid nodule" in all CT and MR imaging reports. The studies included CT and MR imaging scans of the neck, spine, and chest. Radiology reports were divided into those that mentioned the incidental thyroid nodules only in the "Findings" section versus those that reported the incidental thyroid nodules in the "Impression" section as well, because this latter reporting style gives more emphasis to the finding. Univariate and multivariate analyses were performed to identify radiologist, patient, and nodule characteristics that influenced reporting styles. RESULTS: Three hundred seventy five patients met the criterion of having incidental thyroid nodules. One hundred thirty-eight (37%) patients had incidental thyroid nodules reported in the "Impression" section. On multivariate analysis, only radiologists' divisions and nodule size were associated with reporting in "Impression." Chest radiologists and neuroradiologists were more likely to report incidental thyroid nodules in the "Impression" section than their abdominal imaging colleagues, and larger incidental thyroid nodules were more likely to be reported in "Impression" (P <= .03). Seventy-three percent of patients with incidental thyroid nodules of >=20 mm were reported in the "Impression" section, but higher variability in reporting was seen for incidental thyroid nodules measuring 10-14 mm and 15-19 mm, which were reported in "Impression" for 61% and 50% of patients, respectively. CONCLUSIONS: Reporting practices for incidental thyroid nodules detected on CT and MR imaging are predominantly influenced by nodule size and the radiologist's subspecialty. Reporting was highly variable for nodules measuring 10-19 mm; this finding can be partially attributed to different reporting styles among radiology subspecialty divisions. The variability demonstrated in this study further underscores the need to develop CT and MR imaging practice guidelines with the goal of standardizing reporting of incidental thyroid nodules and thereby potentially improving the consistency and quality of patient care. PMID- 25147198 TI - Regional cerebral arterial transit time hemodynamics correlate with vascular risk factors and cognitive function in men with coronary artery disease. AB - BACKGROUND AND PURPOSE: Arterial transit time is the time needed for blood to travel from large arteries to capillaries, as estimated from arterial spin labeling MR imaging. The purpose of this study was to determine whether vascular risk factors and cognitive performance are related to regional differences in cerebral arterial transit time in patients with coronary artery disease who are at risk for cognitive decline. MATERIALS AND METHODS: Arterial transit time was estimated from multiple postlabel delay pseudocontinuous arterial spin-labeling images obtained from 29 men with coronary artery disease. Tests of memory, attention, processing speed, and executive function were administered. Principal component analysis was used to create separate models of cognition and vascular risk, which were related to brain regions through voxelwise analyses of arterial transit time maps. RESULTS: Principal component analysis identified 2 components of vascular risk: 1) "pressor" (age, systolic blood pressure, and pulse pressure) and 2) "obesity" (body fat percentage and body mass index). Obesity was inversely related to arterial transit time in the posterior cingulate, precuneus, lateral occipital cortices, middle temporal gyrus, and frontal pole (P corrected < .05), whereas pressor was not significant. Cognitive scores were factored into a single component. Poor performance was inversely related to precuneus arterial transit time (P corrected < .05). The average arterial transit time in regions identified by obesity was associated with poorer cognitive function (r(2) = 0.21, t = -2.65, P = .01). CONCLUSIONS: Altered cerebral hemodynamics, notably in nodal structures of the default mode network, may be one way that vascular risk factors impact cognition in patients with coronary artery disease. PMID- 25147199 TI - Cavernous carotid aneurysms in the era of flow diversion: a need to revisit treatment paradigms. AB - BACKGROUND AND PURPOSE: Recent techniques of endoluminal reconstruction with flow diverting stents have not been incorporated into treatment algorithms for cavernous carotid aneurysms. This study examines the authors' institutional experience and a systematic review of the literature for outcomes and complications using the Pipeline Embolization Device in unruptured cavernous carotid aneurysms. MATERIALS AND METHODS: A retrospective search for cavernous carotid aneurysms from a prospectively collected data base of aneurysms treated with the Pipeline Embolization Device at our institution was performed. Baseline demographic, clinical, and laboratory values; intrainterventional data; and data at all follow-up visits were collected. A systematic review of the literature for complication data was performed with inquiries sent when clarification of data was needed. RESULTS: Forty-three cavernous carotid aneurysms were included in the study. Our mean radiographic follow-up was 2.05 years. On last follow-up, 88.4% of the aneurysms treated had complete or near-complete occlusion. Aneurysm complete or near-complete occlusion rates at 6 months, 12 months, and 36 months were 81.4%, 89.7%, and 100%, respectively. Of patients with neuro-ophthalmologic deficits on presentation, 84.2% had improvement in their visual symptoms. Overall, we had a 0% mortality rate and a 2.3% major neurologic complication rate. Our systematic review of the literature yielded 227 cavernous carotid aneurysms treated with the Pipeline Embolization Device with mortality and morbidity rates of 0.4% and 3.1%, respectively. CONCLUSIONS: Endoluminal reconstruction with flow diversion for large unruptured cavernous carotid aneurysms can yield high efficacy with low complications. Further long-term data will be helpful in assessing the durability of the cure; however, we advocate a revisiting of current management paradigms for cavernous carotid aneurysms. PMID- 25147200 TI - Intracoronary insulin administered at reperfusion in a porcine model of acute coronary syndrome. AB - BACKGROUND: Experimental studies have demonstrated that insulin elicits cardioprotection in coronary occlusion-reperfusion models. We studied the effects of intracoronary insulin on regional cardiac function in a porcine model with reperfusion after a critical coronary artery stenosis. METHODS: In 20 anaesthetized pigs with an extracorporeal shunt from the brachiocephalic to the left anterior descending coronary artery, a fixed stenosis was applied, obtaining 50% reduction of shunt flow for 60 min. Intracoronary insulin 1 1U [DOSAGE ERROR CORRECTED] or 0.9% saline was infused for 15 min, starting 5 min prior to initiation of 180 min of reperfusion. Microsphere injections confirmed ischaemia and reperfusion. Epicardial echocardiographic multilayer radial tissue Doppler strain and strain rate and one-layer speckle-tracking strain evaluated myocardial function. Apoptosis was evaluated by cleaved caspase-3 activity. Area at risk and infarct size were determined with Evans Blue and triphenyltetrazolium chloride staining. RESULTS: In both groups, the area at risk constituted approximately 26% of the left ventricular mass. Minor areas of infarction were predominantly seen subendocardially, where tissue blood flow rate was severely reduced during stenosis. After 180 min of reperfusion, recovery of speckle-tracking circumferential strain averaged 57.5 +/- 11.4% of baseline values in insulin treated animals compared to 22.3 +/- 8.7% in controls (p = 0.025). Multilayer radial strain and strain rate did not differ between groups. Cleaved caspase-3 activity was most prominent in the subepicardial layer in the saline-treated group. CONCLUSIONS: Intracoronary insulin at the onset of reperfusion alleviated regional myocardial dysfunction in acute ischaemia-reperfusion and was associated with a reduction of apoptosis. PMID- 25147201 TI - Global prevalence of, and risk factors for, uninvestigated dyspepsia: a meta analysis. AB - OBJECTIVES: Many cross-sectional surveys have reported the prevalence of uninvestigated dyspepsia, but there has been no recent systematic review of data from all studies to determine its global prevalence and risk factors. DESIGN: MEDLINE, EMBASE and EMBASE Classic were searched (until January 2014) to identify population-based studies that reported the prevalence of uninvestigated dyspepsia in adults (>= 15 years old); dyspepsia was defined using symptom-based criteria or questionnaires. The prevalence of dyspepsia was extracted for all studies and according to the criteria used to define it. Pooled prevalence, according to study location and certain other characteristics, ORs and 95% CIs were calculated. RESULTS: Of the 306 citations evaluated, 103 reported the prevalence of uninvestigated dyspepsia in 100 separate study populations, containing 312,415 subjects. Overall pooled prevalence in all studies was 20.8% (95% CI 17.8% to 23.9%). The prevalence varied according to country (from 1.8% to 57.0%) and criteria used to define dyspepsia. The greatest prevalence values were found when a broad definition of dyspepsia (29.5%; 95% CI 25.3% to 33.8%) or upper abdominal or epigastric pain or discomfort (20.4%; 95% CI 16.3% to 24.8%) were used. The prevalence was higher in women (OR 1.24; 95% CI 1.13 to 1.36), smokers (OR 1.25; 95% CI 1.12 to 1.40), non-steroidal anti-inflammatory drug (NSAID) users (OR 1.59; 95% CI 1.27 to 1.99) and Helicobacter pylori-positive individuals (OR 1.18; 95% CI 1.04 to 1.33). CONCLUSIONS: The overall pooled prevalence of uninvestigated dyspepsia was 21%, but varied among countries and according to the criteria used to define its presence. Prevalence is significantly higher in women, smokers, NSAID users and H. pylori-positive individuals, although these associations were modest. PMID- 25147202 TI - What we talk about when we talk about low-grade dysplasia. PMID- 25147203 TI - Study of Mendelian forms of Crohn's disease in Saudi Arabia reveals novel risk loci and alleles. PMID- 25147204 TI - The patterns of inheritance in early-onset dementia: Alzheimer's disease and frontotemporal dementia. AB - AIM: To investigate the patterns of inheritance and gene mutation status in early onset dementia (EOD). METHODS: Data were collected on 202 consecutive patients presenting to an EOD clinic. Early-onset Alzheimer's disease (EOAD, n = 120) and early-onset frontotemporal dementia (EOFTD, n = 82) were studied. RESULTS: The majority of participants, 72.5% with EOAD and 74.4% with EOFTD, did not have a positive family history of dementia. An autosomal dominant pattern of inheritance was observed in 14.2% of patients with EOAD and 13.4% of patients with FTD. Of those with an autosomal dominant pattern of inheritance, 11.8% of EOAD and 45.5% of FTD probands had known pathogenic mutations. Only 1.6% of the total population of EOAD and 7.3% of EOFTD possessed known gene mutations. CONCLUSION: Early-onset dementia does not appear to be a strongly inherited autosomal dominant condition. The majority of patients were sporadic. Known mutations were uncommon and do not explain the total autosomal dominant burden. PMID- 25147205 TI - Genomic HEXploring allows landscaping of novel potential splicing regulatory elements. AB - Effective splice site selection is critically controlled by flanking splicing regulatory elements (SREs) that can enhance or repress splice site use. Although several computational algorithms currently identify a multitude of potential SRE motifs, their predictive power with respect to mutation effects is limited. Following a RESCUE-type approach, we defined a hexamer-based 'HEXplorer score' as average Z-score of all six hexamers overlapping with a given nucleotide in an arbitrary genomic sequence. Plotted along genomic regions, HEXplorer score profiles varied slowly in the vicinity of splice sites. They reflected the respective splice enhancing and silencing properties of splice site neighborhoods beyond the identification of single dedicated SRE motifs. In particular, HEXplorer score differences between mutant and reference sequences faithfully represented exonic mutation effects on splice site usage. Using the HIV-1 pre mRNA as a model system highly dependent on SREs, we found an excellent correlation in 29 mutations between splicing activity and HEXplorer score. We successfully predicted and confirmed five novel SREs and optimized mutations inactivating a known silencer. The HEXplorer score allowed landscaping of splicing regulatory regions, provided a quantitative measure of mutation effects on splice enhancing and silencing properties and permitted calculation of the mutationally most effective nucleotide. PMID- 25147206 TI - Processing of double-R-loops in (CAG).(CTG) and C9orf72 (GGGGCC).(GGCCCC) repeats causes instability. AB - R-loops, transcriptionally-induced RNA:DNA hybrids, occurring at repeat tracts (CTG)n, (CAG)n, (CGG)n, (CCG)n and (GAA)n, are associated with diseases including myotonic dystrophy, Huntington's disease, fragile X and Friedreich's ataxia. Many of these repeats are bidirectionally transcribed, allowing for single- and double R-loop configurations, where either or both DNA strands may be RNA-bound. R-loops can trigger repeat instability at (CTG).(CAG) repeats, but the mechanism of this is unclear. We demonstrate R-loop-mediated instability through processing of R loops by HeLa and human neuron-like cell extracts. Double-R-loops induced greater instability than single-R-loops. Pre-treatment with RNase H only partially suppressed instability, supporting a model in which R-loops directly generate instability by aberrant processing, or via slipped-DNA formation upon RNA removal and its subsequent aberrant processing. Slipped-DNAs were observed to form following removal of the RNA from R-loops. Since transcriptionally-induced R loops can occur in the absence of DNA replication, R-loop processing may be a source of repeat instability in the brain. Double-R-loop formation and processing to instability was extended to the expanded C9orf72 (GGGGCC).(GGCCCC) repeats, known to cause amyotrophic lateral sclerosis and frontotemporal dementia, providing the first suggestion through which these repeats may become unstable. These findings provide a mechanistic basis for R-loop-mediated instability at disease-associated repeats. PMID- 25147207 TI - Multivariate inference of pathway activity in host immunity and response to therapeutics. AB - Developing a quantitative view of how biological pathways are regulated in response to environmental factors is central for understanding of disease phenotypes. We present a computational framework, named Multivariate Inference of Pathway Activity (MIPA), which quantifies degree of activity induced in a biological pathway by computing five distinct measures from transcriptomic profiles of its member genes. Statistical significance of inferred activity is examined using multiple independent self-contained tests followed by a competitive analysis. The method incorporates a new algorithm to identify a subset of genes that may regulate the extent of activity induced in a pathway. We present an in-depth evaluation of specificity, robustness, and reproducibility of our method. We benchmarked MIPA's false positive rate at less than 1%. Using transcriptomic profiles representing distinct physiological and disease states, we illustrate applicability of our method in (i) identifying gene-gene interactions in autophagy-dependent response to Salmonella infection, (ii) uncovering gene-environment interactions in host response to bacterial and viral pathogens and (iii) identifying driver genes and processes that contribute to wound healing and response to anti-TNFalpha therapy. We provide relevant experimental validation that corroborates the accuracy and advantage of our method. PMID- 25147208 TI - Essential role of eIF5-mimic protein in animal development is linked to control of ATF4 expression. AB - Translational control of transcription factor ATF4 through paired upstream ORFs (uORFs) plays an important role in eukaryotic gene regulation. While it is typically induced by phosphorylation of eIF2alpha, ATF4 translation can be also induced by expression of a translational inhibitor protein, eIF5-mimic protein 1 (5MP1, also known as BZW2) in mammals. Here we show that the 5MP gene is maintained in eukaryotes under strong purifying selection, but is uniquely missing in two major phyla, nematoda and ascomycota. The common function of 5MP from protozoa, plants, fungi and insects is to control translation by inhibiting eIF2. The affinity of human 5MP1 to eIF2beta was measured as being equivalent to the published value of human eIF5 to eIF2beta, in agreement with effective competition of 5MP with eIF5 for the main substrate, eIF2. In the red flour beetle, Tribolium castaneum, RNA interference studies indicate that 5MP facilitates expression of GADD34, a downstream target of ATF4. Furthermore, both 5MP and ATF4 are essential for larval development. Finally, 5MP and the paired uORFs allowing ATF4 control are conserved in the entire metazoa except nematoda. Based on these findings, we discuss the phylogenetic and functional linkage between ATF4 regulation and 5MP expression in this group of eukaryotes. PMID- 25147209 TI - A 'tool box' for deciphering neuronal circuits in the developing chick spinal cord. AB - The genetic dissection of spinal circuits is an essential new means for understanding the neural basis of mammalian behavior. Molecular targeting of specific neuronal populations, a key instrument in the genetic dissection of neuronal circuits in the mouse model, is a complex and time-demanding process. Here we present a circuit-deciphering 'tool box' for fast, reliable and cheap genetic targeting of neuronal circuits in the developing spinal cord of the chick. We demonstrate targeting of motoneurons and spinal interneurons, mapping of axonal trajectories and synaptic targeting in both single and populations of spinal interneurons, and viral vector-mediated labeling of pre-motoneurons. We also demonstrate fluorescent imaging of the activity pattern of defined spinal neurons during rhythmic motor behavior, and assess the role of channel rhodopsin targeted population of interneurons in rhythmic behavior using specific photoactivation. PMID- 25147211 TI - MYC and EGR1 synergize to trigger tumor cell death by controlling NOXA and BIM transcription upon treatment with the proteasome inhibitor bortezomib. AB - The c-MYC (MYC afterward) oncogene is well known for driving numerous oncogenic programs. However, MYC can also induce apoptosis and this function of MYC warrants further clarification. We report here that a clinically relevant proteasome inhibitor significantly increases MYC protein levels and that endogenous MYC is necessary for the induction of apoptosis. This kind of MYC induced cell death is mediated by enhanced expression of the pro-apoptotic BCL2 family members NOXA and BIM. Quantitative promoter-scanning chromatin immunoprecipitations (qChIP) further revealed binding of MYC to the promoters of NOXA and BIM upon proteasome inhibition, correlating with increased transcription. Both promoters are further characterized by the presence of tri methylated lysine 4 of histone H3, marking active chromatin. We provide evidence that in our apoptosis models cell death occurs independently of p53 or ARF. Furthermore, we demonstrate that recruitment of MYC to the NOXA as well as to the BIM gene promoters depends on MYC's interaction with the zinc finger transcription factor EGR1 and an EGR1-binding site in both promoters. Our study uncovers a novel molecular mechanism by showing that the functional cooperation of MYC with EGR1 is required for bortezomib-induced cell death. This observation may be important for novel therapeutic strategies engaging the inherent pro-death function of MYC. PMID- 25147214 TI - Problematizing "play-for-health" discourses through children's photo-elicited narratives. AB - There are growing concerns in many industrialized Western societies about declining opportunities for children to play, and fears that this will have adverse health consequences for them. Informed by anti-obesity efforts, public health institutions have recently begun to advance active forms of play as a way of improving children's physical health; however, promoting play for physical health might reshape meanings of play for children. We conducted photography and interview sessions with 25 Canadian children aged 7 to 11 years to examine their representations of play. Our findings suggest that for children, (a) play is an end in itself, (b) play involves but is more than active play, (c) there is ambivalence about scheduled play, and (d) risk is considered a pleasurable component of play. These findings point to a dissonance between children's play promoted for physical health and the meaning of play for children as emotionally contingent, intrinsically motivated, and purposeless. PMID- 25147213 TI - Childhood correlates of adult TV viewing time: a 32-year follow-up of the 1970 British Cohort Study. AB - BACKGROUND: To identify, using a longitudinal data set, parental and childhood correlates of adult television (TV) viewing time at 32-year follow-up. METHOD: Data were derived from the 1970 British Cohort Study, a longitudinal observational study of 17 248 British people born in a single week of 1970. The present analyses incorporated data from the age 10 and 42-year surveys. When participants were aged 10 years, their mothers provided information on how often participants watched TV and played sports (never/sometimes/often), and parents' own occupation, as well as height and weight. A health visitor objectively assessed participants' height and weight at age 10. Thirty-two years later, when participants were aged 42 years, they reported their daily TV viewing hours (none/0<=1/1<3/3<5/>=5), physical activity and health status. Associations between putative childhood and parental correlates and adult TV viewing time were investigated using logistic regression. RESULTS: Valid data at both time points were available for 6188 participants. Logistic regression models showed that those who reported 'often' watching TV at baseline were significantly more likely to watch >3 h/days of TV at follow-up (OR 1.42, 95% CI 1.21 to 1.65), as were those whose father was from a lower socio-occupational class (intermediate, routine/manual) compared with managerial (OR 1.55, 95% CI 1.14 to 2.11; OR 2.05, 95% CI 1.47 to 2.87). Body mass index (BMI) at age 10 was inversely associated with high TV in adulthood (per unit increase; OR 0.93, 95% CI 0.90 to 0.96) although fathers BMI when the child was aged 10 was positively associated with high TV in adulthood (per unit increase; OR 1.04, 95% CI 1.02 to 1.06). CONCLUSIONS: Findings suggest that childhood TV viewing time tracks into adulthood. Parents' health behaviours and social position appear to be associated with their children's viewing habits, which may have important implications for the direction of future policy and practice. Specifically, findings support the case for early life interventions, particularly on socioeconomic inequalities, as a way of preventing sedentary behaviour in later life. PMID- 25147212 TI - Molecular mechanisms of retroviral integration site selection. AB - Retroviral replication proceeds through an obligate integrated DNA provirus, making retroviral vectors attractive vehicles for human gene-therapy. Though most of the host cell genome is available for integration, the process of integration site selection is not random. Retroviruses differ in their choice of chromatin associated features and also prefer particular nucleotide sequences at the point of insertion. Lentiviruses including HIV-1 preferentially integrate within the bodies of active genes, whereas the prototypical gammaretrovirus Moloney murine leukemia virus (MoMLV) favors strong enhancers and active gene promoter regions. Integration is catalyzed by the viral integrase protein, and recent research has demonstrated that HIV-1 and MoMLV targeting preferences are in large part guided by integrase-interacting host factors (LEDGF/p75 for HIV-1 and BET proteins for MoMLV) that tether viral intasomes to chromatin. In each case, the selectivity of epigenetic marks on histones recognized by the protein tether helps to determine the integration distribution. In contrast, nucleotide preferences at integration sites seem to be governed by the ability for the integrase protein to locally bend the DNA duplex for pairwise insertion of the viral DNA ends. We discuss approaches to alter integration site selection that could potentially improve the safety of retroviral vectors in the clinic. PMID- 25147215 TI - Barriers to living donation among low-resource Hispanics. AB - Hispanics are disproportionately affected by renal failure. Although living donation has been heralded as a potential means for alleviating the need for transplantable kidneys, a nuanced understanding of the obstacles faced by Hispanics is necessary. In our study, we conducted focus groups with 28 first generation Spanish-dominant Hispanic renal patients. Although some of the barriers that emerged were akin to those reported in previous research (e.g., a lack of knowledge about the process), others were unique. Rarely chronicled barriers include the disqualification of family members because of medical issues, potential donors being unable to miss work, disqualification of family members who are undocumented, concern that potential donors cannot support their family if they donate, and declining social support because of illness. The interaction among this constellation of barriers makes living donation particularly difficult among this population. Investigations focused on the unique barriers faced by these low-resource individuals are warranted. PMID- 25147216 TI - Understanding the life experiences of older adults in Korea following a suicide attempt. AB - The purpose of this article is to describe life experiences following suicide attempts from the perspective of older Korean adults. Both field notes and in depth interviews with 35 elderly Koreans who had attempted suicide were analyzed through qualitative content analysis. With an underlying theme of "life with no way out for those who believe they do not even have any luck in dying," I classified the experiences of participants in the wake of a failed suicide attempt into four categories: (a) facing additional hardships including deteriorating physical health, (b) having more sadness and loneliness than before the suicide attempt, (c) deepening dependency on tranquilizers, and (d) seesawing between despair and faint hope. Based on these research findings, I make four recommendations regarding secondary preventive interventions for elderly suicide attempters. PMID- 25147217 TI - Meanings of being received and met by others as experienced by women with fibromyalgia. AB - Fibromyalgia (FM) is a common chronic pain syndrome that mostly affects middle aged women. Our aim with this study was to elucidate meanings of being received and met by others as experienced by women with FM. Interviews with a narrative approach were conducted with 9 women. We analyzed the transcribed interviews with a phenomenological hermeneutical interpretation. The findings revealed two themes: being seen as a malingerer and being acknowledged. Meanings of being received and met by others, as experienced by women with FM, can be understood as a movement between the two perspectives. When they were acknowledged, their feelings of security and trust increased, but the women could not rely on this because others received and met them in such an unpredictable manner. PMID- 25147218 TI - Untangling the nonrecyclable citizen: a critical reconceptualization of responsibility in recovery. AB - Over the last decades, international research, policy, and practice in the field of mental health care and a complementary variety of social work and social service delivery methods have been focused on recovery as a dominant concept. Emphasizing the service user's responsibility appears to be a central component in the empowering process of recovery. Using a critical disability studies perspective, we aimed to untangle the relationship between the individual citizen with mental health problems and the society in which the recovery discourse operates in Belgium. In this article we explore the social dynamics in the unique life story of Jimmy Sax and analyze a diversity of discourses and practices that turned him into a nonrecyclable citizen. While exploring the different modes through which Jimmy's subjectivity was transformed throughout the course of his life, we expose the convoluted nature of the recovery paradigm, which leads to a reconceptualization of the notion of responsibility in recovery. PMID- 25147219 TI - Communal normalization in an online self-help group for adolescents with a mentally ill parent. AB - Although implications of parental mental illness are well documented, most children of mentally ill parents are left to manage their family situation with limited information and support. We explored the role of a Norwegian online self help group for adolescents (aged 15 to 18) with a mentally ill parent. Through in depth interviews with 13 participants, we found that the online self-help group provided "communal normalization" by which participants, through communication in the forum, made sense of everyday experiences and emotions arising from having a mentally ill parent. We identified three main aspects of this process recognizability, openness, and agency-all of which were important for the adolescents' efforts to obtain support, to be supportive, and to handle everyday life situations better. Communal normalization might provide resources for significantly improving the participants' life situations, and could demonstrate similar potential for users in other situations characterized by stigma, loneliness, silence, and health worries. PMID- 25147220 TI - Narrative transformation among military personnel on an adventurous training and sport course. AB - In the wake of recent wars, some military personnel face considerable physical and mental health problems. In this article I explore the effects of an adapted sport and inclusive adventurous training course for military personnel who have experienced physical injury and/or psychological trauma. Using a dialogical narrative approach, I analyzed stories shared by six soldiers during the course to explore the effects of involvement. Participation in the course seemed to facilitate a narrative transformation or opening corresponding to a broadening identity and sense of self. Story plots progressed from a failing monological narrative, through a chaos narrative, toward a dialogical quest narrative prioritizing immersion in an intense present, a developing self, and a relational orientation. On the basis of narrative theory, I suggest this transformation holds positive consequences for the health and well-being of military personnel who have experienced injury and/or trauma. PMID- 25147221 TI - Female sex workers and their gatekeepers in China: implications for HIV/STI prevention. AB - Female sex workers (FSWs) play a key role in HIV/AIDS transmission and their gatekeepers play a crucial role in shaping their behaviors. Limited studies are available on the relationship between FSWs and gatekeepers. In the current study we used an ethnographic approach to examine the dynamic and multidimensional relationship of FSWs and their gatekeepers from the perspectives of both parties. We recruited 38 FSWs and 16 gatekeepers from different types of commercial sex venues in Guangxi, China, and conducted in-depth individual interviews. Our data suggest that FSWs and gatekeepers maintain an interdependent and reciprocal relationship during their business practice, but gatekeepers exert significant influence and control over FSWs. Designing culturally appropriate HIV/STI prevention programs requires us to take advantage of the unique and crucial roles of gatekeepers. We conclude with a call for structural interventions to protect FSWs' occupational health and safety. PMID- 25147222 TI - Psychiatrists' challenges in considering disclosure of schizophrenia diagnosis in Israel. AB - Doctors' clear disclosure of diagnoses to patients is fundamental to patient autonomy and patient-centered approaches in health care. Although diagnosis disclosure is common in general health, it is less so in psychiatry. The aim of this study was to explore psychiatrists' experiences of schizophrenia diagnosis disclosure to patients and/or family members. We conducted in-depth interviews with 14 psychiatrists from hospital and community settings in Israel and used a phenomenological framework to analyze the interviews. Overall, psychiatrists experienced disclosure as problematic, unproductive, and harmful. We identified 10 themes of psychiatrist experiences and concerns conceptualized under three domains: (a) characteristics of schizophrenia, (b) the doctor-patient/family relationship, and (c) psychiatrists' difficulties with the disclosure task. We discuss the results suggesting a multilayered model of medical, relational, social, and personal disclosure challenges. We suggest that a constructive schizophrenia diagnosis disclosure needs to take into account psychiatrist- and patient-related factors and specify possible directions. PMID- 25147223 TI - Consumer-operated service program members' explanatory models of mental illness and recovery. AB - Incorporating individuals' understandings and explanations of mental illness into service delivery offers benefits relating to increased service relevance and meaning. Existing research delineates explanatory models of mental illness held by individuals in home, outpatient, and hospital-based contexts; research on models held by those in peer-support contexts is notably absent. In this article, I describe themes identified within and across explanatory models of mental illness and recovery held by mental health consumers (N = 24) at one peer center, referred to as a consumer-operated service center (COSP). Participants held explanatory models inclusive of both developmental stressors and biomedical causes, consistent with a stress-diathesis model (although no participant explicitly referenced such). Explicit incorporation of stress-diathesis constructs into programming at this COSP offers the potential of increasing service meaning and relevance. Identifying and incorporating shared meanings across individuals' understandings of mental illness likewise can increase relevance and meaning for particular subgroups of service users. PMID- 25147224 TI - Assistive technology provision within the Navajo Nation: user and provider perceptions. AB - In this study we explored the factors that affect assistive technology (AT) provision within the Navajo Nation using a qualitative approach to inquiry. Focus groups were held in which AT users discussed their awareness of AT and their need for, use of, and satisfaction with AT devices and services. Twenty-eight individuals who used wheelchairs, orthotics or prosthetics, hearing aids, communication aids, vision aids, and other AT participated in one of seven focus groups. Seven AT providers discussed the facilitators and barriers that affect AT provision. The findings revealed six themes common to both stakeholder groups and two additional themes for AT users. The central theme for AT users centered on (not) feeling understood; the central theme for AT providers revolved around the processes, activities, and roles the providers engaged in at times for different clients. Activities to increase awareness and to promote successful AT provision and satisfaction with AT devices were proposed. PMID- 25147225 TI - Association of plasma levels of soluble receptor for advanced glycation end products and risk of kidney disease: the Atherosclerosis Risk in Communities study. AB - BACKGROUND: Advanced glycation end products and their cell-bound receptors are thought to mediate the adverse effects of vascular disease through oxidative stress, inflammation and endothelial dysfunction. We examined the association between the soluble form of receptor for advanced glycation end products (sRAGE) and kidney disease. METHODS: In this case-cohort study nested within the Atherosclerosis Risk in Communities (ARIC) study, baseline sRAGE levels were measured in a cohort random sample of participants without kidney disease (n= 1218), and among participants who developed incident chronic kidney disease (CKD) [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) and >=25% eGFR decline, n = 151] and end-stage renal disease (ESRD) [entry in the US Renal Data System (USRDS) registry, n = 152]. RESULTS: Baseline sRAGE levels were inversely related to baseline eGFR (r = -0.13). After adjusting for age, sex and race, one interquartile range higher log10-transformed sRAGE was associated with development of CKD [odds ratio: 1.39; 95% confidence interval (95% CI) 1.06-1.83; P = 0.02] and ESRD (hazard ratio: 1.97; 95% CI 1.47-2.64; P < 0.001). These associations were not significant after eGFR adjustment. CONCLUSIONS: High sRAGE levels are associated with incident CKD and ESRD risk, but not after adjustment for kidney function at baseline. Future studies are needed to investigate specific mechanisms underlying the association of sRAGE with kidney disease risk. PMID- 25147226 TI - Familial tumoral calcinosis: a valuable vehicle for discovery. PMID- 25147227 TI - Causal effect estimation strategies in a longitudinal study with complex time varying confounders: A tutorial. AB - The Dutch Sciatica Trial represents a longitudinal study with complex time varying confounders as patients with poorer health conditions (e.g. more severe pain) are more likely to opt for surgery, which, in turn, may affect future outcomes (pain severity). A straightforward classical as-treated comparison at the end point would lead to biased estimation of the surgery effect. We present several strategies of causal treatment effect estimation that might be applicable for analyzing such data. These include an inverse probability of treatment weighted regression analysis, a marginal weighted analysis, an unweighted regression analysis, and several propensity score-based approaches. In addition, we demonstrate how to evaluate these approaches in a thorough simulation study where we generate various realistic complex confounding patterns akin to the sciatica study. PMID- 25147228 TI - Accelerated longitudinal designs: An overview of modelling, power, costs and handling missing data. AB - Longitudinal studies are often used to investigate age-related developmental change. Whereas a single cohort design takes a group of individuals at the same initial age and follows them over time, an accelerated longitudinal design takes multiple single cohorts, each one starting at a different age. The main advantage of an accelerated longitudinal design is its ability to span the age range of interest in a shorter period of time than would be possible with a single cohort longitudinal design. This paper considers design issues for accelerated longitudinal studies. A linear mixed effect model is considered to describe the responses over age with random effects for intercept and slope parameters. Random and fixed cohort effects are used to cope with the potential bias accelerated longitudinal designs have due to multiple cohorts. The impact of other factors such as costs and the impact of dropouts on the power of testing or the precision of estimating parameters are examined. As duration-related costs increase relative to recruitment costs the best designs shift towards shorter duration and eventually cross-sectional design being best. For designs with the same duration but differing interval between measurements, we found there was a cutoff point for measurement costs relative to recruitment costs relating to frequency of measurements. Under our model of 30% dropout there was a maximum power loss of 7%. PMID- 25147229 TI - Correlation between cerebral blood volume values and outcomes in endovascular therapy for acute ischemic stroke. AB - BACKGROUND: Neurointerventionalists do not agree about the optimal imaging protocol when evaluating patients with acute stroke for potential endovascular revascularization. Preintervention cerebrovascular blood volume (CBV) has been shown to predict outcomes in patients undergoing intra-arterial stroke therapies. OBJECTIVE: To determine whether CBV can predict hemorrhagic transformation and clinical outcomes in patients selected for endovascular therapy for acute ischemic middle cerebral artery (MCA) stroke using a CT perfusion (CTP)-based imaging protocol. METHODS: We retrospectively reviewed cases of acute ischemic stroke due to MCA M1 segment occlusion and correlated favorable clinical outcomes (modified Rankin scale (mRS) <=2) and radiographic outcomes with preintervention CBV values. All patients underwent whole-brain (320-detector-row) CTP imaging, and absolute CBV values of the affected and contralateral MCA territories were obtained separately for the cortical and basal ganglia regions. RESULTS: Relative CBV (rCBV) of the MCA cortical regions was significantly lower in patients with poor clinical outcomes than in those with favorable clinical outcomes (0.87+/ 0.21 vs 1.02+/-0.09, p=0.0003), and a negative correlation was found between rCBV values and mRS score severity. rCBV of the basal ganglia region was significantly lower in patients with hemorrhagic infarction (p=0.004) and parenchymal hematoma (p=0.04) than in those without hemorrhagic transformation. CONCLUSIONS: We found that cortical CBV loss is predictive of poor clinical outcomes, whereas basal ganglia CBV loss is predictive of hemorrhagic transformation but without translation into poor clinical outcomes. Our study findings support published results of baseline preintervention CBV as a predictor of outcomes in patients undergoing intra-arterial stroke therapies. PMID- 25147230 TI - Hepatic entrapment of esterified cholesterol drives continual expansion of whole body sterol pool in lysosomal acid lipase-deficient mice. AB - Cholesteryl ester storage disease (CESD) results from loss-of-function mutations in LIPA, the gene that encodes lysosomal acid lipase (LAL). Hepatomegaly and deposition of esterified cholesterol (EC) in multiple organs ensue. The present studies quantitated rates of synthesis, absorption, and disposition of cholesterol, and whole body cholesterol pool size in a mouse model of CESD. In 50 day-old lal(-/-) and matching lal(+/+) mice fed a low-cholesterol diet, whole animal cholesterol content equalled 210 and 50 mg, respectively, indicating that since birth the lal(-/-) mice sequestered cholesterol at an average rate of 3.2 mg.day(-1).animal(-1). The proportion of the body sterol pool contained in the liver of the lal(-/-) mice was 64 vs. 6.3% in their lal(+/+) controls. EC concentrations in the liver, spleen, small intestine, and lungs of the lal(-/-) mice were elevated 100-, 35-, 15-, and 6-fold, respectively. In the lal(-/-) mice, whole liver cholesterol synthesis increased 10.2-fold, resulting in a 3.2 fold greater rate of whole animal sterol synthesis compared with their lal(+/+) controls. The rate of cholesterol synthesis in the lal(-/-) mice exceeded that in the lal(+/+) controls by 3.7 mg.day(-1).animal(-1). Fractional cholesterol absorption and fecal bile acid excretion were unchanged in the lal(-/-) mice, but their rate of neutral sterol excretion was 59% higher than in their lal(+/+) controls. Thus, in this model, the continual expansion of the body sterol pool is driven by the synthesis of excess cholesterol, primarily in the liver. Despite the severity of their disease, the median life span of the lal(-/-) mice was 355 days. PMID- 25147231 TI - Innervation of enteric mast cells by primary spinal afferents in guinea pig and human small intestine. AB - Mast cells express the substance P (SP) neurokinin 1 receptor and the calcitonin gene-related peptide (CGRP) receptor in guinea pig and human small intestine. Enzyme-linked immunoassay showed that activation of intramural afferents by antidromic electrical stimulation or by capsaicin released SP and CGRP from human and guinea pig intestinal segments. Electrical stimulation of the afferents evoked slow excitatory postsynaptic potentials (EPSPs) in the enteric nervous system. The slow EPSPs were mediated by tachykinin neurokinin 1 and CGRP receptors. Capsaicin evoked slow EPSP-like responses that were suppressed by antagonists for protease-activated receptor 2. Afferent stimulation evoked slow EPSP-like excitation that was suppressed by mast cell-stabilizing drugs. Histamine and mast cell protease II were released by 1) exposure to SP or CGRP, 2) capsaicin, 3) compound 48/80, 4) elevation of mast cell Ca2+ by ionophore A23187, and 5) antidromic electrical stimulation of afferents. The mast cell stabilizers cromolyn and doxantrazole suppressed release of protease II and histamine when evoked by SP, CGRP, capsaicin, A23187, electrical stimulation of afferents, or compound 48/80. Neural blockade by tetrodotoxin prevented mast cell protease II release in response to antidromic electrical stimulation of mesenteric afferents. The results support a hypothesis that afferent innervation of enteric mast cells releases histamine and mast cell protease II, both of which are known to act in a diffuse paracrine manner to influence the behavior of enteric nervous system neurons and to elevate the sensitivity of spinal afferent terminals. PMID- 25147232 TI - Pediatric eosinophilic esophagitis is associated with changes in esophageal microRNAs. AB - The incidence of eosinophilic esophagitis (EoE) has increased in the past several years, yet our understanding of its pathogenesis remains limited. To test the hypothesis that microRNAs (miRNAs) are altered in children with EoE, miRNAs were profiled in esophageal mucosa biopsies obtained from patients with active disease (n = 5) and healthy control subjects (n = 6). Fourteen miRNAs were significantly altered between groups; four of these miRNAs were decreased in EoE patients. A panel of five miRNAs (miR-203, miR-375, miR-21, miR-223, and miR-142-3p) were selected for validation in an independent set of samples from control (n = 22), active disease (n = 22), inactive disease (n = 22), and gastroesophageal reflux disease (n = 6) patients. Each panel miRNA was significantly altered among groups. miRNA changes in esophageal biopsies were not reflected in the circulating RNA pool, as no differences in panel miRNA levels were observed in sera collected from the four patient groups. In addition, in contrast to previous studies, no change in esophageal miRNA levels was detected following treatment that resolved esophageal eosinophilia. In an effort to identify the ramifications of reduced esophageal miR-203, miR-203 activity was inhibited in cultured epithelial cells via expression of a tough decoy miRNA inhibitor. Luciferase reporter assays demonstrated that miR-203 does not directly regulate human IL-15 through targeting of the IL-15 3'-untranslated region. From these experiments, it is concluded that miRNAs are perturbed in the esophageal mucosa, but not the serum, of pediatric EoE patients. Further investigation is required to decipher pathologically relevant consequences of miRNA perturbation in this context. PMID- 25147233 TI - Effect of Rothia mucilaginosa enzymes on gliadin (gluten) structure, deamidation, and immunogenic epitopes relevant to celiac disease. AB - Rothia mucilaginosa, a natural microbial inhabitant of the oral cavity, cleaves gluten (gliadin) proteins at regions that are resistant to degradation by mammalian enzymes. The aim of this study was to investigate to what extent the R. mucilaginosa cell-associated enzymes abolish gliadin immunogenic properties. Degradation of total gliadins and highly immunogenic gliadin 33-mer or 26-mer peptides was monitored by SDS-PAGE and RP-HPLC, and fragments were sequenced by liquid chromatography and electrospray ionization tandem mass spectrometer (LC ESI-MS/MS). Peptide deamidation by tissue transglutaminase (TG2), a critical step in rendering the fragments more immunogenic, was assessed by TG2-mediated cross linking to monodansyl cadaverine (MDC), and by a +1-Da mass difference by LC-ESI MS. Survival of potential immunogenic gliadin epitopes was determined by use of the R5 antibody-based ELISA. R. mucilaginosa-associated enzymes cleaved gliadins, 33-mer and 26-mer peptides into smaller fragments. TG2-mediated cross-linking showed a perfect inverse relationship with intact 33-mer and 26-mer peptide levels, and major degradation fragments showed a slow rate of MDC cross-linking of 6.18 +/- 2.20 AU/min compared with 97.75 +/- 10.72 and 84.17 +/- 3.25 AU/min for the intact 33-mer and 26-mer, respectively, which was confirmed by reduced TG2-mediated deamidation of the fragments in mass spectrometry. Incubation of gliadins with Rothia cells reduced R5 antibody binding by 20, 82, and 97% after 30 min, 2 h, and 5 h, respectively, which was paralleled by reduced reactivity of enzyme-treated 33-mer and 26-mer peptides in the R5 competitive ELISA. Our broad complementary approach to validate gluten degrading activities qualifies R. mucilaginosa-associated enzymes as promising tools to neutralize T cell immunogenic properties for treatment of celiac disease. PMID- 25147234 TI - Oxytocin regulates gastrointestinal motility, inflammation, macromolecular permeability, and mucosal maintenance in mice. AB - Enteric neurons express oxytocin (OT); moreover, enteric neurons and enterocytes express developmentally regulated OT receptors (OTRs). Although OT (with secretin) opposes intestinal inflammation, physiological roles played by enteric OT/OTR signaling have not previously been determined. We tested hypotheses that OT/OTR signaling contributes to enteric nervous system (ENS)-related gastrointestinal (GI) physiology. GI functions and OT effects were compared in OTR-knockout (OTRKO) and wild-type (WT) mice. Stool mass and water content were greater in OTRKO mice than in WT. GI transit time in OTRKO animals was faster than in WT; OT inhibited in vitro generation of ENS-dependent colonic migrating motor complexes in WT but not in OTRKO mice. Myenteric neurons were hyperplastic in OTRKO animals, and mucosal exposure to cholera toxin (CTX) in vitro activated Fos in more myenteric neurons in OTRKO than WT than in WT mice; OT inhibited the CTX response in WT but not in OTRKO mice. Villi and crypts were shorter in OTRKO than in WT mice, and transit-amplifying cell proliferation in OTRKO crypts was deficient. Macromolecular intestinal permeability in OTRKO was greater than WT mice, and experimental colitis was more severe in OTRKO mice; moreover, OT protected WT animals from colitis. Observations suggest that OT/OTR signaling acts as a brake on intestinal motility, decreases mucosal activation of enteric neurons, and promotes enteric neuronal development and/or survival. It also regulates proliferation of crypt cells and mucosal permeability; moreover OT/OTR signaling is protective against inflammation. Oxytocinergic signaling thus appears to play an important role in multiple GI functions that are subject to neuronal regulation. PMID- 25147235 TI - Transforming growth factor-beta2 and endotoxin interact to regulate homeostasis via interleukin-8 levels in the immature intestine. AB - A balance between pro- and anti-inflammatory signals from milk and microbiota controls intestinal homeostasis just after birth, and an optimal balance is particularly important for preterm neonates that are sensitive to necrotizing enterocolitis (NEC). We suggest that the intestinal cytokine IL-8 plays an important role and hypothesize that transforming growth factor-beta2 (TGF-beta2) acts in synergy with bacterial lipopolysaccharide (LPS) to control IL-8 levels, thereby supporting intestinal homeostasis. Preterm pigs were fed colostrum (containing TGF-beta2) or infant formula (IF) with or without antibiotics (COLOS, n = 27; ANTI, n = 11; IF, n = 40). Intestinal IL-8 levels and NEC incidence were much higher in IF than in COLOS and ANTI pigs (P < 0.001), but IL-8 levels did not correlate with NEC severity. Intestinal TGF-beta2 levels were high in COLOS but low in IF and ANTI pigs. Based on these observations, the interplay among IL 8, TGF-beta2, and LPS was investigated in a porcine intestinal epithelial cell line. TGF-beta2 attenuated LPS-induced IL-6, IL-1beta, and TNF-alpha release by reducing early ERK activation, whereas IL-8 secretion was synergistically induced by LPS and TGF-beta2 via NF-kappaB. The TGF-beta2/LPS-induced IL-8 levels stimulated cell proliferation and migration following epithelial injury, without continuous NF-kappaB activation and cyclooxygenase-2 expression. We suggest that a combined TGF-beta2-LPS induction of IL-8 stimulates epithelial repair just after birth when the intestine is first exposed to colonizing bacteria and TGF beta2-containing milk. Moderate IL-8 levels may act to control intestinal inflammation, whereas excessive IL-8 production may enhance the damaging proinflammatory cascade leading to NEC. PMID- 25147236 TI - The effect of valacyclovir on HIV and HSV-2 in HIV-infected persons on antiretroviral therapy with previously unrecognised HSV-2. AB - In the absence of antiretroviral therapy, valacyclovir may reduce HIV viral load and increase CD4+ T-lymphocyte count. We sought to evaluate the impact of valacyclovir on HIV and HSV-2 in co-infected patients receiving antiretroviral therapy with previously unrecognised HSV-2 infection. A prospective, randomised controlled, 24-week trial of valacyclovir 1000 mg was performed. Mean CD4+ T lymphocyte count at 24 weeks compared to baseline CD4+ T-lymphocyte count was the primary outcome. HIV viral load suppression, HSV-2 outbreaks and asymptomatic HSV 2 shedding were secondary outcomes. Participants were randomised to valacyclovir (N = 66) or placebo (N = 35). Study completion was 64%. There was no change in 24 weeks compared to baseline CD4+ T-lymphocyte count in either group (valacyclovir p = 0.91, placebo p = 0.59) or the proportion with HIV viral load suppression (valacyclovir p = 0.75, placebo p = 1.0). Genital HSV and asymptomatic HSV-2 shedding were rare. Valacyclovir had no effect on CD4+ T-lymphocyte count or HIV viral load in this population. Valacyclovir may reduce clinical outbreaks and asymptomatic HSV-2 shedding, but the rarity of these events, along with its lack of benefit on HIV, does not support its use in this clinical setting. PMID- 25147237 TI - The utility of genotypic tropism testing in clinical practice. AB - A review of a large number of HIV-1 tropism test requests (n = 1148) performed at a London tertiary referral centre was carried out. The aim was to establish whether these were being performed in line with recommendations from published guidelines and whether this represented the most cost-effective use of these tests in informing prescribing decisions of the CCR5 antagonist drug, maraviroc. The cost of these assays within the UK was covered by commercial funding until April 2013 which has subsequently been withdrawn. Furthermore, all healthcare settings are under increasing cost constraints and hence establishing the real utility and appropriate use of these tests is of vital importance. PMID- 25147238 TI - Clostridium difficile Hfq can replace Escherichia coli Hfq for most of its function. AB - A gene for the Hfq protein is present in the majority of sequenced bacterial genomes. Its characteristic hexameric ring-like core structure is formed by the highly conserved N-terminal regions. In contrast, the C-terminal forms an extension, which varies in length, lacks homology, and is predicted to be unstructured. In Gram-negative bacteria, Hfq facilitates the pairing of sRNAs with their mRNA target and thus affects gene expression, either positively or negatively, and modulates sRNA degradation. In Gram-positive bacteria, its role is still poorly characterized. Numerous sRNAs have been detected in many Gram positive bacteria, but it is not yet known whether these sRNAs act in association with Hfq. Compared with all other Hfqs, the C. difficile Hfq exhibits an unusual C-terminal sequence with 75% asparagine and glutamine residues, while the N terminal core part is more conserved. To gain insight into the functionality of the C. difficile Hfq (Cd-Hfq) protein in processes regulated by sRNAs, we have tested the ability of Cd-Hfq to fulfill the functions of the E. coli Hfq (Ec-Hfq) by examining various functions associated with Hfq in both positive and negative controls of gene expression. We found that Cd-Hfq substitutes for most but not all of the tested functions of the Ec-Hfq protein. We also investigated the role of the C-terminal part of the Hfq proteins. We found that the C-terminal part of both Ec-Hfq and Cd-Hfq is not essential but contributes to some functions of both the E. coli and C. difficile chaperons. PMID- 25147239 TI - Detecting translational regulation by change point analysis of ribosome profiling data sets. AB - Ribo-Seq maps the location of translating ribosomes on mature mRNA transcripts. While during normal translation, ribosome density is constant along the length of the mRNA coding region, this can be altered in response to translational regulatory events. In the present study, we developed a method to detect translational regulation of individual mRNAs from their ribosome profiles, utilizing changes in ribosome density. We used mathematical modeling to show that changes in ribosome density should occur along the mRNA at the point of regulation. We analyzed a Ribo-Seq data set obtained for mouse embryonic stem cells and showed that normalization by corresponding RNA-Seq can be used to improve the Ribo-Seq quality by removing bias introduced by deep-sequencing and alignment artifacts. After normalization, we applied a change point algorithm to detect changes in ribosome density present in individual mRNA ribosome profiles. Additional sequence and gene isoform information obtained from the UCSC Genome Browser allowed us to further categorize the detected changes into different mechanisms of regulation. In particular, we detected several mRNAs with known post-transcriptional regulation, e.g., premature termination for selenoprotein mRNAs and translational control of Atf4, but also several more mRNAs with hitherto unknown translational regulation. Additionally, our approach proved useful for identification of new transcript isoforms. PMID- 25147241 TI - Electromyographic analysis of goal-directed grasping behavior in the American lobster. AB - Animals spontaneously initiate goal-directed behavior including foraging action based on their appetitive motivation. The American lobster Homarus americanus exhibits grasping behavior with its crusher claw as feeding behavior that can be initiated after appropriate operant conditioning. In order to quantitatively characterize the goal-directed grasping behavior with a time resolution fine enough for neurophysiological analysis of its initiation and control mechanisms, we made simultaneous electromyographic (EMG) recording from grasping- and reaching-related muscles of the crusher claw while animals initiated grasping behavior. We developed an in vivo extracellular recording chamber that allowed the animal under a semi-restrained condition to perform operant reward learning of claw grasping. Three muscles in the crusher claw (propodite-dactyl closer/opener and coxal protractor) were found to be closely associated with spontaneous grasping behavior. In spontaneous grasping, the activation of those muscles consistently preceded the grasping onset time and exhibited different activity patterns from the grasp induced by a mechanical stimulus. Furthermore, we found that the timing of coxal protractor activation was closer to the grasp onset and its activity was briefer for goal-directed grasping behavior in trained and hungry animals than for non-goal-directed spontaneous grasping behavior in naive or satiated animals. It is suggested that the goal-directed grasping behavior of lobster is characterized, at least partly, by experience-dependent briefer activity of specific muscles involved in reaching action. PMID- 25147240 TI - The interaction of cytoplasmic poly(A)-binding protein with eukaryotic initiation factor 4G suppresses nonsense-mediated mRNA decay. AB - Nonsense-mediated mRNA decay (NMD) eliminates different classes of mRNA substrates including transcripts with long 3' UTRs. Current models of NMD suggest that the long physical distance between the poly(A) tail and the termination codon reduces the interaction between cytoplasmic poly(A)-binding protein (PABPC1) and the eukaryotic release factor 3a (eRF3a) during translation termination. In the absence of PABPC1 binding, eRF3a recruits the NMD factor UPF1 to the terminating ribosome, triggering mRNA degradation. Here, we have used the MS2 tethering system to investigate the suppression of NMD by PABPC1. We show that tethering of PABPC1 between the termination codon and a long 3' UTR specifically inhibits NMD-mediated mRNA degradation. Contrary to the current model, tethered PABPC1 mutants unable to interact with eRF3a still efficiently suppress NMD. We find that the interaction of PABPC1 with eukaryotic initiation factor 4G (eIF4G), which mediates the circularization of mRNAs, is essential for NMD inhibition by tethered PABPC1. Furthermore, recruiting either eRF3a or eIF4G in proximity to an upstream termination codon antagonizes NMD. While tethering of an eRF3a mutant unable to interact with PABPC1 fails to suppress NMD, tethered eIF4G inhibits NMD in a PABPC1-independent manner, indicating a sequential arrangement of NMD antagonizing factors. In conclusion, our results establish a previously unrecognized link between translation termination, mRNA circularization, and NMD suppression, thereby suggesting a revised model for the activation of NMD at termination codons upstream of long 3' UTR. PMID- 25147242 TI - Arginine vasotocin, steroid hormones and social behavior in the green anole lizard (Anolis carolinensis). AB - Arginine vasotocin (AVT) is a potent regulator of social behavior in many species, but little is known about its role in reptilian behavior. Here we examine the effect of exogenous AVT on aggressive responding and courtship behavior in the green anole lizard (Anolis carolinensis). Aggressive behavior was stimulated in two ways: (1) mirror presentation (no relative status formed) and (2) size-matched pairs (where a social status is achieved). To elicit courtship behavior, a novel female was introduced into the home cage of a male. Regardless of the behavior condition, male anoles were injected i.p. with either reptile Ringer solution (vehicle) or AVT prior to testing. Animals treated with AVT performed fewer aggressive display bouts during mirror presentation but AVT treatment did not affect the overall number of aggressive display bouts within size-matched pairs. Male courtship behavior was not affected by AVT; however, untreated females displayed more frequently when paired with an AVT-treated male than a vehicle-injected control, suggesting that AVT-treated males were more attractive to females. Regardless of behavior condition, AVT injections led to increases in circulating corticosterone. Overall, we found that AVT tended to reduce aggressive behavior as has been reported for other territorial species. AVT did not perceptibly alter male courtship but did increase the display behavior of untreated females paired with treated males. Our study supports a role for AVT in the regulation of reptile social behavior. PMID- 25147243 TI - Thermoregulatory strategy may shape immune investment in Drosophila melanogaster. AB - As temperatures change, insects alter the amount of melanin in their cuticle to improve thermoregulation. However, melanin is also central to insect immunity, suggesting that thermoregulatory strategy may indirectly impact immune defense by altering the abundance of melanin pathway components (a hypothesis we refer to as thermoregulatory-dependent immune investment). This may be the case in the cricket Allonemobius socius, where warm environments (both seasonal and geographical) produced crickets with lighter cuticles and increased pathogen susceptibility. Unfortunately, the potential for thermoregulatory strategy to influence insect immunity has not been widely explored. Here we address the relationships between temperature, thermoregulatory strategy and immunity in the fruit fly Drosophila melanogaster. To this end, flies from two separate Canadian populations were reared in either a summer- or autumn-like environment. Shortly after adult eclosion, flies were moved to a common environment where their cuticle color and susceptibility to a bacterial pathogen (Pseudomonas aeruginosa) were measured. As with A. socius, individuals from summer-like environments exhibited lighter cuticles and increased pathogen susceptibility, suggesting that the thermoregulatory-immunity relationship is evolutionarily conserved across the hemimetabolous and holometabolous clades. If global temperatures continue to rise as expected, then thermoregulation might play an important role in host infection and mortality rates in systems that provide critical ecosystem services (e.g. pollination), or influence the prevalence of insect-vectored disease (e.g. malaria). PMID- 25147244 TI - Body temperature stability achieved by the large body mass of sea turtles. AB - To investigate the thermal characteristics of large reptiles living in water, temperature data were continuously recorded from 16 free-ranging loggerhead turtles, Caretta caretta, during internesting periods using data loggers. Core body temperatures were 0.7-1.7 degrees C higher than ambient water temperatures and were kept relatively constant. Unsteady numerical simulations using a spherical thermodynamic model provided mechanistic explanations for these phenomena, and the body temperature responses to fluctuating water temperature can be simply explained by a large body mass with a constant thermal diffusivity and a heat production rate rather than physiological thermoregulation. By contrast, body temperatures increased 2.6-5.1 degrees C in 107-152 min during their emergences to nest on land. The estimated heat production rates on land were 7.4-10.5 times the calculated values in the sea. The theoretical prediction that temperature difference between body and water temperatures would increase according to the body size was confirmed by empirical data recorded from several species of sea turtles. Comparing previously reported data, the internesting intervals of leatherback, green and loggerhead turtles were shorter when the body temperatures were higher. Sea turtles seem to benefit from a passive thermoregulatory strategy, which depends primarily on the physical attributes of their large body masses. PMID- 25147245 TI - The relationship between cardiopulmonary size and aerobic performance in adult deer mice at high altitude. AB - Deer mice (Peromyscus maniculatus sonoriensis) populations in the White Mountains of Eastern California are found across a substantial range of partial pressures of oxygen (PO2). Reduction in PO2 at high altitude can have a negative impact on aerobic performance. We studied plastic changes in organ mass and volume involved in aerobic respiration in response to acclimation to high altitude, and how those changes are matched with aerobic performance measured by VO2,max. Adult deer mice born and raised at 340 m were acclimated at either 340 or 3800 m for a period of 9 weeks. Lung volume increased by 9% in mice acclimated to high altitude. VO2,max was also significantly higher under hypoxic conditions after high altitude acclimation compared with controls. Body mass-corrected residuals of VO2,max were significantly correlated with an index of cardiopulmonary size (summed standardized residuals of lung volume and heart mass) under both hypoxic and normoxic conditions. These data show that phenotypic plasticity in lung volume and heart mass plays an important role in maintaining aerobic performance under hypoxic conditions, and accounts for up to 55% of the variance in aerobic performance. PMID- 25147246 TI - Titin force is enhanced in actively stretched skeletal muscle. AB - The sliding filament theory of muscle contraction is widely accepted as the means by which muscles generate force during activation. Within the constraints of this theory, isometric, steady-state force produced during muscle activation is proportional to the amount of filament overlap. Previous studies from our laboratory demonstrated enhanced titin-based force in myofibrils that were actively stretched to lengths which exceeded filament overlap. This observation cannot be explained by the sliding filament theory. The aim of the present study was to further investigate the enhanced state of titin during active stretch. Specifically, we confirm that this enhanced state of force is observed in a mouse model and quantify the contribution of calcium to this force. Titin-based force was increased by up to four times that of passive force during active stretch of isolated myofibrils. Enhanced titin-based force has now been demonstrated in two distinct animal models, suggesting that modulation of titin-based force during active stretch is an inherent property of skeletal muscle. Our results also demonstrated that 15% of the enhanced state of titin can be attributed to direct calcium effects on the protein, presumably a stiffening of the protein upon calcium binding to the E-rich region of the PEVK segment and selected Ig domain segments. We suggest that the remaining unexplained 85% of this extra force results from titin binding to the thin filament. With this enhanced force confirmed in the mouse model, future studies will aim to elucidate the proposed titin-thin filament interaction in actively stretched sarcomeres. PMID- 25147247 TI - Availability and quality of mobile health app privacy policies. AB - Mobile health (mHealth) customers shopping for applications (apps) should be aware of app privacy practices so they can make informed decisions about purchase and use. We sought to assess the availability, scope, and transparency of mHealth app privacy policies on iOS and Android. Over 35,000 mHealth apps are available for iOS and Android. Of the 600 most commonly used apps, only 183 (30.5%) had privacy policies. Average policy length was 1755 (SD 1301) words with a reading grade level of 16 (SD 2.9). Two thirds (66.1%) of privacy policies did not specifically address the app itself. Our findings show that currently mHealth developers often fail to provide app privacy policies. The privacy policies that are available do not make information privacy practices transparent to users, require college-level literacy, and are often not focused on the app itself. Further research is warranted to address why privacy policies are often absent, opaque, or irrelevant, and to find a remedy. PMID- 25147248 TI - Evaluating the state of the art in disorder recognition and normalization of the clinical narrative. AB - OBJECTIVE: The ShARe/CLEF eHealth 2013 Evaluation Lab Task 1 was organized to evaluate the state of the art on the clinical text in (i) disorder mention identification/recognition based on Unified Medical Language System (UMLS) definition (Task 1a) and (ii) disorder mention normalization to an ontology (Task 1b). Such a community evaluation has not been previously executed. Task 1a included a total of 22 system submissions, and Task 1b included 17. Most of the systems employed a combination of rules and machine learners. MATERIALS AND METHODS: We used a subset of the Shared Annotated Resources (ShARe) corpus of annotated clinical text--199 clinical notes for training and 99 for testing (roughly 180 K words in total). We provided the community with the annotated gold standard training documents to build systems to identify and normalize disorder mentions. The systems were tested on a held-out gold standard test set to measure their performance. RESULTS: For Task 1a, the best-performing system achieved an F1 score of 0.75 (0.80 precision; 0.71 recall). For Task 1b, another system performed best with an accuracy of 0.59. DISCUSSION: Most of the participating systems used a hybrid approach by supplementing machine-learning algorithms with features generated by rules and gazetteers created from the training data and from external resources. CONCLUSIONS: The task of disorder normalization is more challenging than that of identification. The ShARe corpus is available to the community as a reference standard for future studies. PMID- 25147249 TI - A Monte Carlo calibration of a whole body counter using the ICRP computational phantoms. AB - A fast and versatile calibration of a whole body counter (WBC) is presented. The WBC, consisting of four large plastic scintillators, is to be used for measurements after accident or other incident involving ionising radiation. The WBC was calibrated using Monte Carlo modelling and the ICRP computational phantoms. The Monte Carlo model of the WBC was made in GATE, v6.2 (Geant4 Application for Tomographic Emission) and MATLAB. The Monte Carlo model was verified by comparing simulated energy spectrum and simulated counting efficiency with experimental energy spectrum and experimental counting efficiency for high energy monoenergetic gamma-emitting point sources. The simulated results were in good agreement with experimental results except when compared with experimental results from high dead-time (DT) measurements. The Monte Carlo calibration was made for a heterogeneous source distribution of (137)Cs and (40)K, respectively, inside the ICRP computational phantoms. The source distribution was based on the biokinetic model for (137)Cs. PMID- 25147251 TI - Frederick C. Goetz, MD: a profile of the intersection among science, the fine arts, and education. PMID- 25147252 TI - Insights offered by economic analyses. PMID- 25147254 TI - The lifetime cost of diabetes and its implications for diabetes prevention. AB - OBJECTIVE: To assess the cost implications of diabetes prevention, it is important to know the lifetime medical cost of people with diabetes relative to those without. We derived such estimates using data representative of the U.S. national population. RESEARCH DESIGN AND METHODS: We aggregated annual medical expenditures from the age of diabetes diagnosis to death to determine lifetime medical expenditure. Annual medical expenditures were estimated by sex, age at diagnosis, and diabetes duration using data from 2006-2009 Medical Expenditure Panel Surveys, which were linked to data from 2005-2008 National Health Interview Surveys. We combined survival data from published studies with the estimated annual expenditures to calculate lifetime spending. We then compared lifetime spending for people with diabetes with that for those without diabetes. Future spending was discounted at 3% annually. RESULTS: The discounted excess lifetime medical spending for people with diabetes was $124,600 ($211,400 if not discounted), $91,200 ($135,600), $53,800 ($70,200), and $35,900 ($43,900) when diagnosed with diabetes at ages 40, 50, 60, and 65 years, respectively. Younger age at diagnosis and female sex were associated with higher levels of lifetime excess medical spending attributed to diabetes. CONCLUSIONS: Having diabetes is associated with substantially higher lifetime medical expenditures despite being associated with reduced life expectancy. If prevention costs can be kept sufficiently low, diabetes prevention may lead to a reduction in long-term medical costs. PMID- 25147253 TI - Impact of an intensive lifestyle intervention on use and cost of medical services among overweight and obese adults with type 2 diabetes: the action for health in diabetes. AB - OBJECTIVE: To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of health care within the Look AHEAD trial. RESEARCH DESIGN AND METHODS: A total of 5,121 overweight or obese adults with type 2 diabetes were randomly assigned to an ILI that promoted weight loss or to a comparison condition of diabetes support and education (DSE). Use and costs of health-care services were recorded across an average of 10 years. RESULTS: ILI led to reductions in annual hospitalizations (11%, P = 0.004), hospital days (15%, P = 0.01), and number of medications (6%, P < 0.001), resulting in cost savings for hospitalization (10%, P = 0.04) and medication (7%, P < 0.001). ILI produced a mean relative per-person 10-year cost savings of $5,280 (95% CI 3,385 7,175); however, these were not evident among individuals with a history of cardiovascular disease. CONCLUSIONS: Compared with DSE over 10 years, ILI participants had fewer hospitalizations, fewer medications, and lower health-care costs. PMID- 25147255 TI - Birth weight and risk of type 2 diabetes in the black women's health study: does adult BMI play a mediating role? AB - OBJECTIVE: To assess the association of birth weight with incident type 2 diabetes, and the possible mediating influence of obesity, in a large cohort of U.S. black women. RESEARCH DESIGN AND METHODS: The Black Women's Health Study is an ongoing prospective study. We used Cox proportional hazards models to estimate incidence rate ratios (IRRs) and 95% CI for categories of birth weight (very low birth weight [<1,500 g], low birth weight [1,500-2,499 g], and high birth weight [>=4,000 g]) in reference to normal birth weight (2,500-3,999 g). Models were adjusted for age, questionnaire cycle, family history of diabetes, caloric intake, preterm birth, physical activity, years of education, and neighborhood socioeconomic status with and without inclusion of terms for adult BMI. RESULTS: We followed 21,624 women over 16 years of follow-up. There were 2,388 cases of incident diabetes. Women with very low birth weight had a 40% higher risk of disease (IRR 1.40 [95% CI 1.08-1.82]) than women with normal birth weight; women with low birth weight had a 13% higher risk (IRR 1.13 [95% CI 1.02-1.25]). Adjustment for BMI did not appreciably change the estimates. CONCLUSIONS: Very low birth weight and low birth weight appear to be associated with increased risk of type 2 diabetes in African American women, and the association does not seem to be mediated through BMI. The prevalence of low birth weight is especially high in African American populations, and this may explain in part the higher occurrence of type 2 diabetes. PMID- 25147256 TI - Coronary artery calcification in obese youth: what are the phenotypic and metabolic determinants? AB - OBJECTIVE: Obesity in adolescence has been associated with increased risk for coronary heart disease in adulthood. This study evaluated subclinical atherosclerosis in obese youth and the underlying risk factors. RESEARCH DESIGN AND METHODS: Ninety obese adolescents (37 normal glucose tolerant, 27 prediabetes, and 26 type 2 diabetes) underwent evaluation of coronary artery calcifications (CACs) by electron beam computed tomography, aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT), lipids, leptin, inflammatory markers, and body composition (DEXA). A total of 68 underwent evaluation of insulin sensitivity (IS) (hyperinsulinemic-euglycemic clamp) and abdominal adiposity (computed tomography). RESULTS: A total of 50% had CACs (CAC+: Agatston CAC score >=1). CAC+ youth had higher BMI, fat mass, and abdominal fat, with no difference in sex, race, IS per fat-free mass (ISFFM), glucose tolerance, PWV, or IMT compared with the CAC- group. PWV was inversely related to IS. In multiple regression analyses with age, race, sex, HbA1c, BMI (or waist circumference), ISFFM, diastolic blood pressure, non-HDL cholesterol, and leptin as independent variables, BMI (or waist) (R(2) = 0.41; P = 0.001) was the significant determinant of CAC; leptin (R(2) = 0.37; P = 0.034) for PWV; and HbA1c, race, and age (R(2) = 0.34; P = 0.02) for IMT. CONCLUSIONS: Early in the course of obesity, there is evidence of CAC independent of glycemia. The different biomarkers of subclinical atherosclerosis appear to be differentially modulated, adiposity being the major determinant of CAC, hyperglycemia, age, and race for IMT, and leptin and IS for arterial stiffness. These findings highlight the increased cardiovascular disease risk in obese youth and the need for early interventions to reverse obesity and atherosclerosis. PMID- 25147259 TI - Self-management education by group care reduces cardiovascular risk in patients with type 2 diabetes: analysis of the ROMEO clinical trial. PMID- 25147260 TI - Timing of gluten introduction and islet autoimmunity in young children: updated results from the BABYDIET study. PMID- 25147257 TI - Beyond metformin: safety considerations in the decision-making process for selecting a second medication for type 2 diabetes management: reflections from a diabetes care editors' expert forum. AB - The trend toward personalized management of diabetes has focused attention on the differences among available pharmacological agents in terms of mechanisms of action, efficacy, and, most important, safety. Clinicians must select from these features to develop individualized therapy regimens. In June 2013, a nine-member Diabetes Care Editors' Expert Forum convened to review safety evidence for six major diabetes drug classes: insulin, sulfonylureas (SUs), thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium glucose cotransporter 2 inhibitors. This article, an outgrowth of the forum, summarizes well-delineated and theoretical safety concerns related to these drug classes, as well as the panelists' opinions regarding their best use in patients with type 2 diabetes. All of the options appear to have reasonably wide safety margins when used appropriately. Those about which we know the most-metformin, SUs, insulin, and perhaps now also TZDs are efficacious in most patients and can be placed into a basic initial algorithm. However, these agents leave some clinical needs unmet. Selecting next steps is a more formidable process involving newer agents that are understood less well and for which there are unresolved questions regarding risk versus benefit in certain populations. Choosing a specific agent is not as important as implementing some form of early intervention and advancing rapidly to some form of combination therapy as needed. When all options are relatively safe given the benefits they confer, therapeutic decision making must rely on a personalized approach, taking into account patients' clinical circumstances, phenotype, pathophysiological defects, preferences, abilities, and costs. PMID- 25147261 TI - Foot-in-wallet disease: tripped up by "cost-saving" reductions? PMID- 25147262 TI - Idiosyncratic liver injury induced by vildagliptin with successful switch to linagliptin in a hemodialyzed diabetic patient. PMID- 25147263 TI - Comment on Guest et al. Clinical outcomes and cost-effectiveness of continuous positive airway pressure to manage obstructive sleep apnea in patients with type 2 diabetes in the U.K. Diabetes Care 2014;37:1263-1271. PMID- 25147264 TI - Response to comment on Guest et al. Clinical outcomes and cost-effectiveness of continuous positive airway pressure to manage obstructive sleep apnea in patients with type 2 diabetes in the U.K. Diabetes Care 2014;37:1263-1271. PMID- 25147265 TI - Comment on Zhang et Al. Second-line agents for glycemic control for type 2 diabetes: are newer agents better? Diabetes Care 2014;37:1338-1345. PMID- 25147266 TI - Comment on Zhang et al. Second-line agents for glycemic control for type 2 diabetes: are newer agents better? Diabetes Care 2014;37:1338-1345. PMID- 25147267 TI - Response to comments on Zhang et al. Second-line agents for glycemic control for type 2 diabetes: are newer agents better? Diabetes Care 2014;37:1338-1345. PMID- 25147268 TI - Comment on Kramer et al. Glucagon response to oral glucose challenge in type 1 diabetes: lack of impact of euglycemia. Diabetes Care 2014;37:1076-1082. PMID- 25147269 TI - Response to comment on Kramer et al. Glucagon response to oral glucose challenge in type 1 diabetes: lack of impact of euglycemia. Diabetes Care 2014;37:1076 1082. PMID- 25147270 TI - Melatonin promotes ripening and improves quality of tomato fruit during postharvest life. AB - In this study, the effect of melatonin on the postharvest ripening and quality improvement of tomato fruit was carried out. The tomatoes were immersed in exogenous melatonin for 2h, and then the related physiological indicators and the expression of genes during post-harvest life were evaluated. Compared with control check (CK), the 50 uM melatonin treatment significantly increased lycopene levels by 5.8-fold. Meanwhile, the key genes involved in fruit colour development, including phytoene synthase1 (PSY1) and carotenoid isomerase (CRTISO), showed a 2-fold increase in expression levels. The rate of water loss from tomato fruit also increased 8.3%, and the expression of aquaporin genes, such as SlPIP12Q, SlPIPQ, SlPIP21Q, and SlPIP22, was up-regulated 2- to 3-fold under 50 uM melatonin treatment. In addition, 50 uM melatonin treatment enhanced fruit softening, increased water-soluble pectin by 22.5%, and decreased protopectin by 19.5%. The expression of the cell wall modifying proteins polygalacturonase (PG), pectin esterase1 (PE1), beta-galactosidase (TBG4), and expansin1 (Exp1) was up-regulated under 50 uM melatonin treatment. Melatonin increased ethylene production by 27.1%, accelerated the climacteric phase, and influenced the ethylene signalling pathway. Alteration of ethylene production correlated with altered 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS4) expression. The expression of ethylene signal transduction-related genes such as NR, SlETR4, SlEIL1, SlEIL3, and SlERF2, was enhanced by 50 uM melatonin. The effect of melatonin on ethylene biosynthesis, ethylene perception, and ethylene signalling may contribute to fruit ripening and quality improvement in tomato. This research may promote the application of melatonin on postharvest ripening and quality improvement of tomato fruit as well as other horticultural productions in the future. PMID- 25147271 TI - Light and the circadian clock mediate time-specific changes in sensitivity to UV B stress under light/dark cycles. AB - In Arabidopsis, the circadian clock regulates UV-B-mediated changes in gene expression. Here it is shown that circadian clock components are able to inhibit UV-B-induced gene expression in a gene-by-gene-specific manner and act downstream of the initial UV-B sensing by COP1 (CONSTITUTIVE PHOTOMORPHOGENIC 1) and UVR8 (UV RESISTANCE LOCUS 8). For example, the UV-B induction of ELIP1 (EARLY LIGHT INDUCIBLE PROTEIN 1) and PRR9 (PSEUDO-RESPONSE REGULATOR 9) is directly regulated by LUX (LUX ARRYTHMO), ELF4 (EARLY FLOWERING 4), and ELF3. Moreover, time dependent changes in plant sensitivity to UV-B damage were observed. Wild-type Arabidopsis plants, but not circadian clock mutants, were more sensitive to UV-B treatment during the night periods than during the light periods under diel cycles. Experiments performed under short cycles of 6h light and 6h darkness showed that the increased stress sensitivity of plants to UV-B in the dark only occurred during the subjective night and not during the subjective day in wild type seedlings. In contrast, the stress sensitivity of Arabidopsis mutants with a compromised circadian clock was still influenced by the light condition during the subjective day. Taken together, the results show that the clock and light modulate plant sensitivity to UV-B stress at different times of the day. PMID- 25147272 TI - Proline-rich protein-like PRPL1 controls elongation of root hairs in Arabidopsis thaliana. AB - The synthesis and composition of cell walls is dynamically adapted in response to many developmental and environmental signals. In this respect, cell wall proteins involved in controlling cell elongation are critical for cell development. Transcriptome analysis identified a gene in Arabidopsis thaliana, which was named proline-rich protein-like, AtPRPL1, based on sequence similarities from a phylogenetic analysis. The most resemblance was found to AtPRP1 and AtPRP3 from Arabidopsis, which are known to be involved in root hair growth and development. In A. thaliana four proline-rich cell wall protein genes, playing a role in building up the cross-connections between cell wall components, can be distinguished. AtPRPL1 is a small gene that in promoter::GUS (beta-glucuronidase) analysis has high expression in trichoblast cells and in the collet. Chemical or mutational interference with root hair formation inhibited this expression. Altered expression levels in knock-out or overexpression lines interfered with normal root hair growth and etiolated hypocotyl development, but Fourier transform-infrared (FT-IR) analysis did not identify consistent changes in cell wall composition of root hairs and hypocotyl. Co-localization analysis of the AtPRPL1-green fluorescent protein (GFP) fusion protein and different red fluorescent protein (RFP)-labelled markers confirmed the presence of AtPRPL1-GFP in small vesicles moving over the endoplasmic reticulum. Together, these data indicate that the AtPRPL1 protein is involved in the cell's elongation process. How exactly this is achieved remains unclear at present. PMID- 25147273 TI - The role of emotion in dynamic audiovisual integration of faces and voices. AB - We used human electroencephalogram to study early audiovisual integration of dynamic angry and neutral expressions. An auditory-only condition served as a baseline for the interpretation of integration effects. In the audiovisual conditions, the validity of visual information was manipulated using facial expressions that were either emotionally congruent or incongruent with the vocal expressions. First, we report an N1 suppression effect for angry compared with neutral vocalizations in the auditory-only condition. Second, we confirm early integration of congruent visual and auditory information as indexed by a suppression of the auditory N1 and P2 components in the audiovisual compared with the auditory-only condition. Third, audiovisual N1 suppression was modulated by audiovisual congruency in interaction with emotion: for neutral vocalizations, there was N1 suppression in both the congruent and the incongruent audiovisual conditions. For angry vocalizations, there was N1 suppression only in the congruent but not in the incongruent condition. Extending previous findings of dynamic audiovisual integration, the current results suggest that audiovisual N1 suppression is congruency- and emotion-specific and indicate that dynamic emotional expressions compared with non-emotional expressions are preferentially processed in early audiovisual integration. PMID- 25147274 TI - Adaptive hepatic and intestinal alterations in mice after deletion of NADPH cytochrome P450 Oxidoreductase (Cpr) in hepatocytes. AB - Cytochrome P450 enzymes (P450) play an important role in first-pass metabolism in both the intestine and liver. NADPH-cytochrome P450 oxidoreductase (Cpr) is an essential electron transfer protein required for microsomal P450 activity. Mice with conditional knockout of Cpr in hepatocytes develop normally and survive even with complete loss of liver microsomal P450 activity. Our current studies were performed to determine whether alternative drug-metabolizing pathways increase in an attempt to maintain whole-body homeostasis. In addition to the liver, Cpr is mainly expressed in tissues such as lung, kidney, and gastrointestinal tract. In livers of H-Cpr-null mice, there is a marked increase in mRNA expression of phase I enzymes (Aldh1a1, 1a7, 3a2; Ces1b2, 2a6, and 2a12), antioxidant enzymes (Ho-1, Nqo1, and epoxide hydrolase), phase II enzymes (Ugt1a9; Gsta1/2, m3, m4, m6, t1, and t3; and Sult1a1 and 1d1), and drug transporters (Oatp1a4, Oct3, Mate1, Mdr1a, and Mrp3 and 4). In addition, glucuronide-conjugated bilirubin concentrations are doubled in serum of H-Cpr-null mice. Both constitutive androstane receptor (CAR) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein in nuclei are higher in the livers of H-Cpr-null mice, indicating that CAR and Nrf2 are activated. In the small intestine of H-Cpr-null mice, mRNA expression of Cyp3a11 and Mdr1a, two genes critical for intestinal first-pass metabolism, are markedly up-regulated. In addition, nutrient (Pept1) and cholesterol (Npc1l1) transporters are induced in the small intestine of H-Cpr-null mice. In conclusion, in H-Cpr null mice, adaptive regulation of alternative detoxification genes in liver and small intestine appear to partially compensate for the loss of microsomal P450 function in liver. PMID- 25147275 TI - Evaluation of in situ generated valproyl 1-O-beta-acyl glucuronide in valproic acid toxicity in sandwich-cultured rat hepatocytes. AB - Acyl glucuronides are reactive electrophilic metabolites implicated in the toxicity of carboxylic acid drugs. Valproyl 1-O-beta-acyl glucuronide (VPA-G), which is a major metabolite of valproic acid (VPA), has been linked to the development of oxidative stress in VPA-treated rats. However, relatively little is known about the toxicity of in situ generated VPA-G and its contribution to VPA hepatotoxicity. Therefore, we investigated the effects of modulating the in situ formation of VPA-G on lactate dehydrogenase (LDH) release (a marker of necrosis), BODIPY 558/568 C12 accumulation (a marker of steatosis), and cellular glutathione (GSH) content in VPA-treated sandwich-cultured rat hepatocytes. VPA increased LDH release and BODIPY 558/568 C12 accumulation, whereas it had little or no effect on total GSH content. Among the various uridine 5'-diphospho glucuronosyltransferase inducers evaluated, beta-naphthoflavone produced the greatest increase in VPA-G formation. This was accompanied by an attenuation of the increase in BODIPY 558/568 C12 accumulation, but did not affect the change in LDH release or total GSH content in VPA-treated hepatocytes. Inhibition of in situ formation of VPA-G by borneol was not accompanied by substantive changes in the effects of VPA on any of the toxicity markers. In a comparative study, in situ generated diclofenac glucuronide was not toxic to rat hepatocytes, as assessed using the same chemical modulators, thereby demonstrating the utility of the sandwich-cultured rat hepatocyte model. Overall, in situ generated VPA-G was not toxic to sandwich-cultured rat hepatocytes, suggesting that VPA glucuronidation per se is not expected to be a contributing mechanism for VPA hepatotoxicity. PMID- 25147276 TI - Origin of HTLV-1 in hunters of nonhuman primates in Central Africa. AB - Of 78 Gabonese individuals who had received bites from nonhuman primates (NHPs) while hunting, 7 were infected with human T lymphotropic virus (HTLV-1). Five had been bitten by gorillas and were infected with subtype B strains; however, a 12 year-old girl who was severely bitten by a Cercopithecus nictitans was infected with a subtype D strain that was closely related to the simian T lymphotropic virus (STLV-1) that infects this monkey species. Her mother was infected with a subtype B strain. These data confirm that hunters in Africa can be infected by HTLV-1 that is closely related to the strains circulating among local NHP game. Our findings strongly suggest that a severe bite represent a risk factor for STLV 1 acquisition. PMID- 25147277 TI - Decline in hepatitis E virus antibody prevalence in the United States from 1988 1994 to 2009-2010. AB - BACKGROUND: Previous population-based estimates in the United States have shown a relatively high prevalence of hepatitis E virus (HEV) antibody. We sought to determine whether changes in the prevalence of HEV antibody have occurred over time. METHODS: We analyzed data from the 2009-2010 National Health and Nutrition Examination Survey (NHANES) and NHANES III (1988-1994). Using the same serologic assay, we compared the estimated anti-HEV immunoglobulin G (IgG) prevalence and risk factors for antibody positivity for the 2 periods. RESULTS: The prevalence of HEV antibody among those aged >=6 years declined from 10.2% (95% confidence interval [CI], 9.1%-11.4%) during 1988-1994 to 6.0% (5.2%-6.8%) during 2009-2010, and the prevalence for those of US birth ranged from 9.6% (8.4%-10.9%) to 5.2% (4.4%-6.2%). Among US-born persons, the estimated HEV antibody prevalence declined significantly for all subgroups of age, sex, region of residence, and number of persons per room in the household; significant declines also were observed for persons at or above poverty level and for persons of non-Hispanic white, non-Hispanic black, and Mexican American race/ethnicity. No clear associations with food consumption were found. CONCLUSIONS: The anti-HEV prevalence is declining in the United States. Although the decline suggests a decrease in exposure to HEV over time, the risks associated with exposure remain unknown. PMID- 25147278 TI - Quantum simulation. Spectroscopic observation of SU(N)-symmetric interactions in Sr orbital magnetism. AB - SU(N) symmetry can emerge in a quantum system with N single-particle spin states when spin is decoupled from interparticle interactions. Taking advantage of the high measurement precision offered by an ultrastable laser, we report a spectroscopic observation of SU(N <= 10) symmetry in (87)Sr. By encoding the electronic orbital degree of freedom in two clock states while keeping the system open to as many as 10 nuclear spin sublevels, we probed the non-equilibrium two orbital SU(N) magnetism via Ramsey spectroscopy of atoms confined in an array of two-dimensional optical traps; we studied the spin-orbital quantum dynamics and determined the relevant interaction parameters. This study lays the groundwork for using alkaline-earth atoms as testbeds for important orbital models. PMID- 25147280 TI - All-optical control of ferromagnetic thin films and nanostructures. AB - The interplay of light and magnetism allowed light to be used as a probe of magnetic materials. Now the focus has shifted to use polarized light to alter or manipulate magnetism. Here, we demonstrate optical control of ferromagnetic materials ranging from magnetic thin films to multilayers and even granular films being explored for ultra-high-density magnetic recording. Our finding shows that optical control of magnetic materials is a much more general phenomenon than previously assumed and may have a major impact on data memory and storage industries through the integration of optical control of ferromagnetic bits. PMID- 25147279 TI - Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. AB - Aging-associated cognitive decline is affected by factors produced inside and outside the brain. By using multiorgan genome-wide analysis of aged mice, we found that the choroid plexus, an interface between the brain and the circulation, shows a type I interferon (IFN-I)-dependent gene expression profile that was also found in aged human brains. In aged mice, this response was induced by brain-derived signals, present in the cerebrospinal fluid. Blocking IFN-I signaling within the aged brain partially restored cognitive function and hippocampal neurogenesis and reestablished IFN-II-dependent choroid plexus activity, which is lost in aging. Our data identify a chronic aging-induced IFN-I signature, often associated with antiviral response, at the brain's choroid plexus and demonstrate its negative influence on brain function, thereby suggesting a target for ameliorating cognitive decline in aging. PMID- 25147281 TI - Remote Hydrology. Ongoing drought-induced uplift in the western United States. AB - The western United States has been experiencing severe drought since 2013. The solid earth response to the accompanying loss of surface and near-surface water mass should be a broad region of uplift. We use seasonally adjusted time series from continuously operating global positioning system stations to measure this uplift, which we invert to estimate mass loss. The median uplift is 5 millimeters (mm), with values up to 15 mm in California's mountains. The associated pattern of mass loss, ranging up to 50 centimeters (cm) of water equivalent, is consistent with observed decreases in precipitation and streamflow. We estimate the total deficit to be ~240 gigatons, equivalent to a 10-cm layer of water over the entire region, or the annual mass loss from the Greenland Ice Sheet. PMID- 25147283 TI - Impact of stepwise introduction of smoke-free legislation on population rates of acute myocardial infarction deaths in Flanders, Belgium. AB - OBJECTIVE: Many studies demonstrated a decline in hospital admissions for cardiovascular diseases after the implementation of a smoking ban, but evidence for reductions in cardiovascular mortality is more limited. In Belgium, smoke free legislation was implemented in different phases. Public places and most workplaces became smoke-free in January 2006, whereas the legislative ban on smoking in restaurants was introduced in January 2007. These successive steps in legislation provided us the opportunity to investigate possible stepwise changes in fatal acute myocardial infarction (AMI) rates. METHODS: Data on all AMI deaths of 30 years of age or older in Flanders (Belgium) between 2000 and 2009 (n=38 992) were used. Age-standardised AMI death rates were analysed with segmented Poisson regression allowing for secular trends, seasonality, temperature, PM10 and influenza. RESULTS: An immediate decrease in AMI mortality rates was observed in January 2006 (smoking ban at work). The effect was highest for women younger than 60 years of age (-33.8%; 95% CI -49.6 to -13.0), compared with an effect of 13.1% (95% CI -24.3 to -0.3) for male counterparts. Estimates for the elderly (>=60 years) were -9.0% (95% CI -14.1 to -3.7) for men and 7.9% (95% CI -13.5 to 2.0) for women. An additional effect of the smoking ban in restaurants was observed for elderly men, with an annual slope change of -3.8% (95% CI -6.5 to 1.0) after 1 January 2007. CONCLUSIONS: Smoking ban interventions are associated with reductions in the population rate of myocardial mortality, with public health gains even before and during the middle-aged period of life. PMID- 25147284 TI - Increased risk of coronary heart disease in patients with chronic osteomyelitis: a population-based study in a cohort of 23 million. AB - OBJECTIVES: Chronic inflammatory disease may trigger vascular atherosclerosis. This study aimed to determine whether chronic osteomyelitis (COM) is linked to an increased risk of coronary heart disease (CHD). METHODS: A national insurance claim dataset of more than 23 million enrolees was used to identify 15 054 patients with newly diagnosed COM and 60 216 randomly selected age-matched and gender-matched controls between 2001 and 2009 for comparing the risk and incidence of CHD. The study period was from the entry date to the first date of the following events: the diagnosis of CHD, death, withdrawal from the Taiwan National Health Insurance programme or the end of 2010. The analysis of the CHD risk was performed using Cox proportional hazards regression model. RESULTS: During a follow-up period of 67 927 person-years, the overall incidence rate of CHD in COM cohort was 1.95 times higher than non-COM cohort (16.66 vs 8.52 per 1000 person-years). After controlling age, gender and four comorbidities (hypertension, diabetes, hyperlipidaemia and stroke), the risk remained significantly higher in the COM cohort than the control group (adjusted HR=1.65, 95% CI 1.54 to 1.78, p<0.001). In age-stratified analysis, the younger population had a stronger association between COM and CHD risk than the elderly (from HR=3.42, 95% CI 1.60 to 7.32 in age <35 to HR 1.39, 95% CI 1.15 to 1.68 in age >=80). CONCLUSIONS: This study demonstrates that COM is an independent risk factor for CHD, particularly in the younger population. Further studies are necessary to explore the underlying mechanisms linking COM and CHD. PMID- 25147285 TI - Unusual echocardiogram in a 38-year-old man with loss of consciousness and systolic murmur. Radiation-induced valve disease (RIVD). PMID- 25147287 TI - Scrub typhus increases the risk of developing acute coronary syndrome: a nationwide cohort study. AB - BACKGROUND: Studies investigating the epidemiological relationship between scrub typhus and the subsequent development of acute coronary syndrome (ACS) are lacking. Therefore, we conducted a nationwide longitudinal cohort study in Taiwan to explore whether patients with scrub typhus are at an increased risk of developing ACS. METHODS: This study investigated the incidence and risk factors for ACS in 5215 patients newly diagnosed with scrub typhus from the Taiwan National Health Insurance Research Database between 2000 and 2011. The comparison cohort contained 20 860 persons from the general population without scrub typhus. The follow-up period ran from the time of the initial diagnosis for scrub typhus to the date of an ACS event, censoring, or 31 December 2011. We used Cox proportional hazard regression models to analyse the risk of ACS by including the variables of sex, age and comorbidities. RESULTS: The incidence of ACS was higher in patients with scrub typhus than in the comparison cohort (3.10 vs 1.92 per 1000 person-years). The HR of developing ACS increased by 37% in patients with scrub typhus after adjusting for age, sex and comorbidities. Men, increased age, hypertension, diabetes, hyperlipidaemia, chronic obstructive pulmonary disease and coronary artery disease were identified as independent risk factors of developing ACS after controlling for covariates. The prominent effect of scrub typhus on subsequent ACS development appeared within 1 year after infection. CONCLUSIONS: This nationwide study determined that patients with scrub typhus exhibited a 37% increase in the risk of subsequently developing ACS compared with that of the general population. PMID- 25147288 TI - Should lithium be added to the drinking water? PMID- 25147289 TI - Why hasn't the mental health of Australians improved? The need for a national prevention strategy. PMID- 25147290 TI - Health advocacy and the funding of mental health services reform. PMID- 25147291 TI - Does our advocacy need a crisis to be effective? PMID- 25147292 TI - What should psychiatrists be doing to improve the mental health of the community? PMID- 25147293 TI - Mental health advocacy and rhetoric in our time. PMID- 25147294 TI - Lithium the magic ion: restoring and preventing? PMID- 25147295 TI - The severity of retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors. AB - Understanding phenotype-genotype correlations in retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1(rd8/rd8) mutation, we compared the retinal pathology of Crb1(rd8/rd8)/J inbred mice with that of two Crb1(rd8/rd8) lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Muller and microglia activation and telangiectasia-like vascular remodelling features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1(rd8/rd8) line, even at 12 months of age. This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the retinal pathology associated with mutations in Crb1. This study also provides insight into the nature of the retinal vascular lesions that likely represent a clinical correlate for the formation of retinal telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers. PMID- 25147297 TI - A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome. AB - Reduced levels of brain-derived neurotrophic factor (BDNF) are thought to contribute to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as with synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT. Therefore, we examined the ability of LM22A-4, a small-molecule BDNF loop domain mimetic and TrkB partial agonist, to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS) and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants. Patch-clamp recordings in Mecp2-null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in the nTS by reducing the amplitude of evoked excitatory postsynaptic currents and the frequency of spontaneous and miniature excitatory postsynaptic currents. In vivo, acute treatment of Mecp2-null and -heterozygous mutants with LM22A-4 completely eliminated spontaneous apneas in resting animals, without sedation. Moreover, we demonstrate that respiratory dysregulation during behavioral arousal, a feature of human RTT, is also reversed in Mecp2 mutants by acute treatment with LM22A-4. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked, and establish the proof-of-concept that treatment with a small-molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to behavioral arousal in symptomatic RTT mice. PMID- 25147298 TI - Development of hepatocellular adenomas and carcinomas in mice with liver-specific G6Pase-alpha deficiency. AB - Glycogen storage disease type 1a (GSD-1a) is caused by a deficiency in glucose-6 phosphatase-alpha (G6Pase-alpha), and is characterized by impaired glucose homeostasis and a high risk of developing hepatocellular adenomas (HCAs). A globally G6Pase-alpha-deficient (G6pc(-/-)) mouse model that shows pathological features similar to those of humans with GSD-1a has been developed. These mice show a very severe phenotype of disturbed glucose homeostasis and rarely live beyond weaning. We generated liver-specific G6Pase-alpha-deficient (LS-G6pc(-/-)) mice as an alternative animal model for studying the long-term pathophysiology of the liver and the potential treatment strategies, such as cell therapy. LS-G6pc( /-) mice were viable and exhibited normal glucose profiles in the fed state, but showed significantly lower blood glucose levels than their control littermates after 6 hours of fasting. LS-G6pc(-/-) mice developed hepatomegaly with glycogen accumulation and hepatic steatosis, and progressive hepatic degeneration. Ninety percent of the mice analyzed developed amyloidosis by 12 months of age. Finally, 25% of the mice sacrificed at age 10-20 months showed the presence of multiple HCAs and in one case late development of hepatocellular carcinoma (HCC). In conclusion, LS-G6pc(-/-) mice manifest hepatic symptoms similar to those of human GSD-1a and, therefore, represent a valid model to evaluate long-term liver pathogenesis of GSD-1a. PMID- 25147300 TI - If pharmacotherapies for alcohol use disorders are effective, why are they underutilised? PMID- 25147296 TI - Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS) and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease. PMID- 25147301 TI - Rate and rhythm control have comparable effects on mortality and stroke in atrial fibrillation but better data are needed. PMID- 25147302 TI - Prevention of carbon tetrachloride (CCl4)-induced toxicity in testes of rats treated with Physalis peruviana L. fruit. AB - Treatment of rats with carbon tetrachloride (CCl4; 2 ml/kg body weight) once a week for 12 weeks caused a significant decrease in serum levels of testosterone, luteinizing hormone, and follicle-stimulating hormone. These decreases in sex hormones were reduced with Physalis peruviana L. (Cape gooseberry) juice supplementation. In addition, testicular activity of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase suppressed with CCl4 were elevated after P. peruviana juice supplements. P. peruviana juice supplementation significantly increased the testicular glutathione and significantly decreased the level of lipid peroxidation and the nitric oxide production compared with the CCl4 group. In addition, the decline in the activity of antioxidant enzymes after CCl4 was ameliorated by P. peruviana Moreover, degeneration of germ and Leydig cells along with deformities in spermatogenesis induced after CCl4 injections were prevented with the supplementation of P. peruviana juice. Furthermore, P. peruviana juice attenuated CCl4-induced apoptosis in testes tissue by inhibition of caspase-3 activity. The results clearly demonstrate that P. peruviana juice augments the antioxidants defense mechanism against CCl4-induced reproductive toxicity and provides evidence that the juice may have a therapeutic role in free radical mediated diseases and infertility. PMID- 25147303 TI - A population assessment of mercury exposure from two cities of Pakistan with respect to freshwater and marine fish consumption. AB - In this study, we aimed to estimate the level of mercury (Hg) in scalp hair samples of human subjects and its association with consumption of sea- and freshwater fish species. The scalp hairs were collected from both genders (male and female) aged between 15 and 50 years (n = 200), living in coastal areas of Karachi, who mostly consumed sea fish species, referred to as exposed subjects. For comparison purposes, scalp hair samples of both genders (n = 160) were collected from the inhabitants of Karachi and Hyderabad cities who consumed freshwater fish species termed as referent subjects. The frequently consumed fresh and marine fish species were also collected. The level of Hg was determined in fish and scalp hair samples by cold vapor atomic absorption spectrometry, prior to ultrasonic-assisted acid digestion in a mixture of nitric acid and hydrogen peroxide. The validity of methodology was checked by certified reference material (CRM) BCR 397 (human hair) and DORM-2. The concentrations of Hg in sea- and freshwater fish were found in the range of 1.47-2.09 and 0.402-0.676 MUg/g, respectively. The exposed subjects had significantly elevated levels of Hg in scalp hair samples (1.8-4.3 MUg/g) as compared to referent subjects (0.87-1.95 MUg/g) (p < 0.001). A significant positive correlation was obtained between the concentration of Hg in hair and age of study population. Exposed and referent female subjects had higher levels of Hg in scalp hair than that in males of both study groups (p = 0.02-0.031). PMID- 25147304 TI - Histological study on hippocampus, amygdala and cerebellum following low lead exposure during prenatal and postnatal brain development in rats. AB - Neuropsychological studies in children who are exposed to lead during their early brain development have shown to develop behavioural and cognitive deficit. The aim of the present study was to assess the cellular damage in hippocampus, amygdala and cerebellum of rat pups exposed to lead during different periods of early brain development. Five groups of rat pups were investigated. (a) Control group (n = 8) (mothers of these rats were given normal drinking water throughout gestation and lactation), (b) pregestation lead-exposed group (n = 8) (mothers of these rats were exposed to 0.2% lead acetate in the drinking water for one month before conception), (c) gestation lead-exposed group (n = 8) (exposed to 0.2% lead acetate in the drinking water through the mother throughout gestation [gestation day 01 to day 21]), (d) lactation lead-exposed group (n = 8) (exposed to 0.2% lead acetate in the drinking water through the mother throughout lactation [postnatal day 01 to day 21]) and (e) gestation and lactation lead exposed group (n = 8) (exposed to 0.2% lead acetate throughout gestation and lactation). On postnatal day 30, rat pups of all the groups were killed. Numbers of surviving neurons in the hippocampus, amygdala and cerebellum regions were counted using cresyl violet staining technique. Histological data indicate that lead exposure caused significant damage to neurons of hippocampus, amygdala and cerebellum regions in all lead-exposed groups except lactation lead-exposed group. The extent of damage to neurons of hippocampus, amygdala and cerebellum regions in lactation lead-exposed group was comparable to gestation and lactation groups even though the duration of lead exposure was much less in lactation lead exposed group. To conclude, the postnatal period of brain development seems to be more vulnerable to lead neurotoxicity compared to prenatal period of brain development. PMID- 25147305 TI - Effects of extremely low frequency electromagnetic fields on human fetal scleral fibroblasts. AB - This study investigated the effects of extremely low frequency electromagnetic fields (ELF-EMFs) on human fetal scleral fibroblasts (HFSFs). HFSFs were subjected to 50 Hz artificial ELF-EMFs generated by Helmholtz coils with 0.1, 0.2, 0.5, and 1.0 mT field intensities for 6 to 48 h. The viability and factors involved in scleral structuring of HFSFs were determined. The growth rate of HFSFs significantly decreased after only 24 h of exposure to ELF-EMFs (0.2 mT). The messenger RNA (mRNA) expression of collagen type I (COL1A1) decreased and expression of matrix metalloproteinase-2 (MMP-2) increased significantly. There was a decrease in tissue inhibitor of MMP-2 mRNA levels between treated and control cells only at the 1.0 mT intensity level. Transforming growth factor beta 2 mRNA increased in exposed cells, and, simultaneously, fibroblast growth factor 2 mRNA levels decreased. The protein expressions of COL1A1 and MMP-2 were also significantly altered subsequent to exposure (p < 0.05). This study shows that ELF-EMFs had biological effects on HFSFs and could cause abnormality in scleral collagen. PMID- 25147306 TI - Influences of ammonia contamination on leaching from air-pollution-control residues. AB - Application of selective non-catalytic reduction systems at municipal solid waste incinerators (MSWIs) often involves over-stoichiometric injection of ammonia into flue gases. Un-reacted ammonia may be deposited on fly ash particles and can ultimately influence the leaching behaviour of air-pollution-control (APC) residues. Batch tests were conducted to investigate the impacts of ammonia levels on leaching of a range of metals (sodium, potassium, calcium, aluminium, chromium, iron, lead, cadmium, copper, nickel and zinc), as well as chloride and dissolved organic carbon (DOC). Specific conductivity was also identified to reflect the soluble components. The results showed that with ammonia concentrations rising from a background level of 4 to 26,400 mg l(-1), the specific conductivity increased by 2-7 times as pH varied from alkaline to acidic values. DOC release was also significantly enhanced with high ammonia levels of 1400 mg l(-1) or higher at pH > 9; however at these high ammonia concentrations, the role of DOC in cadmium, copper, nickel and zinc leaching was negligible. Based on the experimental data, chloride, sodium and potassium were leached at high concentrations regardless of pH and ammonia concentrations. For aluminium, chromium, iron and lead, ammonia had little impact on their leaching behaviour. With respect to cadmium, copper, nickel and zinc, high ammonia concentrations significantly increased leaching in the pH range of 8-12 due to the formation of metal-ammonia complexes, which was also proved in the speciation calculations. However, the overall results suggest that typical levels of ammonia injection in MSWIs are not likely to affect metal leaching from APC residues. PMID- 25147307 TI - Individualised education reduces anxiety levels in children over 4 years undergoing elective surgery. AB - Implications for practice and research: The content and delivery of preoperative preparation programmes for children should be based on empirically validated evidence. E-health technology may represent a unique and appealing option for delivery of preoperative preparation programmes as part of a stepped-care approach to surgical preparation. Further research exploring the factors that may contribute to preoperative anxiety should be undertaken and used to support the development of e-health interventions. PMID- 25147308 TI - Review: femoral nerve block may be the most effective option for pain relief following total knee replacement. AB - Implications for practice and research: Utilisation of continuous femoral nerve blockade (FNB) following knee replacement surgery can provide superior pain relief and fewer side effects, compared to traditional patient-controlled opioid analgesia. Further research is needed to compare the effectiveness of FNB to other pain management strategies, such as local anaesthetic infiltration and multimodal oral pain medication. PMID- 25147309 TI - Addressing anxiety and insecure attachment in close relationships could improve quality of life for gynaecological cancer survivors. AB - Implications for practice and research: Quality of life (QOL) in long-term survivors of gynaecological cancer is similar to that of women without a cancer history. Demographical and clinical variables do not predict QOL in gynaecological cancer survivors. Physical and mental QOL in gynaecological cancer survivors is most strongly related to psychosocial factors, such as insecure attachment style and current state of anxiety. Further research is needed on how attachment style may affect coping with cancer and ultimately, QOL. PMID- 25147310 TI - DNA barcodes successfully identified Macaronesian Lotus (Leguminosae) species within early diverged lineages of Cape Verde and mainland Africa. AB - Plant DNA barcoding currently relies on the application of a two-locus combination, matK + rbcL. Despite the universality of these two gene regions across plants, it is suspected that this combination might not have sufficient variation to discriminate closely related species. In this study, we tested the performance of this two-locus plant barcode along with the additional plastid regions trnH-psbA, rpoC1 and rpoB and the nuclear region internal transcribed spacer (nrITS) in a group of 38 species of Lotus from the Macaronesian region. The group has radiated into the five archipelagos within this region from mid Miocene to early Pleistocene, and thus provides both early divergent and recent radiations that pose a particularly difficult challenge for barcoding. The group also has 10 species considered under different levels of conservation concern. We found different levels of species discrimination depending on the age of the lineages. We obtained 100 % of the species identification from mainland Africa and Cape Verde when all six regions were combined. These lineages radiated >4.5 Mya; however, in the most recent radiations from the end of the Pliocene to the mid-Pleistocene (3.5-1.5 Mya), only 30 % of the species were identified. Of the regions examined, the intergenic region trnH-psbA was the most variable and had the greatest discriminatory power (18 %) of the plastid regions when analysed alone. The nrITS region was the best region when analysed alone with a discriminatory power of 26 % of the species. Overall, we identified 52 % of the species and 30 % of the endangered or threatened species within this group when all six regions were combined. Our results are consistent with those of other studies that indicate that additional approaches to barcoding will be needed in recently evolved groups, such as the inclusion of faster evolving regions from the nuclear genome. PMID- 25147311 TI - The evolution of models of psychodynamic psychotherapy. AB - OBJECTIVE: The purpose of this article is to give an outline of the evolution of models of psychodynamic psychotherapy. CONCLUSION: Certain concepts about the nature of the relationship between patient and therapist during psychodynamic psychotherapy are crucial to therapeutic benefit. These are attachment, self object function, and the co-construction of an intersubjectivity. The quality of the everyday therapeutic relationship between patient and psychiatrist similarly depends on these concepts. PMID- 25147312 TI - Promoting recovery via an integrated model of care to deliver a bed-based, mental health prevention and recovery centre. AB - OBJECTIVE: This research was conducted in order to explore the experience of care and outcomes for people entering a bed-based step-up/step-down Prevention and Recovery Centre (PARC). METHODS: An audit of files for PARC participants in 2010 collected demographic (age, gender, and marital, housing, employment and education/training status) and clinical measures (length of stay, entry and exit outcome measures, psychiatric hospital use). Participants were also invited to a feedback group to discuss their PARC experience. RESULTS: In 2010, 118 people entered PARC. Most were single and unemployed and 35% were in temporary housing or homeless. In the six months following PARC exit, participants spent significantly less time in psychiatric hospital than in the six months prior to entry (p<0.001). Significant reductions in clinician-rated difficulties were documented at exit (p<0.001). For 40 episodes of care with self-report measures at entry and exit, significant reductions in difficulties with relating to self/others (p=0.004), daily living/role functioning (p=0.006), and depression/anxiety (p=0.019) were seen. Twelve participants attended a feedback group. Positive aspects of PARC included: supportive and caring staff; help with practical issues or community access; therapeutic activities and learning about health; and socialization opportunities. CONCLUSIONS: A step-up/step-down PARC can facilitate recovery for people with mental illness through promoting independence and illness self-management. PMID- 25147313 TI - A new clinical guideline to improve sedation safety in patients transferred under the Mental Health Act from remote parts of Western Australia. AB - OBJECTIVE: Clinicians dealing with referrals under the Mental Health Act in rural and remote parts of Australia face the difficult task of providing safe sedation whilst transferring the patient to an appropriate authorized facility. This paper reviews the efforts to overcome these challenges in the remote north-west of Australia. METHODS: Senior medical staff undertook a review of sedation practice in the region. A search was made of the medical literature to determine whether evidence based treatment may exist elsewhere and this information was used in conjunction with consensus opinion to devise a new guideline. RESULTS: Scant literature exists in the field of sedation and aeronautical evacuation of patients with acute mental health presentations in remote areas. Issues and challenges were identified and a new clinical guideline based on local expert consensus of good practice was developed. CONCLUSIONS: Standardizing the approach to managing agitated patients who are transferred under the Mental Health Act is essential in order to mitigate medical morbidity that may arise from sedation related complications. The sedation guideline developed by our service has been well received by staff, seems practical and feasible to implement and has the potential to reduce sedation related morbidity. PMID- 25147314 TI - Evaluating the introduction of joint crisis plans into routine clinical practice in four community mental health services. AB - OBJECTIVE: Our aim was to evaluate the implementation of joint crisis planning into routine clinical practice in community mental health services in Western Australia. METHOD: Four community mental health services, two metropolitan and two country based, were invited to participate in a 1-year pilot program to field test a crisis planning tool and the implementation process with a view to then rolling it out across Western Australia. Training and extensive support was offered to staff at the four sites. RESULTS: Consumers experienced the process as both empowering and therapeutic. Despite acknowledgement of the value of interagency collaboration in the planning process, almost all plans were completed by consumers with their case managers. The most conspicuous finding was the marked difference in the number of completed plans at each site. CONCLUSIONS: This study supports previous research findings that joint crisis planning enhances the therapeutic relationship and empowers consumers. Organisational readiness was a major factor in the differential uptake of crisis plans between sites. Our study highlights the critical importance of addressing the context and culture of each individual service in which a new intervention is being introduced as part of the implementation process. PMID- 25147315 TI - Paliperidone: another treatment option for delusional parasitosis. AB - OBJECTIVE: Patients with delusional parasitosis (DP) have a fixed belief of being infested by small pathogens. Typical and atypical antipsychotics are widely used for treating DP. There are limited controlled trials about the treatment of DP and the most useful antipsychotic agent is still unknown. Paliperidone treatment for DP will be demonstrated through two cases. One of these cases had previously used pimozide but had not responded to treatment. Both cases had remission from symptoms with paliperidone. There are only two case reports published about paliperidone treatment for DP. CONCLUSION: Paliperidone appears to have promise in the treatment of DP; however, more case reports and controlled trials are required. PMID- 25147316 TI - Antisocial behaviour and lying: a neuropsychiatric presentation of agenesis of the corpus callosum. AB - OBJECTIVE: The purpose of this case study is to describe the case of a person with agenesis of the corpus callosum (ACC), intellectual disability and features of antisocial behaviour and lying. METHODS: A 26-year-old woman with a mild intellectual disability who presented with antisocial behaviour and chronic lying was found to have ACC and associated cerebral abnormalities. RESULTS: Psychiatric, radiological and neuropsychological assessment of this patient provided convergent evidence of the importance of the corpus callosum in enabling understanding of social situations and appropriate social behaviour, particularly via its connectivity with the frontal regions of the brain. CONCLUSION: Antisocial behaviour and lying may be more commonly associated with callosal dysgenesis than is currently realised. PMID- 25147317 TI - Prevalence and nature of antipsychotic polypharmacy among inpatients with schizophrenia spectrum disorders at an Australian mental health service. AB - OBJECTIVE: Though antipsychotic polypharmacy (APP) is widely utilised in many clinical settings for the treatment of people with schizophrenia, the extent of this practice varies considerably between different regions, countries and clinical settings. Studies from Australasia exploring the prevalence and factors associated with APP are sparse and have yielded inconsistent results. METHODS: We conducted a systematic retrospective audit of the medical records of all admissions in 2010 in the adult wards of a metropolitan public mental health service in Western Australia, having a diagnosis of schizophrenia or schizoaffective disorder. We analysed the rates of APP use, and its association with selected demographic and clinical variables. RESULTS: The prevalence of APP among our sample of 229 patients was high, at 43.2%. APP was associated with a longer hospital stay (p=0.033) and voluntary admission (p=0.027); but APP was not significantly related to: age, gender, diagnosis and treatment by different psychiatrists. CONCLUSIONS: Substantial difference exists between everyday clinical practice and recommendations of practice guidelines of schizophrenia, regarding the use of APP. Prospective studies from different settings exploring the relevant clinical, patient, prescriber and system-related issues are warranted, to comprehend the rationale behind high utilisation of APP in clinical practice. PMID- 25147318 TI - Ghost Busting: re-introducing psychotherapy for the psychiatrist. AB - OBJECTIVE: The purpose of this paper is to provide a clinically relevant historical and conceptual overview of psychotherapy as an introduction to a forthcoming series of papers on specific models of psychotherapy. The author offers a selective review of some key ideas in the history and practice of psychotherapy. CONCLUSION: The principles of psychotherapy should inform all psychiatric practice, including the doctor-patient relationship, multidisciplinary teams caring for patients with complex or 'treatment resistant' problems, and patients who are non-compliant with psychotropic medication. PMID- 25147319 TI - Health workers' views of a program to facilitate physical health care in mental health settings: implications for implementation and training. AB - OBJECTIVE: Physical comorbidities shorten the lifespan of people with severe mental illness therefore mental health clinicians need to support service users in risk factor-related behaviour change. We investigated mental health care workers' views of a physical health self-management support program in order to identify implementation requirements. METHOD: Qualitative interviews were conducted with workers who had differing levels of experience with a self management support program. Themes were identified using interpretive descriptive analysis and then matched against domains used in implementation models to draw implications for successful practice change. RESULTS: Three main themes emerged related to: (1) understandings of disease management within job roles; (2) requirements for putting self-management support into practice; and (3) challenges of coordination in disease management. Priority domains from implementation models were inner and outer health service settings. CONCLUSION: While staff training is required, practice change for care which takes account of both mental and physical health also requires changes in organisational frameworks. PMID- 25147320 TI - Meet Dr Jekyll: a case of a psychiatrist with dissociative identity disorder. AB - OBJECTIVE: Dissociative identity disorder (DID) is a controversial psychiatric diagnosis. This case review presents a retired psychiatrist with a history of DID. CONCLUSIONS: This case is used to illustrate current thinking about the characteristics and aetiology of DID. It also argues for the importance of being aware of both our personal and professional biases in our own clinical practice. PMID- 25147321 TI - What has happened to the practice of short term dynamic psychotherapy in Australia's mental health services? A multidisciplinary training programme in Western Sydney. AB - OBJECTIVE: Short term psychodynamic psychotherapies have been markedly phased out of Australia's mental health services. This paper aims to describe the successful introduction of a Conversational Model of Short Term Intensive Psychodynamic Psychotherapy into a public health service in an attempt to revive its practice. METHOD: A brief review of relevant papers in the Royal Australian & New Zealand College of Psychiatrists journals since 1980 gives a background to the decline of dynamic psychotherapy in Australia. The development of a Conversational Model of Short Term Intensive Psychodynamic Psychotherapy in the author's private practice over 20 years, and its introduction into a hospital-based training programme are described. RESULTS: A structured programme by scholarship has been offered yearly since 2011 to 10 multidisciplinary mental health clinicians of the Western Sydney Health District. Trainees see two patients from their own service. Over three years, 29 trainees have treated 57 patients with weekly supervision provided. CONCLUSIONS: The model has been easily learned. Trainees report a sense of re invigoration, refinement of existing skills and acquisition of new skills. Resolution of problems in a significant number of patients is noted and improvement and satisfaction reported by others. A valuable service is provided and research is underway. PMID- 25147322 TI - Airway analysis. PMID- 25147323 TI - Antihistamine use in children. AB - This review provides an overview of the use of antihistamines in children. We discuss types of histamine receptors and their mechanism of action, absorption, onset and duration of action of first-generation and second-generation H(1) antihistamines, as well as elimination of H(1)-antihistamines which has important implications for dosing in children. The rationale for the use of H(1) antihistamines is explored for the relief of histamine-mediated symptoms in a variety of allergic conditions including: non-anaphylactic allergic reactions, atopic eczema (AE), allergic rhinitis (AR) and conjunctivitis, chronic spontaneous urticaria (CSU) and whether they have a role in the management of intermittent and chronic cough, anaphylaxis, food protein-induced gastrointestinal allergy and asthma prevention. Second-generation H(1) antihistamines are preferable to first-generation H(1)-antihistamines in the management of non-anaphylactic allergic reactions, AR, AE and CSU due to: their better safety profile, including minimal cognitive and antimuscarinic side effects and a longer duration of action. We offer some guidance as to the choices of H(1)-antihistamines available currently and their use in specific clinical settings. H(1)-antihistamine class, availability, licensing, age and dosing administration, recommended indications in allergic conditions and modalities of delivery for the 12 more commonly used H(1)-antihistamines in children are also tabulated. PMID- 25147324 TI - Ethanol exposure through medicines commonly used in paediatrics. PMID- 25147325 TI - Levels of soluble TREM-like transcript 1 in patients presenting to the emergency department with chest pain. AB - OBJECTIVE: Recent studies suggest that the soluble triggering receptor expressed on myeloid cells-like transcript 1 (sTLT-1) facilitate atherothrombosis. Therefore, we evaluated sTLT-1 as a functional measure of atherothrombosis in acute coronary syndrome (ACS). METHODS: Levels of sTLT-1 were determined by enzyme-linked immunosorbent assay on plasma from patients with potential ACS and compared with an age-matched control group with similar risk factors for cardiovascular disease. RESULTS: Of 53 patients enrolled, 19 patients were undergoing ACS (15 unstable angina, 2 non-ST-segment elevated myocardial infarction, and 2 ST-segment elevated myocardial infarction), 5 patients were found with noncardiac chest pain, and 29 were in the control group. The mean plasma sTLT-1 values in the ACS group were 4.644 ng/mL +/- 1.277 standard error of the mean (SEM), in the noncardiac chest pain group were 0.708 ng/mL +/- 0.427 SEM, and in the control group were 1.007 ng/mL +/- 0.098 SEM. CONCLUSION: A statistically significant difference exists between patients experiencing cardiogenic chest pain versus controls (P < .05), suggesting sTLT-1 as a potential tool for understanding atherothrombosis in ACS. PMID- 25147326 TI - Acute blood pressure reduction in patients with intracerebral hemorrhage does not result in borderzone region hypoperfusion. AB - BACKGROUND AND PURPOSE: The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH ADAPT) demonstrated blood pressure (BP) reduction does not affect mean perihematoma or hemispheric cerebral blood flow. Nonetheless, portions of the perihematoma and borderzones may reach ischemic thresholds after BP reduction. We tested the hypothesis that BP reduction after intracerebral hemorrhage results in increased critically hypoperfused tissue volumes. METHODS: Patients with Intracerebral hemorrhage were randomized to a target systolic BP (SBP) of <150 or <180 mm Hg and imaged with computed tomographic perfusion 2 hours later. The volumes of tissue below cerebral blood flow thresholds for ischemia (<18 mL/100 g/min) and infarction (<12 mL/100 g/min) were calculated as a percentage of the total volume within the internal and external borderzones and the perihematoma region. RESULTS: Seventy-five patients with intracerebral hemorrhage were randomized a median (interquartile range) of 7.8 (13.3) hours from onset. Acute hematoma volume was 17.8 (27.1) mL and mean SBP was 183+/-22 mm Hg. At the time of computed tomographic perfusion (2.3 [1.0] hours after randomization), SBP was lower in the <150 mm Hg (n=37; 140+/-18 mm Hg) than in the <180 mm Hg group (n=36; 162+/-12 mm Hg; P<0.001). BP treatment did not affect the percentage of total borderzone tissue with cerebral blood flow<18 (14.7+/ 13.6 versus 15.6+/-13.7%; P=0.78) or <12 mL/100 g/min (5.1+/-5.1 versus 5.8+/ 6.8%; P=0.62). Similar results were found in the perihematoma region. Low SBP load (fraction of time with SBP<150 mmHg) did not predict borderzone tissue volume with cerebral blood flow<18 mL/100 g/min (beta=0.023 [-0.073, 0.119]). CONCLUSIONS: BP reduction does not increase the volume of critically hypoperfused borderzone or perihematoma tissue. These data support the safety of early BP reduction in intracerebral hemorrhage. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00963976. PMID- 25147327 TI - TeleStroke units serving as a model of care in rural areas: 10-year experience of the TeleMedical project for integrative stroke care. AB - BACKGROUND AND PURPOSE: Stroke Unit care improves stroke prognosis and is recommended for all patients with stroke. In rural areas, population-wide implementation of Stroke Units is challenging. Therefore, the TeleMedical Project for integrative Stroke Care (TEMPiS) was established in 2003 as a TeleStroke Unit network to overcome this barrier in Southeast Bavaria/Germany. Evaluation of its implementation between 2003 and 2005 had revealed improved process quality and clinical outcomes compared with matched hospitals without TeleStroke Units. Data on sustainability of these effects are lacking. METHODS: Effects on the stroke care of the local population were analyzed by using data from official hospital reports. Prospective registries from 2003 to 2012 describe processes and outcomes of consecutive patients with stroke and transient ischemic attack treated in TEMPiS hospitals. Quality indicators assess diagnostics, treatment, and outcome. Rates and timeliness of intravenous thrombolysis as well as data on teleconsultations and secondary interhospital transfers were reported over time. RESULTS: Within the covered area, network implementation increased the number of patients with stroke and transient ischemic attack treated in hospitals with (Tele-)Stroke Units substantially from 19% to 78%. Between February 2003 and December 2012, 54 804 strokes and transient ischemic attacks were treated in 15 regional hospitals, and 31 864 teleconsultations were performed. Intravenous thrombolysis was applied 3331 stroke cases with proportions increasing from 2.6% to 15.5% of all patients with ischemic stroke. Median onset-to-treatment times decreased from 150 (interquartile range, 127-163) to 120 minutes (interquartile range, 90-160) and door-to-needle times from 80 (interquartile range, 68-101) to 40 minutes (interquartile range, 29-59). CONCLUSIONS: TeleStroke Units can provide sustained high-quality stroke care in rural areas. PMID- 25147328 TI - Effect of high-dose atorvastatin on renal function in subjects with stroke or transient ischemic attack in the SPARCL trial. AB - BACKGROUND AND PURPOSE: Higher low-density lipoprotein cholesterol is associated with more rapid chronic kidney disease progression; reduction in cholesterol with statins, in conjunction with statins' pleiotropic effects, such as decreasing inflammation, may be renoprotective. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial assessed the effect of statin treatment on the risk of nonfatal and fatal stroke in subjects with a noncardioembolic stroke or transient ischemic attack, no known coronary heart disease, and low-density lipoprotein cholesterol between 2.6 and 4.9 mmol/L (100 190 mg/dL). METHODS: We explored the effect of randomization to atorvastatin 80 mg/d or placebo on the change in estimated glomerular filtration rate (eGFR; using the 4-component Modification of Diet in Renal Disease Study equation) in SPARCL subjects (n=4731) with (eGFR, <60 mL/min per 1.73 m2; n=3119) and without (eGFR, >=60 mL/min per 1.73 m2; n=1600) chronic kidney disease overall and by glycemic status at baseline. RESULTS: Mean baseline eGFR was similar between treatment groups (65.5+/-0.26 versus 65.6+/-0.26 mL/min per 1.73 m2 atorvastatin versus placebo; 33% versus 34% had chronic kidney disease, respectively; P=0.55). After 60 months, eGFR increased 3.46+/-0.33 mL/min per 1.73 m2 in those randomized to atorvastatin versus 1.42+/-0.34 mL/min per 1.73 m2 in those randomized to placebo (P<0.001) independent of baseline renal function. In the subgroup with diabetes mellitus at randomization, eGFR increased 1.12+/-0.92 mL/min per 1.73 m2 in the atorvastatin group and decreased 1.69+/-0.92 mL/min per 1.73 m2 in placebo group during a period of 60 months (P=0.016). CONCLUSIONS: This post hoc analysis suggests that atorvastatin treatment may improve renal function in patients with prior stroke or transient ischemic attack with and without chronic kidney disease, and that atorvastatin treatment may prevent eGFR decline in patients with stroke and diabetes mellitus. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00147602. PMID- 25147329 TI - Eligibility and preference of new oral anticoagulants in patients with atrial fibrillation: comparison between patients with versus without stroke. AB - BACKGROUND AND PURPOSE: Recent randomized clinical trials (RCTs) have evaluated the benefit of new oral anticoagulants in reducing the risk of vascular events and bleeding complications in patients with atrial fibrillation (AF). However, abundant and strict enrollment criteria may limit the validity and applicability of results of RCTs to clinical practice. We estimated the eligibility for participation in RCTs of an unselected group of patients with AF. In addition, we compared features favoring new oral anticoagulant use between patients with versus without stroke. Randomized Evaluation of Long-Term Anticoagulation Therapy METHODS: We applied enrollment criteria of 4 RCTs (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48) to 695 patients with AF taking warfarin, prospectively and consecutively collected at a university medical center; 500 patients with and 195 patients without stroke. Time in therapeutic range and bleeding risk scheme (anticoagulation and risk factors in atrial fibrillation) were also measured. RESULTS: The proportions of patients fulfilling the trial enrollment criteria varied, ranging from 39% to 72.8%, depending on the differences in indications/contraindications among studies and presence/absence of stroke. The main reasons for ineligibility for RCTs were hemorrhagic risk (anticoagulation and risk factors in atrial fibrillation [ATRIA] score) (10.8%-40.5%) and planned cardioversion (5.1%-7.7%) for nonstroke patients, and a low creatinine clearance (5.6%-9.2%) and higher risk of bleeding (15.2%-20.8%) for patients with stroke. When compared with nonstroke patients, patients with stroke showed a lower time in therapeutic range (54.4+/-42.8% versus 65.4+/-34.9%, especially with severe disability) and a high hemorrhagic risk (ATRIA score) (3.06+/-2.30 versus 2.18+/ 2.16) (P<0.05 in both cases). CONCLUSIONS: Patients enrolled in RCTs are partly representative of patients with AF in clinical practice. When time in therapeutic range and bleeding tendency with warfarin use were considered, the use of new oral anticoagulants was preferred in patients with stroke than in nonstroke patients, but they were more likely to be excluded in RCTs. PMID- 25147330 TI - Response of day-to-day home blood pressure variability by antihypertensive drug class after transient ischemic attack or nondisabling stroke. AB - BACKGROUND AND PURPOSE: Visit-to-visit variability in systolic blood pressure (SBP) is associated with an increased risk of stroke and was reduced in randomized trials by calcium channel blockers and diuretics but not by renin angiotensin system inhibitors. However, time of day effects could not be determined. Day-to-day variability on home BP readings predicts stroke risk and potentially offers a practical method of monitoring response to variability directed treatment. METHODS: SBP mean, maximum, and variability (coefficient of variation=SD/mean) were determined in 500 consecutive transient ischemic attack or minor stroke patients on 1-month home BP monitoring (3 BPs, 3* daily). Hypertension was treated to a standard protocol. Differences in SBP variability from 3 to 10 days before to 8 to 15 days after starting or increasing calcium channel blockers/diuretics versus renin-angiotensin system inhibitors versus both were compared by general linear models, adjusted for risk factors and baseline BP. RESULTS: Among 288 eligible interventions, variability in SBP was reduced after increased treatment with calcium channel blockers/diuretics versus both versus renin-angiotensin system inhibitors (-4.0 versus 6.9 versus 7.8%; P=0.015), primarily because of effects on maximum SBP (-4.6 versus -1.0 versus 1.0%; P=0.001), with no differences in effect on mean SBP. Class differences were greatest for early-morning SBP variability (3.6 versus 17.0 versus 38.3; P=0.002) and maximum (-4.8 versus -2.0 versus -0.7; P=0.001), with no effect on midmorning (P=0.29), evening (P=0.65), or diurnal variability (P=0.92). CONCLUSIONS: After transient ischemic attack or minor stroke, calcium channel blockers and diuretics reduced variability and maximum home SBP, primarily because of effects on morning readings. Home BP readings enable monitoring of response to SBP variability directed treatment in patients with recent cerebrovascular events. PMID- 25147331 TI - Vagus nerve stimulation during rehabilitative training improves functional recovery after intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Vagus nerve stimulation (VNS) delivered during rehabilitative training enhances neuroplasticity and improves recovery in models of cortical ischemic stroke. However, VNS therapy has not been applied in a model of subcortical intracerebral hemorrhage (ICH). We hypothesized that VNS paired with rehabilitative training after ICH would enhance recovery of forelimb motor function beyond rehabilitative training alone. METHODS: Rats were trained to perform an automated, quantitative measure of forelimb function. Once proficient, rats received an intrastriatal injection of bacterial collagenase to induce ICH. Rats then underwent VNS paired with rehabilitative training (VNS+Rehab; n=14) or rehabilitative training without VNS (Rehab; n=12). Rehabilitative training began >=9 days after ICH and continued for 6 weeks. RESULTS: VNS paired with rehabilitative training significantly improved recovery of forelimb function when compared with rehabilitative training without VNS. The VNS+Rehab group displayed a 77% recovery of function, whereas the Rehab group only exhibited 29% recovery. Recovery was sustained after cessation of stimulation. Both groups performed similar amounts of trials during rehabilitative, and lesion size was not different between groups. CONCLUSIONS: VNS paired with rehabilitative training confers significantly improved forelimb recovery after ICH compared to rehabilitative training without VNS. PMID- 25147332 TI - Trigeminal trophic syndrome: A rare cause of chronic facial pain and skin ulcers. PMID- 25147333 TI - Positive Tuberculosis Blood Test as a Predictor of Health Status Among HIV Infected Persons. AB - This cross-sectional study explored tuberculosis (TB) knowledge, attitudes, practice, and TB interferon-gamma release assay (IGRA) results as the predictor of self-reported poor mental and physical health among HIV-infected persons attending a sexually transmitted diseases clinic (N = 111). The participants correctly responded to only 56.6% of the TB knowledge questions. Most had positive attitudes and would not be ashamed of TB diagnosis. The TB practice was suboptimal with only half having been tested for TB within the past 2 years. Eight percent of the participants had positive IGRA (n = 9). Simultaneous multiple regression models showed that positive IGRA, an indicator of latent TB infection, was the only significant predictor of both poor mental health (p = .006) and physical health days (p = .016). IGRA screening and treatment of latent TB infection in HIV-infected persons could potentially improve their mental and physical health status in addition to reducing the TB reactivation rate. PMID- 25147334 TI - RUC-4: a novel alphaIIbbeta3 antagonist for prehospital therapy of myocardial infarction. AB - OBJECTIVE: Treatment of myocardial infarction within the first 1 to 2 hours with a thrombolytic agent, percutaneous coronary intervention, or an alphaIIbbeta3 antagonist decreases mortality and the later development of heart failure. We previously reported on a novel small molecule alphaIIbbeta3 antagonist, RUC-2, that has a unique mechanism of action. We have now developed a more potent and more soluble congener of RUC-2, RUC-4, designed to be easily administered intramuscularly by autoinjector to facilitate its use in the prehospital setting. Here, we report the properties of RUC-4 and the antiplatelet and antithrombotic effects of RUC-2 and RUC-4 in animal models. APPROACH AND RESULTS: RUC-4 was ~ 20% more potent than RUC-2 in inhibiting human ADP-induced platelet aggregation and much more soluble in aqueous solutions (60-80 mg/mL). It shared RUC-2's specificity for alphaIIbbeta3 versus alphaVbeta3, did not prime the receptor to bind fibrinogen, or induce changes in beta3 identified by a conformation-specific monoclonal antibody. Both RUC-2 and RUC-4 prevented FeCl3-induced thrombotic occlusion of the carotid artery in mice and decreased microvascular thrombi in response to laser injury produced by human platelets infused into transgenic mice containing a mutated von Willebrand factor that reacts with human but not mouse platelets. Intramuscular injection of RUC-4 in nonhuman primates at 1.9 and 3.85 mg/kg led to complete inhibition of platelet aggregation within 15 minutes, with dose-dependent return of platelet aggregation after 4.5 to 24 hours. CONCLUSIONS: RUC-4 has favorable biochemical, pharmacokinetic, pharmacodynamic, antithrombotic, and solubility properties as a prehospital therapy of myocardial infarction, but the possibility of increased bleeding with therapeutic doses remains to be evaluated. PMID- 25147335 TI - Shear stress-activated Wnt-angiopoietin-2 signaling recapitulates vascular repair in zebrafish embryos. AB - OBJECTIVE: Fluid shear stress intimately regulates vasculogenesis and endothelial homeostasis. The canonical Wnt/beta-catenin signaling pathways play an important role in differentiation and proliferation. In this study, we investigated whether shear stress activated angiopoietin-2 (Ang-2) via the canonical Wnt signaling pathway with an implication in vascular endothelial repair. APPROACH AND RESULTS: Oscillatory shear stress upregulated both TOPflash Wnt reporter activities and the expression of Ang-2 mRNA and protein in human aortic endothelial cells accompanied by an increase in nuclear beta-catenin intensity. Oscillatory shear stress-induced Ang-2 and Axin-2 mRNA expression was downregulated in the presence of a Wnt inhibitor, IWR-1, but was upregulated in the presence of a Wnt agonist, LiCl. Ang-2 expression was further downregulated in response to a Wnt signaling inhibitor, DKK-1, but was upregulated by Wnt agonist Wnt3a. Both DKK-1 and Ang-2 siRNA inhibited endothelial cell migration and tube formation, which were rescued by human recombinant Ang-2. Both Ang-2 and Axin-2 mRNA downregulation was recapitulated in the heat-shock-inducible transgenic Tg(hsp70l:dkk1-GFP) zebrafish embryos at 72 hours post fertilization. Ang-2 morpholino injection of Tg (kdrl:GFP) fish impaired subintestinal vessel formation at 72 hours post fertilization, which was rescued by zebrafish Ang-2 mRNA coinjection. Inhibition of Wnt signaling with IWR-1 also downregulated Ang-2 and Axin-2 expression and impaired vascular repair after tail amputation, which was rescued by zebrafish Ang-2 mRNA injection. CONCLUSIONS: Shear stress activated Ang-2 via canonical Wnt signaling in vascular endothelial cells, and Wnt-Ang-2 signaling is recapitulated in zebrafish embryos with a translational implication in vascular development and repair. PMID- 25147336 TI - Nucleoside diphosphate kinase B regulates angiogenesis through modulation of vascular endothelial growth factor receptor type 2 and endothelial adherens junction proteins. AB - OBJECTIVE: Nucleoside diphosphate kinase B (NDPKB) participates in the activation of heterotrimeric and monomeric G proteins, which are pivotal mediators in angiogenic signaling. The role of NDPKB in angiogenesis has to date not been defined. Therefore, we analyzed the contribution of NDPKB to angiogenesis and its underlying mechanisms in well-characterized in vivo and in vitro models. APPROACH AND RESULTS: Zebrafish embryos were depleted of NDPKB by morpholino-mediated knockdown. These larvae displayed severe malformations specifically in vessels formed by angiogenesis. NDPKB-deficient (NDPKB(-/-)) mice were subjected to oxygen-induced retinopathy. In this model, the number of preretinal neovascularizations in NDPKB(-/-) mice was strongly reduced in comparison with wild-type littermates. In accordance, a delayed blood flow recovery was detected in the NDPKB(-/-) mice after hindlimb ligation. In in vitro studies, a small interfering RNA-mediated knockdown of NDPKB was performed in human umbilical endothelial cells. NDPKB depletion impaired vascular endothelial growth factor (VEGF)-induced sprouting and hampered the VEGF-induced spatial redistributions of the VEGF receptor type 2 and VE-cadherin at the plasma membrane. Concomitantly, NDPKB depletion increased the permeability of the human umbilical endothelial cell monolayer. CONCLUSIONS: This is the first report to show that NDPKB is required for VEGF-induced angiogenesis and contributes to the correct localization of VEGF receptor type 2 and VE-cadherin at the endothelial adherens junctions. Therefore, our data identify NDPKB as a novel molecular target to modulate VEGF-dependent angiogenesis. PMID- 25147337 TI - Vascular function. PMID- 25147338 TI - Apolipoprotein A-I increases insulin secretion and production from pancreatic beta-cells via a G-protein-cAMP-PKA-FoxO1-dependent mechanism. AB - OBJECTIVE: Therapeutic interventions that increase plasma levels of high-density lipoproteins and apolipoprotein A-I (apoA-I) A-I, the major high-density lipoprotein apolipoprotein, improve glycemic control in people with type 2 diabetes mellitus. High-density lipoproteins and apoA-I also enhance insulin synthesis and secretion in isolated pancreatic islets and clonal beta-cell lines. This study identifies the signaling pathways that mediate these effects. APPROACH AND RESULTS: Incubation with apoA-I increased cAMP accumulation in Ins-1E cells in a concentration-dependent manner. The increase in cAMP levels was inhibited by preincubating the cells with the cell-permeable, transmembrane adenylate cyclase inhibitor, 2'5' dideoxyadenosine, but not with KH7, which inhibits soluble adenylyl cyclases. Incubation of Ins-1E cells with apoA-I resulted in colocalization of ATP-binding cassette transporter A1 with the Galphas subunit of a heterotrimeric G-protein and a Galphas subunit-dependent increase in insulin secretion. Incubation of Ins-1E cells with apoA-I also increased protein kinase A phosphorylation and reduced the nuclear localization of forkhead box protein O1 (FoxO1). Preincubation of Ins-1E cells with the protein kinase A-specific inhibitors, H89 and PKI amide, prevented apoA-I from increasing insulin secretion and mediating the nuclear exclusion of FoxO1. Transfection of Ins-1E cells with a mutated FoxO1 that is restricted to the nucleus confirmed the requirement for FoxO1 nuclear exclusion by blocking insulin secretion in apoA-I-treated Ins-1E cells. ApoA-I also increased Irs1, Irs2, Ins1, Ins2, and Pdx1 mRNA levels. CONCLUSIONS: ApoA-I increases insulin synthesis and secretion via a heterotrimeric G-protein-cAMP-protein kinase A-FoxO1-dependent mechanism that involves transmembrane adenylyl cyclases and increased transcription of key insulin response and beta-cell survival genes. PMID- 25147339 TI - Neutrophils in atherosclerosis: from mice to man. AB - Infiltration of leukocyte subsets is a driving force of atherosclerotic lesion growth, and during the past decade, neutrophils have received growing attention in chronic inflammatory processes, such as atherosclerosis. Equipped with various ready to be released mediators, evolved to fight invading pathogens, neutrophils may also hold key functions in affecting sterile inflammation, such as in atherosclerosis. Many of their secretion products might instruct or activate other immune cells (particularly monocytes) to, for example, enter atherosclerotic lesions or release proinflammatory mediators. Despite the emerging evidence for the mechanistic contribution of neutrophils to early atherosclerosis in mice, their role in human atherogenesis, atheroprogression, and atherosclerotic plaque destabilization is still poorly understood. This brief review will summarize latest findings on the role of neutrophils in atherosclerosis and will pay special attention to studies describing a translation approach by combining measurements in mouse and human. PMID- 25147340 TI - Canonical Wnt signaling induces vascular endothelial dysfunction via p66Shc regulated reactive oxygen species. AB - OBJECTIVE: Reactive oxygen species regulate canonical Wnt signaling. However, the role of the redox regulatory protein p66(Shc) in the canonical Wnt pathway is not known. We investigated whether p66(Shc) is essential for canonical Wnt signaling in the endothelium and determined whether the canonical Wnt pathway induces vascular endothelial dysfunction via p66(Shc)-mediated oxidative stress. APPROACH AND RESULTS: The canonical Wnt ligand Wnt3a induced phosphorylation (activation) of p66(Shc) in endothelial cells. Wnt3a-stimulated dephosphorylation of beta catenin, and beta-catenin-dependent transcription, was inhibited by knockdown of p66(Shc). Exogenous H2O2-induced beta-catenin dephosphorylation was also mediated by p66(Shc). Moreover, p66(Shc) overexpression dephosphorylated beta-catenin and increased beta-catenin-dependent transcription, independent of Wnt3a ligand. P66(Shc)-induced beta-catenin dephosphorylation was inhibited by antioxidants N acetyl cysteine and catalase. Wnt3a upregulated endothelial NADPH oxidase-4, and beta-catenin dephosphorylation was suppressed by knocking down NADPH oxidase-4 and by antioxidants. Wnt3a increased H2O2 levels in endothelial cells and impaired endothelium-dependent vasorelaxation in mouse aortas, both of which were rescued by p66(Shc) knockdown. P66(Shc) knockdown also inhibited adhesion of monocytes to Wnt3a-stimulated endothelial cells. Furthermore, constitutively active beta-catenin expression in the endothelium increased vascular reactive oxygen species and impaired endothelium-dependent vasorelaxation. In vivo, high fat diet feeding-induced endothelial dysfunction in mice was associated with increased endothelial Wnt3a, dephosphorylated beta-catenin, and phosphorylated p66(Shc). High-fat diet-induced dephosphorylation of endothelial beta-catenin was diminished in mice in which p66(Shc) was knocked down. CONCLUSIONS: p66(Shc) plays a vital part in canonical Wnt signaling in the endothelium and mediates Wnt3a-stimulated endothelial oxidative stress and dysfunction. PMID- 25147341 TI - Gestational loss and growth restriction by angiogenic defects in placental growth factor transgenic mice. AB - OBJECTIVE: Angiogenesis is an important biological process during development, reproduction, and in immune responses. Placental growth factor (PlGF) is a member of vascular endothelial growth factor that is critical for angiogenesis and vasculogenesis. We generated transgenic mice overexpressing PlGF in specifically T cells using the human CD2-promoter to investigate the effects of PlGF overexpression. APPROACH AND RESULTS: Transgenic mice were difficult to obtain owing to high lethality; for this reason, we investigated why gestational loss occurred in these transgenic mice. Here, we report that placenta detachment and inhibition of angiogenesis occurred in PlGF transgenic mice during the gestational period. Moreover, even when transgenic mice were born, their growth was restricted. CONCLUSIONS: Conclusively, PlGF overexpression prevents angiogenesis by inhibiting Braf, extracellular signal-regulated kinase activation, and downregulation of HIF-1alpha in the mouse placenta. Furthermore, it affected regulatory T cells, which are important for maintenance of pregnancy. PMID- 25147342 TI - Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin. AB - OBJECTIVE: Vascular endothelial growth factor (VEGF) has been identified as a crucial regulator of physiological and pathological angiogenesis. Among the intracellular signaling pathways triggered by VEGF, activation of the calcineurin/nuclear factor of activated T cells (NFAT) signaling axis has emerged as a critical mediator of angiogenic processes. We and others previously reported a novel role for the plasma membrane calcium ATPase (PMCA) as an endogenous inhibitor of the calcineurin/NFAT pathway, via interaction with calcineurin, in cardiomyocytes and breast cancer cells. However, the functional significance of the PMCA/calcineurin interaction in endothelial pathophysiology has not been addressed thus far. APPROACH AND RESULTS: Using in vitro and in vivo assays, we here demonstrate that the interaction between PMCA4 and calcineurin in VEGF stimulated endothelial cells leads to downregulation of the calcineurin/NFAT pathway and to a significant reduction in the subsequent expression of the NFAT dependent, VEGF-activated, proangiogenic genes RCAN1.4 and Cox-2. PMCA4-dependent inhibition of calcineurin signaling translates into a reduction in endothelial cell motility and blood vessel formation that ultimately impairs in vivo angiogenesis by VEGF. CONCLUSIONS: Given the importance of the calcineurin/NFAT pathway in the regulation of pathological angiogenesis, targeted modulation of PMCA4 functionality might open novel therapeutic avenues to promote or attenuate new vessel formation in diseases that occur with angiogenesis. PMID- 25147343 TI - Imaging body fat: techniques and cardiometabolic implications. AB - Obesity is a worldwide epidemic and is associated with multiple comorbidities. The mechanisms underlying the relationship between obesity and adverse health outcomes remain poorly understood. This may be because of several factors including the crude measures used to estimate adiposity, the striking heterogeneity between adipose tissue depots, and the influence of fat accumulation in multiple organs. To advance our understanding of fat stores and associated comorbidities in humans, it will be necessary to image adiposity throughout the body and ultimately also assess its functionality. Large clinical studies are demonstrating the prognostic importance of adipose tissue imaging. Newer techniques capable of imaging fat metabolism and other functions of adipose tissue may provide additional prognostic use and may be useful in guiding therapeutic interventions. PMID- 25147344 TI - Geographical variations in the prevalence and management of cardiovascular risk factors in outpatients with CAD: Data from the contemporary CLARIFY registry. AB - AIM: To determine the current prevalence and control of major cardiovascular risk factors in stable CAD outpatients worldwide. METHODS: We analysed variations in cardiovascular risk factors in stable CAD outpatients from CLARIFY, a 5-year observational longitudinal cohort study, in seven geographical zones (Western/Central Europe; Canada/South Africa/Australia/UK; Eastern Europe; Central/South America; Middle East; East Asia; and India). RESULTS: Patient presentation (N=32,954, mean age 64.2 years, 78% male) varied between zones, as did prevalence of risk factors (all p < 0.0001). Obesity ranged from 20% (East Asia) to 42% (Middle East), raised blood pressure from 28% (Central/South America and East Asia) to 48% (Eastern Europe), raised LDL cholesterol from 24% (Canada/South Africa/Australia/UK) to 65% (Eastern Europe), elevated heart rate (>=70 bpm) from 38% (Western/Central Europe) to 78% (India), diabetes from 17% (Eastern Europe) to 60% (Middle East), and smoking from 6% (Central/South America) to 19% (Eastern Europe). Aspirin and lipid-lowering drugs were widely used everywhere (>=84% and >=88%, respectively). Rates of risk factor control varied geographically (all p < 0.0001). Rate of controlled blood pressure in hypertension varied from 47% (Eastern Europe) to 66% (Central/South America), glucose control in diabetes from 23% (India) to 51% (Western/Central Europe and East Asia), controlled LDL cholesterol and dyslipidaemia from 32% (Eastern Europe) to 75% (Canada/South Africa/Australia/UK), heart rate <70 bpm from 22% (India) to 62% (Western/Central Europe), and heart rate <=60 bpm in angina patients from 2% (India) to 29% (Canada/South Africa/Australia/UK and Central/South America). CONCLUSION: Prevalence and control of major cardiovascular risk factors in stable CAD vary markedly worldwide. Many stable CAD outpatients are being treated suboptimally. PMID- 25147345 TI - Impact of eight weeks of repeated ischaemic preconditioning on brachial artery and cutaneous microcirculatory function in healthy males. AB - BACKGROUND: Ischaemic preconditioning has well-established cardiac and vascular protective effects. Short interventions (one week) of daily ischaemic preconditioning episodes improve conduit and microcirculatory function. This study examined whether a longer (eight weeks) and less frequent (three per week) protocol of repeated ischaemic preconditioning improves vascular function. METHODS: Eighteen males were randomly allocated to either ischaemic preconditioning (22.4 +/- 2.3 years, 23.7 +/- 3.1 kg/m(2)) or a control intervention (26.0 +/- 4.8 years, 26.4 +/- 1.9 kg/m(2)). Brachial artery endothelial-dependent (FMD), forearm cutaneous microvascular function and cardiorespiratory fitness were assessed at zero, two and eight weeks. RESULTS: A greater improvement in FMD was evident following ischaemic preconditioning training compared with control at weeks 2 (2.24% (0.40, 4.08); p=0.02) and 8 (1.11% (0.13, 2.10); p=0.03). Repeated ischaemic preconditioning did not change cutaneous microcirculatory function or fitness. CONCLUSIONS: These data indicate that a feasible and practical protocol of regular ischaemic preconditioning episodes improves endothelial function in healthy individuals within two weeks, and these effects persist following repeated ischaemic preconditioning for eight weeks. PMID- 25147346 TI - The oxygen uptake efficiency slope in 1411 Caucasian healthy men and women aged 20-60 years: reference values. AB - BACKGROUND: The oxygen uptake efficiency slope (OUES) has been proposed as an independent, reproducible and objective measure of cardiorespiratory function that does not require maximal exercise testing. Existing reference values have been published for healthy paediatric populations and healthy elderly. However, reference ranges and equations for healthy adults of working age are insufficiently documented. The aim of the present study was to establish prediction equations and to describe reference values for healthy men and women aged 20-60 years. DESIGN: Cross-sectional study. METHODS: One thousand four hundred and eleven (877 men) healthy individuals (mean age 38.6 years; range 20 60) completed a maximal graded cycle exercise test until volitional exhaustion. Subsequently, oxygen uptake was plotted against the logarithm of total ventilation and the OUES was calculated by means of linear regression analysis. RESULTS: Multivariate regression analyses revealed age, sex and body surface area as statistically significant determinants of the OUES. Following this, sex specific prediction equations for the OUES were established and cross-validated. Finally, the distribution of the OUES with age was described and reference values were established for men and women separately. CONCLUSIONS: This study established a comprehensive set of reference values and reference equations for the OUES for a healthy population of men and women aged between 20 and 60 years. PMID- 25147347 TI - N-Acetylcysteine Ameliorates Experimental Autoimmune Myocarditis in Rats via Nitric Oxide. AB - BACKGROUND: Oxidative stress may play an important role in the development of myocarditis. We investigated the effects of N-acetylcysteine (NAC), a potent antioxidant, on experimental autoimmune myocarditis (EAM) in rats. METHODS AND RESULTS: A rat model of porcine myosin-induced EAM was used. After the immunization with myosin, NAC (20 mg/kg/d) or saline was injected intraperitoneally on days 1 to 21. Additional myosin-immunized rats treated with NAC were orally given 25 mg/kg/d of N(G)-nitro-l-arginine methylester (l-NAME), an inhibitor of nitric oxide (NO) synthase, and N(G)-nitro-d-arginine methylester (d-NAME), an inactive enantiomer. The NAC treatment improved cardiac pathology associated with reduced superoxide production. In the EAM rats treated with NAC associated with oral l-NAME, but not with oral d-NAME, the severity of myocarditis was not reduced. Expression of intercellular adhesion molecule 1 was reduced by NAC treatment. Myocardial c-kit(+) cells were demonstrated only in the NAC-treated group. Hemodynamic study showed that the increased left ventricular mass produced by myocardial inflammation tended to be reduced by NAC treatment. CONCLUSION: Treatment with NAC ameliorated myocardial injury via NO system in a rat model of myocarditis. PMID- 25147348 TI - Predictors of efficacy for endobronchial valves in bronchoscopic lung volume reduction: A meta-analysis. AB - Over the last several years, numerous trials have been carried out to check the efficacy of one-way valves in the management of advanced emphysema. While the design of the valves has not altered much, by selectively studying these valves in a select group of participants, such as those with and without intact fissures (FI+ and FI-), and by using different procedural techniques, our understanding of the valves has evolved. In this meta-analysis, we sought to study the effect of these factors on the efficacy of one-way valves. From PubMed and Embase, we included only those studies that provided separate data on fissure integrity or collateral ventilation. Our study outcomes included the mean change in forced expiratory volume in first second (FEV1), 6-minute walk distance (6MWD) and the St George's Respiratory Questionnaire (SGRQ). In the FI+ subgroup of participants, the pooled standardized mean difference in FEV1, 6MWD, and SGRQ were 0.50 (95% confidence interval (CI): 0.34 to 0.67), p <= 0.001, 0.29 (95% CI: 0.13 to 0.45), p <= 0.001 and -6.02 (95% CI: -12.12 to 0.06), p = 0.05, respectively. In comparison, these results were superior to the FI- subgroup of participants. A separate analysis of the FI+ subgroup based on lobar occlusion versus nonlobar occlusion favored the former for superior efficacy. The preliminary findings of our meta-analysis confirm that one-way valves perform better in a select group of patients who show intact fissures on lung imaging pretreatment and in those who achieve lobar occlusion. PMID- 25147349 TI - Pre-hospital care: a critical phase of the acute cardiovascular care management process. PMID- 25147350 TI - A randomized, single-blind cross-over design evaluating the effectiveness of an individually defined, targeted physical therapy approach in treatment of children with cerebral palsy. AB - OBJECTIVE: A pilot study to compare the effectiveness of an individual therapy program with the effects of a general physical therapy program. DESIGN: A randomized, single-blind cross-over design. PARTICIPANTS: Ten ambulant children with bilateral spastic cerebral palsy, age four to nine years. INTERVENTION: Participants were randomly assigned into a ten-week individually defined, targeted or a general program, followed by a cross-over. MAIN OUTCOME MEASURES: Evaluation was performed using the Gross Motor Function Measure-88 and three dimensional gait analysis. General outcome parameters were Gross Motor Function Measure-88 scores, time and distance parameters, gait profile score and movement analysis profiles. Individual goal achievement was evaluated using z-scores for gait parameters and Goal Attainment Scale for gross motor function. RESULTS: No significant changes were observed regarding gross motor function. Only after individualized therapy, step- and stride-length increased significantly (p = 0.022; p = 0.017). Change in step-length was higher after the individualized program (p = 0.045). Within-group effects were found for the pelvis in transversal plane after the individualized program (p = 0.047) and in coronal plane after the general program (p = 0.047). Between-program differences were found for changes in the knee in sagittal plane, in the advantage of the individual program (p = 0.047). A median difference in z-score of 0.279 and 0.419 was measured after the general and individualized program, respectively. Functional goal attainment was higher after the individual therapy program compared with the general program (48 to 43.5). CONCLUSION: The results indicate slightly favorable effects towards the individualized program. To detect clinically significant changes, future studies require a minimal sample size of 72 to 90 participants. PMID- 25147351 TI - Self-monitoring of blood glucose: impact of a time delay between capillary blood sampling and glucose measurement. PMID- 25147352 TI - Pain and recovery are comparable after either uniportal or multiport video assisted thoracoscopic lobectomy: an observation study. AB - OBJECTIVES: Uniportal approaches to video-assisted thoracoscopic surgery (VATS) lobectomy have been described in significant series. Few comparison studies between the two techniques exist. The aim was to determine whether the uniportal technique had more favourable postoperative outcomes than the multiport technique. METHODS: All VATS lobectomies undertaken at a single university hospital during August 2012 to December 2013 were studied. Patients with preoperative opiate use or chronic pain were excluded. Patients were divided into those with uniportal and multiport approaches for analysis. All continuous data were assessed for normality, and analysed with the Mann-Whitney U-tests or t tests as appropriate. Categorical data were analysed by Fisher's exact or chi(2) test for trend as appropriate. RESULTS: One hundred and twenty-nine VATS lobectomies were completed. Six were excluded and data were incomplete for 13, leaving 110 (15 uniportal, 95 multiport) for analysis. The demographics of the two groups were similar. There was no significant difference in the Thoracoscore or American Society of Anesthesiologists grades. The median morphine use in the first 24 postoperative hours was 19 mg in the uniportal group and 23 mg in the multiport group, P = 0.84. The median visual analogue pain score in the first 24 h was 0 in the uniportal group and 0 in the multiport group, P = 0.65. There was no difference in the duration of patient-controlled analgesia (P = 0.97), chest drain duration (P = 0.67) or hospital length of stay (P = 0.54). There was no inpatient mortality and no unplanned admission to critical care in either group. CONCLUSIONS: Uniportal VATS lobectomy is safe, and there is no appreciable negative impact on the hospital stay or morbidity. Patient-reported pain and morphine use in the first 24 h was low with either technique. Larger prospective studies are needed to quantify any benefit to a particular approach for VATS lobectomy. PMID- 25147353 TI - Kissing-stents technique after living-donor lobar lung transplantation. AB - Stent placement has become common practice for bronchial stenosis (BS) after lung transplantation (LT). Especially, segmental BS after lobar LT requires a complex stenting technique. We describe a case of multiple segmental bronchial stenoses treated by the kissing-stents technique using balloon-expandable metallic stents after living-donor lobar LT. Based on the vascular kissing-stents technique, we simultaneously placed two stents, side by side, in the superior segmental bronchus and the basal segmental bronchus of the right transplanted lobar lung. This technique may represent a valuable option for complex segmental BS after lobar LT. PMID- 25147354 TI - Calling all stakeholders: group-level assessment (GLA)-a qualitative and participatory method for large groups. AB - Group-level assessment (GLA) is a qualitative and participatory large group method in which timely and valid data are collaboratively generated and interactively evaluated with relevant stakeholders leading to the development of participant-driven data and relevant action plans. This method is useful across a wide range of evaluation purposes in many environments. GLA involves bringing a large group of participants together to build a common database through the co identification of relevant needs, judgments, and priorities. The GLA process proceeds through the following seven steps: climate setting, generating, appreciating, reflecting, understanding, selecting, and action. This article describes the methodological development and process of conducting a GLA and its various applications across the evaluation spectrum. We highlight several exemplars where GLA was used in order to demonstrate the particular nuances of working with different sizes and types of groups and to elaborate on our learnings from the wide applicability of the method. PMID- 25147355 TI - Flaws in evaluations of social programs: illustrations from randomized controlled trials. AB - BACKGROUND: This article describes eight flaws that occur in impact evaluations. METHOD: The eight flaws are grouped into four categories on how they affect impact estimates: statistical imprecision; biases; failure of impact estimates to measure effects of the planned treatment; and flaws that result from weakening an evaluation design. Each flaw is illustrated with examples from social experiments. Although these illustrations are from randomized controlled trials (RCTs), they can occur in any type of evaluation; we use RCTs to illustrate because people sometimes assume that RCTs might be immune to such problems. A summary table lists the flaws, indicates circumstances under which they occur, notes their potential seriousness, and suggests approaches for minimizing them. RESULTS: Some of the flaws result in minor hurdles, while others cause evaluations to fail-that is, the evaluation is unable to provide a valid test of the hypothesis of interest. The flaws that appear to occur most frequently are response bias resulting from attrition, failure to adequately implement the treatment as designed, and too small a sample to detect impacts. The third of these can result from insufficient marketing, too small an initial target group, disinterest on the part of the target group in participating (if the treatment is voluntary), or attrition. CONCLUSION: To a considerable degree, the flaws we discuss can be minimized. For instance, implementation failures and too small a sample can usually be avoided with sufficient planning, and response bias can often be mitigated-for example, through increased follow-up efforts in conducting surveys. PMID- 25147356 TI - Evaluating response shift in training evaluation: comparing the retrospective pretest with an adapted measurement invariance approach in a classroom management training program. AB - BACKGROUND: Response shift (RS) can threaten the internal validity of pre-post designs. As RS may indicate a redefinition of the target construct, its occurrence in training evaluation is rather likely. The most common approach to deal with RS is to implement a retrospective pretest (then-test) instead of the traditional pre-test. In health psychology, an adapted measurement invariance approach (MIad) was developed as an alternative technique to study RS. Results produced by identifying RS with the two approaches were rarely studied simultaneously or within an experimental framework. OBJECTIVES: To study RS in two different treatment conditions and compare results produced by both techniques in identifying various types of RS. We further studied validity aspects of the then-test. RESEARCH DESIGN: We evaluated RS by applying the then test procedure (TP) and the measurement invariance apporach MIad within an experimental design: Participants either attended a short-term or a long-term classroom management training program. SUBJECTS: Participants were 146 student teachers in their first year of master's study. MEASURES: Pre (before training), post, and then self-ratings (after training) on classroom management knowledge were administered. RESULTS: Results indicated that the two approaches do not yield the same results. The MIad identified more and also group-specific RS as opposed to the findings of the TP, which found less and only little evidence for group-specific RS. CONCLUSIONS: Further research is needed to study the usability and validity of the respective approaches. In particular, the usability of the then-test seems to be challenged. PMID- 25147357 TI - SecureMA: protecting participant privacy in genetic association meta-analysis. AB - MOTIVATION: Sharing genomic data is crucial to support scientific investigation such as genome-wide association studies. However, recent investigations suggest the privacy of the individual participants in these studies can be compromised, leading to serious concerns and consequences, such as overly restricted access to data. RESULTS: We introduce a novel cryptographic strategy to securely perform meta-analysis for genetic association studies in large consortia. Our methodology is useful for supporting joint studies among disparate data sites, where privacy or confidentiality is of concern. We validate our method using three multisite association studies. Our research shows that genetic associations can be analyzed efficiently and accurately across substudy sites, without leaking information on individual participants and site-level association summaries. AVAILABILITY AND IMPLEMENTATION: Our software for secure meta-analysis of genetic association studies, SecureMA, is publicly available at http://github.com/XieConnect/SecureMA. Our customized secure computation framework is also publicly available at http://github.com/XieConnect/CircuitService. PMID- 25147358 TI - MethylAid: visual and interactive quality control of large Illumina 450k datasets. AB - The Illumina 450k array is a frequently used platform for large-scale genome-wide DNA methylation studies, i.e. epigenome-wide association studies. Currently, quality control of 450k data can be performed with Illumina's GenomeStudio and is part of a limited number 450k analysis pipelines. However, GenomeStudio cannot handle large-scale studies, and existing pipelines provide limited options for quality control and neither support interactive exploration by the user. To aid the detection of bad-quality samples in large-scale genome-wide DNA methylation studies as flexible and transparent as possible, we have developed MethylAid; a visual and interactive Web application using RStudio's shiny package. Bad-quality samples are detected using sample-dependent and sample-independent quality control probes present on the array and user-adjustable thresholds. In-depth exploration of bad-quality samples can be performed using several interactive diagnostic plots. Furthermore, plots can be annotated with user-provided metadata, for example, to identify outlying batches. Our new tool makes quality assessment of 450k array data interactive, flexible and efficient and is, therefore, expected to be useful for both data analysts and core facilities. AVAILABILITY AND IMPLEMENTATION: MethylAid is implemented as an R/Bioconductor package (www.bioconductor.org/packages/3.0/bioc/html/MethylAid.html). A demo application is available from shiny.bioexp.nl/MethylAid. PMID- 25147359 TI - PyBamView: a browser-based application for viewing short read alignments. AB - Current sequence alignment browsers allow visualization of large and complex next generation sequencing datasets. However, most of these tools provide inadequate display of insertions and can be cumbersome to use on large datasets. I implemented PyBamView, a lightweight Web application for visualizing short read alignments. It provides an easy-to-use Web interface for viewing alignments across multiple samples, with a focus on accurate visualization of insertions. AVAILABILITY AND IMPLEMENTATION: PyBamView is available as a standard python package. The source code is freely available under the MIT license at https://mgymrek.github.io/pybamview. PMID- 25147360 TI - Visualization of protein sequence features using JavaScript and SVG with pViz.js. AB - pViz.js is a visualization library for displaying protein sequence features in a Web browser. By simply providing a sequence and the locations of its features, this lightweight, yet versatile, JavaScript library renders an interactive view of the protein features. Interactive exploration of protein sequence features over the Web is a common need in Bioinformatics. Although many Web sites have developed viewers to display these features, their implementations are usually focused on data from a specific source or use case. Some of these viewers can be adapted to fit other use cases but are not designed to be reusable. pViz makes it easy to display features as boxes aligned to a protein sequence with zooming functionality but also includes predefined renderings for secondary structure and post-translational modifications. The library is designed to further customize this view. We demonstrate such applications of pViz using two examples: a proteomic data visualization tool with an embedded viewer for displaying features on protein structure, and a tool to visualize the results of the variant_effect_predictor tool from Ensembl. AVAILABILITY AND IMPLEMENTATION: pViz.js is a JavaScript library, available on github at https://github.com/Genentech/pviz. This site includes examples and functional applications, installation instructions and usage documentation. A Readme file, which explains how to use pViz with examples, is available as Supplementary Material A. PMID- 25147361 TI - diCal-IBD: demography-aware inference of identity-by-descent tracts in unrelated individuals. AB - We present a tool, diCal-IBD, for detecting identity-by-descent (IBD) tracts between pairs of genomic sequences. Our method builds on a recent demographic inference method based on the coalescent with recombination, and is able to incorporate demographic information as a prior. Simulation study shows that diCal IBD has significantly higher recall and precision than that of existing single nucleotide polymorphism-based IBD detection methods, while retaining reasonable accuracy for IBD tracts as small as 0.1 cM. AVAILABILITY: http://sourceforge.net/projects/dical-ibd. PMID- 25147363 TI - One-handed chest compression technique for paediatric cardiopulmonary resuscitation: dominant versus non-dominant hand. AB - BACKGROUND: Pediatric resuscitation guidelines do not specify which hand to use for one-handed cardiopulmonary resuscitation (CPR). OBJECTIVE: To determine whether there is a difference in the quality of one-handed chest compressions (OHCCs) using the dominant versus non-dominant hand in simulated paediatric CPR. MATERIALS AND METHODS: 41 doctors took part in the study. Chest compressions were alternately performed with the dominant (test 1) and non-dominant hand (test 2) in a random order at 30 min intervals. Experiments were carried out with a 5-year old paediatric manikin without ventilation for 2 min. Data on average compression rate (per min) and average compression depth (mm) were collected and compared. RESULTS: No significant differences were found in the average compression rate (118.0+/-14.3/min vs 117.3+/-14.5/min, p=0.610) and average compression depth (41.3+/-5.6mm vs 41.9+/-4.1mm, p=0.327) between tests 1 and 2. CONCLUSIONS: No significant difference was found in the quality of OHCCs using the dominant and non-dominant hand in simulated paediatric CPR. The study suggests there is no need for paediatric resuscitation guidelines to state a preferred hand for performing OHCC. PMID- 25147362 TI - Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death. AB - Mitochondrial fusion and fission is a dynamic process critical for the maintenance of mitochondrial function and cell viability. During excitotoxicity neuronal mitochondria are fragmented, but the mechanism underlying this process is poorly understood. Here, we show that Mfn2 is the only member of the mitochondrial fusion/fission machinery whose expression is reduced in in vitro and in vivo models of excitotoxicity. Whereas in cortical primary cultures, Drp1 recruitment to mitochondria plays a primordial role in mitochondrial fragmentation in an early phase that can be reversed once the insult has ceased, Mfn2 downregulation intervenes in a delayed mitochondrial fragmentation phase that progresses even when the insult has ceased. Downregulation of Mfn2 causes mitochondrial dysfunction, altered calcium homeostasis, and enhanced Bax translocation to mitochondria, resulting in delayed neuronal death. We found that transcription factor MEF2 regulates basal Mfn2 expression in neurons and that excitotoxicity-dependent degradation of MEF2 causes Mfn2 downregulation. Thus, Mfn2 reduction is a late event in excitotoxicity and its targeting may help to reduce excitotoxic damage and increase the currently short therapeutic window in stroke. PMID- 25147364 TI - Comparison of intravenous lidocaine versus morphine in alleviating pain in patients with critical limb ischaemia. AB - BACKGROUND: Numerous drugs have been proposed to alleviate ischaemic limb pain, but none have been successful in relieving ischaemic pain thoroughly and rapidly. OBJECTIVE: To compare the effectiveness of intravenous lidocaine and intravenous morphine in decreasing pain in patients with critical limb ischaemia. METHODS: A randomised double-blind controlled trial was performed in 63 patients with critical limb ischaemia recruited from the emergency department between October 2012 and December 2013; 23 patients were excluded and the remainder were randomly divided into two groups of 20 patients. Patients in the lidocaine group received lidocaine infusion (2 mg/kg) while patients in the morphine group received morphine (0.1 mg/kg). Patients' visual analogue pain scores (VAS), from 0 to 10, were reported before and 15 and 30 min after the infusion. RESULTS: Before the infusion the mean+/-SD VAS score was 7.50+/-1.93 in the lidocaine group and 7.65+/-1.92 in the morphine group. At 15 min the mean+/-SD VAS score in the lidocaine group was lower than in the morphine group (5.75+/-1.77 vs 7.00+/-1.83; mean difference 1.25, 95% CI 0.095 to 2.405) and, at 30 min, the mean+/-SD VAS score in the lidocaine group was again lower (4.25+/-1.48 vs 6.50+/-1.73; mean difference 2.25, 95% CI 1.218 to 3.282). CONCLUSIONS: Lidocaine may be helpful in decreasing ischaemic pain in patients with critical limb ischaemia. TRIAL REGISTRATION NUMBER: http://www.irct.irIRCT201210148872N2. PMID- 25147365 TI - Three-year follow-up of posterior chamber toric phakic intraocular lens implantation for the correction of high myopic astigmatism in eyes with keratoconus. AB - AIM: To assess the clinical outcomes following the use of toric implantable collamer lenses (toric ICL, STAAR Surgical) for the correction of high myopic astigmatism with keratoconus. METHODS: This retrospective study evaluated 21 eyes of 11 patients with spherical equivalents of -9.70+/-2.33 D (mean+/-SD) and astigmatism of -3.21+/-1.56 D who underwent toric ICL implantation for keratoconus. Preoperatively, and at 1, 3 and 6 months and 1, 2 and 3 years postoperatively, we assessed the safety, efficacy, predictability, stability and adverse events of the surgery. RESULTS: The logarithm of the minimum angle of resolution (logMAR) uncorrected distance visual acuity (UDVA) and the logMAR corrected distance visual acuity (CDVA) were -0.06+/-0.11 and -0.12+/-0.09, respectively, at 3 years postoperatively. At 3 years, 67% and 86% of the eyes were within +/-0.5 and +/-1.0 D, respectively, of the targeted correction. Manifest refraction changes of 0.04+/-0.33 D occurred from 1 month to 3 years postoperatively. No significant change in manifest refraction (analysis of variance, p=0.989) or keratometry (p=0.951), or vision-threatening complications occurred during the observation period. CONCLUSIONS: Toric ICL implantation is beneficial according to measures of safety, efficacy, predictability and stability for the correction of refractive errors for keratoconus during a 3-year observation period. The disease did not progress even in the late-postoperative period, suggesting the viability of this procedure as a surgical option for the treatment of such eyes. PMID- 25147366 TI - The risk of acute coronary syndrome after retinal artery occlusion: a population based cohort study. AB - AIM: To investigate the risk of acute coronary syndrome (ACS) following retinal artery occlusion (RAO). METHODS: The study cohort included all patients diagnosed with RAO between January 1999 and December 2008 (n=688) in the Taiwan Longitudinal Health Insurance Database 2000. The control group included randomly selected patients (n=4128) from the same database that were matched to the study group, using a propensity score, for age, gender, and comorbid diabetes mellitus, hypertension, hyperlipidaemia, chronic renal disease and atrial fibrillation status. The ACS-free survival rate was calculated using Kaplan-Meier analysis. Cox proportional hazard regression analysis was used to obtain the adjusted HR for ACS after adjustment for potential confounding factors. The incidence and risk of ACS were compared between the RAO and control groups. RESULTS: Thirty seven patients in the RAO group (5.38%) and 138 controls (3.34%) had ACS (p=0.0063) during the follow-up period, resulting in a significantly higher risk of ACS in the RAO group (HR=1.67, 95% CI 1.16 to 2.40). After adjustment for potential confounders, the HR for developing ACS in the RAO group was 1.72 (95% CI 1.20 to 2.47) times higher than that of controls. When stratified by RAO type, the adjusted HR for ACS was 3.57 (95% CI 2.09 to 6.10) for the central RAO subgroup. CONCLUSIONS: We found that RAO increased the risk for ACS. We recommend thorough follow-up cardiovascular examinations and medical prevention for ACS in patients following RAO. PMID- 25147367 TI - Face-down positioning versus non-supine positioning in macular hole surgery. AB - AIM: To evaluate the full thickness macular hole (FTMH) closure rate in patients positioning non-supine (NSP) compared with patients positioning face-down (FDP). METHODS: We retrospectively reviewed two FTMH case series-postoperative positioning was FDP and NSP, respectively. All eyes were pseudophakic and treatment consisted of pars plana vitrectomy, internal limiting membrane peeling and perfluoropropane gas tamponade. Primary outcome measure was FTMH closure verified by optical coherence tomography. Secondary outcome was ETDRS visual acuity 6 months postoperatively. RESULTS: Over 13.7 months 122 eyes were included in this study, 66 eyes in the FDP group and 56 eyes in the NSP group. Closure rates were 95.5% and 96.4% in the FDP group and the NSP group, respectively. Median postoperative visual acuity at 6 months was 69 ETDRS letters in both positioning groups (p=0.64). Neither positioning group fully complied with the recommended positioning protocol. CONCLUSIONS: Results from consistent FTMH repair indicate similar anatomical success rates in FDP and NSP groups, suggesting that FDP is unnecessary. Objective monitoring of positioning would be beneficial in future FTMH studies to be able to adjust for positioning protocol compliance. PMID- 25147368 TI - Changes in angle of optic nerve and angle of ocular orbit with increasing age in Japanese children. AB - PURPOSE: To study changes in the opening angle of the optic nerve and the angle of the ocular orbit with increasing age in normal Japanese children. METHODS: We studied 147 normal children (aged 6 months to 18 years) who had undergone CT as a diagnostic procedure. Measurements were performed on axial CT images that included the entire optic nerve of both eyes. The opening angle of the optic nerve was defined as the angle formed by the intersection of a line running through the left optic nerve and a vertical line passing through the centre of the nose. The opening angle of the orbit was defined as the angle formed by the intersection of a line running tangentially along the deep lateral wall of the left orbit and a vertical line passing through the centre of the nose. The relationship between age and these opening angles was analysed by regression analysis. RESULTS: The correlation between age and opening angle of the optic nerve was not significant. In contrast, the opening angle of the orbit decreased relatively rapidly until about 2-3 years of age, and then it stabilised. The decrease in the opening angle of the orbit with increasing age was significant (p<0.001). The relationship between these two parameters was best fitted by a logarithmic regression curve. CONCLUSIONS: Because the opening angle of the orbit decreased significantly with increasing age, this factor must be considered when diagnosing and treating strabismus in children. PMID- 25147369 TI - Prognostic parameters in uveal melanoma and their association with BAP1 expression. AB - AIM: To determine whether BAP1 gene and protein expression associates with different prognostic parameters in uveal melanoma and whether BAP1 expression correctly identifies patients as being at risk for metastases, following enucleation of the primary tumour. METHODS: Thirty cases of uveal melanoma obtained by enucleation between 1999 and 2004 were analysed for a variety of prognostic markers, including histological characteristics, chromosome aberrations obtained by fluorescence in situ hybridisation (FISH) and single nucleotide polymorphism (SNP) analysis and gene expression profiling. These parameters were compared with BAP1 gene expression and BAP1 immunostaining. RESULTS: The presence of monosomy of chromosome 3 as identified by the different chromosome 3 tests showed significantly increased HRs (FISH on isolated nuclei cut-off 30%: HR 11.6, p=0.002; SNP analysis: HR 20.3, p=0.004) for death due to metastasis. The gene expression profile class 2, based on the 15-gene expression profile, similarly provided a significantly increased HR for a poor outcome (HR 8.5, p=0.005). Lower BAP1 gene expression and negative BAP1 immunostaining (50% of 28 tumours were immunonegative) were both associated with these markers for prognostication: FISH cut-off 30% monosomy 3 (BAP1 gene expression: p=0.037; BAP1 immunostaining: p=0.001), SNP-monosomy 3 (BAP1 gene expression: p=0.008; BAP1 immunostaining: p=0.002) and class 2 profile (BAP1 gene expression: p<0.001; BAP1 immunostaining: p=0.001) and were themselves associated with an increased risk of death due to metastasis (BAP1 gene expression dichotomised: HR 8.7, p=0.006; BAP1 immunostaining: HR 4.0, p=0.010). CONCLUSIONS: Loss of BAP1 expression associated well with all of the methods currently used for prognostication and was itself predictive of death due to metastasis in uveal melanoma after enucleation, thereby emphasising the importance of further research on the role of BAP1 in uveal melanoma. PMID- 25147370 TI - White matter integrity and late-life depression in community-dwelling individuals: diffusion tensor imaging study using tract-based spatial statistics. AB - BACKGROUND: Late-life depression has been associated with white matter changes in studies using the regions of interest approach. AIMS: To investigate the cross sectional and longitudinal relationship between white matter integrity and depression in community-dwelling individuals using diffusion tensor imaging with tract-based spatial statistics. METHOD: The sample comprised 381 participants aged between 72 and 92 years who were assessed twice within 2 years. Depressive symptoms were measured with the Geriatric Depression Scale. Tract-based spatial statistics were applied to investigate white matter integrity in currently depressed v. non-depressed elderly people and in those with a history of depression v. no history of depression. The relationship between white matter integrity and development of depressive symptoms after 2 years were analysed with logistic regression. RESULTS: Individuals with current depression had widespread white matter integrity reduction compared with non-depressed elderly people. Significant fractional anisotropy reductions were found in 45 brain areas with the most notable findings in the frontal lobe, association and projection fibres. A history of depression was not associated with reduced fractional anisotropy. White matter changes in the superior frontal gyrus, posterior thalamic radiation, superior longitudinal fasciculus and in the body of corpus callosum predicted depression at follow-up. CONCLUSIONS: Reduced white matter integrity is associated with late-life depression and predicts future depressive symptoms whereas a history of depression is not related to white matter changes. Disruption to white matter integrity may be a biomarker to predict late-life depression. PMID- 25147371 TI - Childhood family income, adolescent violent criminality and substance misuse: quasi-experimental total population study. AB - BACKGROUND: Low socioeconomic status in childhood is a well-known predictor of subsequent criminal and substance misuse behaviours but the causal mechanisms are questioned. Aims To investigate whether childhood family income predicts subsequent violent criminality and substance misuse and whether the associations are in turn explained by unobserved familial risk factors. METHOD: Nationwide Swedish quasi-experimental, family-based study following cohorts born 1989-1993 (n(total) = 526 167, n(cousins) = 262 267, n(siblings) = 216 424) between the ages of 15 and 21 years. RESULTS: Children of parents in the lowest income quintile experienced a seven-fold increased hazard rate (HR) of being convicted of violent criminality compared with peers in the highest quintile (HR = 6.78, 95% CI 6.23-7.38). This association was entirely accounted for by unobserved familial risk factors (HR = 0.95, 95% CI 0.44-2.03). Similar pattern of effects was found for substance misuse. CONCLUSIONS: There were no associations between childhood family income and subsequent violent criminality and substance misuse once we had adjusted for unobserved familial risk factors. PMID- 25147372 TI - Envelope, please. And the award goes to.... PMID- 25147373 TI - Hematopoietic ontogeny in the axolotl. PMID- 25147374 TI - Asparaginase allergies: it's all in the genes. PMID- 25147375 TI - How to treat old MCL patients: one size fits it all? PMID- 25147376 TI - Solitary bone plasmacytomas need to flow. PMID- 25147377 TI - fHLH: becoming a blended family. PMID- 25147378 TI - How mutant HFE causes hereditary hemochromatosis. PMID- 25147379 TI - Factor XIII and adipocyte biology. PMID- 25147380 TI - VKORC1 ER mislocalization causes rare disease. PMID- 25147381 TI - FFS: an end(point) to our problems in chronic GVHD trials? PMID- 25147383 TI - Early Life Health and Cognitive Function in Old Age. PMID- 25147385 TI - Should TED talks be teaching us something? PMID- 25147386 TI - Academic pharmacy practice fellowships address challenges of evolving pharmacist roles. PMID- 25147387 TI - Four rights of the pharmacy educational consumer. AB - Professional students and their families invest a significant amount of time and finances to obtain a degree. While education is not a typical consumer good and should not be treated as such, there are certain expectations that colleges and schools should be prepared to meet. This article contrasts academic entitlement issues with 4 fundamental rights underpinning colleges' and schools' fiduciary responsibilities to students. The authors submit that students, in their roles as higher education consumers, have the following rights: (1) to have the opportunity to learn, (2) to learn from faculty members dedicated to best teaching practices, (3) to learn within a curriculum designed to prepare them for the profession, and (4) to have access to resources necessary to succeed. PMID- 25147388 TI - Academic entitlement and academic performance in graduating pharmacy students. AB - OBJECTIVES: To determine a measurable definition of academic entitlement, measure academic entitlement in graduating doctor of pharmacy (PharmD) students, and compare the academic performance between students identified as more or less academically entitled. METHODS: Graduating students at a private health sciences institution were asked to complete an electronic survey instrument that included demographic data, academic performance, and 2 validated academic entitlement instruments. RESULTS: One hundred forty-one of 243 students completed the survey instrument. Fourteen (10%) students scored greater than the median total points possible on 1 or both of the academic entitlement instruments and were categorized as more academically entitled. Less academically entitled students required fewer reassessments and less remediation than more academically entitled students. The highest scoring academic entitlement items related to student perception of what professors should do for them. CONCLUSION: Graduating pharmacy students with lower levels of academic entitlement were more academically successful than more academically entitled students. Moving from an expert opinion approach to evidence-based decision-making in the area of academic entitlement will allow pharmacy educators to identify interventions that will decrease academic entitlement and increase academic success in pharmacy students. PMID- 25147389 TI - Bullying in the clinical training of pharmacy students. AB - OBJECTIVE: To determine whether bullying is a significant factor in the clinical training of pharmacy students. METHODS: The literature as well as the Accreditation Council for Pharmacy Education (ACPE) Standards and American Association of Colleges of Pharmacy (AACP) surveys were reviewed for mention and/or measurement of bullying behaviors in the clinical training of pharmacy students. The authors used a Delphi process to define bullying behavior. The consensus definition was used to analyze 2,087 in-house student evaluations of preceptors for evidence of bullying behaviors. The authors mapped strings of text from in-house student comments to different, established categories of bullying behaviors. RESULTS: The ACPE Standards and AACP surveys contained no mention or measures of bullying. The 2013 AACP survey data reported overwhelmingly positive preceptor ratings. Of the 2,087 student evaluations of preceptors, 119 (5.7%) had at least 1 low rating. Within those 119 survey instruments, 34 comments were found describing bullying behaviors. Students' responses to the AACP survey were similar to data from the national cohort. CONCLUSIONS: Given the evidence that bullying behaviors occur in pharmacy education and that bullying has long-term and short-term damaging effects, more attention should be focused on this problem. Efforts should include addressing bullying in ACPE Standards and AACP survey tools developing a consensus definition for bullying and conducting more research into bullying in the clinical training of pharmacy students. PMID- 25147390 TI - Pharmacy students' perceptions of natural science and mathematics subjects. AB - OBJECTIVE: To determine the level of importance pharmacy students placed on science and mathematics subjects for pursuing a career in pharmacy. METHOD: Two hundred fifty-four students completed a survey instrument developed to investigate students' perceptions of the relevance of science and mathematics subjects to a career in pharmacy. Pharmacy students in all 4 years of a master of pharmacy (MPharm) degree program were invited to complete the survey instrument. RESULTS: Students viewed chemistry-based and biology-based subjects as relevant to a pharmacy career, whereas mathematics subjects such as physics, logarithms, statistics, and algebra were not viewed important to a career in pharmacy. CONCLUSION: Students' experience in pharmacy and year of study influenced their perceptions of subjects relevant to a pharmacy career. Pharmacy educators need to consider how they can help students recognize the importance of scientific knowledge earlier in the pharmacy curriculum. PMID- 25147391 TI - Pharmacy students' interpretation of academic integrity. AB - OBJECTIVE: To explore pharmacy students' recognition and interpretation of situations constituting breaches of academic integrity. METHODS: A survey instrument comprising 10 hypothetical student(s) scenarios was completed by 852 students in the bachelor of pharmacy program at an Australian university. The scenarios were relevant to current modes of assessment and presented degrees of ambiguity around academic integrity. RESULTS: Identification of the hypothetical student(s) at fault, particularly in the deliberately ambiguous scenarios, was not related to the respondents' year of study or sex. Students with fewer years of postsecondary education were more definitive in their interpretation of contentious cases. Respondents from all 4 years of study reported witnessing many of these behaviors among their peers. CONCLUSION: This study provided novel insight into the ambiguity surrounding academic integrity and students' perceptions relating to the deliberate or inadvertent involvement of other parties. PMID- 25147392 TI - Rational and experiential decision-making preferences of third-year student pharmacists. AB - OBJECTIVE: To examine the rational (systematic and rule-based) and experiential (fast and intuitive) decision-making preferences of student pharmacists, and to compare these preferences to the preferences of other health professionals and student populations. METHODS: The Rational-Experiential Inventory (REI-40), a validated psychometric tool, was administered electronically to 114 third-year (P3) student pharmacists. Student demographics and preadmission data were collected. The REI-40 results were compared with student demographics and admissions data to identify possible correlations between these factors. RESULTS: Mean REI-40 rational scores were higher than experiential scores. Rational scores for younger students were significantly higher than students aged 30 years and older (p<0.05). No significant differences were found based on gender, race, or the presence of a prior degree. All correlations between REI-40 scores and incoming grade point average (GPA) and Pharmacy College Admission Test (PCAT) scores were weak. CONCLUSION: Student pharmacists favored rational decision making over experiential decision making, which was similar to results of studies done of other health professions. PMID- 25147393 TI - The Test of Logical Thinking as a predictor of first-year pharmacy students' performance in required first-year courses. AB - OBJECTIVES: To investigate the correlation of scores on the Test of Logical Thinking (TOLT) with first-year pharmacy students' performance in selected courses. METHODS: The TOLT was administered to 130 first-year pharmacy students. The examination was administered during the first quarter in a single session. RESULTS: The TOLT scores correlated with grades earned in Pharmaceutical Calculations, Physical Pharmacy, and Basic Pharmacokinetics courses. CONCLUSION: Performance on the TOLT has been correlated to performance in courses that required the ability to use quantitative reasoning to complete required tasks. In the future, it may be possible to recommend remediation, retention, and/or admission based in part on the results from the TOLT. PMID- 25147394 TI - Evaluating the relationship between general health vocabulary and student achievement in pharmacology. AB - OBJECTIVE: To determine whether achievement in pharmacology is related to students' general health vocabulary knowledge. METHODS: Students registered for the pharmacology modules in the second (n=117), third (n=54), and fourth (n=41) years of the bachelor of pharmacy degree program completed a general health vocabulary assessment. Results of the vocabulary assessments in Pharmacology 3 and Pharmacology 4 were used to determine the effects of academic progression. Grades in the summative Pharmacology 2 examination served as indicators of achievement in pharmacology. Focus group sessions were held with a convenience sample of Pharmacology 2 (n=12), Pharmacology 3 (n=10), and Pharmacology 4 (n=5) students. RESULTS: A significant, positive correlation between Pharmacology 2 grades and vocabulary assessment scores was demonstrated. Student perceptions revealed during focus group interviews were that poor pharmacy-related vocabulary knowledge impacted their ability to learn pharmacology. CONCLUSION: Achievement in pharmacology correlated positively with vocabulary knowledge (p=0.031) among a South African, multilingual student cohort in a setting where English is used in teaching and thus is imperative for learning. PMID- 25147395 TI - Impact and application of material learned in a pharmacy residency teaching certificate program. AB - OBJECTIVE: To describe the impact and application of material learned in a pharmacy resident teaching certificate program on the career experiences of alumni 1 to 11 years after completion of the program. DESIGN: A teaching certificate program was established in 2001 that brought together residents from various training programs throughout Wisconsin to discuss essential educational skills in a dynamic learning environment. The purpose of the program was to teach participants the fundamental skills to continue to develop as a pharmacy educator throughout their career. ASSESSMENT: An electronic survey instrument was sent to alumni of the program. Greater than 70% of respondents agreed that the teaching certificate program reinforced their desire to teach in practice and that the program helped qualify them for their current or previous practice position. Alumni in academic positions more strongly agreed that the program changed their career interest to include academia and qualified them for their position in academia. CONCLUSIONS: A teaching certificate program can reinforce or stimulate interest among pharmacy residents in pursuing an academic career and prepare them for this role. Completion of the program led to a high level of confidence among the majority of alumni in their ability to precept students and residents and influenced some alumni involved in the hiring of pharmacists. PMID- 25147396 TI - Implementation of an integrated longitudinal curricular activity for graduating pharmacy students. AB - OBJECTIVES: To evaluate whether a novel integrated longitudinal curricular activity to prepare graduating doctor of pharmacy (PharmD) students for 2 comprehensive examinations was successful, and to assess whether it engaged other pharmacy students in curricular discussion and learning. DESIGN: Thirty-eight of 91graduating third-year (P3) students in a PharmD program formed 11 teams to create and present pharmacotherapeutic posters to their peers. The impact of the novel activity on graduating students' performance on the North American Pharmacist Licensure Examination (NAPLEX) and a comprehensive commercial examination was assessed. All first-year (P1), second-year (P2), and P3 students reviewed and discussed the content of each poster. ASSESSMENT: Participants in the integrated longitudinal curricular activity performed better than nonparticipants on the commercial examination (p=0.023) and NAPLEX (p=0.033). However, regardless of participation, commercial examination scores predicted a significant amount of variance (ie, 34%) in NAPLEX scores. The P3 participants (83%) believed the curricular activity assisted them in their NAPLEX preparation, while 75% of P1 students, 79% of P2 students, and 80% of P3 students agreed that poster review provided an effective summary of different disease states. Ninety percent of faculty poster evaluators reported that the posters were professional, and all evaluators agreed that participants effectively conveyed their message to the intended audience. CONCLUSION: The integrated longitudinal curricular activity provided a positive learning environment for all pharmacy students and may have better prepared graduating students' for the NAPLEX. PMID- 25147397 TI - Use of virtual patients in an advanced therapeutics pharmacy course to promote active, patient-centered learning. AB - OBJECTIVE: To assess student satisfaction and learning of course objectives following the integration of virtual patient cases designed to promote active, patient-centered learning in an advanced therapeutics pharmacy course. DESIGN: A dynamic virtual patient platform that incorporated a branched-narrative, decision making teaching model was used in an advanced therapeutics course to supplement lecture content. ASSESSMENT: Presimulation and postsimulation tests were used to assess student learning. The use of virtual patients significantly enhanced student learning for both higher- and lower-level test questions (p<0.001 and p=0.01, respectively). Students agreed or strongly agreed that the virtual patient cases provided an effective way to learn (72%), were enjoyable (69%), and were appropriate in content (80%), and that more should be incorporated (59%). CONCLUSION: The use of virtual patients in an advanced therapeutics practicum effectively promoted active, patient-centered learning; engaged students in an interactive and dynamic educational technology; encouraged teamwork; enhanced higher-level student learning; and improved student satisfaction in the course. PMID- 25147398 TI - A pharmaceutical industry elective course on practice experience selection and fellowship pursuit by pharmacy students. AB - OBJECTIVE: To design and implement 2 pharmaceutical industry elective courses and assess their impact on students' selection of advanced pharmacy practice experiences (APPEs) and pursuit of pharmaceutical industry fellowships. METHODS: Two 2-credit-hour elective courses that explored careers within the prescription and nonprescription pharmaceutical drug industries were offered for second- and third-year pharmacy students in a doctor of pharmacy (PharmD) degree program. RESULTS: The impact of the courses on pharmacy students' pursuit of a pharmaceutical industry fellowship was evaluated based on responses to annual graduating students' exit surveys. A greater percentage (17.9%) of students who had taken a pharmaceutical industry elective course pursued a pharmaceutical industry fellowship compared to all PharmD graduates (4.8%). Of the students who enrolled in pharmaceutical industry APPEs, 31% had taken 1 of the 2 elective courses. CONCLUSION: Exposure to a pharmaceutical industry elective course within a college or school of pharmacy curriculum may increase students' interest in pursuing pharmaceutical industry fellowships and enrolling in pharmaceutical industry APPEs. PMID- 25147399 TI - Impact of a residency interest group on students applying for residency. AB - OBJECTIVE: To determine the impact of a faculty-directed, residency interest group on the knowledge, confidence, and preparedness about residency-related topics of third-year (P3) and fourth-year (P4) pharmacy students. DESIGN: Faculty members implemented residency interest group sessions on residency and career preparation for P3 and P4 students. Group meetings consisted of four 2- to 3-hour sessions that covered topics such as residency timeline and resources, letter of intent and CV development, proper interview techniques, and navigating the midyear clinical meeting. Residency directors throughout Mississippi, current pharmacy residents, P3 and P4 students, and other faculty members were invited to attend these sessions. ASSESSMENT: Surveys were administered prior to and after completion of the interest group sessions. Students who attended the sessions demonstrated increased knowledge, confidence, and preparedness on residency related topics. However, non-attendees also demonstrated increased knowledge, confidence, and preparedness from baseline. CONCLUSION: The majority of students who accepted a residency position had attended at least 1 residency interest group session, suggesting this program had a positive influence. PMID- 25147400 TI - Advanced screencasting with embedded assessments in pathophysiology and therapeutics course modules. AB - OBJECTIVE: To implement and assess the effectiveness of a hybrid learning model using advanced screencasting with embedded assessments in pathophysiology and therapeutics modules. DESIGN: Two pathophysiology and therapeutics course modules on viral hepatitis and the clinical pharmacokinetics of aminoglycosides were chosen for study. The preclass portion of the hybrid model involved student completion of interactive e-lectures that were created with the use of advanced screencasting and included embedded assessments. Students viewed the e-lectures and completed the assessment questions prior to in-class lecture. ASSESSMENT: Preimplementation and postimplementation test scores were compared and student survey data were analyzed. Test scores improved significantly and students' perceptions of the learning method were favorable. Test scores improved most significantly on higher-level Bloom's taxonomy questions. CONCLUSION: A hybrid model that used advanced screencasting with embedded assessments offered a novel method to afford students active-learning opportunities to progress to higher cognitive domains of learning. PMID- 25147401 TI - US and international health professions' requirements for continuing professional development. AB - There is not a comprehensive global analysis of continuing professional development (CPD) and continuing education (CE) in the major health professions in published literature. The aim of this article is to summarize findings from the US and international literature on CPD and CE practices in the health professions, comparing the different requirements and frameworks to see what similarities and challenges exist and what the future focus should be for the pharmacy profession. A literature review was conducted on CPD and CE in selected health professions, namely pharmacy, medicine, nursing, ophthalmology, dentistry, public health, and psychology. Over 300 papers from the health professions were retrieved and screened. Relevant articles based on the abstracts and introductions were summarized into tabular form by profession, minimum requirements for licensure, nature of credits, guidelines on how to record CE and CPD activities, and specific CE and CPD definitions. Wide variations exist among the health professions. Lessons learned from this information can be used to further clarify and define the role of CE and CPD and self-directed lifelong learning in pharmacy and the health professions. PMID- 25147402 TI - Comparison of anti-fouling surface coatings for applications in bacteremia diagnostics. AB - To accurately diagnose microbial infections in blood, it is essential to recover as many microorganisms from a sample as possible. Unfortunately, recovering such microorganisms depends significantly on their adhesion to the surfaces of diagnostic devices. Consequently, we sought to minimize the adhesion of methicillin-sensitive Staphylococcus aureus (MSSA) to the surface of polypropylene- and acrylic-based bacteria concentration devices. These devices were treated with 11 different coatings having various charges and hydrophobicities. Some coatings promoted bacterial adhesion under centrifugation, whereas others were more likely to prevent it. Experiments were run using a simple buffer system and lysed blood, both inoculated with MSSA. Under both conditions, Hydromer's 7-TS-13 and Aqua65JL were most effective at reducing bacterial adhesion. PMID- 25147403 TI - THE CYCLE OF VIOLENCE IN CONTEXT: EXPLORING THE MODERATING ROLES OF NEIGHBORHOOD DISADVANTAGE AND CULTURAL NORMS. AB - Although the cycle of violence theory has received empirical support (Widom, 1989a, 1989b), in reality, not all victims of child physical abuse become involved in violence. Therefore, little is known regarding factors that may moderate the relationship between abuse and subsequent violence, particularly contextual circumstances. The current investigation used longitudinal data from 1,372 youth living in 79 neighborhoods who participated in the Project on Human Development in Chicago Neighborhoods (PHDCN), and it employed a multivariate, multilevel Rasch model to explore the degree to which neighborhood disadvantage and cultural norms attenuate or strengthen the abuse-violence relationship. The results indicate that the effect of child physical abuse on violence was weaker in more disadvantaged communities. Neighborhood cultural norms regarding tolerance for youth delinquency and fighting among family and friends did not moderate the child abuse-violence relationship, but each had a direct effect on violence, such that residence in neighborhoods more tolerant of delinquency and fighting increased the propensity for violence. These results suggest that the cycle of violence may be contextualized by neighborhood structural and cultural conditions. PMID- 25147404 TI - Infant Imitation After a 1-Week Delay: Long-Term Memory for Novel Acts and Multiple Stimuli. AB - Deferred imitation after a 1-week delay was examined in 14-month-old infants. Six actions, each using a different object, were demonstrated to each infant. One of the six actions was a novel behavior that had a zero probability of occurrence in spontaneous play. In the imitation condition, infants observed the demonstration but were not allowed to touch the objects, thus preventing any immediate imitation. After the 1-week delay, infants returned to the laboratory and their imitation of the adult's previous actions was scored. Infants in the imitation condition produced significantly more of the target actions than infants in control groups who were not exposed to the modeling; there was also strong evidence for the imitation of the novel act. From a cognitive perspective deferred imitation provides a means of assessing recall memory and representation in children. From a social-developmental viewpoint the findings illustrate that the behavioral repertoire of infants and their knowledge about objects can expand as a result of seeing the actions of others. PMID- 25147405 TI - Imitation in Newborn Infants: Exploring the Range of Gestures Imitated and the Underlying Mechanisms. AB - This study evaluated the psychological mechanisms underlying imitation of facial actions in young infants. A novel aspect of the study was that it used a nonoral gesture that had not been tested before (head movement), as well as a tongue protrusion gesture. Results showed imitation of both displays. Imitation was not limited to the intervals during which the experimenter's movements were displayed; Ss also imitated from memory after the display had stopped. The results established that newborn imitation is not constrained to a few privileged oral movements. The findings support Meltzoff and Moore's hypothesis that early imitation is mediated by an active cross-modal matching process. A common representational code may unite the perception and production of basic human acts. PMID- 25147406 TI - Understanding the Intentions of Others: Re-Enactment of Intended Acts by 18-Month Old Children. AB - Investigated was whether children would re-enact what an adult actually did or what the adult intended to do. In Experiment 1 children were shown an adult who tried, but failed, to perform certain target acts. Completed target acts were thus not observed. Children in comparison groups either saw the full target act or appropriate controls. Results showed that children could infer the adult's intended act by watching the failed attempts. Experiment 2 tested children's understanding of an inanimate object that traced the same movements as the person had followed. Children showed a completely different reaction to the mechanical device than to the person: They did not produce the target acts in this case. Eighteen-month-olds situate people within a psychological framework that differentiates between the surface behavior of people and a deeper level involving goals and intentions. They have already adopted a fundamental aspect of folk psychology-persons (but not inanimate objects) are understood within a framework involving goals and intentions. PMID- 25147407 TI - Neurosteroids as endogenous regulators of seizure susceptibility and use in the treatment of epilepsy. AB - Neurosteroids such as allopregnanolone are positive allosteric modulators of GABAA receptors with powerful antiseizure activity in diverse animal models. Neurosteroids may be endogenous regulators of seizure susceptibility, for example, in catamenial epilepsy. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of refractory partial seizures and infantile spasms have been encouraging. Neurosteroids and analogs such as ganaxolone show promise in the treatment of diverse forms of epilepsy. For an expanded treatment of this topic see Jasper's basic mechanisms of the epilepsies, 4th ed. (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at www.ncbi.nlm.nih.gov/books). PMID- 25147408 TI - Racial/Ethnic Differences in the Relationship Between Neighborhood Disadvantage and Adolescent Substance Use. AB - Although social disorganization theory hypothesizes that neighborhood characteristics influence youth delinquency, the impact of neighborhood disadvantage on adolescent substance use and racial/ethnic differences in this relationship have not been widely investigated. The present study examines these issues using longitudinal data from 1,856 African American, Hispanic, and Caucasian adolescents participating in the Project on Human Development in Chicago Neighborhoods (PHDCN). The results indicated that neighborhood disadvantage did not significantly increase the likelihood of substance use for the full sample. When relationships were analyzed by race/ethnicity, one significant (p <= .10) effect was found; disadvantage increased alcohol use among African Americans only. The size of this effect differed significantly between African American and Hispanic youth. In no other cases did race/ethnicity moderate the impact of disadvantage on substance use. These results suggest that disadvantage is not a strong predictor of adolescent substance use, although other features of the neighborhood may affect such behaviors. PMID- 25147409 TI - Optimize the Separation of Fluorinated Amphiles Using High-Performance Liquid Chromatography. AB - Using the set of fluorinated amphiles that contain the same fluorocarbon moiety but differ in their fluorine content percentage F% (25-45%), the optimal condition for a F%-based separation of these analytes using reverse-phase chromatography was explored. It is found that optimal separation can be achieved by pairing a regular reverse-phase column (such as C8) with a fluorinated eluent (such as trifluoroethanol). Separation is further improved at higher chromatographic temperature with baseline separation achieved at 45 degrees C. This result indicates that the separation of fluorocarbon-tagged molecules can be based on the fluorine content percentage rather than the number of fluorine atoms. PMID- 25147410 TI - Two Decades of Stability and Change in Age at First Union Formation. AB - The landscape of union formation has been shifting; Americans are now marrying at the highest ages on record and the majority of young adults have cohabited. Yet little attention has been paid to the timing of cohabitation relative to marriage. Using the National Survey of Families and Households and 4 cycles of the National Survey of Family Growth, the authors examined the timing of marriage, cohabitation, and unions over 20 years. As the median age at first marriage has climbed, the age at cohabitation has remained stable for men and women. The changes in the timing of union formation have been similar according to race/ethnicity. The marked delay in marriage among women and men with low educational attainment has resulted in a near-convergence in the age at first marriage according to education. The authors conclude that the rise in cohabitation has offset changes in the levels and timing of marriage. PMID- 25147411 TI - An Application of Berman's Work on Pool-Model Invariants in Analyzing Indistinguishable Models for Whole-Body Cholesterol Metabolism. AB - Berman and Schoenfeld used matrix transformations to study unidentifiable pool models. It is possible to use the method to examine if two models are output indistinguishable, that is, if given the nature of tracer injections and observations, the two models have the same responses. The method is applied to two three-pool models for whole-body cholesterol metabolism. The indistinguishabilily of a mammillary model from a catenary model is proved using matrix transformations. The method is used in two ways, directly as well as after simplifying the problem. The two ways, as well as an analysis of the converse, help to show how the method is to be applied as well as the strengths and weaknesses of the method. PMID- 25147413 TI - Computationally efficient banding of large covariance matrices for ordered data and connections to banding the inverse Cholesky factor. AB - In this article, we propose a computationally efficient approach to estimate (large) p-dimensional covariance matrices of ordered (or longitudinal) data based on an independent sample of size n. To do this, we construct the estimator based on a k-band partial autocorrelation matrix with the number of bands chosen using an exact multiple hypothesis testing procedure. This approach is considerably faster than many existing methods and only requires inversion of (k + 1) dimensional covariance matrices. The resulting estimator is positive definite as long as k < n (where p can be larger than n). We make connections between this approach and banding the Cholesky factor of the modified Cholesky decomposition of the inverse covariance matrix (Wu and Pourahmadi, 2003) and show that the maximum likelihood estimator of the k-band partial autocorrelation matrix is the same as the k-band inverse Cholesky factor. We evaluate our estimator via extensive simulations and illustrate the approach using high-dimensional sonar data. PMID- 25147412 TI - Asymmetric oxidative dearomatizations promoted by hypervalent iodine(III) reagents: an opportunity for rational catalyst design? AB - The use of and lambda3- and lambda5-iodanes in the oxidative dearomatization of phenols is a well-established and general procedure for the construction of cyclohexadienone structures. However, their use in asymmetric dearomatization reactions is quite underdeveloped and, despite work by several research groups over the past several years, a general chiral aryl iodide catalyst has yet to emerge. This article will serve to highlight the significant progress that has been made in this area and will reveal some of deficiencies in the literature that the author believes may be hindering further progress. PMID- 25147414 TI - Identification of a novel structure in heparin generated by potassium permanganate oxidation. AB - The worldwide heparin contamination crisis in 2008 led health authorities to take fundamental steps to better control heparin manufacture, including implementing appropriate analytical and bio-analytical methods to ensure production and release of high quality heparin sodium product. Consequently, there is an increased interest in the identification and structural elucidation of unusually modified structures that may be present in heparin. Our study focuses on the structural elucidation of species that give rise to a signal observed at 2.10 ppm in the N-acetyl region of the 1H NMR spectrum of some pharmaceutical grade heparin preparations. Structural elucidation experiments were carried out using homonuclear (COSY, TOSCY and NOESY) and heteronuclear (HSQC, HSQC-DEPT, HMQC COSY, HSQC-TOCSY, and HMBC) 2D NMR spectroscopy on both heparin as well as heparin-like model compounds. Our results identify a novel type of oxidative modification of the heparin chain that results from a specific step in the manufacturing process used to prepare heparin. PMID- 25147415 TI - Early Imitation Within a Functional Framework: The Importance of Person Identity, Movement, and Development. AB - Facial imitation was investigated in infants 6 weeks and 2 to 3 months of age. Three findings emerged: (a) early imitation did not vary as a function of familiarity with the model-infants imitated a stranger as well as their own mothers; (b) infants imitated both static facial postures and dynamic facial gestures; and (c) there was no disappearance of facial imitation in the 2- to 3 month age range, contrary to previous reports. Two broad theoretical points are developed. First, a proposal is made about the social and psychological functions that early imitation serves in infants' encounters with people. It is argued that infants deploy imitation to enrich their understanding of persons and actions and that early imitation is used for communicative purposes. Second, a theoretical bridge is formed between early imitation and the "object concept." The bridge is formed by considering the fundamental role that identity plays in infants' understanding of people and things. One of the psychological functions that early imitation subserves is to identify people. Infants use the nonverbal behavior of people as an identifier of who they are and use imitation as a means of verifying this identity. Data and theory are adduced in favor of viewing early imitation as an act of social cognition. PMID- 25147416 TI - Imitation, Memory, and the Representation of Persons. AB - Imitation was tested both immediately and after a 24-hr retention interval in 6 week-old infants. The results showed immediate imitation, which replicates past research, and also imitation from memory, which is new. The latter finding implicates recall memory and establishes that 6-week-olds can generate actions on the basis of stored representations. The motor organization involved in imitation was investigated through a microanalysis of the matching response. Results revealed that infants gradually modified their behavior towards more accurate matches over successive trials. It is proposed that early imitation serves a social identity function. Infants are motivated to imitate after a 24-hr delay as a means of clarifying whether the person they see before them is the same one they previously encountered. They use the reenactment of a person's behavior to probe whether this is the same person. In the domain of inanimate objects, infants use physical manipulations (e.g., shaking) to perform this function. Imitation is to understanding people as physical manipulation is to understanding things. Motor imitation, the behavioral reenactment of things people do, is a primitive means of understanding and communicating with people. PMID- 25147417 TI - Deferred Imitation Across Changes in Context and Object: Memory and Generalization in 14-Month-Old Infants. AB - The influence of changes in context and object characteristics on deferred imitation was assessed in 14-month-old infants. In Experiment 1, infants in the imitation group saw an adult demonstrate target acts on miniature objects in an unusual context (an orange polka-dot tent). When later presented with larger objects in a normal laboratory room, these infants performed significantly more target acts than did controls. In Experiment 2, three groups of infants were tested. Infants in an imitation(no change) group saw an adult demonstrate target acts and were subsequently tested in the same room using the same objects as the adult. Infants in the imitation (context + object size & color change) group followed the same procedure, but both the context and two salient featural characteristics of the objects (size and color) were changed between encoding and the recall test of deferred imitation. Control infants did not see the target demonstrations. Results showed that the combined changes in context and object features led to a significant decrease in imitative performance. Nonetheless, in comparison to the controls, infants exhibited significant recall as indexed by deferred imitation. The results show that imitation generalizes across changes in object size, object color, and test context. The implications for theories of memory and representational development are discussed. PMID- 25147418 TI - OBJECT REPRESENTATION, IDENTITY, AND THE PARADOX OF EARLY PERMANENCE: Steps Toward a New Framework. AB - The sensorimotor theory of infancy has been overthrown, but there is little consensus on a replacement. We hypothesize that a capacity for representation is the starting point for infant development, not its culmination. Logical distinctions are drawn between object representation, identity, and permanence. Modern experiments on early object permanence and deferred imitation suggest: (a) even for young infants, representations persist over breaks in sensory contact, (b) numerical identity of objects (Os) is initially specified by spatiotemporal criteria (place and trajectory), (c) featural and functional identity criteria develop, (d) events are analyzed by comparing representations to current perception, and (e) representation operates both prospectively, anticipating future contacts with an O, and retrospectively, reidentifying an O as the "same one again." A model of the architecture and functioning of the early representational system is proposed. It accounts for young infants' behavior toward absent people and things in terms of their efforts to determine the identity of objects. Our proposal is developmental without denying innate structure and elevates the power of perception and representation while being cautious about attributing complex concepts to young infants. PMID- 25147419 TI - Cohabitation Expectations among Young Adults in the United States: Do They Match Behavior? AB - Cohabitation continues to rise, but there is a lack of knowledge about expectations to cohabit and the linkage between expectations and subsequent cohabitation. We capitalize on a new opportunity to study cohabitation expectations by drawing on the National Longitudinal Study of Youth (NLSY79) main youth and two waves (2008 and 2010) of the NLSY young adult (YA) surveys (n=1,105). We find considerable variation in cohabitation expectations: 39.9% have no expectation of cohabiting in the future and 16.6% report high odds of cohabiting in the next two years. Cohabitation expectations are associated with higher odds of entering a cohabiting relationship, but are not perfectly associated. Only 38% of young adults with certain cohabitation expectations in 2008 entered a cohabiting union by 2010. Further investigation of the mismatch between expectations and behaviors indicates that a substantial minority (30%) who entered a cohabiting union had previously reported no or low expectations, instances of what we term "unplanned cohabitation." Our findings underscore the importance of considering not just behavior, but also individuals' expectations for understanding union formation, and more broadly, family change. PMID- 25147420 TI - Do Personality Traits Conform to Lists or Hierarchies? AB - Are personality traits mostly related to one another in hierarchical fashion, or as a simple list? Does extracting an additional personality factor in a factor analysis tend to subdivide an existing factor, or does it just add a new one? Goldberg's "bass-ackwards" method was used to address this question, based on rotations of 1 to 12 factors. Two sets of data were employed: ratings by 320 undergraduates using 435 personality-descriptive adjectives, and 512 Oregon community members' responses to 184 scales from 8 personality inventories. In both, the view was supported that personality trait structure tends not to be strongly hierarchical: allowing an additional dimension usually resulted in a new substantive dimension rather than in the splitting of an old one, and once traits emerged they tended to persist. PMID- 25147421 TI - Does Baseline Heart Rate Variability Reflect Stable Positive Emotionality? AB - Several recent studies have found significant correlations, medium in effect size, between baseline heart rate variability (HRV) and measures of positive functioning, such as extraversion, agreeableness, and trait positive affectivity. Other research, however, has suggested an optimal level of HRV and found nonlinear effects. In the present study, a diverse sample of 239 young adults completed a wide range of measures that reflect positive psychological functioning, including personality traits, an array of positive emotions (measured with the Dispositional Positive Emotions Scale), and depression, anxiety, and stress symptoms (measured with the DASS and CESD). HRV was measured with a 6-minute baseline period and quantified using many common HRV metrics (e.g., respiratory sinus arrhythmia, root mean square of successive differences, and others), and potentially confounding behavioral and lifestyle variables (e.g., BMI, caffeine and nicotine use, sleep quality) were assessed. Neither linear nor non-linear effects were found, and the effect sizes were small and near zero. The findings suggest that the cross-sectional relationship between HRV and positive experience deserves more attention and meta-analytic synthesis. PMID- 25147422 TI - Treating apraxia of speech with an implicit protocol that activates speech motor areas via inner speech. AB - BACKGROUND: Treatments of apraxia of speech (AOS) have traditionally relied on overt practice. One alternative to this method is implicit phoneme manipulation which was derived from early models on inner speech. Implicit phoneme manipulation requires the participant to covertly move and combine phonemes to form a new word. This process engages a system of self-monitoring which is referred to as fully conscious inner speech. AIMS: The present study aims to advance the understanding and validity of a new treatment for AOS, implicit phoneme manipulation. Tasks were designed to answer the following questions. 1. Would the practice of implicit phoneme manipulation improve the overt production of complex consonant blends in words? 2. Would this improvement generalize to untrained complex and simpler consonant blends in words? 3. Would these treatment tasks activate regions known to support motor planning and programming as verified by fMRI? METHOD & PROCEDURES: The participant was asked to covertly manipulate phonemes to create a new word and to associate this newly formed word to a target picture among 4 phonologically-related choices. To avoid overt practice, probes were collected only after each block of training was completed. Probe sessions assessed the effects of implicit practice on the overt production of simple and complex consonant blends in words. An imaging protocol compared semantic baseline tasks to treatment tasks to verify that implicit phoneme manipulation activated brain regions of interest. OUTCOMES & RESULTS: Behavioral: Response to implicit training of complex consonant blends resulted in improvements which were maintained 6 weeks after treatment. Further, this treatment generalized to simpler consonant blends in words. Imaging: Functional imaging during implicit phoneme manipulation showed significant activation in brain regions responsible for phonological processing when compared to the baseline semantic task. CONCLUSIONS: Implicit phoneme manipulation offers an alternative to traditional methods that require overt production for treatment of AOS. Additionally, this implicit treatment method was shown to activate neural areas known to be involved in phonological processing, motor planning and programming. PMID- 25147423 TI - The role of haptoglobin genotypes in Chagas disease. AB - Although the number of people infected with T. cruzi is on the rise, host genetic and immune components that are crucial in the development of the Chagas disease have been discovered. We investigated the frequency of polymorphisms in the gene encoding haptoglobin of patients with chronic Chagas disease. The results suggest that while the HP1-1 genotype may confer protection against infection and the development of chronic Chagas disease due to the rapid metabolism of the Hp1-1-Hb complex and its anti-inflammatory activity, the presence of HP2-2 genotype may increase susceptibility towards a chronic condition of the disease due to a slow metabolism of the Hp2-2-Hb complex, lower antioxidant activity, and increased inflammatory reactivity, which lead to cell damage and a deterioration of the cardiac function. Finally, correlations between HP genotypes in different age groups and cardiac manifestations suggest that HP polymorphism could influence the prognosis of this infectious disease. This study shows some of the relevant aspects of the haptoglobin gene polymorphism and its implications in the T. cruzi infection. PMID- 25147424 TI - Protonation, Hydrolysis, and Condensation of Mono- and Trifunctional Silanes at the Air/Water Interface. AB - The protonation, hydrolysis, and condensation kinetics of octadecyldimethylmethoxysilane (OMMS) and octadecyltrimethoxysilane (OTMS) at the air/water interface were investigated using a monolayer trough. OTMS chemical condensation within physically condensed phases was observed in transferred monolayers using fluorescence microscopy. Molecular area increases and decreases attributed to protonation and hydrolysis, respectively, of silane methoxy groups were measured by a surface balance. These area changes at constant surface pressure suggested a stepwise protonation and hydrolysis of the three OTMS methoxy groups. In contrast, only a single protonation and hydrolysis event was observed for monofunctional OMMS. The influences of monolayer spreading time, silane packing density, and subphase pH on the reaction kinetics are presented. PMID- 25147425 TI - Manipulation of Proteins on Mica by Atomic Force Microscopy. AB - The atomic force microscope was used to image adsorption of a monoclonal IgM on mica in real time. Under the smallest possible force we could achieve (<4 nN), the cantilever tip behaved as a molecular broom and was observed to orient protein aggregates in strands oriented perpendicularly to the facet of the cantilever tip. Rotating the scan direction preserved the orientational relationship, as seen by the formation of rotated strands. When the applied force was increased, the distance between the strands increased, indicating the amount of protein that can be swept depends on the applied force. The effect of scanning increased the apparent surface coverage of IgM. Manipulation of a deposited fibrinogen layer with a 4-nN repulsive force was observed only after tens of minutes, but not to the extent that strands formed, indicating a greater adhesion between the fibrinogen and mica than between IgM and mica. With an applied repulsive force of 30 nN, fibrinogen strands formed and the protein was manipulated to produce the block letter U. At a much higher repulsive force, the entire scanning area was swept clean. PMID- 25147426 TI - Single-molecule detection of a guanine(C8) - thymine(N3) cross-link using ion channel recording. AB - The capability to identify and sequence DNA damage within the context of the genome is an important goal for medical diagnostics. However, currently available methods are not suitable for this purpose. Ion channel nanopore analysis shows promise as a potential single-molecule method to sequence genomic DNA in such a way that also allows detection of base or backbone modifications. Recent studies in human cell lines demonstrated the occurrence of a new DNA cross-link between guanine(C8) and thymine(N3) (5'-G*CT*-3'). The current work presents immobilization and translocation studies of the 5'-G*CT*-3' cross-link in a single-stranded oligodeoxynucleotide using the alpha-hemolysin (alpha-HL) ion channel. A 3'-biotinylated DNA strand containing the 5'-G*CT*-3' cross-link was incubated with streptavidin that allowed immobilization of the DNA in the beta barrel of alpha-HL. In this experiment, the 5'-G*CT*-3' cross-link was placed near the sensitive constriction zone of alpha-HL, yielding a 2.5% deeper blockage to the ion current level when compared to the unmodified strand. Next, free translocation of a cross-link-containing strand was studied, and an inverse relationship of the time constant with respect to an increase in the applied voltage was found, indicating that the cross-link can easily fit into the beta barrel and traverse through the ion channel. However, a modulation in the ion current level was not observed. These studies suggest that higher resolution ion channels or mechanisms to slow the translocation process, or both, might ultimately provide a mechanism for single-molecule sequencing for G-T cross links. PMID- 25147427 TI - Dietary combination of sucrose and linoleic acid causes skeletal muscle metabolic abnormalities in Zucker fatty rats through specific modification of fatty acid composition. AB - A dietary combination of sucrose and linoleic acid strongly contributes to the development of metabolic disorders in Zucker fatty rats. However, the underlying mechanisms of the metabolic disorders are poorly understood. We hypothesized that the metabolic disorders were triggered at a stage earlier than the 8 weeks we had previously reported. In this study, we investigated early molecular events induced by the sucrose and linoleic acid diet in Zucker fatty rats by comparison with other combinations of carbohydrate (sucrose or palatinose) and fat (linoleic acid or oleic acid). Skeletal muscle arachidonic acid levels were significantly increased in the sucrose and linoleic acid group compared to the other dietary groups at 4 weeks, while there were no obvious differences in the metabolic phenotype between the groups. Expression of genes related to arachidonic acid synthesis was induced in skeletal muscle but not in liver and adipose tissue in sucrose and linoleic acid group rats. In addition, the sucrose and linoleic acid group exhibited a rapid induction in endoplasmic reticulum stress and abnormal lipid metabolism in skeletal muscle. We concluded that the dietary combination of sucrose and linoleic acid primarily induces metabolic disorders in skeletal muscle through increases in arachidonic acid and endoplasmic reticulum stress, in advance of systemic metabolic disorders. PMID- 25147428 TI - Human serum albumin adsorption onto octadecyldimethylsilyl-silica gradient surface. AB - The effects of long-range electrostatic repulsion and short-range hydrophobic attraction on human serum albumin adsorption were studied as a function of the surface density of octadecyldimethylsilyl chains (C18) on silica. A C18 surface density gradient was prepared on fused silica plates. The water contact angles increased smoothly from 12 degrees to 105 degrees in the 12.5 mm long gradient region. The maximal fractional surface coverage of the C18 chains was calculated to be 0.92. Fluorescein-5-isothiocyanate-labeled human serum albumin (FITC-HSA) adsorption from dilute buffer solution onto the C18 gradient surface was measured using spatially resolved total internal reflection fluorescence (TIRF) spectroscopy. FITC-HSA adsorbed progressively more onto the surfaces with higher hydrophobicity. When the fractional surface coverage of C18 chains was larger than 0.42 the adsorption saturation of FITC-HSA leveled off. The adsorption kinetics of FITC-HSA changed from a transport-limited process at moderate-to-high C18 surface coverages to an adsorption-limited process at lower C18 surface coverages. The kinetics of FITC-HSA adsorption, including the convective diffusive transport of protein to the surface, were modeled as a simple binding process with a single forward and reverse rate. The apparent binding constant, derived from the initial forward and reverse binding rates, depended more strongly on the C18 surface coverage in 0.165 M buffer than in 0.025 M buffer. PMID- 25147429 TI - The surface density gradient of grafted poly (ethylene glycol): preparation, characterization and protein adsorption. AB - A surface density gradient of grafted poly (ethylene glycol) (PEG) chains was prepared using two-phase silanization of a flat silica surface. The first step was to create the surface density gradient of isocyanatopropyldimethylsilyl groups and to hydrolyze the isocyanato moiety into an amine. These surface amines were reacted with an excess of aldehyde-terminated PEG. The PEG-silica surface was characterized by dynamic contact angle measurements, X-ray photoelectron spectroscopy and ellipsometry. The length of the PEG gradient region was approximately 7 mm and the thickness in air ranged from zero to 1.1 nm. The maximum surface density of the PEG layer, as calculated from ellipsometric data, amounted to an average 0.4 PEG (molecular weight Mw = 2000 Da) molecule nm-2, while the surface density average of the amine groups was 1.4 molecules nm-2, indicating that only a fraction of the surface amines reacted with aldehyde terminated PEG. The PEG segment density profile in the gradient PEG region was computed by a self-consistent mean field theory. The PEG (Mw = 2000 Da) segments profile was not parabolic, but showed a thin depletion zone next to the surface. The influence of the surface density of the grafted PEG chains on protein repellence was tested by the adsorption of fibrinogen from solution and from a ternary protein solution mixture containing fibrinogen, albumin and immunoglobulin G. Fibrinogen adsorption onto the silica end of the gradient was extremely low, both in the presence of the other two proteins and in their absence. As the surface density of the grafted PEG chains increased, so did the fibrinogen adsorption (up to 0.024 MUg cm-2). It is not clear whether this low fibrinogen adsorption resulted from the interactions of the protein with the grafted PEG chains or with residual surface amines that were available due to some imperfections in the grafted PEG layer. PMID- 25147430 TI - NEW BASE-ALTERED ADENOSINE ANALOGUES: SYNTHESIS AND AFFINITY AT ADENOSINE A1 and A2A RECEPTORS. AB - N6-Substituted adenosine analogues containing cyclic hydrazines or chiral hydroxy (ar)alkyl groups, designed to interact with the S2 and S3 receptor subregions, have been synthesized and their binding to the adenosine A1 and A2A receptors have been investigated. Examples of both types of compounds were found to exhibit highly selective binding (Ki in low nM range) to the rat A1 receptor. PMID- 25147431 TI - Interleukin-17 gene polymorphisms contribute to cancer risk. AB - Epidemiological studies have suggested that interleukin-17 (IL-17) polymorphisms are associated with cancer risk. However, the results of these studies are inconsistent. Therefore, we performed a meta-analysis to obtain a precise conclusion. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association of the IL-17A rs2275913G>A and IL-17F rs763780T>C polymorphisms with cancer risk. Publication bias and sensitivity analyses were performed to ensure the statistical power. Overall, 10 relevant case-control studies involving 4,516 cases and 5,645 controls were included. The pooled ORs with 95% CIs indicated that the IL-17A rs2275913G>A polymorphism was significantly associated with increased cancer risk (for A versus G: OR = 1.28, 95% CI: 1.16-1.41, P < 0.001, I (2) = 61.1%; for GA versus GG: OR = 1.12, 95% CI: 1.02-1.23, P = 0.015, I (2) = 27.8%; for AA versus GG: OR = 1.71, 95% CI: 1.38 2.41, P < 0.001, I (2) = 69.6%; for GA + AA versus GG: OR = 1.23, 95% CI: 1.13 1.34, P < 0.001, I (2) = 6.4%; for AA versus GG + GA: OR = 1.62, 95% CI: 1.27 2.07, P < 0.001, I (2) = 81.4%). Succeeding analysis of HWE and stratified analysis of gastric cancer and the Asian (and Chinese) population revealed similar results. The IL-17F rs763780T>C polymorphism was also significantly associated with gastric cancer development. Overall, the present meta-analysis suggests that IL-17 polymorphisms increase the risk of developing cancer, particularly gastric cancer, in the Asian (and Chinese) population. PMID- 25147432 TI - Assessment of the E-selectin rs5361 (561A>C) polymorphism and soluble protein concentration in acute coronary syndrome: association with circulating levels. AB - INTRODUCTION: The acute coronary syndrome (ACS) is a complex disease where genetic and environmental factors are involved. E-selectin gene is a candidate for ACS progression due to its contribution in the inflammatory process and endothelial function. The rs5361 (561A>C) polymorphism in the E-selectin gene has been linked to changes in gene expression, affinity for its receptor, and plasmatic levels; therefore it is associated with an increased risk of cardiovascular disease. The aim of this study was to determine the association of the rs5361 polymorphism with ACS and to measure serum levels of soluble E selectin (sE-selectin). MATERIALS AND METHODS: 283 ACS patients and 205 healthy subjects (HS) from Western Mexico were included. The polymerase chain reaction restriction fragment length polymorphism was used to determine the rs5361 polymorphism. The sE-selectin levels were measured by enzyme-linked immunosorbent assay. RESULTS: Neither genotype nor allele frequencies of the rs5361 polymorphism showed statistical differences between groups. The sE-selectin levels were significantly higher in ACS patients compared to HS (54.58 versus 40.41 ng/ml, P = 0.02). The C allele had no effect on sE-selectin levels. CONCLUSIONS: The rs5361 E-selectin gene polymorphism is not a susceptibility marker for ACS in Western Mexico population. However, sE-selectin may be a biological marker of ACS. PMID- 25147434 TI - Cytokines and chemokines: disease models, mechanisms, and therapies. PMID- 25147433 TI - Serum matrix metalloproteinase-3 as a noninvasive biomarker of histological synovitis for diagnosis of rheumatoid arthritis. AB - OBJECTIVE: To explore the correlation between matrix metalloproteinase- (MMP-) 3 and histological synovitis in rheumatoid arthritis (RA). METHODS: Serum MMP-3 of 62 patients with active RA was detected by ELISA. Serial synovial tissue sections from all RA patients, 13 osteoarthritis, and 10 orthopedic arthropathies patients were stained with hematoxylin and eosin and immunohistochemically for MMP-3, CD3, CD20, CD38, CD68, and CD15. RESULTS: The percentage of lining MMP3+ cells was significantly higher in RA patients especially with high grade synovitis and it was significantly correlated with Krenn's synovitis score (r = 0.574, P < 0.001) and sublining inflammatory cells. Multivariate stepwise linear regression analysis revealed that the association of the percentage of lining MMP3+ cells with activation of synovial stroma, sublining CD68+ macrophages, and CD15+ neutrophils was stronger than other histological indicators. The percentage of lining MMP3+ cells was significantly correlated with serum MMP-3 in RA (r = 0.656, P < 0.001). Serum MMP-3 was higher in RA patients with high grade synovitis than that of low grade synovitis and significantly correlated with synovitis score and activation of synovial stroma subscore (all P < 0.05). CONCLUSION: Serum MMP-3 may be an alternative noninvasive biomarker of histological synovitis and RA diagnosis. PMID- 25147435 TI - Red ginseng extract ameliorates autoimmune arthritis via regulation of STAT3 pathway, Th17/Treg balance, and osteoclastogenesis in mice and human. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation. Red ginseng is a steamed and dried Panax ginseng C.A. Meyer, which has been used as alternative medicine for thousands of years. This study was undertaken to investigate the effects of red ginseng extracts (RGE) on autoimmune arthritis in mice and humans and to delineate the underlying mechanism. RGE was orally administered three times a week to mice with arthritis. Oral administration of RGE markedly ameliorated clinical arthritis score and histologically assessed joint inflammation in mice with CIA. A significant reduction in STAT3 phosphorylation and a decrease in the number of Th17 cells were observed with RGE treatment. There was also a marked reduction in RANKL induced osteoclastogenesis with treatment of RGE. The inhibitory effect of RGE on Th17 differentiation and osteoclastogenesis observed in mice was also confirmed in the subsequent experiments performed using human peripheral blood mononuclear cells. Our findings provide the first evidence that RGE can regulate Th17 and reciprocally promote Treg cells by inhibiting the phosphorylation of STAT3. Therefore, RGE can ameliorate arthritis in mice with CIA by targeting pathogenic Th17 and osteoclast differentiation, suggesting a novel therapy for treatment of RA. PMID- 25147436 TI - Association between peak neutrophil count, clopidogrel loading dose, and left ventricular systolic function in patients with primary percutaneous coronary intervention. AB - Inflammation plays an important role in plaque development and left ventricular remodeling during acute myocardial infarction (AMI). Clopidogrel may exhibit some anti-inflammatory properties and high loading dose of clopidogrel results in improved clinical outcomes in patients with AMI. 357 patients who received successful primary percutaneous coronary intervention from January 2008 to March 2011 in Peking University Third Hospital were included in this study. Different loading dose of clopidogrel (300 mg, 450 mg, or 600 mg) was given at the discretion of the clinician. Neutrophils reached their peak values on the first day after AMI. Higher levels of peak neutrophil and lower left ventricular ejection fraction (LVEF) were found in patients of low clopidogrel loading dose group (300 mg or 450 mg). After adjusting for the related confounders, a logistic regression model showed that low clopidogrel loading dose remained an independent predictor of low LVEF (LVEF <= 50%) [OR: 1.97, 95% CI: 1.03-3.79, P = 0.04]. Low clopidogrel loading dose was associated with higher peak neutrophil count and poor left ventricular systolic function, suggesting an important role of clopidogrel loading dose in the improvement of left ventricular function and high loading dose may exhibit better anti-inflammatory properties. PMID- 25147437 TI - Auricular electroacupuncture reduced inflammation-related epilepsy accompanied by altered TRPA1, pPKCalpha, pPKCepsilon, and pERk1/2 signaling pathways in kainic acid-treated rats. AB - BACKGROUND: Inflammation is often considered to play a crucial role in epilepsy by affecting iron status and metabolism. In this study, we investigated the curative effect of auricular acupuncture and somatic acupuncture on kainic acid- (KA-) induced epilepsy in rats. METHODS: We established an epileptic seizure model in rats by KA (12 mg, ip). The 2 Hz electroacupuncture (EA) was applied at auricular and applied at Zusanli and Shangjuxu (ST36-ST37) acupoints for 20 min for 3 days/week for 6 weeks beginning on the day following the KA injection. RESULTS: The electrophysiological results indicated that neuron overexcitation occurred in the KA-treated rats. This phenomenon could be reversed among either the auricular EA or ST36-ST37 EA treatment, but not in the sham-control rats. The Western blot results revealed that TRPA1, but not TRPV4, was upregulated by injecting KA and could be attenuated by administering auricular or ST36-ST37 EA, but not in the sham group. In addition, potentiation of TRPA1 was accompanied by increased PKCalpha and reduced PKCepsilon. Furthermore, pERK1/2, which is indicated in inflammation, was also increased by KA. Furthermore, the aforementioned mechanisms could be reversed by administering auricular EA and could be partially reversed by ST36-ST37 EA. CONCLUSIONS: These results indicate a novel mechanism for treating inflammation-associated epilepsy and can be translated into clinical therapy. PMID- 25147439 TI - Palmitoleic acid (n-7) attenuates the immunometabolic disturbances caused by a high-fat diet independently of PPARalpha. AB - Palmitoleic acid (PMA) has anti-inflammatory and antidiabetic activities. Here we tested whether these effects of PMA on glucose homeostasis and liver inflammation, in mice fed with high-fat diet (HFD), are PPAR-alpha dependent. C57BL6 wild-type (WT) and PPAR-alpha-knockout (KO) mice fed with a standard diet (SD) or HFD for 12 weeks were treated after the 10th week with oleic acid (OLA, 300 mg/kg of b.w.) or PMA 300 mg/kg of b.w. Steatosis induced by HFD was associated with liver inflammation only in the KO mice, as shown by the increased hepatic levels of IL1-beta, IL-12, and TNF-alpha; however, the HFD increased the expression of TLR4 and decreased the expression of IL1-Ra in both genotypes. Treatment with palmitoleate markedly attenuated the insulin resistance induced by the HFD, increased glucose uptake and incorporation into muscle in vitro, reduced the serum levels of AST in WT mice, decreased the hepatic levels of IL1-beta and IL-12 in KO mice, reduced the expression of TLR-4 and increased the expression of IL-1Ra in WT mice, and reduced the phosphorylation of NF ????B (p65) in the livers of KO mice. We conclude that palmitoleate attenuates diet-induced insulin resistance, liver inflammation, and damage through mechanisms that do not depend on PPAR-alpha. PMID- 25147438 TI - Sphingosine-1-phosphate/S1P receptors signaling modulates cell migration in human bone marrow-derived mesenchymal stem cells. AB - The recruitment of bone marrow-derived mesenchymal stem cells (BMSCs) to damaged tissues and sites of inflammation is an essential step for clinical therapy. However, the signals regulating the motility of these cells are still not fully understood. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, is known to have a variety of biological effects on various cells. Here, we investigated the roles of S1P and S1P receptors (S1PRs) in migration of human BMSCs. We found that S1P exerted a powerful migratory action on human BMSCs. Moreover, by employing RNA interference technology and pharmacological tools, we demonstrated that S1PR1 and S1PR3 are responsible for S1P-induced migration of human BMSCs. In contrast, S1PR2 mediates the inhibition of migration. Additionally, we explored the downstream signaling pathway of the S1P/S1PRs axis and found that activation of S1PR1 or S1PR3 increased migration of human BMSCs through a G i /extracellular regulated protein kinases 1/2- (ERK1/2-) dependent pathway, whereas activation of S1PR2 decreased migration through the Rho/Rho associated protein kinase (ROCK) pathway. In conclusion, we reveal that the S1P/S1PRs signaling axis regulates the migration of human BMSCs via a dual directional mechanism. Thus, selective modulation of S1PR's activity on human BMSCs may provide an effective approach to immunotherapy or tissue regeneration. PMID- 25147440 TI - The effects of amphiregulin induced MMP-13 production in human osteoarthritis synovial fibroblast. AB - Osteoarthritis (OA) belongs to a group of degenerative diseases. Synovial inflammation, cartilage abrasion, and subchondral sclerosis are characteristics of OA. Researchers do not fully understand the exact etiology of OA. However, matrix metalloproteinases (MMPs), which are responsible for cartilage matrix degradation, play a pivotal role in the progression of OA. Amphiregulin (AREG) binds to the EGF receptor (EGFR) and activates downstream proteins. AREG is involved in a variety of pathological processes, such as the development of tumors, inflammatory diseases, and rheumatoid arthritis. However, the relationship between AREG and MMP-13 in OA synovial fibroblasts (SFs) remains unclear. We investigated the signaling pathway involved in AREG-induced MMP-13 production in SFs. AREG caused MMP-13 production in a concentration- and time dependent manner. The results of using pharmacological inhibitors and EGFR siRNA to block EGFR revealed that the EGFR receptor was involved in the AREG-mediated upregulation of MMP-13. AREG-mediated MMP-13 production was attenuated by PI3K and Akt inhibitors. The stimulation of cells by using AREG activated p65 phosphorylation and p65 translocation from the cytosol to the nucleus. Our results provide evidence that AREG acts through the EGFR and activates PI3K, Akt, and finally NF-kappaB on the MMP-13 promoter, thus contributing to cartilage destruction during osteoarthritis. PMID- 25147441 TI - Chitosan oligosaccharides attenuate ocular inflammation in rats with experimental autoimmune anterior uveitis. AB - We investigated the protective effects and mechanisms of chitosan oligosaccharides (COS) on experimental autoimmune anterior uveitis (EAAU) in rats. EAAU was induced in Lewis rats by footpad and intraperitoneal injections of melanin-associated antigen. The rats received intraperitoneal injections of low dose (5 mg/kg) or high-dose (10 mg/kg) COS or PBS daily after the immunization. The effects of COS were evaluated by determining the clinical scores and the morphology of the iris/ciliary body (ICB). The expression of inflammatory mediators was evaluated using western blot, immunofluorescence, and ELISA. Treatment with COS significantly attenuated the clinical scores and the leukocyte infiltration in the ICB in a dose-dependent manner. COS effectively reduced the expression of inflammatory mediators (TNF-alpha, iNOS, MCP-1, RANTES, fractalkine, and ICAM-1). Moreover, COS decreased the IkappaB degradation and p65 presence in the ICB, which resulted in the inhibition of NF-kappaB/DNA binding activity. In an in vitro study, sensitized spleen-derived lymphocytes of the COS treated group showed less chemotaxis toward their aqueous humor and decreased secretion of the above inflammatory mediators in the culture media. COS treated EAAU by inhibiting the activation of NF-kappaB and reducing the expression of inflammatory mediators. COS might be a potential treatment for acute anterior uveitis. PMID- 25147442 TI - IL-10 counteracts proinflammatory mediator evoked oxidative stress in Caco-2 cells. AB - Oxidative stress is thought to play a key role in the development of intestinal damage in intestinal inflammatory diseases. Several molecules are involved in the intestinal inflammation, either as pro- or anti-inflammatory factors; however, their effects on intestinal oxidative stress seem to be controversial. This work analyzes the contribution of pro- and anti-inflammatory molecules to the balance of oxidative damage in intestinal epithelial cells, as well as their effects on cellular antioxidant enzyme activity. With this purpose, the lipid and protein oxidation, together with the activity of catalase, superoxide dismutase, and glutathione peroxidase, were determined in the Caco-2 cells treated with serotonin, adenosine, melatonin, and TNFalpha, as proinflammatory factors, and IL 10, as an anti-inflammatory cytokine. The results have shown that all the proinflammatory factors assayed increased oxidative damage. In addition, these factors also inhibited the activity of antioxidant enzymes in the cells, except melatonin. In contrast, IL-10 did not alter these parameters but was able to reduce the prooxidant effects yielded by serotonin, adenosine, melatonin, or TNFalpha, in part by restoring the antioxidant enzymes activities. In summary, proinflammatory factors may induce oxidative damage in intestinal epithelial cells, whereas IL-10 seems to be able to restore the altered redox equilibrium in Caco-2 cells. PMID- 25147444 TI - NEUROLOGICAL INFECTIONS IN THE RETURNING INTERNATIONAL TRAVELER. AB - Clinicians may encounter international travelers returning with exotic infections, emerging infectious diseases, or resurgent old-world infections. Many of these infectious diseases can affect the nervous system directly or indirectly. The contemporary neurologist should therefore be cognizant of the clinical manifestations, potential complications, and appropriate management of common travel-related infections. This chapter focuses on five important infections that affect the central nervous system and that may be encountered in returning travelers: Japanese encephalitis, malaria, rabies, dengue, and neurocysticercosis. The clinical manifestations, suggested evaluation, and treatment are discussed for each infection. PMID- 25147443 TI - LINEs and SINEs of primate evolution. PMID- 25147446 TI - A new species of Paramunida Baba, 1988 from the Central Pacific Ocean and a new genus to accommodate P. granulata (Henderson, 1885). AB - The genus Paramunida belongs to the most diverse family of galatheoids and it is commonly reported from the continental slope across the Indian and Pacific Oceans. Examination of material collected by the NOAA RV Townsend Cromwell Cruise near Christmas (Kiritimati) Island, Kiribati, revealed the existence of a new species of Paramunida (P. haigae), which represents the fourth record of the genus for the Central Pacific. Furthermore, recent efforts to unravel phylogenetic relationships and diversification patterns in Paramunida revealed P. granulata (Henderson, 1885) to be the most basally diverging taxon within the genus. This species is clearly distinguished from other species of Paramunida by the spinulation of the carapace and the length of the distomesial spine of the second antennal peduncle article, which in combination with a high level of genetic divergence suggest that this species represents a separate monotypic lineage. A new genus, Hendersonida gen. n., is proposed to accommodate this species based on morphological and molecular evidence. An updated dichotomous identification key for all species of Paramunida is presented. PMID- 25147445 TI - A new species of pterodectine feather mites (Acarina, Analgoidea, Proctophyllodidae) from the Little Spiderhunter Arachnothera longirostra (Passeriformes, Nectariniidae) in Meghalaya, India. AB - The article describes a new species of the feather mite subfamily Pterodectinae from the Little Spiderhunter Arachnothera longirostra Temminck, 1826 (Passeriformes, Nectariniidae) in India. Pedanodectes angustilobus sp. n. differs from all known Pedanodectes species by having opisthosomal lobes short, at base wider than long, roughly rounded apically in males, and strongly elongated and narrowed lobar region with wide terminal appendages in females. A key to species of the genus Pedanodectes is presented. PMID- 25147447 TI - Morphology and identification of the final instar nymphs of three cicadas (Hemiptera, Cicadidae) in Guanzhong Plain, China based on comparative morphometrics. AB - The present investigation provides comparative morphometrics of the final instar nymphs of three dominant cicada species, i.e., Cryptotympana atrata (Fabricius), Meimuna mongolica (Distant) and Platypleura kaempferi (Fabricius), in Guanzhong Plain, China. Particularly, characters on the antennae, legs, and apex of abdomen of both males and females of these three species were investigated and analyzed. In addition, the numbers of hind tibial spines of the final instar nymphs of 21 representatives of Cicadoidea were compared. The results provide useful characteristics for nymph identification of related species and for further taxonomic and phylogenetic analysis of Cicadoidea. PMID- 25147448 TI - A new species of Dendrocerus (Hymenoptera, Megaspilidae) from southern Brazil. AB - A new species of the megaspiline genus Dendrocerus Ratzeburg is described and figured. Dendrocerus riograndensis sp. n., is known from a series of males from the central region of Rio Grande do Sul, Brazil, and were captured with Malaise traps from an agricultural tobacco field. PMID- 25147449 TI - An interactive multi-entry key to the species of Megalostomis Chevrolat, with description of a new species from Paraguay (Chrysomelidae, Cryptocephalinae). AB - The main goal of this contribution is to release an interactive multi-entry key to all known species of the genus Megalostomis Chevrolat. This key constitutes a new tool created to aid the identification of the species of this diverse genus, which occasionally may be difficult to identify to the species-level, due to the lack of reference collections for most countries within its distribution range, and to the presence of intra-specific variation and secondary sexual characters. It is expected that this on-line key will facilitate future periodic updates, and will benefit all those persons interested in identifying these taxa. The present paper also includes the description of Megalostomis juanenrique sp. n., a new species from Paraguay. In addition, Megalostomis gigas Lacordaire, and Megalostomis robustipes Monros are newly cited for the fauna of Paraguay. The online interactive Lucid key is available at http://keys.lucidcentral.org/keys/v3/megalostomis. Offline Lucid data files in LIF and SDD formats are also available at doi: 10.3897/zookeys.425.7631.app1 and doi: 10.3897/zookeys.425.7631.app2. PMID- 25147450 TI - A new and aberrant species of Dugesia (Platyhelminthes, Tricladida, Dugesiidae) from Madagascar. AB - In this paper we report a new species of Dugesia of the family Dugesiidae from Madagascar, representing the fourth species of freshwater planarian known from this global biodiversity hotspot. In some respects the new species is aberrant, when compared with its congeners, being characterized by a head with smoothly rounded auricles, a peculiar course of the oviducts, including the presence of a common posterior extension, and by the asymmetrical openings of the vasa deferentia at about halfway along the seminal vesicle. Further, it is characterized by a ventral course of the ejaculatory duct with a terminal opening, very long spermiducal vesicles and unstalked cocoons. Its diploid chromosome complement with 18 chromosomes represents an uncommon feature among fissiparous species of Dugesia. PMID- 25147451 TI - A new species of Litarachna (Acari, Hydrachnidia, Pontarachnidae) from a Caribbean mesophotic coral ecosystem. AB - NEW RECORDS OF PONTARACHNID MITES (ACARI: Hydrachnidia) from the Caribbean island of Puerto Rico are presented. Litarachna lopezae sp. n., from substrata collected from Bajo de Sico, a mesophotic coral reef ecosystem in Mona Passage off Puerto Rico, is described as new to science. The new species was collected from nearly 70 m depth, the greatest depth from which pontarachnid mites have been found until now. In addition, a Litarachna sp. was also found in association with the tube of the polychaete Sabellastarte magnifica (Shaw, 1800) at the shallow waters of north Puerto Rico. PMID- 25147452 TI - Onychiurid species from Wanda Mountains in China, with descriptions of two new species (Collembola, Onychiuridae). AB - A checklist of onychiurid species from the Wanda Mountains in China is presented. Eighteen species belonging to twelve genera have been found, including two new species. Bionychiurus qinglongensis sp. n. can be easily distinguished from other known species of the genus by the absence of pseudocelli on Th. I tergum and fewer number of vesicles in postantennal organ. Onychiurus heilongjiangensis sp. n. is diagnosed by pseudocellar formulae as 32/133/33352 dorsally and 3/011/31120 ventrally, parapseudocellar formula as 0/000/111001+1(m), ratio of anal spine/unguis as 0.6, unguiculus without inner basal lamella, and male ventral organ absent. PMID- 25147453 TI - Two more new species of Aphidura (Hemiptera, Aphididae), and a note on variation in Aphidura bozhkoae Narzikulov. AB - Two new species of Aphidura Hille Ris Lambers, 1956 (Hemiptera, Aphididae, Macrosiphini) are described; Aphidura libanensis sp. n. from Prunus prostrata in Lebanon, and Aphidura corsicensis sp. n. from Cerastium soleirolii in Corsica (France). Studies of Aphidura bozhkoae specimens from different localities have revealed that this species varies in its pattern of dorsal sclerotisation and other morphological characters, within and between populations. An updated key for identifying the world's species of Aphidura is presented. PMID- 25147454 TI - A survey of East Palaearctic Gnaphosidae (Araneae). 2. Two new Gnaphosa Latreille, 1804 species from Western Mongolia. AB - TWO NEW SPECIES: Gnaphosa khovdensis sp. n. (?) and G. esyunini sp. n. (??) are described from Khovd Aimag of Mongolia. Descriptions, figures, diagnosis and map of the records are provided. The new species are assigned to a monophyletic group together with the recently described G. ustyuzhanini Fomichev et al., 2013. PMID- 25147455 TI - The myriapodological legacy of Victor Ivanovich Motschoulsky (1810-1871). AB - The little that remains of Motschoulsky's myriapodological legacy in the collection of Moscow's Zoological Museum proves to be of very limited value. Only one species of Diplopoda described by Motschoulsky, the Caucasian Hirudisoma roseum (Victor, 1839), is still in use, yet requiring a neotype designation, whereas the remaining few myriapod names he proposed are either nomina dubia or nomina nuda. The former include Scolopendra pentagramma Motschoulsky, 1866 (Chilopoda, Scolopendromorpha, Scolopendridae) and Strongylosoma carinulatum Motschoulsky, 1866 (Diplopoda, Polydesmida, Paradoxosomatidae), both from Japan, as well as Julus costulatus Motschoulsky, 1851 (Diplopoda, Callipodida, Schizopetalidae?), from Montenegro, because their type material is either inadequate or missing. PMID- 25147456 TI - Three new species from the subfamily Phyllocoptinae (Acari, Trombidiformes, Eriophyidae) in Iran. AB - Three new eriophyid species (Phyllocoptinae), Shevtchenkella denticulata sp. n., Notallus pestehae sp. n. and Echinacrus ruthenicus sp. n., were described from Eryngium thyrsoideum Boiss. (Apiaceae), Pistacia vera L. (Anacardiaceae) and Lycium ruthenicum Murray (Solanaceae), respectively. All the three new species were collected from southwest of the East Azerbaijan province, Iran in 2011. It is the first record of an eriophyoid mite collected from E. thyrsoideum and L. ruthenicum and the first record of Notallus from Anacardiaceae plant family. PMID- 25147457 TI - The taxonomy and diversity of Platerodrilus (Coleoptera, Lycidae) inferred from molecular data and morphology of adults and larvae. AB - The Oriental neotenic net-winged beetles attracted attention of biologists due to conspicuous large-bodied females; nevertheless phylogenetic relationships remain contentious and only a few species are known in both the fully metamorphosed males and neotenic females. The phylogenetic analyses and morphology of larvae and adults provide data for investigation of relationships and species delineation. Platrilus Kazantsev, 2009, Platerodriloplesius Wittmer, 1944, and Falsocalochromus Pic, 1942 are synonymized to Platerodrilus Pic, 1921. Platrilus hirtus (Wittmer, 1938) and Pl. crassicornis (Pic, 1923) are transferred to Platerodrilus Pic, 1921. Platerodrilus hoiseni Wong, 1996 is proposed as a junior subjective synonym of Falsocalochromus ruficollis Pic, 1942. Platerodrilus is divided in three species-groups: P. paradoxus, P. major, and P. sinuatus groups defined based on the shape of genitalia and molecular phylogeny. The following species are described: Platerodrilus foliaceus sp. n., P. wongi sp. n. (P. paradoxus group); P. ngi sp. n., P. wittmeri (P. major group), P. ijenensis sp. n., P. luteus sp. n., P. maninjauensis sp. n., P. montanus sp. n., P. palawanensis sp. n., P. ranauensis sp. n., P. sibayakensis sp. n., P. sinabungensis sp. n., P. talamauensis sp. n., and P. tujuhensis sp. n. (P. sinuatus group). P. korinchiana robinsoni Blair, 1928 is elevated to the species rank as P. robinsoni Blair, 1928, stat. n. The conspecific semaphoronts are identified using molecular phylogeny for P. foliaceus sp. n., P. tujuhensis sp. n., P. montanus sp. n., P. maninjauensis sp. n.; additional female larvae are assigned to the species-groups. Diagnostic characters are illustrated and keys are provided for P. paradoxus and P. major groups. PMID- 25147458 TI - Review of the genus Fontidessus Miller & Spangler, 2008 (Coleoptera, Dytiscidae, Hydroporinae, Bidessini) with description of four new species. AB - The genus Fontidessus Miller & Spangler, 2008 (Coleoptera: Dytiscidae: Hydroporinae: Bidessini) is reviewed. The genus now includes seven species with three previously described, and four new species described here: F. microphthalmus Miller & Montano, sp. n.; F. bettae Miller & Montano, sp. n.; F. christineae Miller & Montano, sp. n., and F. aquarupe Miller & Montano, sp. n. Each species is diagnosed and described, including the previously known species, based on new specimens and new information. Habitus, male genitalia and other diagnostic features are illustrated for each species. A key to the seven species is provided. Fontidessus species are unique to hygropetric habitats in the Guiana Shield craton of northern South American. PMID- 25147459 TI - An update to the taxonomy of the genus Gastroserica Brenske (Coleoptera, Scarabaeidae, Sericini). AB - Based on the examination of newly collected material and additional specimens housed in Chinese collections, our knowledge of Gastroserica Brenske, 1897, is expanded. Here, seven new species are described, including habitus photographs and illustrations of the male genitalia: Gastroserica haoyui sp. n. (China: Zhejiang Prov.), G. fengduana sp. n. (China: Sichuan Prov.), G. wenzhui sp. n. (China: Guangxi Prov.), G. damingshanica sp. n. (from China: Guangxi Prov.), G. jinxiuensis sp. n. (China: Guangxi Prov.), G. liboensis sp. n. (China: Yunnan Prov.) and G. carolusi sp. n. (Laos). Additionally, we provide a distribution map of the new taxa and new distribution records of the known taxa. PMID- 25147460 TI - Taxonomy of the Nacerdes (Xanthochroa) carniolica species-group from China (Coleoptera, Oedemeridae, Nacerdini). AB - This paper deals with a species-group carniolica of the genus Nacerdes from China. This species-group has seven known species/subspecies in the world and two of them are known from China. Nacerdes (Xanthochroa) arcuata sp. n. is a new species belonging to carniolica group. The species were collected from Anhui (Eastern China, 30 degrees 02'17.37"N, 118 degrees 50'1.72"E). A key to the species of the species-group from China is given along with a distribution map. PMID- 25147461 TI - The genus Macroteleia Westwood in Middle Miocene amber from Peru (Hymenoptera, Platygastridae s.l., Scelioninae). AB - A new species of the scelionine genus Macroteleia Westwood (Platygastridae s.l., Scelioninae) is described and figured from a female beautifully preserved in Middle Miocene amber from Peru. Macroteleia yaguarum Perrichot & Engel, sp. n., shows a unique combination of characters otherwise seen independently within its congeners. It is most similar to the modern M. surfacei Brues, but differs from it by the non-foveolate notauli, the contiguous punctures of the vertex, and the continuous propodeum. The new species is the first New World fossil of the genus, suggesting a Cretaceous origin for the group and a relatively old age of the South American, tropical African, and Australian faunas, and a younger age of the modern Holarctic faunas. PMID- 25147462 TI - Re-description of Xysticus bimaculatus L. Koch, 1867 (Araneae, Thomisidae) and characterization of its subsocial lifestyle. AB - Spiders have become an important model to study the evolution of sociality, but a lack of their detailed natural history and taxonomy hinders broader comparative studies. Group-living crab spiders (Thomisidae) provide an excellent contrast to other social spiders since they lack a communal capture web, which was thought to be a critical factor in the evolution of sociality. Only three non-webbuilding crab-spider species are known to be subsocial or social, all of which belong to the genus Diaea Thorell, 1869. The aim of this study is to describe the social lifestyle of Xysticus bimaculatus L. Koch, 1867 for the first time. Furthermore, we present a detailed re-description of this species and discuss its taxonomic implications. Like other subsocial crab spiders, X. bimaculatus builds nests from tree leaves. Nests contain up to 38 spiders and sometimes several adult females, indicating the species may be at a transitory stage between subsociality and permanent sociality. PMID- 25147463 TI - Revision of the East Mediterranean Orthomus (Coleoptera, Carabidae, Pterostichini), with description of Parorthomus gen. n. socotranus sp. n. from Socotra Island and key to the Old World genera of subtribe Euchroina. AB - The East Mediterranean species of Orthomus Chaudoir, 1838 are revised. The type series of Feronia longula Reiche & Saulcy, 1855, F. berytensis Reiche & Saulcy, 1855, F. proelonga Reiche & Saulcy, 1855, Orthomus longior Chaudoir, 1873, O. sidonicus Chaudoir, 1873, and O. berytensis akbensis Mateu, 1955 were studied and lectotypes for the first four are designated. Also, the following nomenclatural acts are proposed: Feronia proelonga Reiche & Saulcy, 1855, syn. n. of Orthomus berytensis (Reiche & Saulcy, 1855); Feronia elongata Chaudoir, 1859, syn. n. of Orthomus berytensis (Reiche & Saulcy, 1855); Orthomus sidonicus Chaudoir, 1873, syn. n. of Orthomus longior Chaudoir, 1873; Orthomus velocissimus andalusiacus Mateu, 1957, syn. n. of Orthomus velocissimus akbensis Mateu, 1955, new assignment for Orthomus berytensis akbensis Mateu, 1955. As a result, three species of the genus inhabit the East Mediterranean biogeographical region: O. berytensis, O. longior, and O. longulus. A key to these three species is given. O. longior is recorded for Turkey and Syria for the first time. In addition, a new synonymy of two West Mediterranean taxa is proposed: O. szekessyi (Jedlicka, 1956), syn. n. of O. balearicus (Piochard de la Brulerie, 1868), and a new genus and a species are described: Parorthomus gen. n. socotranus sp. n. (type locality: Republic of Yemen, Socotra Archipelago, Socotra Island, Fimihin env., 530 m.a.s.l.). Illustrations of the species dealt with here are provided including external characters, habitus, mentum and submentum, and genitalia are provided. Nine genera of the "African Series" of subtribe Euchroina Chaudoir, 1874 are keyed for the first time. Checklists of the species of Orthomus and of the Old World euchroine genera are given. PMID- 25147464 TI - The genus Spathius Nees (Hymenoptera, Braconidae, Doryctinae) in Mexico: occurrence of a highly diverse Old World taxon in the Neotropics. AB - Two new species of the parasitoid wasp genus Spathius Nees (Braconidae: Doryctinae) from Mexico, S. mexicanus sp. n. and S. chamelae sp. n., are described and illustrated. These represent the second and third described species of this highly diverse Old World genus in the Neotropics, and the first described species recorded for the Mexican territory. PMID- 25147465 TI - Intertidal and nearshore Nereididae (Annelida) of the Falkland Islands, southwestern Atlantic, including a new species of Gymnonereis. AB - The intertidal and nearshore Nereididae of the Falkland Islands are detailed and a new species of Gymnonereis described. The new species, Gymnonereis tenera sp. n., is the first record of the genus for the Falkland Islands. It is, so far, only known from a few intertidal locations in fine and muddy sands. Main distinguishing characters are: jaw teeth absent (in adults), 3 papillae in Area V VI, falcigers absent, second ventral cirrus present throughout. Nereis atlantica McIntosh, 1885, known only from the description of a single specimen and one doubtful record from the Falkland Islands, is reviewed and transferred to Perinereis on the basis of the presence of shield-shaped bars in Area VI of the proboscis and the absence of notopodial falcigers. A key to all seven species discussed is provided. PMID- 25147466 TI - Sarandibrinus, a new genus of Saprininae subfamily from Madagascar (Coleoptera, Histeridae) (Second contribution to the knowledge of the Histeridae of Madagascar). AB - Sarandibrinus araceliae, a new genus and species of the Saprininae subfamily is described from southern Madagascar. The new taxon exhibits autapomorphic characters for the Saprininae subfamily and is unusual especially for its large and deep prosternal foveae and the shape of spiculum gastrale. The description is accompanied by color habitus images, SEM micrographs, mouthparts and antenna line drawings and drawings of the male genitalia. Key to the genera of the Saprininae of Madagascar and the adjacent archipelagos is given. Hypocaccus (Baeckmanniolus) rubiciliae (Lewis, 1899) is newly reported from Madagascar and Hypocaccus (Nessus) perparvulus (Desbordes, 1916) is new to Mauritius. PMID- 25147467 TI - Milnesium berladnicorum sp. n. (Eutardigrada, Apochela, Milnesiidae), a new species of water bear from Romania. AB - In a lichen sample collected from a tree in Barlad town (Vaslui County, Romania), a new tardigrade species belonging to the genus Milnesium (granulatum group) was found. Milnesium berladnicorum sp. n. is most similar (in the type of dorsal sculpture) to Milnesium beasleyi Kaczmarek et al., 2012 but differs from it mainly by having a different claw configuration and some morphometric characters. Additionally, the new species differs from other congeners of the granulatum group by the different type of dorsal sculpture, claw configuration and some morphometric characters. PMID- 25147468 TI - Replacement names and nomenclatural comments for problematic species-group names in Europe's Neogene freshwater Gastropoda. Part 2. AB - In the course of a new database project on Miocene to Recent freshwater gastropods of Europe, a great many of primary and secondary homonyms were revealed. Such nomenclatural issues need clarification in order to avoid misunderstandings and wrong statements about geographical distributions and temporal ranges. The following 16 new names are introduced to replace existing homonyms: Theodoxus militaris jurisicpolsakae nom. n., Viviparus stevanovici nom. n., Melanopsis haueri ripanjensis nom. n., Melanopsis wolfgangfischeri nom. n., Micromelania ramacanensis nom. n., Pseudamnicola welterschultesi nom. n., Muellerpalia haszprunari nom. n., Muellerpalia pseudovalvatoides nom. n., Lithoglyphus gozhiki nom. n., Valvata heidemariae willmanni nom. n., Radix macaleti nom. n., Gyraulus okrugljakensis nom. n., Gyraulus rasseri nom. n., Gyraulus vrapceanus nom. n., Planorbarius halavatsi nom. n., and Segmentina mosbachensis nom. n. Additionally, six cases of homonyms are discussed that are not replaced by new names, because they are considered junior synonyms. PMID- 25147469 TI - Status of the enigmatic Oriental genus Rhithrogeniella Ulmer, 1939 (Ephemeroptera, Heptageniidae). AB - Based on historic collections and new material from Sumatra and Java, the species Rhithrogeniella ornata Ulmer, 1939, type species of the genus Rhithrogeniella, is reinvestigated. The nymph is described for the first time and is closely related to the continental Southeast Asian species Rhithrogeniella tonkinensis Soldan and Braasch, 1986. Rhithrogeniella belongs to the subfamily Ecdyonurinae, and is related to the genera Nixe Flowers, 1980 and/or Paracinygmula Bajkova, 1975 based on characters of the nymphal stage. Species described from Taiwan in the genus Nixe are transferred to the genus Rhithrogeniella: Rh. littoralis (Kang and Yang, 1994) comb. n., Rh. mitifica (Kang and Yang, 1994) comb. n. and Rh. obscura (Kang and Yang, 1994) comb. n. PMID- 25147470 TI - A new species of Dictyotenguna Song & Liang, 2012 from China (Hemiptera, Fulgoromorpha, Dictyopharidae). AB - A new planthopper species Dictyotenguna angusta sp. n. is described and illustrated from Guangxi, China. The photographs of the adults of the species are presented. PMID- 25147471 TI - Taxonomic revision of the Pyrgulopsis gilae (Caenogastropoda, Hydrobiidae) species complex, with descriptions of two new species from the Gila River basin, New Mexico. AB - We describe two new species of springsnails (genus Pyrgulopsis) for populations from the middle Fork and upper East Fork of the Gila River Basin (New Mexico) that had been previously identified as P. gilae. We also restrict P. gilae to its originally circumscribed geographic range which consists of a short reach of the East Fork Gila River and a single spring along the Gila River (below the East Fork confluence). These three species form genetically distinct lineages that differ from each other by 3.9-6.3% for mtCOI and 3.7-8.7% for mtNDI (the latter data were newly obtained for this study), and are diagnosable by shell and penial characters. Collectively the three species form a strongly supported clade that is distinguished from other congeners by the unique presence of two glandular strips on the dorsal surface of the penial filament. These findings suggest that the conservation status of P. gilae, which was recently removed from the list of candidates for listing as endangered or threatened by the United States Fish and Wildlife Service, should be revisited and that the two new species may also merit protective measures given their narrow geographic ranges. PMID- 25147472 TI - A remarkable new pygmy grasshopper (Orthoptera, Tetrigidae) in Miocene amber from the Dominican Republic. AB - A NEW GENUS AND SPECIES OF PYGMY GRASSHOPPER (ORTHOPTERA: Tetrigidae) is described from Early Miocene (Burdigalian) Dominican amber. Electrotettix attenboroughi Heads & Thomas, gen. et sp. n. is assigned to the subfamily Cladonotinae based on the deeply forked frontal costa, but is remarkable for the presence of tegmina and hind wings, hitherto unknown in this subfamily. PMID- 25147473 TI - Revision of the genus Hemisaprinus Kryzhanovskij, 1976 (Coleoptera, Histeridae, Saprininae). AB - The monophyletic genus Hemisaprinus Kryzhanovskij in Kryzhanovskij & Reichardt, 1976 is revised herein. All three species Hemisaprinus subvirescens (Menetries, 1832), H. lutshniki (Reichardt, 1941) and H. cyprius (Dahlgren, 1981) are found to be correctly assigned to the genus and their monophyly is supported by the synapomorphy of the presence of prosternal foveae. The three species are re described and supplemented with colour photographs as well as SEM micrographs outlining their differences. Male genitalia drawing of H. subvirescens and H. lutshniki are provided and a key to the species is given. Hemisaprinus subvirescens (Menetries, 1832) is newly reported from Armenia, Azerbaijan, Kyrgyzstan, Uzbekistan, Turkmenistan, Tajikistan, Jordan, Cyprus and Mongolia. The lectotypes and paralectotypes of the following species are designated herein: Saprinus foveisternus Schmidt, 1884, Saprinus syriacus Marseul, 1855 and Saprinus viridulus Marseul, 1855. PMID- 25147474 TI - Benchmark measurements and simulations of dose perturbations due to metallic spheres in proton beams. AB - Monte Carlo simulations are increasingly used for dose calculations in proton therapy due to its inherent accuracy. However, dosimetric deviations have been found using Monte Carlo code when high density materials are present in the proton beam line. The purpose of this work was to quantify the magnitude of dose perturbation caused by metal objects. We did this by comparing measurements and Monte Carlo predictions of dose perturbations caused by the presence of small metal spheres in several clinical proton therapy beams as functions of proton beam range, spread-out Bragg peak width and drift space. Monte Carlo codes MCNPX, GEANT4 and Fast Dose Calculator (FDC) were used. Generally good agreement was found between measurements and Monte Carlo predictions, with the average difference within 5% and maximum difference within 17%. The modification of multiple Coulomb scattering model in MCNPX code yielded improvement in accuracy and provided the best overall agreement with measurements. Our results confirmed that Monte Carlo codes are well suited for predicting multiple Coulomb scattering in proton therapy beams when short drift spaces are involved. PMID- 25147475 TI - Long-term memory, forgetting, and deferred imitation in 12-month-old infants. AB - Long-term recall memory, as indexed by deferred imitation, was assessed in 12 month-old infants. Independent groups of infants were tested after retention intervals of 3 min, 1 week and 4 weeks. Deferred imitation was assessed using the 'observation-only' procedure in which infants were not allowed motor practice on the tasks before the delay was imposed. Thus, the memory could not have been based on re-accessing a motor habit, because none was formed in the first place. After the delay, memory was assessed either in the same or a different environmental context from the one in which the adult had originally demonstrated the acts. In Experiments 1 and 3, infants observed the target acts while in an unusual environment (an orange and white polka-dot tent), and recall memory was tested in an ordinary room. In Experiment 2, infants observed the target acts in their homes and were tested for memory in a university room. The results showed recall memory after all retention intervals, including the 4 week delay, with no effect of context change. Interestingly, the forgetting function showed that the bulk of the forgetting occurred during the first week. The findings of recall memory without motor practice support the view that infants as young as 12 months old use a declarative (nonprocedural) memory system to span delay intervals as long as 4 weeks. PMID- 25147476 TI - Children's coding of human action: cognitive factors influencing imitation in 3 year-olds. AB - We used imitation as a tool for investigating how young children code action. The study was designed to examine the errors children make in re-enacting manual gestures they see. Thirty-two 3-year-old children served as subjects. Each child was shown 24 gestures, generated by systematically crossing four factors: visual monitoring, spatial endpoint, movement path, and number of hands. The results showed no difference as a function of whether the children could visually monitor their own responses. Interestingly, children made significantly more errors when the adult's action terminated on a body part than they did when the same movement terminated near the body part. There were also significantly more errors when the demonstrated act involved crossing midline than when it did not, and more errors when it involved one hand rather than two hands. Our hypothesis is that human acts are coded in terms of goals. The goals are hierarchically organized, and because young children have difficulty simultaneously integrating multiple goals into one act they often re-enact the goals that are ranked higher, which leads to the errors observed. We argue that imitation is an active reconstruction of perceived events and taps cognitive processing. We suggest that the goal-based imitation in 3-year-olds is a natural developmental outgrowth of the perceptual motor mapping and goal-directed coding of human acts found in infancy. PMID- 25147478 TI - Ion mobility spectrometry: A personal view of its development at UCSB. AB - Ion mobility is not a newly discovered phenomenon. It has roots going back to Langevin at the beginning of the 20th century. Our group initially got involved by accident around 1990 and this paper is a brief account of what has transpired here at UCSB the past 25 years in response to this happy accident. We started small, literally, with transition metal atomic ions and transitioned to carbon clusters, synthetic polymers, most types of biological molecules and eventually peptide and protein oligomeric assembly. Along the way we designed and built several generations of instruments, a process that is still ongoing. And perhaps most importantly we have incorporated theory with experiment from the beginning; a necessary wedding that allows an atomistic face to be put on the otherwise interesting but not fully informative cross section measurements. PMID- 25147479 TI - A Randomised Controlled Trial Comparing the Impact of Yoga and Physical Education on the Emotional and Behavioural Functioning of Middle School Children. AB - BACKGROUND: Yoga programs geared for school children have become more widespread, but research regarding its impact on children is lacking. Several studies have reported positive outcomes, though there is a need for more randomised controlled trials. OBJECTIVES: To determine the effects of yoga on children's emotional and behavioural functioning when compared with physical education (PE) classes. METHODS: Thirty middle school children were randomised to participate in either a school-based Ashtanga-informed yoga or PE class three times a week for 12 weeks. Emotional (i.e. affect, self-perceptions) and behavioural (i.e. internalising and externalising problems, aggression) functioning were measured pre and post intervention. RESULTS: There were no significant changes between groups in self reported positive affect, global self-worth, aggression indices or parent reports of their children's externalising and internalising problems. However, negative affect increased for those children participating in yoga when compared to the PE program. CONCLUSIONS: In general, findings suggest that yoga and PE classes do not differentially impact on middle school children's emotional and behavioural functioning. However, children reported experiencing increased negative emotions after receiving yoga while children in the PE group reported a decrease in these feelings. Implications of these results and potential directions for future research on children's yoga are discussed. PMID- 25147481 TI - Is a good death possible in Australian critical and acute settings?: physician experiences with end-of-life care. AB - BACKGROUND: In Australia approximately 70% of all deaths are institutionalised but over 15% of deaths occur in intensive care settings where the ability to provide a "good death" is particularly inhibited. Yet, there is a growing trend for death and dying to be managed in the ICU and physicians are increasingly challenged to meet the new expectations of their specialty. This study examined the unexplored interface between specialised Australian palliative and intensive care and the factors influencing a physician's ability to manage deaths well. METHOD: A qualitative investigation was focused on palliative and critical/acute settings. A thematic analysis was conducted on semi-structured in-depth interviews with 13 specialist physicians. Attention was given to eliciting meanings and experiences in Australian end-of-life care. RESULTS: Physicians negotiated multiple influences when managing dying patients and their families in the ICU. The way they understood and experienced end-of-life care practices was affected by cultural, institutional and professional considerations, and personal values and beliefs. Interpersonal and intrapsychic aspects highlighted the emotional and psychological relationship physicians have with patients and others. Many physicians were also unaware of what their cross-disciplinary colleagues could or could not do; poor professional recognition and collaboration, and ineffective care goal transition impaired their ability to assist good deaths. Experience was subject to the efficacy of physicians in negotiating complex bedside dynamics. CONCLUSIONS: Regardless of specialty, all physicians identified the problematic nature of providing expert palliation in critical and acute settings. Strategies for integrating specialised palliative and intensive care were offered with corresponding directions for future research and clinical development. PMID- 25147482 TI - Estimation of whole body fat from appendicular soft tissue from peripheral quantitative computed tomography in adolescent girls. AB - OBJECTIVE: Assess the utility of peripheral quantitative computed tomography (pQCT) for estimating whole body fat in adolescent girls. RESEARCH METHODS AND PROCEDURES: Our sample included 458 girls (aged 10.7 +/- 1.1y, mean BMI = 18.5 +/ 3.3 kg/m2) who had DXA scans for whole body percent fat (DXA %Fat). Soft tissue analysis of pQCT scans provided thigh and calf subcutaneous percent fat and thigh and calf muscle density (muscle fat content surrogates). Anthropometric variables included weight, height and BMI. Indices of maturity included age and maturity offset. The total sample was split into validation (VS; n = 304) and cross validation (CS; n = 154) samples. Linear regression was used to develop prediction equations for estimating DXA %Fat from anthropometric variables and pQCT-derived soft tissue components in VS and the best prediction equation was applied to CS. RESULTS: Thigh and calf SFA %Fat were positively correlated with DXA %Fat (r = 0.84 to 0.85; p <0.001) and thigh and calf muscle densities were inversely related to DXA %Fat (r = -0.30 to -0.44; p < 0.001). The best equation for estimating %Fat included thigh and calf SFA %Fat and thigh and calf muscle density (adj. R2 = 0.90; SEE = 2.7%). Bland-Altman analysis in CS showed accurate estimates of percent fat (adj. R2 = 0.89; SEE = 2.7%) with no bias. DISCUSSION: Peripheral QCT derived indices of adiposity can be used to accurately estimate whole body percent fat in adolescent girls. PMID- 25147483 TI - Learning Stimulus-Location Associations in 8- and 11-Month-Old Infants: Multimodal versus Unimodal Information. AB - Research on the influence of multimodal information on infants' learning is inconclusive. While one line of research finds that multimodal input has a negative effect on learning, another finds positive effects. The present study aims to shed some new light on this discussion by studying the influence of multimodal information and accompanying stimulus complexity on the learning process. We assessed the influence of multimodal input on the trial-by-trial learning of 8- and 11-month-old infants. Using an anticipatory eye movement paradigm, we measured how infants learn to anticipate the correct stimulus location associations when exposed to visual-only, auditory-only (unimodal), or auditory and visual (multimodal) information. Our results show that infants in both the multimodal and visual-only conditions learned the stimulus-location associations. Although infants in the visual-only condition appeared to learn in fewer trials, infants in the multimodal condition showed better anticipating behavior: as a group, they had a higher chance of anticipating correctly on more consecutive trials than infants in the visual-only condition. These findings suggest that effects of multimodal information on infant learning operate chiefly through effects on infants' attention. PMID- 25147480 TI - Seasonal effects in a lake sediment archaeal community of the Brazilian Savanna. AB - The Cerrado is a biome that corresponds to 24% of Brazil's territory. Only recently microbial communities of this biome have been investigated. Here we describe for the first time the diversity of archaeal communities from freshwater lake sediments of the Cerrado in the dry season and in the transition period between the dry and rainy seasons, when the first rains occur. Gene libraries were constructed, using Archaea-specific primers for the 16S rRNA and amoA genes. Analysis revealed marked differences between the archaeal communities found in the two seasons. I.1a and I.1c Thaumarchaeota were found in greater numbers in the transition period, while MCG Archaea was dominant on the dry season. Methanogens were only found in the dry season. Analysis of 16S rRNA sequences revealed lower diversity on the transition period. We detected archaeal amoA sequences in both seasons, but there were more OTUs during the dry season. These sequences were within the same cluster as Nitrosotalea devanaterra's amoA gene. The principal coordinate analysis (PCoA) test revealed significant differences between samples from different seasons. These results provide information on archaeal diversity in freshwater lake sediments of the Cerrado and indicates that rain is likely a factor that impacts these communities. PMID- 25147484 TI - Building Efficient Crime Prevention Strategies: Considering the Economics of Investing in Human Development. PMID- 25147485 TI - Large scale affinity calculations of cyclodextrin host-guest complexes: Understanding the role of reorganization in the molecular recognition process. AB - Host-guest inclusion complexes are useful models for understanding the structural and energetic aspects of molecular recognition. Due to their small size relative to much larger protein-ligand complexes, converged results can be obtained rapidly for these systems thus offering the opportunity to more reliably study fundamental aspects of the thermodynamics of binding. In this work, we have performed a large scale binding affinity survey of 57 beta-cyclodextrin (CD) host guest systems using the binding energy distribution analysis method (BEDAM) with implicit solvation (OPLS-AA/AGBNP2). Converged estimates of the standard binding free energies are obtained for these systems by employing techniques such as parallel Hamitionian replica exchange molecular dynamics, conformational reservoirs and multistate free energy estimators. Good agreement with experimental measurements is obtained in terms of both numerical accuracy and affinity rankings. Overall, average effective binding energies reproduce affinity rank ordering better than the calculated binding affinities, even though calculated binding free energies, which account for effects such as conformational strain and entropy loss upon binding, provide lower root mean square errors when compared to measurements. Interestingly, we find that binding free energies are superior rank order predictors for a large subset containing the most flexible guests. The results indicate that, while challenging, accurate modeling of reorganization effects can lead to ligand design models of superior predictive power for rank ordering relative to models based only on ligand receptor interaction energies. PMID- 25147487 TI - Unipolar resistive switching of ZnO-single-wire memristors. AB - Well unipolar resistive switching (RS) behaviors were observed from Ag/ZnO single microwire/Ag memristors. The reset voltages were larger than the set voltages, and all of them were less than 1 V. The resistance ratios of high-resistance state (HRS) to low-resistance state (LRS) reached 10(3). The bistable RS behaviors were entirely reversible and steady within 100 cycles. It was found that the dominant conduction mechanisms in LRS and HRS were ohmic behavior and space-charge-limited current (SCLC), respectively. PMID- 25147486 TI - Comparative studies of salinomycin-loaded nanoparticles prepared by nanoprecipitation and single emulsion method. AB - To establish a satisfactory delivery system for the delivery of salinomycin (Sal), a novel, selective cancer stem cell inhibitor with prominent toxicity, gelatinase-responsive core-shell nanoparticles (NPs), were prepared by nanoprecipitation method (NR-NPs) and single emulsion method (SE-NPs). The gelatinase-responsive copolymer was prepared by carboxylation and double amination method. We studied the stability of NPs prepared by nanoprecipitation method with different proportions of F68 in aqueous phase to determine the best proportion used in our study. Then, the NPs were prepared by nanoprecipitation method with the best proportion of F68 and single emulsion method, and their physiochemical traits including morphology, particle size, zeta potential, drug loading content, stability, and in vitro release profiles were studied. The SE NPs showed significant differences in particle size, drug loading content, stability, and in vitro release profiles compared to NR-NPs. The SE-NPs presented higher drug entrapment efficiency and superior stability than the NR-NPs. The drug release rate of SE-NPs was more sustainable than that of the NR-NPs, and in vivo experiment indicated that NPs could prominently reduce the toxicity of Sal. Our study demonstrates that the SE-NPs could be a satisfactory method for the preparation of gelatinase-responsive NPs for intelligent delivery of Sal. PMID- 25147488 TI - DNA stretching on the wall surfaces in curved microchannels with different radii. AB - DNA molecule conformation dynamics and stretching were made on semi-circular surfaces with different radii (500 to 5,000 MUm) in microchannels measuring 200 MUm * 200 MUm in cross section. Five different buffer solutions - 1* Tris-acetate EDTA (TAE), 1* Tris-borate-EDTA (TBE), 1* Tris-EDTA (TE), 1* Tris-phosphate-EDTA (TPE), and 1* Tris-buffered saline (TBS) solutions - were used with a variety of viscosity such as 40, 60, and 80 cP, with resultant 10(-4) <= Re <= 10(-3) and the corresponding 5 <= Wi <= 12. The test fluids were seeded with JOJO-1 tracer particles for flow visualization and driven through the test channels via a piezoelectric (PZT) micropump. Micro particle image velocimetry (MUPIV) measuring technique was applied for the centered-plane velocity distribution measurements. It is found that the radius effect on the stretch ratio of DNA dependence is significant. The stretch ratio becomes larger as the radius becomes small due to the larger centrifugal force. Consequently, the maximum stretch was found at the center of the channel with a radius of 500 MUm. PMID- 25147489 TI - Functionalized silicon quantum dots by N-vinylcarbazole: synthesis and spectroscopic properties. AB - Silicon quantum dots (Si QDs) attract increasing interest nowadays due to their excellent optical and electronic properties. However, only a few optoelectronic organic molecules were reported as ligands of colloidal Si QDs. In this report, N vinylcarbazole - a material widely used in the optoelectronics industry - was used for the modification of Si QDs as ligands. This hybrid nanomaterial exhibits different spectroscopic properties from either free ligands or Si QDs alone. Possible mechanisms were discussed. This type of new functional Si QDs may find application potentials in bioimaging, photovoltaic, or optoelectronic devices. PMID- 25147490 TI - Nonlinear magnetic vortex dynamics in a circular nanodot excited by spin polarized current. AB - We investigate analytically and numerically nonlinear vortex spin torque oscillator dynamics in a circular magnetic nanodot induced by a spin-polarized current perpendicular to the dot plane. We use a generalized nonlinear Thiele equation including spin-torque term by Slonczewski for describing the nanosize vortex core transient and steady orbit motions and analyze nonlinear contributions to all forces in this equation. Blue shift of the nano-oscillator frequency increasing the current is explained by a combination of the exchange, magnetostatic, and Zeeman energy contributions to the frequency nonlinear coefficient. Applicability and limitations of the standard nonlinear nano oscillator model are discussed. PMID- 25147491 TI - Temperature dependence of electronic behaviors in quantum dimension junctionless thin-film transistor. AB - The high temperature dependence of junctionless (JL) gate-all-around (GAA) poly Si thin-film transistors (TFTs) with 2-nm-thick nanosheet channel is compared with that of JL planar TFTs. The variation of SS with temperature for JL GAA TFTs is close to the theoretical value (0.2 mV/dec/K), owing to the oxidation process to form a 2-nm-thick channel. The bandgap of 1.35 eV in JL GAA TFTs by fitting experimental data exhibits the quantum confinement effect, indicating greater suppression of Ioff than that in JL planar TFTs. The measured [Formula: see text] of -1.34 mV/ degrees C in JL GAA nanosheet TFTs has smaller temperature dependence than that of -5.01 mV/ degrees C in JL planar TFTs. PMID- 25147492 TI - Inhibitory Effect of Curcumin-Cu(II) and Curcumin-Zn(II) Complexes on Amyloid Beta Peptide Fibrillation. AB - Mononuclear complexes of Curcumin with Cu(II) and Zn(II) have been synthesized and, characterized and their effects on the fibrillization and aggregation of amyloid-beta (Abeta) peptide have been studied. FTIR spectroscopy and atomic force microscopy (AFM) observations demonstrate that the complexes can inhibit the transition from less structured oligomers to beta-sheet rich protofibrils which act as seeding factors for further fibrillization. The metal complexes also impart more improved inhibitory effects than Curcumin on peptide fibrillization. PMID- 25147493 TI - Synthesis, spectral characterization, and biological evaluation of transition metal complexes of bidentate N, o donor schiff bases. AB - New series of three bidentate N, O donor type Schiff bases (L (1) )-(L (3) ) were prepared by using ethylene-1,2-diamine with 5-methyl furfural, 2-anisaldehyde, and 2-hydroxybenzaldehyde in an equimolar ratio. These ligands were further complexed with Co(II), Cu(II), Ni(II), and Zn(II) metals to produce their new metal complexes having an octahedral geometry. These compounds were characterized on the basis of their physical, spectral, and analytical data. Elemental analysis and spectral data of the uncomplexed ligands and their metal(II) complexes were found to be in good agreement with their structures, indicating high purity of all the compounds. All ligands and their metal complexes were screened for antimicrobial activity. The results of antimicrobial activity indicated that metal complexes have significantly higher activity than corresponding ligands. This higher activity might be due to chelation process which reduces the polarity of metal ion by coordinating with ligands. PMID- 25147494 TI - Calcium and vitamin D supplementation: state of the art for daily practice. AB - BACKGROUND: Calcium and vitamin D play an essential role in bone metabolism but deficiency and/or inadequate intake are common. OBJECTIVES: To describe a practical approach based on the literature regarding clinically important aspects of calcium and vitamin D supplementation. METHODS: A systematic evaluation of relevant literature in Medline was conducted. We included physiological studies, publications on relevant guidelines, meta-analysis, randomized clinical trials, and cohort studies. RESULTS: An adequate calcium intake and vitamin D supplementation is recommended in most guidelines xon fracture prevention. Daily supplementation with 800 IU is advocated in most guidelines, appears to be safe, and with this approach it is generally not necessary to determine vitamin D levels. There are no data on additional effects of loading doses of vitamin D on fracture or fall prevention. Calcium supplementation should be tailored to the patient's need: usually 500 mg per day is required. The intestinal absorption of calcium citrate is approximately 24% better than that of calcium carbonate independent of intake with meals. Data on difference between calcium absorption with calcium carbonate compared to calcium citrate with simultaneous use of proton pump inhibitors are lacking. Concern has arisen about a possible link between calcium supplementation and an increased risk of myocardial infarction. Probably only well-designed prospective randomized controlled trials will be able to allow definite conclusions on this subject. CONCLUSION: Daily supplementation with 800 IU vitamin D is a practical and safe strategy without the need for prior determination of vitamin D levels. Calcium supplementation should be tailored to the patient's need based on total daily dietary calcium intake. In most patients 500 mg per day is required to achieve a total intake of 1,200 mg, or in some 1,000 mg per day. More calcium is absorbed from calcium citrate compared to calcium carbonate. PMID- 25147495 TI - Free school fruit: can an extra piece of fruit every school day contribute to the prevention of future weight gain? A cluster randomized trial. AB - BACKGROUND: Several school fruit programs are initiated with the aim to improve diet and thereby contribute to reduce the prevalence of overweight. To date, no published studies have demonstrated that school fruit schemes do prevent overweight. OBJECTIVE: The aim of the present study was to assess if increased consumption of fruits and vegetables, due to free school fruit, have an impact on future weight status. DESIGN: An intervention study including 10- to 12-year-old children from nine schools in two Norwegian counties (Hedmark and Telemark) participating in the Norwegian School Fruit Program for free during the school year 2001/2002 and children from 29 control schools. Follow-up studies were performed in 2005 and 2009. The cohort includes 1950 pupils (984 boys, 966 girls) at baseline, 1,602 participants in 2005 and 320 participants in the 2009 survey, of which 282 also had participated in 2005. RESULTS: In 2005, there was no significant difference between the free fruit group and the control group regarding weight status, Body mass index, or perceived weight status. In 2009, a significant difference in prevalence of overweight was observed (15% vs. 25%, p=0.04). In the crude logistic analysis, the OR for being overweight was 0.52 (95% CI: 0.28-0.97) for the intervention group compared to controls. When adjusting for school, sex, grade level and parental education, the association was no longer statistically significant. CONCLUSIONS: These results indicate that free school fruit might contribute to prevent future excessive weight gain. However, the study results are limited by low participation rate. PMID- 25147496 TI - Homeostasis in anorexia nervosa. AB - Brainstem and hypothalamic "orexigenic/anorexigenic" networks are thought to maintain body weight homeostasis in response to hormonal and metabolic feedback from peripheral sites. This approach has not been successful in managing over- and underweight patients. It is suggested that concept of homeostasis has been misinterpreted; rather than exerting control, the brain permits eating in proportion to the amount of physical activity necessary to obtain food. In support, animal experiments have shown that while a hypothalamic "orexigen" excites eating when food is abundant, it inhibits eating and stimulates foraging when food is in short supply. As the physical price of food approaches zero, eating and body weight increase without constraints. Conversely, in anorexia nervosa body weight is homeostatically regulated, the high level of physical activity in anorexia is displaced hoarding for food that keeps body weight constantly low. A treatment based on this point of view, providing patients with computerized mealtime support to re-establish normal eating behavior, has brought 75% of patients with eating disorders into remission, reduced the rate of relapse to 10%, and eliminated mortality. PMID- 25147497 TI - The plastic ear and perceptual relearning in auditory spatial perception. AB - The auditory system of adult listeners has been shown to accommodate to altered spectral cues to sound location which presumably provides the basis for recalibration to changes in the shape of the ear over a life time. Here we review the role of auditory and non-auditory inputs to the perception of sound location and consider a range of recent experiments looking at the role of non-auditory inputs in the process of accommodation to these altered spectral cues. A number of studies have used small ear molds to modify the spectral cues that result in significant degradation in localization performance. Following chronic exposure (10-60 days) performance recovers to some extent and recent work has demonstrated that this occurs for both audio-visual and audio-only regions of space. This begs the questions as to the teacher signal for this remarkable functional plasticity in the adult nervous system. Following a brief review of influence of the motor state in auditory localization, we consider the potential role of auditory-motor learning in the perceptual recalibration of the spectral cues. Several recent studies have considered how multi-modal and sensory-motor feedback might influence accommodation to altered spectral cues produced by ear molds or through virtual auditory space stimulation using non-individualized spectral cues. The work with ear molds demonstrates that a relatively short period of training involving audio-motor feedback (5-10 days) significantly improved both the rate and extent of accommodation to altered spectral cues. This has significant implications not only for the mechanisms by which this complex sensory information is encoded to provide spatial cues but also for adaptive training to altered auditory inputs. The review concludes by considering the implications for rehabilitative training with hearing aids and cochlear prosthesis. PMID- 25147498 TI - A central role for ubiquitination within a circadian clock protein modification code. AB - Circadian rhythms, endogenous cycles of about 24 h in physiology, are generated by a master clock located in the suprachiasmatic nucleus of the hypothalamus and other clocks located in the brain and peripheral tissues. Circadian disruption is known to increase the incidence of various illnesses, such as mental disorders, metabolic syndrome, and cancer. At the molecular level, periodicity is established by a set of clock genes via autoregulatory translation-transcription feedback loops. This clock mechanism is regulated by post-translational modifications such as phosphorylation and ubiquitination, which set the pace of the clock. Ubiquitination in particular has been found to regulate the stability of core clock components but also other clock protein functions. Mutation of genes encoding ubiquitin ligases can cause either elongation or shortening of the endogenous circadian period. Recent research has also started to uncover roles for deubiquitination in the molecular clockwork. Here, we review the role of the ubiquitin pathway in regulating the circadian clock and we propose that ubiquitination is a key element in a clock protein modification code that orchestrates clock mechanisms and circadian behavior over the daily cycle. PMID- 25147499 TI - Neuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain. AB - The development of neuropathic pain in response to peripheral nerve lesion for a large part depends on microglia located at the dorsal horn of the spinal cord. Thus the injured nerve initiates a response of microglia, which represents the start of a cascade of events that leads to neuropathic pain development. For long it remained obscure how a nerve injury in the periphery would initiate a microglia response in the dorsal horn of the spinal cord. Recently, two chemokines have been suggested as potential factors that mediate the communication between injured neurons and microglia namely CCL2 and CCL21. This assumption is based on the following findings. Both chemokines are not found in healthy neurons, but are expressed in response to neuronal injury. In injured dorsal root ganglion cells CCL2 and CCL21 are expressed in vesicles in the soma and transported through the axons of the dorsal root into the dorsal horn of the spinal cord. Finally, microglia in vitro are known to respond to CCL2 and CCL21. Whereas the microglial chemokine receptor involved in CCL21-induced neuropathic pain is not yet defined the situation concerning the receptors for CCL2 in microglia in vivo is even less clear. Recent results obtained in transgenic animals clearly show that microglia in vivo do not express CCR2 but that peripheral myeloid cells and neurons do. This suggests that CCL2 expressed by injured dorsal root neurons does not act as neuron-microglia signal in contrast to CCL21. Instead, CCL2 in the injured dorsal root ganglia (DRG) may act as autocrine or paracrine signal and may stimulate first or second order neurons in the pain cascade and/or attract CCR2-expressing peripheral monocytes/macrophages to the spinal cord. PMID- 25147500 TI - Interleukin-18 alters protein expressions of neurodegenerative diseases-linked proteins in human SH-SY5Y neuron-like cells. AB - Chronic inflammation and oxidative stress (OS) are present in Alzheimer's disease (AD) brains in addition to neuronal loss, Amyloid-beta (Abeta) plaques and hyperphosphorylated tau-protein neurofibrillary tangles (NFTs). Previously we showed that levels of the pro-inflammatory cytokine, interleukin-18 (IL-18), are elevated in post-mortem AD brains. IL-18 can modulate the tau kinases, Cdk5 and GSK3beta, as well as Abeta-production. IL-18 levels are also increased in AD risk diseases, including type-2 diabetes and obesity. Here, we explored other IL-18 regulated proteins in neuron-like SH-SY5Y cells. Differentiated SH-SY5Y cells, incubated with IL-18 for 24, 48, or 72 h, were analyzed by two-dimensional gel electrophoresis (2D-DIGE). Specific altered protein spots were chosen and identified with mass spectrometry (MS) and verified by western immunoblotting (WIB). IL-18 had time-dependent effects on the SH-SY5Y proteome, modulating numerous protein levels/modifications. We concentrated on those related to OS (DDAH2, peroxiredoxins 2, 3, and 6, DJ-1, BLVRA), Abeta-degradation (MMP14, TIMP2), Abeta-aggregation (Septin-2), and modifications of axon growth and guidance associated, collapsin response mediator protein 2 (CRMP2). IL-18 significantly increased antioxidative enzymes, indicative of OS, and altered levels of glycolytic alpha- and gamma-enolase and multifunctional 14-3-3gamma and -epsilon, commonly affected in neurodegenerative diseases. MMP14, TIMP2, alpha enolase and 14-3-3epsilon, indirectly involved in Abeta metabolism, as well as Septin-2 showed changes that increase Abeta levels. Increased 14-3-3gamma may contribute to GSK3beta driven tau hyperphosphorylation and CRMP2 Thr514 and Ser522 phosphorylation with the Thr555-site, a target for Rho kinase, showing time-dependent changes. IL-18 also increased caspase-1 levels and vacuolization of the cells. Although our SH-SY5Y cells were not aged, as neurons in AD, our work suggests that heightened or prolonged IL-18 levels can drive protein changes of known relevance to AD pathogenesis. PMID- 25147501 TI - The role of alpha-E-catenin in cerebral cortex development: radial glia specific effect on neuronal migration. AB - During brain development, radial glial cells possess an apico-basal polarity and are coupled by adherens junctions (AJs) to an F-actin belt. To elucidate the role of the actin, we conditionally deleted the key component alpha-E-catenin in the developing cerebral cortex. Deletion at early stages resulted in severe disruption of tissue polarity due to uncoupling of AJs with the intracellular actin fibers leading to the formation of subcortical band heterotopia. Interestingly, this phenotype closely resembled the phenotype obtained by conditional RhoA deletion, both in regard to the macroscopic subcortical band heterotopia and the subcellular increase in G-actin/F-actin ratio. These data therefore together corroborate the role of the actin cytoskeleton and its anchoring to the AJs for neuronal migration disorders. PMID- 25147502 TI - Proteostasis in striatal cells and selective neurodegeneration in Huntington's disease. AB - Selective neuronal loss is a hallmark of neurodegenerative diseases, including Huntington's disease (HD). Although mutant huntingtin, the protein responsible for HD, is expressed ubiquitously, a subpopulation of neurons in the striatum is the first to succumb. In this review, we examine evidence that protein quality control pathways, including the ubiquitin proteasome system, autophagy, and chaperones, are significantly altered in striatal neurons. These alterations may increase the susceptibility of striatal neurons to mutant huntingtin-mediated toxicity. This novel view of HD pathogenesis has profound therapeutic implications: protein homeostasis pathways in the striatum may be valuable targets for treating HD and other misfolded protein disorders. PMID- 25147503 TI - Nerve growth factor is primarily produced by GABAergic neurons of the adult rat cortex. AB - Within the cortex, nerve growth factor (NGF) mediates the innervation of cholinergic neurons during development, maintains cholinergic corticopetal projections during adulthood and modulates cholinergic function through phenotypic control of the cholinergic gene locus. Recent studies suggest NGF may also play an important role in cortical plasticity in adulthood. Previously, NGF producing cells have been shown to colocalize with GABAergic cell markers within the hippocampus, striatum, and basal forebrain. Classification of cells producing NGF in the cortex is lacking, however, and cholinergic corticopetal projections have been shown to innervate both pyramidal and GABAergic neurons in the cortex. In order to clarify potential trophic interactions between cortical neurons and cholinergic projections, we used double-fluorescent immunohistochemistry to classify NGF-expressing cells in several cortical regions, including the prefrontal cortex, primary motor cortex, parietal cortex and temporal cortex. Our results show that NGF colocalizes extensively with GABAergic cell markers in all cortical regions examined, with >91% of NGF-labeled cells coexpressing GAD65/67. Conversely, NGF-labeled cells exhibit very little co-localization with the excitatory cell marker CaMKIIalpha (<5% of cells expressing NGF). NGF expression was present in 56% of GAD-labeled cells, suggesting that production is confined to a specific subset of GABAergic neurons. These findings demonstrate that GABAergic cells are the primary source of NGF production in the cortex, and likely support the maintenance and function of basal forebrain cholinergic projections in adulthood. PMID- 25147504 TI - Robust quantification of orientation selectivity and direction selectivity. AB - Neurons in the visual cortex of all examined mammals exhibit orientation or direction tuning. New imaging techniques are allowing the circuit mechanisms underlying orientation and direction selectivity to be studied with clarity that was not possible a decade ago. However, these new techniques bring new challenges: robust quantitative measurements are needed to evaluate the findings from these studies, which can involve thousands of cells of varying response strength. Here we show that traditional measures of selectivity such as the orientation index (OI) and direction index (DI) are poorly suited for quantitative evaluation of orientation and direction tuning. We explore several alternative methods for quantifying tuning and for addressing a variety of questions that arise in studies on orientation- and direction-tuned cells and cell populations. We provide recommendations for which methods are best suited to which applications and we offer tips for avoiding potential pitfalls in applying these methods. Our goal is to supply a solid quantitative foundation for studies involving orientation and direction tuning. PMID- 25147505 TI - Supraspinal gene transfer by intrathecal adeno-associated virus serotype 5. AB - We report the pattern of transgene expression across brain regions after intrathecal delivery of adeno-associated virus serotype 5 (AAV5). Labeling in hindbrain appeared to be primarily neuronal, and was detected in sensory nuclei of medulla, pontine nuclei, and all layers of cerebellar cortex. Expression in midbrain was minimal, and generally limited to isolated neurons and astrocytes in the cerebral peduncles. GFP immunoreactivity (-ir) in thalamus was most prominent in medial geniculate nucleus, and otherwise limited to posterior nuclei of the dorsal and lateral margins. Labeling was also observed in neurons and astrocytes of the hippocampal formation and amygdaloid complex. In the hippocampal formation, GFP-ir was found in neuronal cell bodies of the rostral ventral portion, but was largely restricted to fiber-like staining in the molecular layer of dentate gyrus and stratum lacunosum-moleculare of the rostral dorsal region. GFP-ir was seen in neurons and astroglia throughout caudal cortex, whereas in rostral regions of neocortex it was limited to isolated neurons and non-neuronal cells. Labeling was also present in olfactory bulb. These results demonstrate that intrathecal delivery of AAV5 vector leads to transgene expression in discrete CNS regions throughout the rostro-caudal extent of the neuraxis. A caudal-to-rostral gradient of decreasing GFP-ir was present in choroid plexus and Purkinje cells, suggesting that spread of virus through cerebrospinal fluid plays a role in the resulting transduction pattern. Other factors contributing to the observed expression pattern likely include variations in cell-surface receptors and inter-parenchymal space. PMID- 25147506 TI - Conserved localization of Pax6 and Pax7 transcripts in the brain of representatives of sarcopterygian vertebrates during development supports homologous brain regionalization. AB - Many of the genes involved in brain patterning during development are highly conserved in vertebrates and similarities in their expression patterns help to recognize homologous cell types or brain regions. Among these genes, Pax6 and Pax7 are expressed in regionally restricted patterns in the brain and are essential for its development. In the present immunohistochemical study we analyzed the distribution of Pax6 and Pax7 cells in the brain of six representative species of tetrapods and lungfishes, the closest living relatives of tetrapods, at several developmental stages. The distribution patterns of these transcription factors were largely comparable across species. In all species only Pax6 was expressed in the telencephalon, including the olfactory bulbs, septum, striatum, and amygdaloid complex. In the diencephalon, Pax6 and Pax7 were distinct in the alar and basal parts, mainly in prosomeres 1 and 3. Pax7 specifically labeled cells in the optic tectum (superior colliculus) and Pax6, but not Pax7, cells were found in the tegmentum. Pax6 was found in most granule cells of the cerebellum and Pax7 labeling was detected in cells of the ventricular zone of the rostral alar plate and in migrated cells in the basal plate, including the griseum centrale and the interpeduncular nucleus. Caudally, Pax6 cells formed a column, whereas the ventricular zone of the alar plate expressed Pax7. Since the observed Pax6 and Pax7 expression patterns are largely conserved they can be used to identify subdivisions in the brain across vertebrates that are not clearly discernible with classical techniques. PMID- 25147507 TI - The degeneration and replacement of dopamine cells in Parkinson's disease: the role of aging. AB - Available data show marked similarities for the degeneration of dopamine cells in Parkinson's disease (PD) and aging. The etio-pathogenic agents involved are very similar in both cases, and include free radicals, different mitochondrial disturbances, alterations of the mitophagy and the ubiquitin-proteasome system. Proteins involved in PD such as alpha-synuclein, UCH-L1, PINK1 or DJ-1, are also involved in aging. The anomalous behavior of astrocytes, microglia and stem cells of the subventricular zone (SVZ) also changes similarly in aging brains and PD. Present data suggest that PD could be the expression of aging on a cell population with high vulnerability to aging. The future knowledge of mechanisms involved in aging could be critical for both understanding the etiology of PD and developing etiologic treatments to prevent the onset of this neurodegenerative illness and to control its progression. PMID- 25147508 TI - rTMS neuromodulation improves electrocortical functional measures of information processing and behavioral responses in autism. AB - OBJECTIVES: Reports in autism spectrum disorders (ASD) of a minicolumnopathy with consequent deficits of lateral inhibition help explain observed behavioral and executive dysfunctions. We propose that neuromodulation based on low frequency repetitive Transcranial Magnetic Stimulation (rTMS) will enhance lateral inhibition through activation of inhibitory double bouquet interneurons and will be accompanied by improvements in the prefrontal executive functions. In addition we proposed that rTMS will improve cortical excitation/inhibition ratio and result in changes manifested in event-related potential (ERP) recorded during cognitive tests. MATERIALS AND METHODS: Along with traditional clinical behavioral evaluations the current study used ERPs in a visual oddball task with illusory figures. We compared clinical, behavioral and electrocortical outcomes in two groups of children with autism (TMS, wait-list group). We predicted that 18 session long course in autistic patients will have better behavioral and ERP outcomes as compared to age- and IQ-matched WTL group. We used 18 sessions of 1 Hz rTMS applied over the dorso-lateral prefrontal cortex in 27 individuals with ASD diagnosis. The WTL group was comprised of 27 age-matched subjects with ASD tested twice. Both TMS and WTL groups were assessed at the baseline and after completion of 18 weekly sessions of rTMS (or wait period) using clinical behavioral questionnaires and during performance on visual oddball task with Kanizsa illusory figures. RESULTS: Post-TMS evaluations showed decreased irritability and hyperactivity on the Aberrant Behavior Checklist (ABC), and decreased stereotypic behaviors on the Repetitive Behavior Scale (RBS-R). Following rTMS course we found decreased amplitude and prolonged latency in the frontal and fronto-central N100, N200 and P300 (P3a) ERPs to non-targets in active TMS treatment group. TMS resulted in increase of P2d (P2a to targets minus P2a to non-targets) amplitude. These ERP changes along with increased centro parietal P100 and P300 (P3b) to targets are indicative of more efficient processing of information post-TMS treatment. Another important finding was decrease of the latency and increase of negativity of error-related negativity (ERN) during commission errors that may reflect improvement in error monitoring and correction function. Enhanced information processing was also manifested in lower error rate. In addition we calculated normative post-error treaction time (RT) slowing response in both groups and found that rTMS treatment was accompanied by post-error RT slowing and higher accuracy of responses, whereas the WTL group kept on showing typical for ASD post-error RT speeding and higher commission and omission error rates. CONCLUSION: RESULTS from our study indicate that rTMS improves executive functioning in ASD as evidenced by normalization of ERP responses and behavioral reactions (RT, accuracy) during executive function test, and also by improvements in clinical evaluations. PMID- 25147509 TI - An electrocorticographic BCI using code-based VEP for control in video applications: a single-subject study. AB - A brain-computer-interface (BCI) allows the user to control a device or software with brain activity. Many BCIs rely on visual stimuli with constant stimulation cycles that elicit steady-state visual evoked potentials (SSVEP) in the electroencephalogram (EEG). This EEG response can be generated with a LED or a computer screen flashing at a constant frequency, and similar EEG activity can be elicited with pseudo-random stimulation sequences on a screen (code-based BCI). Using electrocorticography (ECoG) instead of EEG promises higher spatial and temporal resolution and leads to more dominant evoked potentials due to visual stimulation. This work is focused on BCIs based on visual evoked potentials (VEP) and its capability as a continuous control interface for augmentation of video applications. One 35 year old female subject with implanted subdural grids participated in the study. The task was to select one out of four visual targets, while each was flickering with a code sequence. After a calibration run including 200 code sequences, a linear classifier was used during an evaluation run to identify the selected visual target based on the generated code-based VEPs over 20 trials. Multiple ECoG buffer lengths were tested and the subject reached a mean online classification accuracy of 99.21% for a window length of 3.15 s. Finally, the subject performed an unsupervised free run in combination with visual feedback of the current selection. Additionally, an algorithm was implemented that allowed to suppress false positive selections and this allowed the subject to start and stop the BCI at any time. The code-based BCI system attained very high online accuracy, which makes this approach very promising for control applications where a continuous control signal is needed. PMID- 25147510 TI - Valenced action/inhibition learning in humans is modulated by a genetic variant linked to dopamine D2 receptor expression. AB - Motivational salience plays an important role in shaping human behavior, but recent studies demonstrate that human performance is not uniformly improved by motivation. Instead, action has been shown to dominate valence in motivated tasks, and it is particularly difficult for humans to learn the inhibition of an action to obtain a reward, but the neural mechanism behind this behavioral specificity is yet unclear. In all mammals, including humans, the monoamine neurotransmitter dopamine is particularly important in the neural manifestation of appetitively motivated behavior, and the human dopamine system is subject to considerable genetic variability. The well-studied TaqIA restriction fragment length polymorphism (rs1800497) has previously been shown to affect striatal dopamine metabolism. In this study we investigated a potential effect of this genetic variation on motivated action/inhibition learning. Two independent cohorts consisting of 87 and 95 healthy participants, respectively, were tested using the previously described valenced go/no-go learning paradigm in which participants learned the reward-associated no-go condition significantly worse than all other conditions. This effect was modulated by the TaqIA polymorphism, with carriers of the A1 allele showing a diminished learning-related performance enhancement in the rewarded no-go condition compared to the A2 homozygotes. This result highlights a modulatory role for genetic variability of the dopaminergic system in individual learning differences of action-valence interaction. PMID- 25147512 TI - Mixed housing with DBA/2 mice induces stress in C57BL/6 mice: implications for interventions based on social enrichment. AB - Several behavioral interventions, based on social enrichment and observational learning are applied in treatment of neuropsychiatric disorders. However, the mechanism of such modulatory effect and the safety of applied methods on individuals involved in social support need further investigation. We took advantage of known differences between inbred mouse strains to reveal the effect of social enrichment on behavior and neurobiology of animals with different behavioral phenotypes. C57BL/6 and DBA/2 female mice displaying multiple differences in cognitive, social, and emotional behavior were group-housed either in same-strain or in mixed-strain conditions. Comprehensive behavioral phenotyping and analysis of expression of several plasticity- and stress-related genes were done to measure the reciprocal effects of social interaction between the strains. Contrary to our expectation, mixed housing did not change the behavior of DBA/2 mice. Nevertheless, the level of serum corticosterone and the expression of glucocorticoid receptor Nr3c1 in the brain were increased in mixed housed DBA/2 as compared with those of separately housed DBA/2 mice. In contrast, socially active C57BL/6 animals were more sensitive to the mixed housing, displaying several signs of stress: alterations in learning, social, and anxiety like behavior and anhedonia. These behavioral impairments were accompanied by the elevated serum corticosterone and the reduced expression of Nr3c1, as well as the elevated Bdnf levels in the cortex and hippocampus. Our results demonstrate the importance of social factors in modulation of both behavior and the underlying neurobiological mechanisms in stress response, and draw attention to the potential negative impact of social interventions for individuals involved in social support. PMID- 25147511 TI - Neuroimaging of amblyopia and binocular vision: a review. AB - Amblyopia is a cerebral visual impairment considered to derive from abnormal visual experience (e.g., strabismus, anisometropia). Amblyopia, first considered as a monocular disorder, is now often seen as a primarily binocular disorder resulting in more and more studies examining the binocular deficits in the patients. The neural mechanisms of amblyopia are not completely understood even though they have been investigated with electrophysiological recordings in animal models and more recently with neuroimaging techniques in humans. In this review, we summarize the current knowledge about the brain regions that underlie the visual deficits associated with amblyopia with a focus on binocular vision using functional magnetic resonance imaging. The first studies focused on abnormal responses in the primary and secondary visual areas whereas recent evidence shows that there are also deficits at higher levels of the visual pathways within the parieto-occipital and temporal cortices. These higher level areas are part of the cortical network involved in 3D vision from binocular cues. Therefore, reduced responses in these areas could be related to the impaired binocular vision in amblyopic patients. Promising new binocular treatments might at least partially correct the activation in these areas. Future neuroimaging experiments could help to characterize the brain response changes associated with these treatments and help devise them. PMID- 25147513 TI - Oxytocin in the medial prefrontal cortex regulates maternal care, maternal aggression and anxiety during the postpartum period. AB - The neuropeptide oxytocin (OT) acts on a widespread network of brain regions to regulate numerous behavioral adaptations during the postpartum period including maternal care, maternal aggression, and anxiety. In the present study, we examined whether this network also includes the medial prefrontal cortex (mPFC). We found that bilateral infusion of a highly specific oxytocin receptor antagonist (OTR-A) into the prelimbic (PL) region of the mPFC increased anxiety like behavior in postpartum, but not virgin, females. In addition, OTR blockade in the postpartum mPFC impaired maternal care behaviors and enhanced maternal aggression. Overall, these results suggest that OT in the mPFC modulates maternal care and aggression, as well as anxiety-like behavior, during the postpartum period. Although the relationship among these behaviors is complicated and further investigation is required to refine our understanding of OT actions in the maternal mPFC, these data nonetheless provide new insights into neural circuitry of OT-mediated postpartum behaviors. PMID- 25147514 TI - The effects of sertraline administration from adolescence to adulthood on physiological and emotional development in prenatally stressed rats of both sexes. AB - Sertraline (SERT) is a clinically effective Selective Serotonin Reuptake Inhibitor (SSRI) known to increase and stabilize serotonin levels. This neurotransmitter plays an important role in adolescent brain development in both rodents and humans, and its dysregulation has been correlated with deficits in behavior and emotional regulation. Since prenatal stress may disturb serotoninergic homeostasis, the aim of this study was to examine the long-lasting effects of exposure to SERT throughout adolescence on behavioral and physiological developmental parameters in prenatally stressed Wistar rats. SERT was administered (5 mg/kg/day p.o.) from the age of 1-3 months to half of the progeny, of both sexes, of gestating dams stressed by use of a restraint (PS) or not stressed. Our data reveal that long-term SERT treatment slightly reduced weight gain in both sexes, but reversed the developmental disturbed "catch-up" growth found in PS females. Neither prenatal stress nor SERT treatment induced remarkable alterations in behavior and had no effects on mean startle reflex values. However, a sex-dependent effects of PS was found: in males the PS paradigm slightly increased anxiety-like behavior in the open field, while in females, it impaired startle habituation. In both cases, SERT treatment reversed the phenomena. Additionally, the PS animals exhibited a disturbed leukocyte profile in both sexes, which was reversed by SERT. The present findings are evidence that continuous SERT administration from adolescence through adulthood is safe in rodents and lessens the impact of prenatal stress in rats. PMID- 25147516 TI - The neural correlates of the decoy effect in decisions. AB - Human choices are remarkably susceptible to the context in which options are presented. The introduction of an inferior option (a decoy) into the choice set can make one of the original options (the target) more attractive than and the other original option (the competitor). This so called "decoy effect" represents a striking violation of the "context-invariant" axiom, yet its underlying neural mechanisms are not well understood. Here, we used a novel gambling task in conjunction with functional magnetic resonance imaging (fMRI) to elucidate its neural basis. At both the stimulus and decision phases, choice sets with decoys activated the occipital gyrus and deactivated the inferior parietal gyrus. At the decision phase, choosing the targets vs. the competitors elicited stronger anterior insula activation, suggesting that perceptual salience drives heuristic decision making in the decoy effect. Moreover, across participants, activity in anterior cingulate cortex (ACC) predicted a reduced susceptibility to the decoy effect, indicating that resisting the tendency to make heuristic decisions is taxing. Our findings highlight the power of the decoy effect in laboratory settings and document the neural mechanisms underlying the decoy effect. PMID- 25147515 TI - GAD65 haplodeficiency conveys resilience in animal models of stress-induced psychopathology. AB - GABAergic mechanisms are critically involved in the control of fear and anxiety, but their role in the development of stress-induced psychopathologies, including post-traumatic stress disorder (PTSD) and mood disorders is not sufficiently understood. We studied these functions in two established mouse models of risk factors for stress-induced psychopathologies employing variable juvenile stress and/or social isolation. A battery of emotional tests in adulthood revealed the induction of contextually generalized fear, anxiety, hyperarousal and depression like symptoms in these paradigms. These reflect the multitude and complexity of stress effects in human PTSD patients. With factor analysis we were able to identify parameters that reflect these different behavioral domains in stressed animals and thus provide a basis for an integrated scoring of affectedness more closely resembling the clinical situation than isolated parameters. To test the applicability of these models to genetic approaches we further tested the role of GABA using heterozygous mice with targeted mutation of the GABA synthesizing enzyme GAD65 [GAD65(+/-) mice], which show a delayed postnatal increase in tissue GABA content in limbic and cortical brain areas. Unexpectedly, GAD65(+/-) mice did not show changes in exploratory activity regardless of the stressor type and were after the variable juvenile stress procedure protected from the development of contextual generalization in an auditory fear conditioning experiment. Our data demonstrate the complex nature of behavioral alterations in rodent models of stress-related psychopathologies and suggest that GAD65 haplodeficiency, likely through its effect on the postnatal maturation of GABAergic transmission, conveys resilience to some of these stress-induced effects. PMID- 25147517 TI - Near-infrared spectroscopy (NIRS) as a new tool for neuroeconomic research. AB - Over the last decade, the application of neuroscience to economic research has gained in importance and the number of neuroeconomic studies has grown extensively. The most common method for these investigations is fMRI. However, fMRI has limitations (particularly concerning situational factors) that should be countered with other methods. This review elaborates on the use of functional Near-Infrared Spectroscopy (fNIRS) as a new and promising tool for investigating economic decision making both in field experiments and outside the laboratory. We describe results of studies investigating the reliability of prototype NIRS studies, as well as detailing experiments using conventional and stationary fNIRS devices to analyze this potential. This review article shows that further research using mobile fNIRS for studies on economic decision making outside the laboratory could be a fruitful avenue helping to develop the potential of a new method for field experiments outside the laboratory. PMID- 25147519 TI - Transcranial direct current stimulation and power spectral parameters: a tDCS/EEG co-registration study. AB - Transcranial direct current stimulation (tDCS) delivers low electric currents to the brain through the scalp. Constant electric currents induce shifts in neuronal membrane excitability, resulting in secondary changes in cortical activity. Concomitant electroencephalography (EEG) monitoring during tDCS can provide valuable information on the tDCS mechanisms of action. This study examined the effects of anodal tDCS on spontaneous cortical activity in a resting brain to disclose possible modulation of spontaneous oscillatory brain activity. EEG activity was measured in ten healthy subjects during and after a session of anodal stimulation of the postero-parietal cortex to detect the tDCS-induced alterations. Changes in the theta, alpha, beta, and gamma power bands were investigated. Three main findings emerged: (1) an increase in theta band activity during the first minutes of stimulation; (2) an increase in alpha and beta power during and after stimulation; (3) a widespread activation in several brain regions. PMID- 25147518 TI - Visuo-motor coordination ability predicts performance with brain-computer interfaces controlled by modulation of sensorimotor rhythms (SMR). AB - Modulation of sensorimotor rhythms (SMR) was suggested as a control signal for brain-computer interfaces (BCI). Yet, there is a population of users estimated between 10 to 50% not able to achieve reliable control and only about 20% of users achieve high (80-100%) performance. Predicting performance prior to BCI use would facilitate selection of the most feasible system for an individual, thus constitute a practical benefit for the user, and increase our knowledge about the correlates of BCI control. In a recent study, we predicted SMR-BCI performance from psychological variables that were assessed prior to the BCI sessions and BCI control was supported with machine-learning techniques. We described two significant psychological predictors, namely the visuo-motor coordination ability and the ability to concentrate on the task. The purpose of the current study was to replicate these results thereby validating these predictors within a neurofeedback based SMR-BCI that involved no machine learning.Thirty-three healthy BCI novices participated in a calibration session and three further neurofeedback training sessions. Two variables were related with mean SMR-BCI performance: (1) a measure for the accuracy of fine motor skills, i.e., a trade for a person's visuo-motor control ability; and (2) subject's "attentional impulsivity". In a linear regression they accounted for almost 20% in variance of SMR-BCI performance, but predictor (1) failed significance. Nevertheless, on the basis of our prior regression model for sensorimotor control ability we could predict current SMR-BCI performance with an average prediction error of M = 12.07%. In more than 50% of the participants, the prediction error was smaller than 10%. Hence, psychological variables played a moderate role in predicting SMR BCI performance in a neurofeedback approach that involved no machine learning. Future studies are needed to further consolidate (or reject) the present predictors. PMID- 25147520 TI - The relative contributions of frontal and parietal cortex for generalized quantifier comprehension. AB - Quantifiers, like "some" or "few," are frequent in daily language. Linguists posit at least three distinct classes of quantifiers: cardinal quantifiers that rely on numerosity, majority quantifiers that additionally depend on executive resources, and logical quantifiers that rely on perceptual attention. We used BOLD fMRI to investigate the roles of frontal and parietal regions in quantifier comprehension. Participants performed a sentence-picture verification task to determine whether a sentence containing a quantifier accurately describes a picture. A whole-brain analysis identified a network involved in quantifier comprehension: This implicated bilateral inferior parietal, superior parietal and dorsolateral prefrontal cortices, and right inferior frontal cortex. We then performed region-of-interest analyses to assess the relative contribution of each region for each quantifier class. Inferior parietal cortex was equally activated across all quantifier classes, consistent with prior studies implicating the region for quantifier comprehension due in part to its role in the representation of number knowledge. Right superior parietal cortex was up-regulated in comparison to frontal regions for cardinal and logical quantifiers, but parietal and frontal regions were equally activated for majority quantifiers and each frontal region is most highly activated for majority quantifiers. This finding is consistent with the hypothesis that majority quantifiers rely on numerosity mechanisms in parietal cortex and executive mechanisms in frontal cortex. Also, right inferior frontal cortex was up-regulated for logical compared to cardinal quantifiers, which may be related to selection demands associated with logical quantifier comprehension. We conclude that distinct components of a large-scale fronto-parietal network contribute to specific aspects of quantifier comprehension, and that this biologically defined network is consistent with cognitive theories of quantifier meaning. PMID- 25147521 TI - Neurorehabilitation of social dysfunctions: a model-based neurofeedback approach for low and high-functioning autism. AB - Autism Spectrum Disorder (ASD) is an increasingly prevalent condition with core deficits in the social domain. Understanding its neuroetiology is critical to providing insights into the relationship between neuroanatomy, physiology and social behaviors, including imitation learning, language, empathy, theory of mind, and even self-awareness. Equally important is the need to find ways to arrest its increasing prevalence and to ameliorate its symptoms. In this review, we highlight neurofeedback studies as viable treatment options for high functioning as well as low-functioning children with ASD. Lower-functioning groups have the greatest need for diagnosis and treatment, the greatest barrier to communication, and may experience the greatest benefit if a treatment can improve function or prevent progression of the disorder at an early stage. Therefore, we focus on neurofeedback interventions combined with other kinds of behavioral conditioning to induce neuroplastic changes that can address the full spectrum of the autism phenotype. PMID- 25147522 TI - Subclass-based multi-task learning for Alzheimer's disease diagnosis. AB - In this work, we propose a novel subclass-based multi-task learning method for feature selection in computer-aided Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI) diagnosis. Unlike the previous methods that often assumed a unimodal data distribution, we take into account the underlying multipeak distribution of classes. The rationale for our approach is that it is highly likely for neuroimaging data to have multiple peaks or modes in distribution, e.g., mixture of Gaussians, due to the inter-subject variability. In this regard, we use a clustering method to discover the multipeak distributional characteristics and define subclasses based on the clustering results, in which each cluster covers a peak in the underlying multipeak distribution. Specifically, after performing clustering for each class, we encode the respective subclasses, i.e., clusters, with their unique codes. In encoding, we impose the subclasses of the same original class close to each other and those of different original classes distinct from each other. By setting the codes as new label vectors of our training samples, we formulate a multi-task learning problem in a l2,1-penalized regression framework, through which we finally select features for classification. In our experimental results on the ADNI dataset, we validated the effectiveness of the proposed method by improving the classification accuracies by 1% (AD vs. Normal Control: NC), 3.25% (MCI vs. NC), 5.34% (AD vs. MCI), and 7.4% (MCI Converter: MCI-C vs. MCI Non-Converter: MCI-NC) compared to the competing single-task learning method. It is remarkable for the performance improvement in MCI-C vs. MCI-NC classification, which is the most important for early diagnosis and treatment. It is also noteworthy that with the strategy of modality-adaptive weights by means of a multi-kernel support vector machine, we maximally achieved the classification accuracies of 96.18% (AD vs. NC), 81.45% (MCI vs. NC), 73.21% (AD vs. MCI), and 74.04% (MCI-C vs. MCI-NC), respectively. PMID- 25147523 TI - Short-latency afferent inhibition is a poor predictor of individual susceptibility to rTMS-induced plasticity in the motor cortex of young and older adults. AB - Cortical plasticity, including long-term potentiation (LTP)-like plasticity, can be assessed non-invasively with repetitive transcranial magnetic stimulation (rTMS) protocols. In this study, we examined age differences in responses to intermittent theta burst stimulation (iTBS) in a group of 20 young and 18 healthy older adults. Because the cholinergic system plays a role in the neural processes underlying learning and memory, including LTP, we also investigated whether short latency afferent inhibition (SAI), a neurophysiological marker of central cholinergic activity, would be associated with age-related differences in LTP like plasticity induced by iTBS. METHODS: SAI was first assessed by examining the modulation of motor evoked potentials (MEPs) in response to median nerve conditioning 20 ms prior to TMS. Participants then underwent iTBS (3 pulses at 50 Hz every 200 ms for 2 s with 8 s between trains, repeated 20 times). MEP responses (120% resting motor threshold (RMT)) were assessed immediately after iTBS and 5, 10, and 20 min post-application. RESULTS: Responses to iTBS were quite variable in both age groups, with only approximately 60% of the participants (n = 13 young and 10 older adults) showing the expected facilitation of MEP responses. There were no significant age group differences in MEP facilitation following iTBS. Although older adults exhibited reduced SAI, individual variations were not associated with susceptibility to express LTP-like induced plasticity after iTBS. CONCLUSION: Overall, these results are consistent with reports of high inter-individual variability in responses to iTBS. Although SAI was reduced in older adults, consistent with a deterioration of the cholinergic system with age, SAI levels were not associated with LTP-like plasticity as assessed with iTBS. PMID- 25147524 TI - Engaging novel cell types, protein targets and efficacy biomarkers in the treatment of diabetic nephropathy. PMID- 25147525 TI - Na(+) current expression in human atrial myofibroblasts: identity and functional roles. AB - In the mammalian heart fibroblasts have important functional roles in both healthy conditions and diseased states. During pathophysiological challenges, a closely related myofibroblast cell population emerges, and can have distinct, significant roles. Recently, it has been reported that human atrial myofibroblasts can express a Na(+) current, INa. Some of the biophysical properties and molecular features suggest that this INa is due to expression of Nav 1.5, the same Na(+) channel alpha subunit that generates the predominant INa in myocytes from adult mammalian heart. In principle, expression of Nav 1.5 could give rise to regenerative action potentials in the fibroblasts/myofibroblasts. This would suggest an active as opposed to passive role for fibroblasts/myofibroblasts in both the "trigger" and the "substrate" components of cardiac rhythm disturbances. Our goals in this preliminary study were: (i) to confirm and extend the electrophysiological characterization of INa in a human atrial fibroblast/myofibroblast cell population maintained in conventional 2-D tissue culture; (ii) to identify key molecular properties of the alpha and beta subunits of these Na(+) channel(s); (iii) to define the biophysical and pharmacological properties of this INa; (iv) to integrate the available multi disciplinary data, and attempt to illustrate its functional consequences, using a mathematical model in which the human atrial myocyte is coupled via connexins to fixed numbers of fibroblasts/myofibroblasts in a syncytial arrangement. Our experimental findings confirm that a significant fraction (approximately 40-50%) of these human atrial myofibroblasts can express INa. However, our data suggest that INa may be generated by a combination of Nav 1.9, Nav 1.2, and Nav 1.5. Our results, when complemented with mathematical modeling, provide a background for re-evaluating pharmacological management of supraventricular rhythm disorders, e.g., persistent atrial fibrillation. PMID- 25147527 TI - Neurological abnormalities in recent-onset schizophrenia and asperger-syndrome. AB - BACKGROUND: Neurological abnormalities including a variety of subtle deficits such as discrete impairments in sensory integration, motor coordination (MOCO), and sequencing of complex motor acts are frequently found in patients with schizophrenia (SZ) and commonly referred to as neurological soft signs (NSS). Asperger-syndrome (AS) is characterized by sensory-motor difficulties as well. However, the question whether the two disorders share a common or a disease specific pattern of NSS remains unresolved. METHOD: A total of 78 age- and education-matched participants [26 patients with recent-onset SZ, 26 individuals with AS, and 26 healthy controls (HC)] were recruited for the study. Analyses of covariance (ANCOVAs), with age, years of education, and medication included as covariates, were used to examine group differences on total NSS and the five subscale scores. Discriminant analyses were employed to identify the NSS subscales that maximally discriminate between the three groups. RESULTS: Significant differences among the three groups were found in NSS total score and on the five NSS subscales. The clinical groups differed significantly in the NSS subscale MOCO. The correct discriminant rate between patients with SZ and individuals with AS was 61.5%. The correct discriminant rate was 92.3% between individuals with AS and HC, and 80.8% between SZ patients and HC, respectively. CONCLUSION: Our findings provide new evidence for the presence of NSS in AS and lend further support to previously reported difficulties in movement control in this disorder. According to the present results, SZ and AS seem to be characterized by both quantitative and qualitative NSS expression. PMID- 25147526 TI - Cardiac magnetic resonance and computed tomography angiography for clinical imaging of stable coronary artery disease. Diagnostic classification and risk stratification. AB - Despite advances in the pharmacologic and interventional treatment of coronary artery disease (CAD), atherosclerosis remains the leading cause of death in Western societies. X-ray coronary angiography has been the modality of choice for diagnosing the presence and extent of CAD. However, this technique is invasive and provides limited information on the composition of atherosclerotic plaque. Coronary computed tomography angiography (CCTA) and cardiac magnetic resonance (CMR) have emerged as promising non-invasive techniques for the clinical imaging of CAD. Hereby, CCTA allows for visualization of coronary calcification, lumen narrowing and atherosclerotic plaque composition. In this regard, data from the CONFIRM Registry recently demonstrated that both atherosclerotic plaque burden and lumen narrowing exhibit incremental value for the prediction of future cardiac events. However, due to technical limitations with CCTA, resulting in false positive or negative results in the presence of severe calcification or motion artifacts, this technique cannot entirely replace invasive angiography at the present time. CMR on the other hand, provides accurate assessment of the myocardial function due to its high spatial and temporal resolution and intrinsic blood-to-tissue contrast. Hereby, regional wall motion and perfusion abnormalities, during dobutamine or vasodilator stress, precede the development of ST-segment depression and anginal symptoms enabling the detection of functionally significant CAD. While CT generally offers better spatial resolution, the versatility of CMR can provide information on myocardial function, perfusion, and viability, all without ionizing radiation for the patients. Technical developments with these 2 non-invasive imaging tools and their current implementation in the clinical imaging of CAD will be presented and discussed herein. PMID- 25147529 TI - Social values as arguments: similar is convincing. AB - Politicians, philosophers, and rhetors engage in co-value argumentation: appealing to one value in order to support another value (e.g., "equality leads to freedom"). Across four experiments in the United Kingdom and India, we found that the psychological relatedness of values affects the persuasiveness of the arguments that bind them. Experiment 1 found that participants were more persuaded by arguments citing values that fulfilled similar motives than by arguments citing opposing values. Experiments 2 and 3 replicated this result using a wider variety of values, while finding that the effect is stronger among people higher in need for cognition and that the effect is mediated by the greater plausibility of co-value arguments that link motivationally compatible values. Experiment 4 extended the effect to real-world arguments taken from political propaganda and replicated the mediating effect of argument plausibility. The findings highlight the importance of value relatedness in argument persuasiveness. PMID- 25147528 TI - The development of sensorimotor influences in the audiovisual speech domain: some critical questions. AB - Speech researchers have long been interested in how auditory and visual speech signals are integrated, and the recent work has revived interest in the role of speech production with respect to this process. Here, we discuss these issues from a developmental perspective. Because speech perception abilities typically outstrip speech production abilities in infancy and childhood, it is unclear how speech-like movements could influence audiovisual speech perception in development. While work on this question is still in its preliminary stages, there is nevertheless increasing evidence that sensorimotor processes (defined here as any motor or proprioceptive process related to orofacial movements) affect developmental audiovisual speech processing. We suggest three areas on which to focus in future research: (i) the relation between audiovisual speech perception and sensorimotor processes at birth, (ii) the pathways through which sensorimotor processes interact with audiovisual speech processing in infancy, and (iii) developmental change in sensorimotor pathways as speech production emerges in childhood. PMID- 25147531 TI - Wearable biosensor systems and resilience: a perfect storm in health care? AB - We begin by placing our discussion in the context of the chronic crisis in medical care, noting key features, including economic, safety and conceptual challenges. Then we review the most promising elements of a broadened conceptual approach to health and wellbeing, which include an expanded role for psychological, social, cultural, spiritual and environmental variables. The contributions of positive and evolutionary psychology, complex adaptive systems theory, genomics and neuroscience are described and the rapidly developing synthetic field of resilience as a catalytic unifying development is traced in some detail, including analysis of the rapidly growing empirical literature on resilience and its constituents, particularly heart rate variability. Finally, a review of the use of miniaturized ambulatory data collection, analysis and self management and health management systems points out an exemplar, the Extensive Care System (ECS), which takes advantage of the continuing advances in biosensor technology, computing power, networking dynamics and social media to facilitate not only personalized health and wellbeing, but higher quality evidence-based preventive, treatment and epidemiological outcomes. This development will challenge the acute care episode model typified by the ER or ICU stay and replace it with an ECS capable of facilitating not only healthy autonomic functioning, but both ipsative/individual and normative/population health. PMID- 25147530 TI - Leptin and insulin signaling in dopaminergic neurons: relationship between energy balance and reward system. AB - The central actions of leptin and insulin are essential for the regulation of energy and glucose homeostasis. In addition to the crucial effects on the hypothalamus, emerging evidence suggests that the leptin and insulin signaling can act on other brain regions to mediate the reward value of nutrients. Recent studies have indicated the midbrain dopaminergic neurons as a potential site for leptin' and insulin's actions on mediating the feeding behaviors and therefore affecting the energy balance. Although molecular details about the integrative roles of leptin and insulin in this subset of neurons remain to be investigated, substantial body of evidence by far imply that the signaling pathways regulated by leptin and insulin may play an essential role in the regulation of energy balance through the control of food-associated reward. This review therefore describes the convergence of energy regulation and reward system, particularly focusing on leptin and insulin signaling in the midbrain dopaminergic neurons. PMID- 25147533 TI - Studying real-world perceptual expertise. AB - Significant insights into visual cognition have come from studying real-world perceptual expertise. Many have previously reviewed empirical findings and theoretical developments from this work. Here we instead provide a brief perspective on approaches, considerations, and challenges to studying real-world perceptual expertise. We discuss factors like choosing to use real-world versus artificial object domains of expertise, selecting a target domain of real-world perceptual expertise, recruiting experts, evaluating their level of expertise, and experimentally testing experts in the lab and online. Throughout our perspective, we highlight expert birding (also called birdwatching) as an example, as it has been used as a target domain for over two decades in the perceptual expertise literature. PMID- 25147532 TI - From memory to prospection: what are the overlapping and the distinct components between remembering and imagining? AB - Reflecting on past events and reflecting on future events are two fundamentally different processes, each traveling in the opposite direction of the other through conceptual time. But what we are able to imagine seems to be constrained by what we have previously experienced, suggesting a close link between memory and prospection. Recent theories suggest that recalling the past lies at the core of imagining and planning for the future. The existence of this link is supported by evidence gathered from neuroimaging, lesion, and developmental studies. Yet it is not clear exactly how the novel episodes people construct in their sense of the future develop out of their historical memories. There must be intermediary processes that utilize memory as a basis on which to generate future oriented thinking. Here, we review studies on goal-directed processing, associative learning, cognitive control, and creativity and link them with research on prospection. We suggest that memory cooperates with additional functions like goal-directed learning to construct and simulate novel events, especially self referential events. The coupling between memory-related hippocampus and other brain regions may underlie such memory-based prospection. Abnormalities in this constructive process may contribute to mental disorders such as schizophrenia. PMID- 25147534 TI - Teachers' expertise in feedback application adapted to the phases of the learning process. PMID- 25147535 TI - Reduction of environmental distraction to facilitate cognitive performance. PMID- 25147536 TI - Combined compared to dissociated oral and intestinal sucrose stimuli induce different brain hedonic processes. AB - The characterization of brain networks contributing to the processing of oral and/or intestinal sugar signals in a relevant animal model might help to understand the neural mechanisms related to the control of food intake in humans and suggest potential causes for impaired eating behaviors. This study aimed at comparing the brain responses triggered by oral and/or intestinal sucrose sensing in pigs. Seven animals underwent brain single photon emission computed tomography ((99m)Tc-HMPAO) further to oral stimulation with neutral or sucrose artificial saliva paired with saline or sucrose infusion in the duodenum, the proximal part of the intestine. Oral and/or duodenal sucrose sensing induced differential cerebral blood flow changes in brain regions known to be involved in memory, reward processes and hedonic (i.e., pleasure) evaluation of sensory stimuli, including the dorsal striatum, prefrontal cortex, cingulate cortex, insular cortex, hippocampus, and parahippocampal cortex. Sucrose duodenal infusion only and combined sucrose stimulation induced similar activity patterns in the putamen, ventral anterior cingulate cortex and hippocampus. Some brain deactivations in the prefrontal and insular cortices were only detected in the presence of oral sucrose stimulation. Finally, activation of the right insular cortex was only induced by combined oral and duodenal sucrose stimulation, while specific activity patterns were detected in the hippocampus and parahippocampal cortex with oral sucrose dissociated from caloric load. This study sheds new light on the brain hedonic responses to sugar and has potential implications to unravel the neuropsychological mechanisms underlying food pleasure and motivation. PMID- 25147538 TI - Thinking about thinking: implications of the introspective error for default interventionist type models of dual processes. PMID- 25147537 TI - Children's identification of familiar songs from pitch and timing cues. AB - The goal of the present study was to ascertain whether children with normal hearing and prelingually deaf children with cochlear implants could use pitch or timing cues alone or in combination to identify familiar songs. Children 4-7 years of age were required to identify the theme songs of familiar TV shows in a simple task with excerpts that preserved (1) the relative pitch and timing cues of the melody but not the original instrumentation, (2) the timing cues only (rhythm, meter, and tempo), and (3) the relative pitch cues only (pitch contour and intervals). Children with normal hearing performed at high levels and comparably across the three conditions. The performance of child implant users was well above chance levels when both pitch and timing cues were available, marginally above chance with timing cues only, and at chance with pitch cues only. This is the first demonstration that children can identify familiar songs from monotonic versions-timing cues but no pitch cues-and from isochronous versions-pitch cues but no timing cues. The study also indicates that, in the context of a very simple task, young implant users readily identify songs from melodic versions that preserve pitch and timing cues. PMID- 25147539 TI - Music expertise shapes audiovisual temporal integration windows for speech, sinewave speech, and music. AB - This psychophysics study used musicians as a model to investigate whether musical expertise shapes the temporal integration window for audiovisual speech, sinewave speech, or music. Musicians and non-musicians judged the audiovisual synchrony of speech, sinewave analogs of speech, and music stimuli at 13 audiovisual stimulus onset asynchronies (+/-360, +/-300 +/-240, +/-180, +/-120, +/-60, and 0 ms). Further, we manipulated the duration of the stimuli by presenting sentences/melodies or syllables/tones. Critically, musicians relative to non musicians exhibited significantly narrower temporal integration windows for both music and sinewave speech. Further, the temporal integration window for music decreased with the amount of music practice, but not with age of acquisition. In other words, the more musicians practiced piano in the past 3 years, the more sensitive they became to the temporal misalignment of visual and auditory signals. Collectively, our findings demonstrate that music practicing fine-tunes the audiovisual temporal integration window to various extents depending on the stimulus class. While the effect of piano practicing was most pronounced for music, it also generalized to other stimulus classes such as sinewave speech and to a marginally significant degree to natural speech. PMID- 25147540 TI - Muscle tenderness and psychiatric comorbidity: a vicious cycle in migraine chronicization. PMID- 25147541 TI - Detection of high-frequency oscillations by hybrid depth electrodes in standard clinical intracranial EEG recordings. AB - High-frequency oscillations (HFOs) have been proposed as a novel marker for epileptogenic tissue, spurring tremendous research interest into the characterization of these transient events. A wealth of continuously recorded intracranial electroencephalographic (iEEG) data is currently available from patients undergoing invasive monitoring for the surgical treatment of epilepsy. In contrast to data recorded on research-customized recording systems, data from clinical acquisition systems remain an underutilized resource for HFO detection in most centers. The effective and reliable use of this clinically obtained data would be an important advance in the ongoing study of HFOs and their relationship to ictogenesis. The diagnostic utility of HFOs ultimately will be limited by the ability of clinicians to detect these brief, sporadic, and low amplitude events in an electrically noisy clinical environment. Indeed, one of the most significant factors limiting the use of such clinical recordings for research purposes is their low signal to noise ratio, especially in the higher frequency bands. In order to investigate the presence of HFOs in clinical data, we first obtained continuous intracranial recordings in a typical clinical environment using a commercially available, commonly utilized data acquisition system and "off the shelf" hybrid macro-/micro-depth electrodes. These data were then inspected for the presence of HFOs using semi-automated methods and expert manual review. With targeted removal of noise frequency content, HFOs were detected on both macro- and micro-contacts, and preferentially localized to seizure onset zones. HFOs detected by the offline, semi-automated method were also validated in the clinical viewer, demonstrating that (1) this clinical system allows for the visualization of HFOs and (2) with effective signal processing, clinical recordings can yield valuable information for offline analysis. PMID- 25147543 TI - Methane production from protozoan endosymbionts following stimulation of microbial metabolism within subsurface sediments. AB - Previous studies have suggested that protozoa prey on Fe(III)- and sulfate reducing bacteria that are enriched when acetate is added to uranium contaminated subsurface sediments to stimulate U(VI) reduction. In order to determine whether protozoa continue to impact subsurface biogeochemistry after these acetate amendments have stopped, 18S rRNA and beta-tubulin sequences from this phase of an in situ uranium bioremediation field experiment were analyzed. Sequences most similar to Metopus species predominated, with the majority of sequences most closely related to M. palaeformis, a cilitated protozoan known to harbor methanogenic symbionts. Quantification of mcrA mRNA transcripts in the groundwater suggested that methanogens closely related to Metopus endosymbionts were metabolically active at this time. There was a strong correlation between the number of mcrA transcripts from the putative endosymbiotic methanogen and Metopus beta-tubulin mRNA transcripts during the course of the field experiment, suggesting that the activity of the methanogens was dependent upon the activity of the Metopus species. Addition of the eukaryotic inhibitors cyclohexamide and colchicine to laboratory incubations of acetate-amended subsurface sediments significantly inhibited methane production and there was a direct correlation between methane concentration and Metopus beta-tubulin and putative symbiont mcrA gene copies. These results suggest that, following the stimulation of subsurface microbial growth with acetate, protozoa harboring methanogenic endosymbionts become important members of the microbial community, feeding on moribund biomass and producing methane. PMID- 25147542 TI - Historical account on gaining insights on the mechanism of crown gall tumorigenesis induced by Agrobacterium tumefaciens. AB - The plant tumor disease known as crown gall was not called by that name until more recent times. Galls on plants were described by Malpighi (1679) who believed that these extraordinary growth are spontaneously produced. Agrobacterium was first isolated from tumors in 1897 by Fridiano Cavara in Napoli, Italy. After this bacterium was recognized to be the cause of crown gall disease, questions were raised on the mechanism by which it caused tumors on a variety of plants. Numerous very detailed studies led to the identification of Agrobacterium tumefaciens as the causal bacterium that cleverly transferred a genetic principle to plant host cells and integrated it into their chromosomes. Such studies have led to a variety of sophisticated mechanisms used by this organism to aid in its survival against competing microorganisms. Knowledge gained from these fundamental discoveries has opened many avenues for researchers to examine their primary organisms of study for similar mechanisms of pathogenesis in both plants and animals. These discoveries also advanced the genetic engineering of domesticated plants for improved food and fiber. PMID- 25147544 TI - Effect of crude plant extracts from some Oaxacan flora on two deleterious fungal phytopathogens and extract compatibility with a biofertilizer strain. AB - The antimicrobial activity of 12 plant extracts was tested against the phytopathogens Alternaria alternata and Fusarium solani. In addition, the compatibility of the extracts toward Bacillus liqueniformis, a biofertilizer and a non-target microorganism, was assessed. Plants tested belong to the Euphorbiaceae, Asteraceae, Crassulaceae, Rubiaceae, Convolvulaceae, Verbenaceae, Orchidaceae, Nyctaginaceae, Boraginaceae, and Tiliaceae families and were collected in the State of Oaxaca. The antifungal activity of the plant extracts (50-100 mg/mL) against A. alternata and F. solani, was determined by measuring the mycelium radial growth and obtaining the minimum inhibitory concentration (MIC) of fungal growth. In addition, with the aim of finding plant extracts which are compatible with a B. licheniformis biofertilizer strain and to test the non toxic nature of the treatments, the toxicity of the extracts toward this strain was evaluated using the agar diffusion method. Azoxystrobin (12 MUg) and chloramphenicol (30 MUg) were used as positive controls for the pathogens and for the non-target bacteria, respectively. Plant extracts inhibited fungal growth in the ranges of 0.76-56.17% against F. solani and 2.02-69.07% against A. alternata. The extracts of Acalypha subviscida, Ipomoea murucoides, Tournefortia densiflora and Lantana achyranthifolia showed MIC values between 5.77-12.5 mg/mL for at least one of the fungal species. The best treatment, Adenophyllum aurantium, exhibited a maximum inhibition for both F. solani (56.17%, MIC = 7.78 mg/mL) and A. alternata (68.64% MIC = 7.78 mg/mL), and resulted innocuous toward B. licheniformis. Therefore, this plant has an outstanding potential for the agroecological control of fungal phytopathogens in industrial crops. PMID- 25147547 TI - Characterization of denitrifying activity by the alphaproteobacterium, Sphingomonas wittichii RW1. AB - Sphingomonas wittichii RW1 has no reported denitrifying activity yet encodes nitrite and nitric oxide reductases. The aims of this study were to determine conditions under which S. wittichii RW1 consumes nitrite (NO(-) 2) and produces nitrous oxide (N2O), examine expression of putative genes for N-oxide metabolism, and determine the functionality of chromosomal (ch) and plasmid (p) encoded quinol-dependent nitric oxide reductases (NorZ). Batch cultures of wildtype (WT) and a norZ ch mutant of S. wittichii RW1 consumed NO(-) 2 and produced N2O during stationary phase. The norZ ch mutant produced N2O, although at significantly lower levels (c.a. 66-87%) relative to the WT. Rates of N2O production were 2-3 times higher in cultures initiated at low relative to atmospheric O2 per unit biomass, although rates of NO(-) 2 consumption were elevated in cultures initiated with atmospheric O2 and 1 mM NaNO2. Levels of mRNA encoding nitrite reductase (nirK), plasmid-encoded nitric oxide dioxygenase (hmp p) and plasmid encoded nitric oxide reductase (norZ p) were significantly higher in the norZ ch mutant over a growth curve relative to WT. The presence of NO(-) 2 further increased levels of nirK and hmp p mRNA in both the WT and norZ ch mutant; levels of norZ p mRNA compensated for the loss of norZ ch expression in the norZ ch mutant. Together, the results suggest that S. wittichii RW1 denitrifies NO(-) 2 to N2O and expresses gene products predicted to detoxify N-oxides. So far, only S. wittichii strains within four closely related taxa have been observed to encode both nirK and norZ genes, indicating a species-specific lateral gene transfer that may be relevant to the niche preference of S. wittichii. PMID- 25147546 TI - Biogeography of anaerobic ammonia-oxidizing (anammox) bacteria. AB - Anaerobic ammonia-oxidizing (anammox) bacteria are able to oxidize ammonia and reduce nitrite to produce N2 gas. After being discovered in a wastewater treatment plant (WWTP), anammox bacteria were subsequently characterized in natural environments, including marine, estuary, freshwater, and terrestrial habitats. Although anammox bacteria play an important role in removing fixed N from both engineered and natural ecosystems, broad scale anammox bacterial distributions have not yet been summarized. The objectives of this study were to explore global distributions and diversity of anammox bacteria and to identify factors that influence their biogeography. Over 6000 anammox 16S rRNA gene sequences from the public database were analyzed in this current study. Data ordinations indicated that salinity was an important factor governing anammox bacterial distributions, with distinct populations inhabiting natural and engineered ecosystems. Gene phylogenies and rarefaction analysis demonstrated that freshwater environments and the marine water column harbored the highest and the lowest diversity of anammox bacteria, respectively. Co-occurrence network analysis indicated that Ca. Scalindua strongly connected with other Ca. Scalindua taxa, whereas Ca. Brocadia co-occurred with taxa from both known and unknown anammox genera. Our survey provides a better understanding of ecological factors affecting anammox bacterial distributions and provides a comprehensive baseline for understanding the relationships among anammox communities in global environments. PMID- 25147545 TI - The intimate relationship between human cytomegalovirus and the dendritic cell lineage. AB - Primary infection of healthy individuals with human cytomegalovirus (HCMV) is normally asymptomatic but results in the establishment of a lifelong infection of the host. One important cellular reservoir of HCMV latency is the CD34+ haematopoietic progenitor cells resident in the bone marrow. Viral gene expression is highly restricted in these cells with an absence of viral progeny production. However, cellular differentiation into mature myeloid cells is concomitant with the induction of a full lytic transcription program, DNA replication and, ultimately, the production of infectious viral progeny. Such reactivation of HCMV is a major cause of morbidity and mortality in a number of immune-suppressed patient populations. Our current understanding of HCMV carriage and reactivation is that cellular differentiation of the CD34+ progenitor cells through the myeloid lineage, resulting in terminal differentiation to either a macrophage or dendritic cell (DC) phenotype, is crucial for the reactivation event. In this mini-review, we focus on the interaction of HCMV with DCs, with a particular emphasis on their role in reactivation, and discuss how the critical regulation of viral major immediate-early gene expression appears to be delicately entwined with the activation of cellular pathways in differentiating DCs. Furthermore, we also explore the possible immune consequences associated with reactivation in a professional antigen presenting cell and potential countermeasures HCMV employs to abrogate these. PMID- 25147548 TI - Spatial patterns and links between microbial community composition and function in cyanobacterial mats. AB - We imaged reflectance and variable fluorescence in 25 cyanobacterial mats from four distant sites around the globe to assess, at different scales of resolution, spatial variabilities in the physiological parameters characterizing their photosynthetic capacity, including the absorptivity by chlorophyll a (A chl), maximum quantum yield of photosynthesis (Y max), and light acclimation irradiance (I k). Generally, these parameters significantly varied within individual mats on a sub-millimeter scale, with about 2-fold higher variability in the vertical than in the horizontal direction. The average vertical profiles of Ymax and I k decreased with depth in the mat, while A chl exhibited a sub-surface maximum. The within-mat variability was comparable to, but often larger than, the between sites variability, whereas the within-site variabilities (i.e., between samples from the same site) were generally lowest. When compared based on averaged values of their photosynthetic parameters, mats clustered according to their site of origin. Similar clustering was found when the community composition of the mats' cyanobacterial layers were compared by automated ribosomal intergenic spacer analysis (ARISA), indicating a significant link between the microbial community composition and function. Although this link is likely the result of community adaptation to the prevailing site-specific environmental conditions, our present data is insufficient to identify the main factors determining these patterns. Nevertheless, this study demonstrates that the spatial variability in the photosynthetic capacity and light acclimation of benthic phototrophic microbial communities is at least as large on a sub-millimeter scale as it is on a global scale, and suggests that this pattern of variability scaling is similar for the microbial community composition. PMID- 25147549 TI - Temperature and injection water source influence microbial community structure in four Alaskan North Slope hydrocarbon reservoirs. AB - A fundamental knowledge of microbial community structure in petroleum reservoirs can improve predictive modeling of these environments. We used hydrocarbon profiles, stable isotopes, and high-density DNA microarray analysis to characterize microbial communities in produced water from four Alaskan North Slope hydrocarbon reservoirs. Produced fluids from Schrader Bluff (24-27 degrees C), Kuparuk (47-70 degrees C), Sag River (80 degrees C), and Ivishak (80-83 degrees C) reservoirs were collected, with paired soured/non-soured wells sampled from Kuparuk and Ivishak. Chemical and stable isotope data suggested Schrader Bluff had substantial biogenic methane, whereas methane was mostly thermogenic in deeper reservoirs. Acetoclastic methanogens (Methanosaeta) were most prominent in Schrader Bluff samples, and the combined deltaD and delta(13)C values of methane also indicated acetoclastic methanogenesis could be a primary route for biogenic methane. Conversely, hydrogenotrophic methanogens (e.g., Methanobacteriaceae) and sulfide-producing Archaeoglobus and Thermococcus were more prominent in Kuparuk samples. Sulfide-producing microbes were detected in all reservoirs, uncoupled from souring status (e.g., the non-soured Kuparuk samples had higher relative abundances of many sulfate-reducers compared to the soured sample, suggesting sulfate-reducers may be living fermentatively/syntrophically when sulfate is limited). Sulfate abundance via long-term seawater injection resulted in greater relative abundances of Desulfonauticus, Desulfomicrobium, and Desulfuromonas in the soured Ivishak well compared to the non-soured well. In the non-soured Ivishak sample, several taxa affiliated with Thermoanaerobacter and Halomonas predominated. Archaea were not detected in the deepest reservoirs. Functional group taxa differed in relative abundance among reservoirs, likely reflecting differing thermal and/or geochemical influences. PMID- 25147550 TI - Potential drivers of microbial community structure and function in Arctic spring snow. AB - The Arctic seasonal snowpack can extend at times over a third of the Earth's land surface. This chemically dynamic environment interacts constantly with different environmental compartments such as atmosphere, soil and meltwater, and thus, strongly influences the entire biosphere. However, the microbial community associated with this habitat remains poorly understood. Our objective was to investigate the functional capacities, diversity and dynamics of the microorganisms in snow and to test the hypothesis that their functional signature reflects the snow environment. We applied a metagenomic approach to nine snow samples taken over 2 months during the spring season. Fungi, Bacteroidetes, and Proteobacteria were predominant in metagenomic datasets and changes in community structure were apparent throughout the field season. Functional data that strongly correlated with chemical parameters like mercury or nitrogen species supported that this variation could be explained by fluctuations in environmental conditions. Through inter-environmental comparisons we examined potential drivers of snowpack microbial community functioning. Known cold adaptations were detected in all compared environments without any apparent differences in their relative abundance, implying that adaptive mechanisms related to environmental factors other than temperature may play a role in defining the snow microbial community. Photochemical reactions and oxidative stress seem to be decisive parameters in structuring microbial communities inside Arctic snowpacks. PMID- 25147551 TI - Localization of aggregating proteins in bacteria depends on the rate of addition. AB - Many proteins are observed to localize to specific subcellular regions within bacteria. Recent experiments have shown that proteins that have self-interactions that lead them to aggregate tend to localize to the poles. Theoretical modeling of the localization of aggregating protein within bacterial cell geometries shows that aggregates can spontaneously localize to the pole due to nucleoid occlusion. The resulting polar localization, whether it be to a single pole or to both was shown to depend on the rate of protein addition. Motivated by these predictions we selected a set of genes from Escherichia coli, whose protein products have been reported to localize when tagged with green fluorescent protein (GFP), and explored the dynamics of their localization. We induced protein expression from each gene at different rates and found that in all cases unipolar patterning is favored at low rates of expression whereas bipolar is favored at higher rates of expression. Our findings are consistent with the predictions of the model, suggesting that localization may be due to aggregation plus nucleoid occlusion. When we expressed GFP by itself under the same conditions, no localization was observed. These experiments highlight the potential importance of protein aggregation, nucleoid occlusion and rate of protein expression in driving polar localization of functional proteins in bacteria. PMID- 25147552 TI - NIR and Py-mbms coupled with multivariate data analysis as a high-throughput biomass characterization technique: a review. AB - Optimizing the use of lignocellulosic biomass as the feedstock for renewable energy production is currently being developed globally. Biomass is a complex mixture of cellulose, hemicelluloses, lignins, extractives, and proteins; as well as inorganic salts. Cell wall compositional analysis for biomass characterization is laborious and time consuming. In order to characterize biomass fast and efficiently, several high through-put technologies have been successfully developed. Among them, near infrared spectroscopy (NIR) and pyrolysis-molecular beam mass spectrometry (Py-mbms) are complementary tools and capable of evaluating a large number of raw or modified biomass in a short period of time. NIR shows vibrations associated with specific chemical structures whereas Py-mbms depicts the full range of fragments from the decomposition of biomass. Both NIR vibrations and Py-mbms peaks are assigned to possible chemical functional groups and molecular structures. They provide complementary information of chemical insight of biomaterials. However, it is challenging to interpret the informative results because of the large amount of overlapping bands or decomposition fragments contained in the spectra. In order to improve the efficiency of data analysis, multivariate analysis tools have been adapted to define the significant correlations among data variables, so that the large number of bands/peaks could be replaced by a small number of reconstructed variables representing original variation. Reconstructed data variables are used for sample comparison (principal component analysis) and for building regression models (partial least square regression) between biomass chemical structures and properties of interests. In this review, the important biomass chemical structures measured by NIR and Py mbms are summarized. The advantages and disadvantages of conventional data analysis methods and multivariate data analysis methods are introduced, compared and evaluated. This review aims to serve as a guide for choosing the most effective data analysis methods for NIR and Py-mbms characterization of biomass. PMID- 25147553 TI - Extension of GWAS results for lipid-related phenotypes to extreme obesity using electronic health record (EHR) data and the Metabochip. AB - A variety of health-related data are commonly deposited into electronic health records (EHRs), including laboratory, diagnostic, and medication information. The digital nature of EHR data facilitates efficient extraction of these data for research studies, including genome-wide association studies (GWAS). Previous GWAS have identified numerous SNPs associated with variation in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). These findings have led to the development of specialized genotyping platforms that can be used for fine-mapping and replication in other populations. We have combined the efficiency of EHR data and the economic advantages of the Illumina Metabochip, a custom designed SNP chip targeted to traits related to coronary artery disease, myocardial infarction, and type 2 diabetes, to conduct an array-wide analysis of lipid traits in a population with extreme obesity. Our analyses identified associations with 12 of 21 previously identified lipid-associated SNPs with effect sizes similar to prior results. Association analysis using several approaches to account for lipid-lowering medication use resulted in fewer and less strongly associated SNPs. The availability of phenotype data from the EHR and the economic efficiency of the specialized Metabochip can be exploited to conduct multi faceted genetic association analyses. PMID- 25147554 TI - Genomic factors that shape craniofacial outcome and neural crest vulnerability in FASD. AB - Prenatal alcohol exposure (PAE) causes distinctive facial characteristics in some pregnancies and not others; genetic factors may contribute to this differential vulnerability. Ethanol disrupts multiple events of neural crest development, including induction, survival, migration, and differentiation. Animal models and genomic approaches have substantially advanced our understanding of the mechanisms underlying these facial changes. PAE during gastrulation produces craniofacial changes corresponding with human fetal alcohol syndrome. These result because PAE reduces prechordal plate extension and suppresses sonic hedgehog, leading to holoprosencephaly and malpositioned facial primordia. Haploinsufficiency in sonic hedgehog signaling increases vulnerability to facial deficits and may influence some PAE pregnancies. In contrast, PAE during early neurogenesis produces facial hypoplasia, preceded by neural crest reductions due to significant apoptosis. Factors mediating this apoptosis include intracellular calcium mobilization, elevated reactive oxygen species, and loss of trophic support from beta-catenin/calcium, sonic hedgehog, and mTOR signaling. Genome wide SNP analysis links PDGFRA with facial outcomes in human PAE. Multiple genomic-level comparisons of ethanol-sensitive and - resistant early embryos, in both mouse and chick, independently identify common candidate genes that may potentially modify craniofacial vulnerability, including ribosomal proteins, proteosome, RNA splicing, and focal adhesion. In summary, research using animal models with genome-level differences in ethanol vulnerability, as well as targeted loss-and gain-of-function mutants, has clarified the mechanisms mediating craniofacial change in PAE. The findings additionally suggest that craniofacial deficits may represent a gene-ethanol interaction for some affected individuals. Genetic-level changes may prime individuals toward greater sensitivity or resistance to ethanol's neurotoxicity. PMID- 25147555 TI - Approaches to identify genetic variants that influence the risk for onset of fragile X-associated primary ovarian insufficiency (FXPOI): a preliminary study. AB - Fragile X-associated primary ovarian insufficiency (FXPOI) is due to an X-linked mutation that results from the expansion of a CGG repeat sequence located in the 5' untranslated region of the FMR1 gene (premutation, PM). About 20% of women who carry the PM have cessation of menses before age 40, a clinical condition known as premature ovarian failure (POF). This leads to a 20-fold increased risk over women in the general population. Thus, this single gene mutation has a major effect on reducing a woman's reproductive life span. Based on survival analysis of about 1300 women, we showed that the mean age at menopause among PM carriers is reduced compared with noncarriers, even after removing women who reported POF. This suggests that the majority of women with the PM, not just a subset, experience ovarian insufficiency earlier than noncarriers. To better understand the underlying mechanism of the PM and to identify genes that modify the variable expressivity of FXPOI, we conducted two pilot studies. The first focused on five common variants known to reduce age at menopause. We genotyped these SNPs in 72 women with a PM who experienced menopause and found a significant association with the total SNP risk burden and age at menopause. This suggests that these SNPs influence onset of FXPOI, after adjusting for the effect of the PM allele. In the second approach, we conducted whole genome sequencing on 10 PM carriers, five with onset of FXPOI prior to age 30 and five who experienced menopause after age 47 years. Although only a pilot study, we describe our preliminary approach to identify potential variants that may play a role in modifying onset of FXPOI and potentially play a role in idiopathic primary ovarian insufficiency. The overarching goal of both approaches is to identify predictor variants that may identify women predisposed to early onset FXPOI and to further identify genes involved in defining a woman's reproductive life span. PMID- 25147557 TI - The use of semantic similarity measures for optimally integrating heterogeneous Gene Ontology data from large scale annotation pipelines. AB - With the advancement of new high throughput sequencing technologies, there has been an increase in the number of genome sequencing projects worldwide, which has yielded complete genome sequences of human, animals and plants. Subsequently, several labs have focused on genome annotation, consisting of assigning functions to gene products, mostly using Gene Ontology (GO) terms. As a consequence, there is an increased heterogeneity in annotations across genomes due to different approaches used by different pipelines to infer these annotations and also due to the nature of the GO structure itself. This makes a curator's task difficult, even if they adhere to the established guidelines for assessing these protein annotations. Here we develop a genome-scale approach for integrating GO annotations from different pipelines using semantic similarity measures. We used this approach to identify inconsistencies and similarities in functional annotations between orthologs of human and Drosophila melanogaster, to assess the quality of GO annotations derived from InterPro2GO mappings compared to manually annotated GO annotations for the Drosophila melanogaster proteome from a FlyBase dataset and human, and to filter GO annotation data for these proteomes. Results obtained indicate that an efficient integration of GO annotations eliminates redundancy up to 27.08 and 22.32% in the Drosophila melanogaster and human GO annotation datasets, respectively. Furthermore, we identified lack of and missing annotations for some orthologs, and annotation mismatches between InterPro2GO and manual pipelines in these two proteomes, thus requiring further curation. This simplifies and facilitates tasks of curators in assessing protein annotations, reduces redundancy and eliminates inconsistencies in large annotation datasets for ease of comparative functional genomics. PMID- 25147558 TI - Examples of overlooking common sense solutions: the domestication gene and selection against mortality. PMID- 25147556 TI - Deciphering the glycogenome of schistosomes. AB - Schistosoma mansoni and other Schistosoma sp. are multicellular parasitic helminths (worms) that infect humans and mammals worldwide. Infection by these parasites, which results in developmental maturation and sexual differentiation of the worms over a period of 5-6 weeks, induces antibodies to glycan antigens expressed in surface and secreted glycoproteins and glycolipids. There is growing interest in defining these unusual parasite-synthesized glycan antigens and using them to understand immune responses, their roles in immunomodulation, and in using glycan antigens as potential vaccine targets. A key problem in this area, however, has been the lack of information about the enzymes involved in elaborating the complex repertoire of glycans represented by the schistosome glycome. Recent availability of the nuclear genome sequences for Schistosoma sp. has created the opportunity to define the glycogenome, which represents the specific genes and cognate enzymes that generate the glycome. Here we describe the current state of information in regard to the schistosome glycogenome and glycome and highlight the important classes of glycans and glycogenes that may be important in their generation. PMID- 25147559 TI - Embryonic ionizing radiation exposure results in expression alterations of genes associated with cardiovascular and neurological development, function, and disease and modified cardiovascular function in zebrafish. AB - The relationship between ionizing radiation (IR) and carcinogenesis is long established, but recently the association between IR and other diseases is starting to be recognized. Currently, there is limited information on the genetic mechanisms governing the role of IR in non-cancer related adverse health effects and in regards to an early developmental exposure. In this study, zebrafish embryos were exposed to a range of IR doses (0, 1, 2, 5, 10 Gy) at 26 h post fertilization (hpf). No significant increase in mortality or hatching rate was observed, but a significant decrease in total larval length, head length, and eye diameter was observed in the 10 Gy dose. Transcriptomic analysis was conducted at 120 hpf to compare gene expression profiles between the control and highest IR dose at which no significant differences were observed in morphological measurements (5 Gy). 253 genes with well-established function or orthology to human genes were significantly altered. Gene ontology and molecular network analysis revealed enrichment of genes associated with cardiovascular and neurological development, function, and disease. Expression of a subset of genetic targets with an emphasis on those associated with the cardiovascular system was assessed using Quantitative PCR (qPCR) to confirm altered expression at 5 Gy and then to investigate alterations at lower doses (1 and 2 Gy). Strong correlation between microarray and qPCR expression values was observed, but zebrafish exposed to 1 or 2 Gy resulted in a significant expression alteration in only one of these genes (LIN7B). Moreover, heart rate was analyzed through 120 hpf following IR dosing at 26 hpf. A significant decrease in heart rate was observed at 10 Gy, while a significant increase in heart rate was observed at 1, 2, and 5 Gy. Overall these findings indicate IR exposure at doses below those that induce gross morphological changes alters heart rate and expression of genes associated with cardiovascular and neurological functions. PMID- 25147560 TI - Alzheimer's patient feedback to complement research using model systems for cognitive aging and dementia. PMID- 25147561 TI - Physicochemical mechanisms of protein regulation by phosphorylation. AB - Phosphorylation offers a dynamic way to regulate protein activity and subcellular localization, which is achieved through its reversibility and fast kinetics. Adding or removing a dianionic phosphate group somewhere on a protein often changes the protein's structural properties, its stability and dynamics. Moreover, the majority of signaling pathways involve an extensive set of protein protein interactions, and phosphorylation can be used to regulate and modulate protein-protein binding. Losses of phosphorylation sites, as a result of disease mutations, might disrupt protein binding and deregulate signal transduction. In this paper we focus on the effects of phosphorylation on protein stability, dynamics, and binding. We describe several physico-chemical mechanisms of protein regulation through phosphorylation and pay particular attention to phosphorylation in protein complexes and phosphorylation in the context of disorder-order and order-disorder transitions. Finally we assess the role of multiple phosphorylation sites in a protein molecule, their possible cooperativity and function. PMID- 25147562 TI - PPARalpha: A Master Regulator of Bilirubin Homeostasis. AB - Hypolipidemic fibrates activate the peroxisome proliferator-activated receptor (PPAR) alpha to modulate lipid oxidation and metabolism. The present study aimed at evaluating how 3 PPARalpha agonists, namely, fenofibrate, gemfibrozil, and Wy14,643, affect bilirubin synthesis and metabolism. Human umbilical vein epithelial cells (HUVEC) and coronary artery smooth muscle cells (CASMC) were cultured in the absence or presence of the 3 activators, and mRNA, protein, and/or activity levels of the bilirubin synthesizing heme oxygenase- (HO-) 1 and biliverdin reductase (BVR) enzymes were determined. Human hepatocytes (HH) and HepG2 cells sustained similar treatments, except that the expression of the bilirubin conjugating UDP-glucuronosyltransferase (UGT) 1A1 enzyme and multidrug resistance-associated protein (MRP) 2 transporter was analyzed. In HUVECs, gemfibrozil, fenofibrate, and Wy14,643 upregulated HO-1 mRNA expression without affecting BVR. Wy14,643 and fenofibrate also caused HO-1 protein accumulation, while gemfibrozil and fenofibrate favored the secretion of bilirubin in cell media. Similar positive regulations were also observed with the 3 PPARalpha ligands in CASMCs where HO-1 mRNA and protein levels were increased. In HH and HepG2 cells, both UGT1A1 and MRP2 transcripts were also accumulating. These observations indicate that PPARalpha ligands activate bilirubin synthesis in vascular cells and metabolism in liver cells. The clinical implications of these regulatory events are discussed. PMID- 25147563 TI - Difference in Early Activation of NF-kappaB and MCP-1 in Acinar-Cell-Rich versus Fibrotic Human Pancreas Exposed to Surgical Trauma and Hypoxia. AB - Objectives. Previously we have shown that a pancreas with over 40% acinar cells is exposed to postoperative pancreatitis and other complications after pancreaticoduodenectomy (PD). Our aim was to analyze the expression of NF-kappaB and MCP-1 in the cut edge of human pancreas after PD in both acinar-cell-rich and fibrotic pancreata. Methods. Several pancreatic samples from six patients, three with acinar-cell-rich and three with fibrotic pancreata, were exposed to surgical trauma in PD, and thereafter to hypoxemia for 15 minutes, 2-2.5 hours, 4 hours, or 6 hours, to mimic postoperative conditions of the pancreatic remnant in a patient. Immunohistochemical analysis of inflammation markers (NF-kappaB, MCP-1) was performed. Results. In the acinar-cell-rich pancreata, intra-acinar NF-kappaB and MCP-1 expression increased from mild at 15 minutes to high during the first 4 hours, whereas in ductal cells MCP-1 staining was highly intense at both time points. Acinar cell NF-kappaB and MCP-1 expression and ductal cell MCP-1 expression were also observed in the fibrotic pancreata, but the activation remained low throughout the 6 hours. Conclusions. In acinar-cell-rich pancreas, an extensive inflammatory cascade begins almost immediately after surgical trauma. Fibrosis may limit the progression of inflammatory process in pancreas. PMID- 25147564 TI - Prediction of epitope-based peptides for the utility of vaccine development from fusion and glycoprotein of nipah virus using in silico approach. AB - This study aims to design epitope-based peptides for the utility of vaccine development by targeting glycoprotein G and envelope protein F of Nipah virus (NiV) that, respectively, facilitate attachment and fusion of NiV with host cells. Using various databases and tools, immune parameters of conserved sequence(s) from G and F proteins of different isolates of NiV were tested to predict probable epitope(s). Binding analyses of the peptides with MHC class-I and class-II molecules, epitope conservancy, population coverage, and linear B cell epitope prediction were analyzed. Predicted peptides interacted with seven or more MHC alleles and illustrated population coverage of more than 99% and 95%, for G and F proteins, respectively. The predicted class-I nonamers, SLIDTSSTI and EWISIVPNF, superimposed on the putative decameric B cell epitopes, were also identified as core sequences of the most probable class-II 15-mer peptides GPKVSLIDTSSTITI and EWISIVPNFILVRNT. These peptides were further validated for their binding to specific HLA alleles using in silico docking technique. Our in silico analysis suggested that the predicted epitopes, either GPKVSLIDTSSTITI or EWISIVPNFILVRNT, could be a better choice as universal vaccine component against NiV irrespective of different isolates which may elicit both humoral and cell mediated immunity. PMID- 25147566 TI - Baicalein Protects against Type 2 Diabetes via Promoting Islet beta-Cell Function in Obese Diabetic Mice. AB - In both type 1 (T1D) and type 2 diabetes (T2D), the deterioration of glycemic control over time is primarily caused by an inadequate mass and progressive dysfunction of beta-cell, leading to the impaired insulin secretion. Here, we show that dietary supplementation of baicalein, a flavone isolated from the roots of Chinese herb Scutellaria baicalensis, improved glucose tolerance and enhanced glucose-stimulated insulin secretion (GSIS) in high-fat diet (HFD-) induced middle-aged obese mice. Baicalein had no effect on food intake, body weight gain, circulating lipid profile, and insulin sensitivity in obese mice. Using another mouse model of type 2 diabetes generated by high-fat diet (HFD) feeding and low doses of streptozotocin injection, we found that baicalein treatment significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in these middle-aged obese diabetic mice, which are associated with the improved islet beta-cell survival and mass. In the in vitro studies, baicalein significantly augmented GSIS and promoted viability of insulin-secreting cells and human islets cultured either in the basal medium or under chronic hyperlipidemic condition. These results demonstrate that baicalein may be a naturally occurring antidiabetic agent by directly modulating pancreatic beta cell function. PMID- 25147568 TI - Evaluating the efficacy of primary treatment for graves' disease complicated by thyrotoxic periodic paralysis. AB - Objective. Thyrotoxic periodic paralysis (TPP) is a potentially life-threatening complication of Graves' disease (GD). The present study compared the long-term efficacy of antithyroid drugs (ATD), radioactive iodine (RAI), and surgery in GD/TPP. Methods. Sixteen patients with GD/TPP were followed over a 14-year period. ATD was generally prescribed upfront for 12-18 months before RAI or surgery was considered. Outcomes such as thyrotoxic or TPP relapses were compared between the three modalities. Results. Eight (50.0%) patients had ATD alone, 4 (25.0%) had RAI, and 4 (25.0%) had surgery as primary treatment. Despite being able to withdraw ATD in all 8 patients for 37.5 (22-247) months, all subsequently developed thyrotoxic relapses and 4 (50.0%) had >=1 TPP relapses. Of the four patients who had RAI, two (50%) developed thyrotoxic relapse after 12 and 29 months, respectively, and two (50.0%) became hypothyroid. The median required RAI dose to render hypothyroidism was 550 (350-700) MBq. Of the 4 patients who underwent surgery, none developed relapses but all became hypothyroid. Conclusion. To minimize future relapses, more definitive primary treatment such as RAI or surgery is preferred over ATD alone. If RAI is chosen over surgery, a higher dose (>550 MBq) is recommended. PMID- 25147567 TI - The importance of the prenyl group in the activities of osthole in enhancing bone formation and inhibiting bone resorption in vitro. AB - Osteoporosis treatment always aimed at keeping the balance of bone formation and bone resorption. Recently, prenyl group in natural products has been proposed as an active group to enhance the osteogenesis process. Osthole has both the prenyl group and bone-protective activities, but the relationship is still unknown. In this study we found that osthole exerted a potent ability to promote proliferation and osteogenic function of rat bone marrow stromal cells and osteoblasts, including improved cell viability, alkaline phosphatase activity, enhanced secretion of collagen-I, bone morphogenetic protein-2, osteocalcin and osteopontin, stimulated mRNA expression of insulin-like growth factor-1, runt related transcription factor-2, osterix, OPG (osteoprotegerin), RANKL (receptor activator for nuclear factor-kappaB ligand), and the ratio of OPG/RANKL, as well as increasing the formation of mineralized nodules. However, 7-methoxycoumarin had no obvious effects. Osthole also inhibited osteoclastic bone resorption to a greater extent than 7-methoxycoumarin, as shown by a lower tartrate-resistant acid phosphatase activity and lower number and smaller area of resorption pits. Our findings demonstrate that osthole could be a potential agent to stimulate bone formation and inhibit bone resorption, and the prenyl group plays an important role in these bone-protective effects. PMID- 25147569 TI - The TIR Domain Containing Locus of Enterococcus faecalis Is Predominant among Urinary Tract Infection Isolates and Downregulates Host Inflammatory Response. AB - Based on Toll/interleukin-1 receptor (TIR) domain structure homology, we detected a previously uncharacterized gene encoding for a TIR domain containing protein (Tcp) in the genome of Enterococcus faecalis. We assigned this gene the name tcpF (as in Tcp of E. faecalis). Screening of E. faecalis samples revealed that tcpF is more common in isolates from urinary tract infections (UTIs) than in human faecal flora. tcpF alleles showed moderate single nucleotide polymorphism (SNP) among UTI isolates. Infection of mouse RAW264.7 macrophages with a tcpF knock-out mutant led to elevated cytokine response compared to the isogenic wild type E. faecalis strain. In silico analysis predicted significant tertiary structure homology to the TIR domain of human TLR1 (TLR1-TIR). When transiently expressed in cultured eukaryotic cells, TcpF caused suppression of TLR2-dependent NF-kappaB activation suggesting for TcpF a role as a factor in E. faecalis that benefits colonization by modulating the host's immune responses. PMID- 25147570 TI - Risk of sensitization and allergy in Ragweed workers - a pilot study. AB - BACKGROUND: Due to its high allergenic potential Ambrosia artemisiifolia has become a health threat in many European countries during the last few decades. Hence, several cities and communities initiated ragweed eradication campaigns. In Berlin, Germany, so-called Ambrosia scouts are being assigned the task of finding and eliminating this weed. We sought to evaluate the potential risk of sensitization and allergy in these individuals. FINDINGS: In order to assess the risk of sensitization and allergy, we followed-up 20 Ambrosia scouts by skin prick test with inhalant allergens, immunoserological and pulmonary function tests. Additionally, medical conditions were evaluated by a questionnaire especially designed for this study. Despite close contact to ragweed over a median duration of 13.8 months, none of the participants became sensitized or allergic to ragweed. One individual developed a clinical non-relevant sensitization towards the taxiconomically-related plant mugwort. A decline in relative FEV1 was most probably due to heavy smoking. CONCLUSIONS: Our surprising findings suggest that intensive contact and exposure to high ragweed pollen concentrations do not necessarily result in sensitization and/or allergy, meaning that the allergenic potential of this weed might be lower than hitherto expected. However, it is also conceivable that continuous exposure to high allergen levels induced tolerance in the ragweed workers. Due to the relatively small number of subjects studied, our results might be biased and therefore investigations on larger study groups are needed. PMID- 25147571 TI - Idiopathic colonic varices: case report and review of literature. AB - INTRODUCTION: Colonic varices represent a very rare entity, either an incidental finding at colonoscopy or discovered due to its complication, the lower gastrointestinal bleeding. The most common cause of colonic varices is portal hypertension associated with liver disease or secondary to pancreatic conditions, like chronic pancreatitis or malignancies. The incidence of colonic varices is very low, even in liver cirrhosis where the patients frequently develop varices in the upper gastrointestinal tract, but surprisingly uncommon present with varices localized in the colon. CASE PRESENTATION: We report a case of idiopathic colonic varices, diagnosed at a routine colonoscopy performed for nespecific abdominal disturbances in a female patient without liver disease or pancreatic conditions responsible for portal hypertension development. CONCLUSIONS: The development of colonic varices in the absence of a certain trigger represents a major issue for practitioners due to its major complication, lower gastrointestinal bleeding. PMID- 25147572 TI - Plasma Interleukin-10: A Likely Predictive Marker for Hepatitis B Virus-Related Acute-on-Chronic Liver Failure. AB - BACKGROUND: The pathogenesis of HBV-related acute-on-chronic liver failure (HBV ACLF) is mainly based on a heightened immune-inflammatory reaction; however, the intimate underlying mechanism remains unclear. OBJECTIVES: The aim of the study was to explore potential key immune molecular targets that could serve as early predictive markers for HBV-ACLF. PATIENTS AND METHODS: Twenty-seven patients with acute exacerbation of chronic hepatitis B (CHB) (defined by: alanine transaminase >= 20 ULN, total bilirubin >= 5 ULN, 40% < prothrombin time activity <= 60%) and without cirrhosis were divided into 18 cases which did not progress to HBV-ACLF (defined by: prothrombin time activity < 40% and development within four weeks of hepatic encephalopathy and/or ascites) and nine cases that developed HBV-ACLF. Nine healthy people defined the normal control group (NC). Interleukin-1beta (IL 1beta), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha and IFN-gamma protein levels were assayed by Cytometric Bead Array (CBA) in blood plasma. The ELISA method was applied to confirm IL-10 detection using the CBA method. RESULTS: IL 4, IL-12p70 and IFN-gamma were undetectable; IL-1beta, IL-6, IL-8, IL-10 and TNF alpha levels were significantly higher than in NC. Moreover, cytokines reached the highest levels in acute exacerbation of CHB, with the exception of IL-2 and IL-8. When comparing the HBV-ACLF patients prior to and at the time of ACLF diagnosis, IL-10 was the only cytokine that exhibited a significant decrease (P = 0.008). IL-10 concentrations were positively correlated to ALT levels (r = 0.711, P < 0.001). CONCLUSIONS: The assessment of plasma IL-10 levels in chronic hepatitis B acute exacerbation may provide an early predictive marker for progression to HBV-ACLF. PMID- 25147573 TI - Review on prescription compatibility of shaoyao gancao decoction and reflection on pharmacokinetic compatibility mechanism of traditional chinese medicine prescription based on in vivo drug interaction of main efficacious components. AB - Shaoyao Gancao Decoction (SGD) derived from Zhang Zhongjing's "Typhoid Theory" is composed of peony and licorice, having the efficacy of nourishing liver, relaxing spasm, and relieving pain. Modern compatibility studies of SGD on chemistry, pharmacology, and pharmacokinetics all demonstrate the reasonable compatibility of peony and licorice. However, the present research on pharmacokinetics is only descriptive and limited to the influence on in vivo dynamic process of certain ingredients; correspondingly, there is lack of studies on the essence of these efficacious substances' in vivo changes; that is, whether it is because there exists in vivo drug interaction in absorption, distribution, metabolism, and excretion (ADME) of active ingredients that leads to the improvement of bioavailability. We herein take SGD as an example and suggest that it is necessary to study in vivo drug interaction of main efficacious components mediated by metabolic enzymes, transport proteins, or plasma protein binding in the course of ADME, which is helpful to illustrate the principle of pharmacokinetic compatibility from the essence leading to the changes of effective substances in vivo. PMID- 25147565 TI - Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis. AB - Background. Growth hormone (GH) and insulin-like growth factor (IGF-1) are fundamental in skeletal growth during puberty and bone health throughout life. GH increases tissue formation by acting directly and indirectly on target cells; IGF 1 is a critical mediator of bone growth. Clinical studies reporting the use of GH and IGF-1 in osteoporosis and fracture healing are outlined. Methods. A Pubmed search revealed 39 clinical studies reporting the effects of GH and IGF-1 administration on bone metabolism in osteopenic and osteoporotic human subjects and on bone healing in operated patients with normal GH secretion. Eighteen clinical studies considered the effect with GH treatment, fourteen studies reported the clinical effects with IGF-1 administration, and seven related to the GH/IGF-1 effect on bone healing. Results. Both GH and IGF-1 administration significantly increased bone resorption and bone formation in the most studies. GH/IGF-1 administration in patients with hip or tibial fractures resulted in increased bone healing, rapid clinical improvements. Some conflicting results were evidenced. Conclusions. GH and IGF-1 therapy has a significant anabolic effect. GH administration for the treatment of osteoporosis and bone fractures may greatly improve clinical outcome. GH interacts with sex steroids in the anabolic process. GH resistance process is considered. PMID- 25147574 TI - Auricular point acupressure to manage chronic low back pain in older adults: a randomized controlled pilot study. AB - This prospective, randomized clinical trial (RCT) pilot study was designed to (1) assess the feasibility and tolerability of an easily administered, auricular point acupressure (APA) intervention and (2) provide an initial assessment of effect size as compared to a sham treatment. Thirty-seven subjects were randomized to receive either the real or sham APA treatment. All participants were treated once a week for 4 weeks. Self-report measures were obtained at baseline, weekly during treatment, at end-of-intervention (EOI), and at a 1-month follow-up. A dropout rate of 26% in the real APA group and 50% in the sham group was observed. The reduction in worst pain from baseline to EOI was 41% for the real and 5% for the sham group with a Cohen's effect size of 1.22 (P < 0.00). Disability scores on the Roland Morris Disability Questionnaire (RMDQ) decreased in the real group by 29% and were unchanged in the sham group (+3%) (P < 0.00). Given the high dropout rate, results must be interpreted with caution; nevertheless, our results suggest that APA may provide an inexpensive and effective complementary approach for the management of back pain in older adults, and further study is warranted. PMID- 25147576 TI - Analysis of epileptic seizures with complex network. AB - Epilepsy is a disease of abnormal neural activities involving large area of brain networks. Until now the nature of functional brain network associated with epilepsy is still unclear. Recent researches indicate that the small world or scale-free attributes and the occurrence of highly clustered connection patterns could represent a general organizational principle in the human brain functional network. In this paper, we seek to find whether the small world or scale-free property of brain network is correlated with epilepsy seizure formation. A mass neural model was adopted to generate multiple channel EEG recordings based on regular, small world, random, and scale-free network models. Whether the connection patterns of cortical networks are directly associated with the epileptic seizures was investigated. The results showed that small world and scale-free cortical networks are highly correlated with the occurrence of epileptic seizures. In particular, the property of small world network is more significant during the epileptic seizures. PMID- 25147577 TI - PLI cancellation in ECG signal based on adaptive filter by using Wiener-Hopf equation for providing initial condition. AB - This paper presents a technique for finding the optimal initial weight for adaptive filter by using difference equation. The obtained analytical response of the system identifies the appropriate weights for the system and shows that the MSE depends on the initial weight. The proposed technique is applied to eliminate the known frequency power line interference (PLI) signal in the electrocardiogram (ECG) signal. The PLI signal is considered as a combination of cosine and sine signals. The adaptive filter, therefore, attempts to adjust the amplitude of cosine and sine signals to synthesize a reference signal very similar to the contaminated PLI signal. To compare the potential of the proposed technique to other techniques, the system is simulated by using the Matlab program and the TMS320C6713 digital board. The simulation results demonstrate that the proposed technique enables the system to eliminate the PLI signal with the fastest time and gains the superior results of the recovered ECG signal. PMID- 25147575 TI - Medicinal Plants and Other Living Organisms with Antitumor Potential against Lung Cancer. AB - Lung cancer is a disease with high morbidity and mortality rates. As a result, it is often associated with a significant amount of suffering and a general decrease in the quality of life. Herbal medicines are recognized as an attractive approach to lung cancer therapy with little side effects and are a major source of new drugs. The aim of this work was to review the medicinal plants and other living organisms with antitumor potential against lung cancer. The assays were conducted with animals and humans, and Lewis lung carcinoma was the most used experimental model. China, Japan, South Korea, and Ethiopia were the countries that most published studies of species with antitumor activity. Of the 38 plants evaluated, 27 demonstrated antitumor activity. In addition, six other living organisms were cited for antitumor activity against lung cancer. Mechanisms of action, combination with chemotherapeutic drugs, and new technologies to increase activity and reduce the toxicity of the treatment are discussed. This review was based on the NAPRALERT databank, Web of Science, and Chemical Abstracts. This work shows that natural products from plants continue to be a rich source of herbal medicines or biologically active compounds against cancer. PMID- 25147578 TI - Computerized neuropsychological assessment in aging: testing efficacy and clinical ecology of different interfaces. AB - Digital technologies have opened new opportunities for psychological testing, allowing new computerized testing tools to be developed and/or paper and pencil testing tools to be translated to new computerized devices. The question that rises is whether these implementations may introduce some technology-specific effects to be considered in neuropsychological evaluations. Two core aspects have been investigated in this work: the efficacy of tests and the clinical ecology of their administration (the ability to measure real-world test performance), specifically (1) the testing efficacy of a computerized test when response to stimuli is measured using a touch-screen compared to a conventional mouse-control response device; (2) the testing efficacy of a computerized test with respect to different input modalities (visual versus verbal); and (3) the ecology of two computerized assessment modalities (touch-screen and mouse-control), including preference measurements of participants. Our results suggest that (1) touch screen devices are suitable for administering experimental tasks requiring precise timings for detection, (2) intrinsic nature of neuropsychological tests should always be respected in terms of stimuli presentation when translated to new digitalized environment, and (3) touch-screen devices result in ecological instruments being proposed for the computerized administration of neuropsychological tests with a high level of preference from elderly people. PMID- 25147579 TI - Neurophysiological tools to investigate consumer's gender differences during the observation of TV commercials. AB - Neuromarketing is a multidisciplinary field of research whose aim is to investigate the consumers' reaction to advertisements from a neuroscientific perspective. In particular, the neuroscience field is thought to be able to reveal information about consumer preferences which are unobtainable through conventional methods, including submitting questionnaires to large samples of consumers or performing psychological personal or group interviews. In this scenario, we performed an experiment in order to investigate cognitive and emotional changes of cerebral activity evaluated by neurophysiologic indices during the observation of TV commercials. In particular, we recorded the electroencephalographic (EEG), galvanic skin response (GSR), and heart rate (HR) in a group of 28 healthy subjects during the observation of a series of TV advertisements that have been grouped by commercial categories. Comparisons of cerebral indices have been performed to highlight gender differences between commercial categories and scenes of interest of two specific commercials. Findings show how EEG methodologies, along with the measurements of autonomic variables, could be used to obtain hidden information to marketers not obtainable otherwise. Most importantly, it was suggested how these tools could help to analyse the perception of TV advertisements and differentiate their production according to the consumer's gender. PMID- 25147580 TI - Psychometric Properties of the SCARED in Youth with Autism Spectrum Disorder. PMID- 25147581 TI - Effect of social support on depression of internet addicts and the mediating role of loneliness. AB - BACKGROUND: Many studies have determined the existence of an extremely close association between Internet addiction and depression. However, the reasons for the depression of Internet addicts have not been fully investigated. AIM: This cross-sectional study aims to explore the factors that influence depression among Internet addicts. METHODS: A total of 162 male Internet addicts completed the Emotional and Social Loneliness Scale, Multidimensional Scale of Perceived Social Support, and Self-Rating Depression Scale. RESULTS: Loneliness and lack of social support are significantly correlated with depression among Internet addicts. Structural Equation Modeling results indicate that social support partially mediates loneliness and depression. CONCLUSIONS: Both social support and loneliness were negatively associated with depression of Internet addicts whereas loneliness plays a mediating role between social support and depression. PMID- 25147582 TI - Metabolic profile response to administration of epigallocatechin-3-gallate in high-fat-fed mice. AB - BACKGROUND: Obesity is associated with increased adipose tissue and glucose intolerance. High-fat diets (HFDs) are known to induce obesity and increase proinflammatory adipokines. The consumption of green tea may improve the health of obese individuals because it contains a potent antioxidant that has effects on body weight, energy expenditure and serum cholesterol concentrations. METHODS: We examined the effects of epigallocatechin-3-gallate (EGCG) (50 mg/kg body weight per day) or saline after 30 or 60 days of treatment. Mice were distributed into four groups: 1) NS: normolipidic diet receiving saline; 2) NE: normolipidic diet receiving EGCG; 3) HFS: high-fat diet receiving saline; 4) HFE: high-fat diet receiving EGCG. RESULTS: We observed that administration of a HFD plus EGCG treatment for 60 days reduced delta weight, the relative weights of the mesenteric adipose tissue (MES), retroperitonial adipose tissue (RET), epididymal adipose tissue (EPI), the sum of the adipose tissues (SAT), reduced triacylglycerol (TG) and improved both high-density lipoprotein (HDL) cholesterol levels and the adiponectin/STA ratio when compared with HFS. CONCLUSIONS: Our results suggest that the chronic administration of EGCG (60 days) promoted a significant improvement in glucose tolerance, decreased adipose tissue deposits, weight mass, TG and HDL-C only when associated with high-fat diet treatment. PMID- 25147583 TI - Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI). AB - Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5' untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP's function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI. PMID- 25147584 TI - High-throughput DNA analysis shows the importance of methylation in the control of immune inflammatory gene transcription in chronic periodontitis. AB - BACKGROUND: Chronic periodontitis represents a complex disease that is hard to control and is not completely understood. Evidence from past studies suggests that there is a key role for DNA methylation in the pathogenesis of periodontitis. However, all reports have applied technologies that investigate genes in a low throughput. In order to advance in the knowledge of the disease, we analyzed DNA methylation variations associated with gene transcription using a high-throughput assay. Infinium(r) HumanMethylation450 (Illumina) was performed on gingival samples from 12 periodontitis cases and 11 age-matched healthy individuals. Methylation data of 1,284 immune-related genes and 1,038 cell cycle related genes from Gene Ontology (GO) and 575 genes from a dataset of stably expressed genes (genes with consistent expression in different physiological states and tissues) were extracted from a microarray dataset and analyzed using bioinformatics tools. DNA methylation variations ranging from -2,000 to +2,000 bp from the transcription start site (TSS) were analyzed, and the results were tested against a differential expression microarray dataset between healthy and periodontitis gingival tissues. Differences were evaluated using tests from the R Statistical Project. RESULTS: The comparison of probes between periodontitis and normal gingival tissues showed that the mean methylation scores and the frequency of methylated probes were significantly lower in genes related to the immune process. In the immune group, these parameters were negatively correlated with gene expression (Mann-Whitney test, p < 2.2e - 16). CONCLUSIONS: Our results show that variations in DNA methylation between healthy and periodontitis cases are higher in genes related to the immune-inflammatory process. Thus, DNA methylation must be modulating chromatin regions and, consequently, modulating the mRNA transcription of immune-inflammatory genes related with periodontitis, impacting the prognosis of disease. PMID- 25147585 TI - Association Between Elevated Liver Enzymes and Metabolic Syndrome Among Thai Adults. AB - BACKGROUND: To examine the relation between elevated liver marker concentrations (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) and risk of metabolic syndrome (MetS). METHODS: This cross sectional study was comprised of 1,391 Thai participants (451 men and 940 women) receiving annual health check-ups. Multivariable logistic regression procedures were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI) of MetS risk according to quartiles of each liver marker concentration with the lowest quartile specified as the referent group. RESULTS: Overall, mean concentrations of AST, ALT and ALP increased and mean AST:ALT ratio decreased with increasing presence of metabolic abnormalities (p-value=0.059 for AST in men, all other p-values <0.001). After adjusting for confounders, men with ALT concentrations in the extreme quartiles (>40 units/L), had a 2.77-fold increased risk of MetS (95%CI: 1.18-6.53), as compared with men who had values in the lowest quartile (<=21 units/L). The OR for extreme quartiles of ALP concentrations was 3.72 (95%CI: 1.49-9.29). In women, elevated ALT concentrations were also associated with MetS risk. Those with the highest ALT concentrations (>23 units/L) had a 2.55-fold increased risk of MetS (95%CI: 1.22-5.35) compared to women with concentrations <=13 units/L. CONCLUSIONS: These findings add to an emerging body of literature that suggests elevated liver enzymes may be related with MetS risk. However, prospective studies are needed to more fully determine the practical value of elevated liver enzymes as a clinical risk predictor of MetS and related disorders among Thai adults. PMID- 25147586 TI - Adherence: a review of education, research, practice and policy in Australia. AB - Community pharmacists are well placed to deliver adherence support services as well as other pharmaceutical services to patients. They are often the last point of contact with patients collecting medicines in the healthcare chain, and they tend to be visited by patients on a regular basis to collect prescription medicines. They have the opportunity to reinforce information already received from other health practitioners, provide further information and monitor adherence to therapy. The past decade has seen an increase in focus on the importance of adherence to therapy, not only in the higher education sector, but also in government policy and community pharmacy practice. Adherence monitoring and promotion has not only become the foundation of courses taught in pharmacy schools, but has become an essential component of disease management and pharmaceutical services delivered by community pharmacists. AIMS: This article aims to describe the education, research, practice and policy in the area of adherence to therapy in Australia with a focus on community pharmacists. METHODS: A search of MEDLINE and International Pharmaceutical Abstracts as well as hand searches of the bibliographies of retrieved articles was conducted for the period 2000-2008. All pharmacy schools in Australia were also contacted to obtain information on the patient adherence to therapy content of their courses. RESULTS: Ten studies met the inclusion criteria. Only one study had a specific adherence focus, with the remainder including adherence support and monitoring as part of the overall interventions delivered by the community pharmacists. In the majority of cases the interventions resulted in an improvement in patients' adherence to therapy. The research was supported by government and pharmacy professional organisation initiatives in the area of cognitive pharmaceutical services. All universities which responded delivered specific patient adherence courses. CONCLUSIONS: Australian pharmacy schools are educating cohorts of students who will have the skills to monitor and support patient medication adherence in the context of contemporary pharmacy practice. This is supported by research evidence, government policy and fits well into the move to expand community pharmacy services to include chronic disease state management and primary health care. PMID- 25147587 TI - Role of the pharmacist in pre-exposure chemoprophylaxis (PrEP) therapy for HIV prevention. AB - With a global estimate of 2.5 million new infections of HIV occurring yearly, discovering novel methods to help stem the spread of the virus is critical. The use of antiretroviral chemoprophylaxis for preventing HIV after accidental or occupational exposure and in maternal to fetal transmission has become a widely accepted method to combat HIV. Based on this success, pre-exposure chemoprophylaxis (PrEP) is being explored in at-risk patient populations such as injecting drug users, female sex workers and men who have sex with men. This off label and unmonitored use has created a need for education and intervention by pharmacists and other healthcare professionals. Pharmacists should educate themselves on PrEP and be prepared to counsel patients about their means of obtaining it (e.g. borrowing or sharing medications and ordering from disreputable Internet pharmacies). They should also be proactive about medication therapy management in these patients due to clinically important drug interactions with PrEP medications. Only one trial exploring the safety and efficacy of tenofovir as PrEP has been completed thus far. However, five ongoing trials are in various stages and two additional studies are scheduled for the near future. Unfortunately, studies in this arena have met with many challenges that have threatened to derail progress. Ethical controversy surrounding post trial care of participants who seroconvert during studies, as well as concerns over emerging viral resistance and logistical site problems, have already halted several PrEP trials. Information about these early trials has already filtered down to affected individuals who are experimenting with this unproven therapy as an "evening before pill". The potential for PrEP is promising; however, more extensive trials are necessary to establish its safety and efficacy. Pharmacists are well-positioned to play a key role in helping patients make choices about PrEP, managing their therapy, and developing policy with an eye towards the future. PMID- 25147588 TI - The applicability of the tetraclass model to the management of the patient satisfaction in the pharmacies. AB - The objective of this work is to study the possibilities of the tetraclass model for the evaluation of the changes in the consumer satisfaction from the provided pharmacy services during the time. METHODS: Within the same 4 months period in 2004 and 2006 were questioned at approximately 10 pharmacy consumers per working day. Every consumer evaluated the 34 service elements on a 5 points semantic differential scale. The technique of the correspondence data analysis was used for the categorisation of the services. RESULTS: Most of the services have been categorized as basic ones. For the age group up to 40 years the access to pharmacy became a key element and external aspects became a secondary element in 2006 year. For the group of patients that are using the services of the pharmacy for more than 2 years, availability of phone connection, quality of answers and product prices move from plus to secondary element. The ratio quality/price moves from the group of basic to key services, visibility of the prices and hygiene became basic elements from secondary ones. During the two years period, all the service elements connected with the staff as availability, identification, good looking, confidence, dressing, advices, technical competence, explanation, and time spent with clients remain basic services. The confidentiality of the staff remains always a key element. CONCLUSION: Our study shows that the tetraclass model allows taking more informed managerial decisions in the pharmacies, as well as, is providing information for the concrete area of services and possible measures. In case of a development of a simple statistical program for quick processing of the inquiry data, the method will became applicable and affordable even for small pharmacies. PMID- 25147589 TI - Drugs in upper respiratory tract infections in paediatric patients in North Trinidad. AB - OBJECTIVE: We explored the prescribing patterns of physicians in North Trinidad in treating upper respiratory tract infections (URTI) in paediatric patients and the appropriateness of drugs prescribed. METHODS: A retrospective observational study was conducted, with a sample size of 523 paediatric patients, diagnosed with an URTI during the period of June 2003 to 22 June 2005. The study was conducted at five Primary Health Care Facilities in North Trinidad. RESULTS: The three most frequent URTIs diagnosed were non-specific URTI, common cold, and acute tonsillitis in rank order. Four patterns of prescribing were identified, (1) no drug therapy [1.9%]; (2) antibiotic therapy alone [6.1%]; (3) antibiotic and symptomatic therapy [53.0%]; and (4) symptomatic therapy alone [39.0%]. The, most frequently prescribed antibiotics were penicillins (amoxicillin [46.3%] and amoxicillin/clavulanate [5.3%]) and a macrolide (erythromycin [6.1%]). The three symptomatic agents most frequently prescribed were paracetamol [40.1%]; diphenhydramine [29.1%]; and normal saline nasal drops [14.2%]. In 112 cases with swab analyses done, of these, 98.2% revealed a growth of commensals only, while 1.8% grew pathogenic micro-organisms. Of the cases showing commensal growth only, 84.6% were treated with an antibiotic, 14.5% were treated with symptomatic agents alone and 0.9% received no drug therapy at all. CONCLUSIONS: A large proportion of paediatric patients diagnosed with an URTI in North Trinidad was prescribed antibiotics although not indicated The inappropriate use of antibiotics can potentiate the worldwide trend of antimicrobial resistance. PMID- 25147590 TI - Relationship between drug interactions and drug-related negative clinical outcomes. AB - Drug interactions may represent an iatrogenic risk that should be controlled in community pharmacies at the dispensing level. AIM: We analyzed the association between potential drug-drug interactions (DDIs) and negative clinical outcomes. METHODS: WE USED DISPENSING DATA FROM TWO COMMUNITY PHARMACIES: instances where drug dispensing was associated with a potential DDI and a comparison group of randomized dispensing operations with no potential DDI. In cases where potential DDIs were detected, we analyzed the underlying negative clinical outcomes. Age and gender data were included in the analysis. RESULTS: During the study period, we registered 417 potential DDIs. The proportion of women and age were higher in the study group than in the comparison group. The average potential DDIs per patient was 1.31 (SD=0.72). The Consejo General de Colegios Oficiales de Farmaceuticos (CGCOF) database did not produce an alert in 2.4% of the cases. Over-the-counter medication use was observed in 5% of the potential DDI cases. The drugs most frequently involved in potential DDIs were acenocoumarol, calcium salts, hydrochlorothiazide, and alendronic acid, whereas the most predominant potential DDIs were calcium salts and bisphosphonates, oral antidiabetics and thiazide diuretics, antidiabetics and glucose, and oral anticoagulant and paracetamol. The existence of a drug-related negative clinical outcome was observed only in 0.96% of the potential DDI cases (50% safety cases and 50% effectiveness cases). CONCLUSIONS: Only a small proportion of the detected potential DDIs lead to medication negative outcomes. Considering the drug-related negative clinical outcomes encountered, tighter control would be recommended in potential DDIs with NSAIDs or benzodiazepines. PMID- 25147591 TI - Evaluation of antihypertensive therapy in diabetic hypertensive patients: impact of ischemic heart disease. AB - Macrovascular complications are common in diabetic hypertensive patients. Appropriate antihypertensive therapy and tight blood pressure control are believed to prevent or delay such complication. OBJECTIVE: To evaluate utilization patterns of antihypertensive agents and blood pressure (BP) control among diabetic hypertensive patients with and without ischemic heart disease (IHD). METHODS: Retrospective cohort study of all diabetic hypertensive patients attending Al-watani medical center from August 2006 until August 2007. Proportions of use of different antihypertensive drug classes were compared for all patients receiving 1, 2, 3, or 4 or more drugs, and separately among patients with and without IHD. Blood pressure control (equal or lower 130/80 mmHg) was compared for patients receiving no therapy, monotherapy, or combination therapy and separately among patients with and without IHD. RESULTS: 255 patients were included in the study; their mean age was 64.4 (SD=11.4) years. Sixty one (23.9%) of the included patients was on target BP. Over 60% of the total patients were receiving angiotensin-converting enzyme inhibitors (ACEI)/ angiotensin receptor blocker (ARB), followed by diuretics (40.8%), calcium channel blockers (25.1%) and beta-blockers (12.5%). The majority (> 55%) of patients were either on mono or no drug therapy. More than 55% of patients with controlled BP were using ACE I. More than half (50.8%) of the patients with controlled BP were on combination therapy while 42.3% of patients with uncontrolled BP were on combination therapy (p=0.24). More patient in the IHD achieved target BP than those in non-IHD group (p=0.019). Comparison between IHD and non-IHD groups indicated no significant difference in the utilization of any drug class with ACE-I being the most commonly utilized in both groups. CONCLUSIONS: Patterns of antihypertensive therapy were generally but not adequately consistent with international guidelines. Areas of improvement include increasing ACE-I drug combinations, decreasing the number of untreated patients, and increasing the proportion of patients with controlled BP in this population. PMID- 25147592 TI - Preceptor preferences for participating in electronic preceptor development. AB - OBJECTIVES: New guidelines require preceptors to deliver approximately 30% of the doctor of pharmacy curricula. With preceptor's increasing responsibilities, colleges are faced with the task of training preceptors as educators. Identifying preceptor's training format preferences (i.e. electronic vs. live) should contribute to the more effective and efficient creation of training materials and programs. METHODS: A preceptor training video was created and made available electronically and was distributed to 400 preceptors with a brief 2-part questionnaire about preceptor training preferences, electronic training preferences after viewing the video, and available technology resources for participating in electronic training. RESULTS: 38.25% of the questionnaires were returned. The majority of respondents (57%) preferred electronic to live preceptor developing training and the majority (53%) had not previously attended the live annual preceptor development conference offered by the college. 51.6% participants reviewed the electronic training video created by the OU College of Pharmacy. Of the respondents who did not watch the video, 73% cited having too little time, problems accessing the video, or technical reasons for not watching the training video. The majority of responders in all age groups preferred electronic training to face-to-face training except those ages 61-65 and the majority (55.7%) would participate in on-line training again in the future. The majority of respondents have the technical resources to participate in electronic training. CONCLUSION: Preceptors have limited time to participate in preceptor development training, although they view training as an important activity. This study reveals three main findings: (1) the majority of preceptors prefer electronic preceptor development training programs regardless of age; (2) would participate in future electronic training after having participated in electronic training; and (3) have the available resources to participate in electronic training. Future preceptor development programs should have flexible formats to accommodate preferences for live and electronic programming. PMID- 25147593 TI - General medications utilization and cost patterns in hospitalized children. AB - Drug utilization in the in-patient setting can provide mechanisms to assess drug prescribing trends, efficiency and cost-effectiveness of hospital formularies and examine sub-populations such as children for which prescribing habits are different from adults. OBJECTIVES: The aim of this descriptive study was to analyze general medication utilization patterns and costs excluding antimicrobials prescriptions and to compare two pediatric admission units in a tertiary care university hospital. METHODS: The total number of admitted children was 1,521 and 1,467 for the A and B admission units, respectively. The electronic data from 252 and 253 hospitalized children in the A and B admission unit were prospectively screened for general medication prescriptions, children on antimicrobials were excluded from the analysis. Their electronic charts were viewed once weekly from October 15, 2007 up to April 7, 2008 using the prescription-point prevalence method. One medication was considered to be one prescription. RESULTS: The general medications prescription number was 790 for 94 children (8.4 prescription/patient) in A and 959 for 88 children (10.9 prescription/patient) in B (p=0.02). The general medications defined daily dose (DDD) and drug utilization 90% (DU90%) index were 2,509.63, 2,259 for A; and 6,110.35, 5,499 for B, respectively. The DU90% index placed salbutamol inhalation with 835 DDD and sodium heparin with 2,102 DDD in the first place for the A and B admission units, respectively. A net increment in medication cost was registered according to the calculated cost from the depicted DU90% when the A (20,263 NIS) and B (6,269 NIS) admission units were compared (p=0.04). CONCLUSIONS: A significant difference in the prescription utilization of general medications was shown between the A and B admission units. The A admission unit had lower prescriptions measured by the DU90% index with higher medication cost. Potential drug-drug interactions were depicted in 18 (19%) and 17 (19%) subjects in the A and B admission unit, respectively. PMID- 25147594 TI - The effect of one-dose package on medication adherence for the elderly care in Japan. AB - Deterioration of the medication adherence for elderly could result in wasteful medical expenditure in a long-term span as well as aggravating the patient's medical condition. OBJECTIVE: This study surveyed the effect of one-dose package medication made up by a pharmacist on the patient's behavior towards medication, what is expected to be one of the measures to improve the medication adherence for elderly. METHODS: With support activity of the Pharmacist Association in Ueda city in Nagano Prefecture, Japan, the survey form of one-dose package was sent to 86 pharmacy directors located in Ueda-city. RESULTS: The most frequent reasons of one dose packaging was "Patient's request" though, "Large number of doses", "Prevent the improper drug use" and "Improved medication adherence" which is considered that the pharmacists are willing to utilize one dose package for patient's care in order to improve the medication adherence were chosen as well. The influences of one dose package for patient's medication adherence were very positive, and most answers indicated that medication adherence was improved. CONCLUSION: It is noticed that the pharmacists were willing to dispense one dose packaging by own decision, not physician's order, in order to improve the medication adherence, prevent improper drug use and optimize the medication therapy. It is also noticed that there are great improvement of patient's compliance by one dose package, and patients felt advantage to reduce the improper drug use as well. PMID- 25147597 TI - Stabilized helical peptides: a strategy to target protein-protein interactions. AB - Protein-protein interactions are critical for cell proliferation, differentiation, and function. Peptides hold great promise for clinical applications focused on targeting protein-protein interactions. Advantages of peptides include a large chemical space and potential diversity of sequences and structures. However, peptides do present well-known challenges for drug development. Progress has been made in the development of stabilizing alpha helices for potential therapeutic applications. Advantages and disadvantages of different methods of helical peptide stabilization are discussed. PMID- 25147595 TI - Multimarker screening of oxidative stress in aging. AB - Aging is a complex process of organism decline in physiological functions. There is no clear theory explaining this phenomenon, but the most accepted one is the oxidative stress theory of aging. Biomarkers of oxidative stress, substances, which are formed during oxidative damage of phospholipids, proteins, and nucleic acids, are present in body fluids of diseased people as well as the healthy ones (in a physiological concentration). 8-iso prostaglandin F2alpha is the most prominent biomarker of phospholipid oxidative damage, o-tyrosine, 3 chlorotyrosine, and 3-nitrotyrosine are biomarkers of protein oxidative damage, and 8-hydroxy-2(')-deoxyguanosine and 8-hydroxyguanosine are biomarkers of oxidative damage of nucleic acids. It is thought that the concentration of biomarkers increases as the age of people increases. However, the concentration of biomarkers in body fluids is very low and, therefore, it is necessary to use a sensitive analytical method. A combination of HPLC and MS was chosen to determine biomarker concentration in three groups of healthy people of a different age (twenty, forty, and sixty years) in order to find a difference among the groups. PMID- 25147598 TI - MoGAT-2 Inhibitors May Provide Effective Treatment for Hypertriglyceridemia. PMID- 25147596 TI - Subanesthetic isoflurane reduces zymosan-induced inflammation in murine Kupffer cells by inhibiting ROS-activated p38 MAPK/NF-kappaB signaling. AB - Volatile anesthetic isoflurane (ISO) has immunomodulatory effects. The fungal component zymosan (ZY) induces inflammation through toll-like receptor 2 or dectin-1 signaling. We investigated the molecular actions of subanesthetic (0.7%) ISO against ZY-induced inflammatory activation in murine Kupffer cells (KCs), which are known as the resident macrophages within the liver. We observed that ISO reduced ZY-induced cyclooxygenase 2 upregulation and prostaglandin E2 release, as determined by western blot and radioimmunoassay, respectively. ISO also reduced the production of tumor necrosis factor-alpha, interleukin-1beta, IL 6, high-mobility group box-1, macrophage inflammatory protein-1alpha, macrophage inflammatory protein-2, and monocyte chemoattractant protein-1 as assessed by enzyme-linked immunosorbent assays. ISO blocked the ZY-induced nuclear translocation and DNA-binding activity of nuclear factor- (NF)-kappaB p65. Moreover, ISO attenuated ZY-induced p38 mitogen-activated protein kinase (MAPK) activation partly by scavenging reactive oxygen species (ROS); the interregulation that ROS activated p38 MAPK followed by NF-kappaB activation was crucial for the ZY-induced inflammatory responses in KCs. An in vivo study by peritoneal injection of ZY into BALB/C mice confirmed the anti-inflammatory properties of 0.7% ISO against ZY in KCs. These results suggest that ISO ameliorates ZY-induced inflammatory responses in murine KCs by inhibiting the interconnected ROS/p38 MAPK/NF-kappaB signaling pathways. PMID- 25147599 TI - Antiparasitic compounds may potentially treat malaria and other parasitic diseases. PMID- 25147600 TI - RORgammat Modulators Are Potentially Useful for the Treatment of the Immune Mediated Inflammatory Diseases. PMID- 25147601 TI - Repurposing cryptosporidium inosine 5'-monophosphate dehydrogenase inhibitors as potential antibacterial agents. AB - Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the pivotal step in guanine nucleotide biosynthesis. IMPDH is a target for immunosuppressive, antiviral, and anticancer drugs, but, as of yet, has not been exploited for antimicrobial therapy. We have previously reported potent inhibitors of IMPDH from the protozoan parasite Cryptosporidium parvum (CpIMPDH). Many pathogenic bacteria, including Bacillus anthracis, Staphylococcus aureus, and Listeria monocytogenes, contain IMPDHs that should also be inhibited by these compounds. Herein, we present the structure-activity relationships for the inhibition of B. anthracis IMPDH (BaIMPDH) and antibacterial activity of 140 compounds from five structurally distinct compound series. Many potent inhibitors of BaIMPDH were identified (78% with IC50 <= 1 MUM). Four compounds had minimum inhibitory concentrations (MIC) of less than 2 MUM against B. anthracis Sterne 770. These compounds also displayed antibacterial activity against S. aureus and L. monocytogenes. PMID- 25147602 TI - Discovery of Spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as Potent NOP and Opioid Receptor Agonists. AB - We report the discovery of spiro[cyclohexane-pyrano[3,4-b]indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models of acute and neuropathic pain. Utilizing 4 (dimethylamino)-4-phenylcyclo-hexanone 1 and tryptophol in an oxa-Pictet-Spengler reaction led to the formation of spiroether 2, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of 1, which resulted in alcohols 3-5, ethers 6 and 7, amines 8-10, 22-24, and 26-28, amides 11 and 25, and urea 12, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors. PMID- 25147603 TI - Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol. AB - In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain. PMID- 25147604 TI - Total Synthesis and Biological Studies of TMC-205 and Analogues as Anticancer Agents and Activators of SV40 Promoter. AB - TMC-205 is a natural fungal metabolite with antiproliferative activity against cancer cell lines. The light- and air-sensitivity prevented in-depth exploitation of this novel indole derivative. Herein, we report the first synthesis of TMC 205. On the basis of its reactivity with reactive oxygen species, we developed air-stable analogues of TMC-205. These analogues are 2-8-fold more cytotoxic than TMC-205 against HCT-116 colon cancer cell line. Importantly, at noncytotoxic dose levels, these analogues activated the transcription of luciferase reporter gene driven by simian virus 40 promoter (SV40). Further, these small molecules also inhibit firefly luciferase, presumably by direct interaction. PMID- 25147605 TI - Synthesis and Pharmacology of a Novel kappa Opioid Receptor (KOR) Agonist with a 1,3,5-Trioxazatriquinane Skeleton. AB - We designed and synthesized the 1,3,5-trioxazatriquinane derivatives with m hydroxyphenyl groups. These compounds include the phenethylamine structure within them, which is a common structure observed in morphinan derivatives like morphine. Among the synthesized compounds, (-)-8c with two m-hydroxyphenyl groups selectively bound and exerted full agonist activity toward the kappa opioid receptor (KOR). Subcutaneously administered (-)-8c exhibited significant antinociceptive effects via the KOR in a dose-dependent manner. These results suggest the emergence of a novel class of KOR agonist. PMID- 25147606 TI - Factors influencing in vivo disposition of polymeric micelles on multiple administrations. AB - Lactosome is a polymeric micelle composed of amphiphilic polydepsipeptide, poly(sarcosine)64-block-poly(l-lactic acid)30 (AB-type), which accumulates in solid tumors through the enhanced permeability and retention (EPR) effect. However, lactosome on multiple administrations changed its pharmacokinetics from accumulation in tumors to liver due to the production of antilactosome IgM, which was triggered by the first administration. This phenomenon is called the accelerated blood clearance (ABC). In order to reduce the production of antilactosome IgM, a novel nanoparticle composed of (poly(sarcosine)23)3-block poly(l-lactic acid)30 (A3B-type) was prepared. The A3B-type lactosome at the second administration showed an in vivo disposition similar to that at the first administration due to suppression of antibody production. This study involving the AB- and A3B-type lactosomes, with variation of conditions, revealed that the high local density of poly(sarcosine) chains of the A3B-type lactosome should relate to the prevention of a polymeric micelle from interacting B-cell receptors. PMID- 25147607 TI - Identification of novel phenyl butenonyl C-glycosides with ureidyl and sulfonamidyl moieties as antimalarial agents. AB - A new series of C-linked phenyl butenonyl glycosides bearing ureidyl(thioureidyl) and sulfonamidyl moieties in the phenyl rings were designed, synthesized, and evaluated for their in vitro antimalarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains. Among all the compounds screened the C-linked phenyl butenonyl glycosides bearing sulfonamidyl moiety (5a) and ureidyl moiety in the phenyl ring (7d and 8c) showed promising antimalarial activities against both 3D7 and K1 strains with IC50 values in micromolar range and low cytotoxicity offering new HITS for further exploration. PMID- 25147608 TI - Optimization of Rutaecarpine as ABCA1 Up-Regulator for Treating Atherosclerosis. AB - ATP-binding cassette transporter A1 (ABCA1) is a key transporter and receptor in promoting cholesterol efflux, and increasing the expression level of ABCA1 is antiatherogenic. In our previous study, rutaecarpine (RUT) was found to protect ApoE(-/-) mice from developing atherosclerosis through preferentially up regulating ABCA1 expression. In the present work, a series of RUT derivatives were synthesized and examined as ABCA1 expression up-regulators. Compounds CD1, CD6, and BCD1-2 were found to possess the most potential activity as antiatherosclerotic agents among all compounds tested. PMID- 25147609 TI - Conformationally Restricted GABA with Bicyclo[3.1.0]hexane Backbone as the First Highly Selective BGT-1 Inhibitor. AB - On the basis of the three-dimensional diversity-oriented conformational restriction strategy using key chiral cyclopropane units, we previously identified 3 ((2S,3R)-4-amino-3,4-methanobutyric acid) with a chiral trans cyclopropane structure as a gamma-aminobutyric acid (GABA) transporter inhibitor selective for GABA transporter (GAT) subtypes GAT-3 and BGT-1 (betaine/GABA transporter-1). Further conformational restriction of 3 with the rigid bicyclo[3.1.0]hexane backbone led to the successful development of the first highly potent and selective BGT-1 inhibitor 4 (IC50 = 0.59 MUM). The bioactive conformation of 3 for BGT-1 was also identified. PMID- 25147610 TI - Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction. AB - Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model. PMID- 25147611 TI - An uncharged oxetanyl sulfoxide as a covalent modifier for improving aqueous solubility. AB - Low aqueous solubility is a common challenge in drug discovery and development and can lead to inconclusive biological assay results. Attaching small, polar groups that do not interfere with the bioactivity of the pharmacophore often improves solubility, but there is a dearth of viable neutral moieties available for this purpose. We have modified several poorly soluble drugs or drug candidates with the oxetanyl sulfoxide moiety of the DMSO analog MMS-350 and noted in most cases a moderate to large improvement of aqueous solubility. Furthermore, the membrane permeability of a test sample was enhanced compared to the parent compound. PMID- 25147612 TI - Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties. AB - Largazole is a potent and class I-selective histone deacetylase (HDAC) inhibitor purified from marine cyanobacteria and was demonstrated to possess antitumor activity. Largazole employs a unique prodrug strategy, via a thioester moiety, to liberate the bioactive species largazole thiol. Here we report alternate prodrug strategies to modulate the pharmacokinetic and pharmacodynamics profiles of new largazole-based compounds. The in vitro effects of largazole analogues on cancer cell proliferation and enzymatic activities of purified HDACs were comparable to the natural product. However, in vitro and in vivo histone hyperacetylation in HCT116 cells and implanted tumors, respectively, showed differences, particularly in the onset of action and oral bioavailability. These results indicate that, by employing a different approach to disguise the "warhead" moiety, the functional consequence of these prodrugs can be significantly modulated. Our data corroborate the role of the pharmacokinetic properties of this class of compounds to elicit the desired and timely functional response. PMID- 25147613 TI - Fluorescent Probes for Subcellular Localization during Osteclast Formation. AB - Labeling of a small bioactive molecule with fluorescent probe has been becoming an essential tool in cell biology to reveal the subcellular distribution and the location of a molecular target. QOA-8a is a novel molecule with potent antiosteoporotic effect in vivo. To investigate the molecular mechanism of QOA 8a, novel fluorescence-tagged chemical probes as bioactive as their parent molecule were designed and synthesized. The fluorescent compound 12 showed a more potent inhibitory activity on RANKL-induced osteoclastogenesis at 2 MUM compared with that of QOA-8a. Microscopy experiments revealed that almost all of probe 12 accumulated in the fusing region, with little in the osteoclast precursors or the mature osteoclasts during osteoclast formation. The result suggests the location of the binding target of QOA-8a, which might greatly narrow down the search field of the target protein(s). PMID- 25147614 TI - Alkylidene Oxapenem beta-Lactamase Inhibitors Revisited: Potent Broad Spectrum Activity but New Stability Challenges. AB - We present a comprehensive study of C6-alkylidene containing oxapenems. We show that this class of beta-lactamase inhibitors possesses an unprecedented spectrum with activity against class A, C, and D enzymes. Surprisingly, this class of compounds displayed significant photolytic instability in addition to the known hydrolytic instability. Quantum mechanical calculations were used to develop models to predict the stability of new analogues. PMID- 25147615 TI - Discovery of Imigliptin, a Novel Selective DPP-4 Inhibitor for the Treatment of Type 2 Diabetes. AB - We report our discovery of a novel series of potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. Starting from a lead identified by scaffold hopping approach, our discovery and development efforts were focused on exploring structure-activity relationships, optimizing pharmacokinetic profile, improving in vitro and in vivo efficacy, and evaluating safety profile. The selected candidate, Imigliptin, is now undergoing clinical trial. PMID- 25147616 TI - Carbonic Anhydrase Inhibition with Benzenesulfonamides and Tetrafluorobenzenesulfonamides Obtained via Click Chemistry. AB - A series of novel benzene- and 2,3,5,6-tetrafluorobenzenesulfonamide was synthesized by using a click chemistry approach starting from azido-substituted sulfonamides and alkynes, incorporating aryl, alkyl, cycloalkyl, and amino /hydroxy-/halogenoalkyl moieties. The new compounds were medium potency inhibitors of the cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isoforms I and II and low nanomolar/subnanomolar inhibitors of the tumor-associated hCA IX and XII isoforms. The X-ray crystal structure of two such sulfonamides in adduct with hCA II allowed us to understand the factors governing inhibitory power. PMID- 25147617 TI - Quantification of the effects of ionic strength, viscosity, and hydrophobicity on protein-ligand binding affinity. AB - In order to quantify the interactions between molecules of biological interest, the determination of the dissociation constant (K d) is essential. Estimation of the binding affinity in this way is routinely performed in "favorable" conditions for macromolecules. Crucial data for ligand-protein binding elucidation is mainly derived from techniques (e.g., macromolecular crystallography) that require the addition of high concentration of salts and/or other additives. In this study we have evaluated the effect of temperature, ionic strength, viscosity, and hydrophobicity on the K d of three previously characterized protein-ligand systems, based on variation in their binding sites, in order to provide insight into how these often overlooked unconventional circumstances impact binding affinity. Our conclusions are as follows: (1) increasing solvent viscosity in general is detrimental to ligand binding, (2) moderate increases in temperature have marginal effects on the dissociation constant, and (3) the degree of hydrophobicity of the ligand and the binding site determines the extent of the influence of cosolvents and salt concentration on ligand binding affinity. PMID- 25147618 TI - Discovery and structure-based optimization of adenain inhibitors. AB - The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2. The screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain. PMID- 25147619 TI - Identification and synthesis of quinolizidines with anti-influenza a virus activity. AB - Influenza A virus infection causes a contagious respiratory illness that poses a threat to human health. However, there are limited anti-influenza A therapeutics available, which is further compounded by the emergence of drug resistant viruses. In this study, Sophora quinolizidine alkaloids were identified as a new class of anti-influenza A virus agents. Among the tested Sophora alkaloids, dihydroaloperine exhibited the most potent activity with an EC50 of 11.2 MUM. The potency of the quinolizidine alkaloids was improved by approximately 5-fold with chemical modifications on the aloperine molecule. These compounds were effective against an H1N1 influenza A virus that was resistant to the two antiflu drugs oseltamivir and amantadine. The identification of the quinolizidine alkaloids as effective and novel anti-influenza A agents may aid in the development of new therapeutics. PMID- 25147621 TI - Cytogenetic analysis on geographically distant parthenogenetic populations of Tityus trivittatus Kraepelin, 1898 (Scorpiones, Buthidae): karyotype, constitutive heterochromatin and rDNA localization. AB - Tityus trivittatus Kraepelin, 1898 is the most medically important scorpion species of Argentina, and parthenogenetic populations are present in the major cities of this country. We performed a detailed cytogenetic analysis of specimens of three synanthropic parthenogenetic populations, all distant about 900 km from each other, using Ag-NOR, C-banding, DAPI/CMA3 staining and FISH with autologous 28S rDNA probes. The karyotype of females and embryos from the three populations showed 2n=6, with two large and four middle-sized holokinetic chromosomes. Constitutive heterochromatin was found in terminal and interstitial location and its pattern allowed the identification of three chromosome pairs. NORs were found on the terminal heterochromatic region of one pair of middle-sized chromosomes. The use of fluorochromes to characterize heterochromatin showed the absence of GC rich heterochromatin and a low and variable number of AT-rich heterochromatic regions. We propose that a possible explanation for the lack of karyotypic variation between these geographically distant populations could be a recent colonization of urban areas by human means of synanthropic specimens from a single lineage of northeastern Argentina. PMID- 25147620 TI - Lead optimization of imidazopyrazines: a new class of antimalarial with activity on Plasmodium liver stages. AB - Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite P. yoelii (Py) as well as hypnozoites of the simian parasite P. cynomolgi (Pc). We applied these various assays to the cell based lead optimization of the imidazopyrazines, exemplified by 3 (KAI407), and show that optimized compounds within the series with improved pharmacokinetic properties achieve causal prophylactic activity in vivo and may have the potential to target the dormant stages of P. vivax malaria. PMID- 25147622 TI - Karyotypes of six spider species belonging to the families Gnaphosidae, Salticidae, Thomisidae, and Zodariidae (Araneae) from Turkey. AB - In this study, the karyotypes of six spider species from Turkey belonging to the families Gnaphosidae, Salticidae, Thomisidae, and Zodariidae were analyzed. Male chromosomal features including diploid chromosome numbers and sex chromosome systems were determined as 2n=22, X1X20 in Drassyllus sur Tuneva & Esyunin, 2003, Nomisia exornata (C. L. Koch, 1839), and Nomisia orientalis Dalmas, 1921; 2n=28, X1X20 in Sitticus caricis (Westring, 1861); 2n=23, X0 in Xysticus gallicus Simon, 1875 and 2n=42, X1X20 in Pax islamita (Simon, 1873), respectively. The chromosome morphology of all species was acrocentric. Data obtained contribute to knowledge of the karyotype evolution of araneomorphs. PMID- 25147623 TI - Comparative cytogenetics of Physalaemus albifrons and Physalaemus cuvieri species groups (Anura, Leptodactylidae). AB - Recently, Physalaemus albifrons (Spix, 1824) was relocated from the Physalaemus cuvieri group to the same group as Physalaemus biligonigerus (Cope, 1861), Physalaemus marmoratus (Reinhardt & Lutken, 1862) and Physalaemus santafecinus Barrio, 1965. To contribute to the analysis of this proposition, we studied the karyotypes of Physalaemus albifrons, Physalaemus santafecinus and three species of the Physalaemus cuvieri group. The karyotype of Physalaemus santafecinus was found to be very similar to those of Physalaemus biligonigerus and Physalaemus marmoratus, which were previously described. A remarkable characteristic that these three species share is a conspicuous C-band that extends from the pericentromeric region almost to the telomere in the short arm of chromosome 3. This characteristic is not present in the Physalaemus albifrons karyotype and could be a synapomorphy of Physalaemus biligonigerus, Physalaemus marmoratus and Physalaemus santafecinus. The karyotype of Physalaemus santafecinus is also similar to those of Physalaemus marmoratus and Physalaemus biligonigerus owing to the presence of several terminal C-bands and the distal localization of the NOR in a small metacentric chromosome. In contrast, the Physalaemus albifrons karyotype has no terminal C-bands and its NOR is located interstitially in the long arm of submetacentric chromosome 8. The NOR-bearing chromosome of Physalaemus albifrons very closely resembles those found in Physalaemus albonotatus (Steindachner, 1864), Physalaemus cuqui Lobo, 1993 and some populations of Physalaemus cuvieri Fitzinger, 1826. Additionally, the Physalaemus albifrons karyotype has an interstitial C-band in chromosome 5 that has been exclusively observed in species of the Physalaemus cuvieri group. Therefore, we were not able to identify any chromosomal feature that supports the reallocation of Physalaemus albifrons. PMID- 25147624 TI - Cytotaxonomy of two species of genus Chrysolaena H. Robinson, 1988 (Vernonieae, Asteraceae) from Northeast Paraguay. AB - Chromosome counts and karyotypes of two species of Chrysolaena H. Robinson 1988 are presented in this paper. Mitotic analysis revealed that both taxa have x=10, a basic chromosome number considered characteristic of the genus. The chromosome number and the karyotype of Chrysolaena cristobaliana are reported for the first time, as well as a new cytotype and the karyotype of Chrysolaena sceptrum. Chrysolaena cristobaliana showed heptaploid cytotype with 2n=7x=70 and a karyotype composed of 46 m + 24 sm chromosomes. On the other hand, Chrysolaena sceptrum presented tetraploid cytotype with 2n=4x=40 and a karyotype with 30 m + 10 sm chromosomes. Accessory chromosomes were observed in cells of both species. The chromosome analysis showed that these species differ in the chromosome number and the total chromosome length, although they showed similar chromosome morphology and asymmetry indexes. The results support the use of chromosome data in taxonomic treatments of the American members of the tribe Vernonieae. PMID- 25147625 TI - Genomic organization of repetitive DNAs and its implications for male karyotype and the neo-Y chromosome differentiation in Erythrinus erythrinus (Characiformes, Erythrinidae). AB - Studies have demonstrated the effective participation of repetitive DNA sequences in the origin and differentiation of the sex chromosomes in some biological groups. In this study several microsatellites and retrotranposable sequences were cytogenetically mapped in the Erythrinus erythrinus (Bloch & Schneider, 1801) male genome (karyomorph C), focusing on the distribution of these sequences in the sex chromosomes and in the evolutionary processes related to their differentiation. Males of E. erythrinus - karyomorph C - present 2n = 51 chromosomes (7m + 2sm + 6st + 36a), including the X1X2Y sex chromosomes. The C positive heterochromatin has a predominant localization on the centromeric region of most chromosome pairs, but also in some telomeric regions. The 5S rDNA sites are located in the centromeric region of 27 chromosomes, including 26 acrocentric ones and the metacentric Y chromosome. The retrotransposons Rex 1 and Rex 6 show a dispersed pattern in the karyotype, contrasting with the Rex 3 distribution which is clearly co-localized with all the 27 5S rDNA sites. The microsatellite sequences show a differential distribution, some of them restricted to telomeric and/or interstitial regions and others with a scattered distribution on the chromosomes. However, no preferential accumulation of these elements were observed in the neo-Y chromosome, in contrast to what usually occurs in simple sex chromosome systems. PMID- 25147626 TI - Similarities and differences among the chromosomes of the wild guinea pig Cavia tschudii and the domestic guinea pig Cavia porcellus (Rodentia, Caviidae). AB - Cavia tschudii Fitzinger, 1867 is a wild guinea pig species living in South America that according to the analysis of mitochondrial genes is the closest wild form of the domestic guinea pig. To investigate the genetic divergence between the wild and domestic species of guinea pigs from a cytogenetic perspective, we characterized and compared the C, G and AgNOR banded karyotypes of molecularly identified Cavia tschudii and Cavia porcellus Linnaeus, 1758 specimens for the first time. Both species showed 64 chromosomes of similar morphology, although C. tschudii had four medium size submetacentric pairs that were not observed in the C. porcellus karyotype. Differences in the C bands size and the mean number of AgNOR bands between the karyotypes of the two species were detected. Most of the two species chromosomes showed total G band correspondence, suggesting that they probably represent large syntenic blocks conserved over time. Partial G band correspondence detected among the four submetacentric chromosomes present only in the C. tschudii karyotype and their subtelocentric homologues in C. porcellus may be explained by the occurrence of four pericentric inversions that probably emerged and were fixed in the C. tschudii populations under domestication. The role of the chromosomal and genomic differences in the divergence of these two Cavia species is discussed. PMID- 25147627 TI - Osteomyelitis in the diabetic foot. AB - Osteomyelitis (OM) is a common complication of diabetic foot ulcers and/or diabetic foot infections. This review article discusses the clinical presentation, diagnosis, and treatment of OM in the diabetic foot. Clinical features that point to the possibility of OM include the presence of exposed bone in the depth of a diabetic foot ulcer. Medical imaging studies include plain radiographs, magnetic resonance imaging, and bone scintigraphy. A high index of suspicion is also required to make the diagnosis of OM in the diabetic foot combined with clinical and radiological studies. PMID- 25147628 TI - Chronic pain patients with possible co-morbid post-traumatic stress disorder admitted to multidisciplinary pain rehabilitation-a 1-year cohort study. AB - BACKGROUND: Although post-traumatic stress disorder (PTSD) is a common co morbidity in chronic pain, little is known about the association between PTSD and pain in the context of chronic pain rehabilitation. OBJECTIVE: The aim of the present study was two-fold: (1) to investigate the association of a possible PTSD diagnosis with symptoms of pain, physical and mental functioning, as well as the use of opioids, and (2) to compare the outcome of multidisciplinary chronic pain rehabilitation for patients with a possible PTSD diagnosis at admission with patients without PTSD at admission. METHOD: A consecutively referred cohort of 194 patients completed a baseline questionnaire at admission covering post traumatic stress, pain symptoms, physical and mental functioning, as well as self reported sleep quality and cognitive difficulties. Medication use was calculated from their medical records. A total of 95 were admitted to further multidisciplinary treatment and included in the outcome study. RESULTS: A high prevalence of possible PTSD was found (26.3%). Patients with possible co-morbid PTSD experienced significantly poorer general and mental health, poorer sleep quality, and more cognitive problems as well as inferior social functioning compared to patients without PTSD. Possible co-morbid PTSD did not result in higher use of opioids or sedatives. Surprisingly, possible co-morbid PTSD at admission was not associated with lower levels of symptom reduction from pre- to post-treatment. CONCLUSIONS: Possible co-morbid PTSD in chronic pain is a major problem associated with significantly poorer functioning on several domains. Nevertheless, our results indicate that pain-related symptoms could be treated with success despite possible co-morbid PTSD. However, since PTSD was only measured at admission it is not known whether rehabilitation actually reduced PTSD. PMID- 25147629 TI - Recurrent aspiration pneumonia after laparoscopic adjustable gastric banding for obesity surgery. AB - Laparoscopic adjustable gastric banding (LAGB) is an increasingly common therapeutic option in the management of obesity and certain obesity-related comorbid conditions. As it gains popularity for its advantages of being minimally invasive and reversible, clinicians should be aware of growing evidence of esophageal and pulmonary complications, which may be irreversible and associated with long-term morbidity. We report a case of esophageal and pulmonary complications in a patient with successful weight loss after lap-band surgery necessitating its removal. PMID- 25147630 TI - Feasibility of an innovative third-year chief resident system: an internal medicine residency leadership study. AB - INTRODUCTION: The role of the internal medicine chief resident includes various administrative, academic, social, and educational responsibilities, fulfillment of which prepares residents for further leadership tasks. However, the chief resident position has historically only been held by a few residents. As fourth year chief residents are becoming less common, we considered a new model for rotating third-year residents as the chief resident. METHODS: Online surveys were given to all 29 internal medicine residents in a single university-based program after implementation of a leadership curriculum and specific job description for the third-year chief resident. Chief residents evaluated themselves on various aspects of leadership. Participation was voluntary. Descriptive statistics were generated using SPSS version 21. RESULTS: Thirteen junior (first- or second-year) resident responses reported that the chief residents elicited input from others (mean rating 6.8), were committed to the team (6.8), resolved conflict (6.7), ensured efficiency, organization and productivity of the team (6.7), participated actively (7.0), and managed resources (6.6). Responses from senior residents averaged 1 point higher for each item; this pattern repeated itself in teaching evaluations. Chief resident self-evaluators were more comfortable running a morning report (8.4) than with being chief resident (5.8). CONCLUSION: The feasibility of preparing internal medicine residents for leadership roles through a rotating PGY-3 (postgraduate year) chief residency curriculum was explored at a small internal medicine residency, and we suggest extending the study to include other programs. PMID- 25147631 TI - The red hearing: swollen ear in a patient with ulcerative colitis. AB - Relapsing polychondritis is a rare connective tissue disease of unknown etiology characterized by recurrent inflammation, degeneration and deformity of auricular cartilage. The autoimmune inflammation may also affect cartilage at other sites including nose, larynx, trachea and bronchi. Here, we present a case of relapsing polychondritis in a patient with ulcerative colitis. We also review the presentation, diagnosis and management of this condition. PMID- 25147632 TI - Large pituitary incidentaloma in a patient with sarcoidosis. AB - A 60 year old male with a medical history of pulmonary sarcoidosis and chronic low testosterone presented to his allergist for excessive lacrimation. Computed tomography (CT) scan of sinuses ordered for possible blocked nasolacrimal duct revealed an abnormal expansion of the sella turcica. Magnetic resonance imaging suggested a homogeneously enhancing 4 cm soft tissue mass enveloping the internal carotid and abutting the optic nerves. Since the patient indicated no symptoms, it was felt to be consistent with a pituitary incidentaloma. Laboratory investigation showed only minimally elevated prolactin. Visual field testing at the office was normal but computed campimetry was suggestive of few minimally depressed points in the supra-temporal quadrant on the right. Even with high suspicion of neurosarcoidosis, the patient had a surgical indication so he underwent transsphenoidal excision of the mass with no complications. Pathology was consistent with a null-cell pituitary adenoma. PMID- 25147633 TI - Barriers to success for female physicians in academic medicine. AB - Despite the fact that women now comprise half of the medical student and resident populations, women remain underrepresented in prominent leadership positions in academia. Women are challenging themselves to live up to the expectations of their professional peers, society, and their patients in order to 'have it all.' These pressures are leading to professional and personal dissatisfaction. Is this a problem that will resolve itself as the younger generations of female physicians graduate into faculty positions, or does it require more attention from both male and female medical professionals? PMID- 25147634 TI - Would you admit your mother to the residency service? Introducing the JCHIMP resident safety column. AB - There remain tremendous opportunities to improve the stability and safety of American health care. Within this context, residents and residency programs face two essential questions: how to reduce the risk to patients resulting from resident inexperience, and how to change our programs to create the safer physician of the future? The spread of side-by-side teaching and non-teaching services creates a natural setting to study these questions and improve both services. When asked the question, "Would you admit your mother to the resident service?", many of us respond, "It depends". We are focusing this column on helping programs answer this question definitively in the positive, share potential best practices, and underscore community hospital's contribution to our understanding of patient safety. PMID- 25147635 TI - Management of hypertension in the hemodialysis population: a review of the literature. AB - OBJECTIVE: The objective of this paper was to propose an algorithm for approaching hypertensive hemodialysis patients admitted to the hospital for hypertensive urgency. METHODS: A literature search was conducted using PubMed (Medline). Articles selected were limited to humans and the English language. RESULTS: WE IDENTIFIED EIGHT MANAGEMENT MODALITIES INCLUDING: short-daily and nocturnal dialysis, sodium restriction, sodium profiling, antihypertensive medications, sympathetic denervation, bilateral nephrectomy, and bioimpedance spectroscopy. The benefits and drawbacks of each were investigated and discussed before implementation into the algorithm. DISCUSSION: The algorithm presented suggests a linear approach to patient care, but treatment modalities may not be mutually exclusive, and additional factors, such as patient compliance and individual health status, should be taken into account to provide patients with optimum care. PMID- 25147636 TI - Minocycline-induced hyperpigmentation. AB - A 62-year-old male with a long history of rosacea, which was well controlled on minocycline, presented to his primary care physician for routine examination. Physical examination was noted for non-palpable, non-pruritic blue patches of hyperpigmentation on the medial aspects of his lower extremities bilaterally. Recognition and management of the findings are discussed. PMID- 25147637 TI - Recurrent neurocysticercosis. PMID- 25147638 TI - Low-pressure cardiac tamponade masquerading as severe sepsis diagnosed with a bedside ultrasound and as the initial presentation of malignancy. AB - OBJECTIVE: We report a patient with low-pressure cardiac tamponade masquerading as sepsis and as the initial presentation of malignancy. A quick diagnosis was done by the intensivist performing a bedside ultrasound. BACKGROUND: The diagnosis of low-pressure cardiac tamponade is a challenge because the classic physical signs of cardiac tamponade can be absent. It is made even more challenging when the vital sign changes and physical examination findings mimic severe sepsis. One of the benefits of a bedside ultrasound in the assessment of a patient with an initial diagnosis of severe sepsis or septic shock is the rapid diagnosis of cardiac tamponade if it is present. DATA SOURCE AND SYNTHESIS: A 55 year-old male presented to the emergency department with weakness, cough, and syncope. His examination was notable only for dusky mottling of his cheeks, chest, and neck. Specifically, there was no jugular venous distension or pulsus paradoxus. A chest radiograph showed a right upper lobe infiltrate, whereas his electrocardiogram showed only sinus tachycardia. His white blood cell count and lactic acid were elevated. The sepsis protocol was started and a bedside ultrasound revealed signs of cardiac tamponade. The patient immediately improved after a pericardiocentesis. Analysis of the pericardial biopsy revealed adenocarcinoma, later determined to be from a pulmonary primary source. CONCLUSIONS: Because low-pressure cardiac tamponade is life-threatening and difficult to diagnose, evaluation of the pericardium with a bedside ultrasound should be considered in patients with syncope, severe sepsis, or shock. PMID- 25147639 TI - Primary cardiac sarcoma presenting as acute left-sided heart failure. AB - Primary cardiac sarcomas are rare malignant tumors of the heart. Clinical features depend on the site of tumor and vary from symptoms of congestive heart failure to thromboembolism and arrhythmias. Echocardiography is helpful but definitive diagnosis is established by histopathology. Surgical resection is the mainstay of treatment, and the role of chemotherapy and radiotherapy is unclear. We report a case of primary cardiac sarcoma which presented with signs and symptoms of acute left-sided heart failure. PMID- 25147640 TI - Patients crash more than airlines: a medical emergency at 35,000 ft. AB - An estimated 1 in 600 commercial flights will have an onboard medical emergency and approximately half of the time a passenger physician will provide medical assistance. A medical emergency on an aircraft can be a daunting task for even the most seasoned physician. This article is a narrative case report from a physician passenger who found himself in the midst of such an emergency on a 15 hour international flight. PMID- 25147641 TI - Editor's Note. PMID- 25147642 TI - Performance of severity of illness classification for Clostridium difficile infection to predict need-for-colectomy or inpatient death. AB - BACKGROUND: In current state of practice, disease severity assessment for Clostridium difficile infection (CDI) lacks consensus between different organizations. In the latest guidelines for management of CDI, authors have proposed a new disease severity classification. This classification has been derived from expert opinion and includes previously reported patient related factors that predict unfavorable outcome in CDI. OBJECTIVE: To evaluate the performance of new disease severity classification to predict CDI-related colectomy or in-patient deaths. METHODS: This observational study was performed at a 300-bed community hospital catering to a suburban population. All the adult patients discharged during October 2005 through September 2012 and diagnosed with CDI were included in the study. Cases of CDI were identified using the billing database. Demographic and clinical characteristics of CDI cases were extracted from medical chart reviews performed by two physician researchers. Cases were classified as mild-to-moderate, severe, or severe and complicated CDI. Major outcomes measured were in-patient deaths and colectomy attributed to CDI. For risk stratification, each variable of severe and complicated CDI was counted. RESULTS: In total, 59,897 patients were discharged from our hospital during the study period; 894 of them were diagnosed with CDI. Mean age of CDI cases was 74 years (standard deviation 15 years), 345 (39%) were male, and median length of hospital stay was 7 days (interquartile range 4-13). One hundred ninety-one patients (21%) were classified as mild-to-moderate, 93 patients (10%) as severe, and 610 patients (68%) as severe and complicated. In total, 14 patients underwent colectomy for CDI and 53 patients expired. In 35 of these patients, the cause of death was thought to be CDI. The combined outcome (CDI-related colectomy and/or death in hospital) occurred in 47 patients. None of the patients in mild-to moderate disease or severe disease had combined outcome. On severe and complicated cases, as the score increased, rate of combined outcome increased significantly (z-12.7, p<0.0001). On plotting receiver-operating curve, the simple variable count had area under the curve of 0.91. CONCLUSION: The newly proposed disease severity classification for CDI categorized more than two-thirds of patients as severe and complicated. Increase in number of severe and complicated classifying variables increases the chance of adverse outcomes significantly. Patients meeting only one variable could be potentially treated as a severe case instead of severe and complicated. This data needs to validated prospectively before could be used in clinical practice. PMID- 25147643 TI - Zinc-deficiency acrodermatitis in a patient with chronic alcoholism and gastric bypass: a case report. AB - Acquired adult-onset zinc deficiency is occasionally reported in patients with malnutrition states, such as alcoholism, or malabsorptive states, such as post bariatric surgery. The defining symptoms of hypozincemia include a classic triad of necrolytic dermatitis, diffuse alopecia, and diarrhea. We report a case of zinc deficiency in a 39-year-old man with history of gastric bypass surgery and alcoholism. For this patient, severe hypozincemia confirmed acrodermatitis, and zinc supplementation was met with gradual improvement. PMID- 25147644 TI - Medical eponyms. AB - Eponyms are a long-standing tradition in medicine. Eponyms usually involve honoring a prominent physician scientist who played a major role in the identification of the disease. Under the right circumstances, a disease becomes well known through the name of this individual. There are no rules on eponym development. It may take an extraordinary period of time, be different in different languages and cultures, and evolve as more is known about the physician or the disease. PMID- 25147645 TI - An immunohistochemical approach for monitoring effects of exercise on tumor stromal cells in old mice. AB - Epidemiological evidence supports a protective effect of physical activity for breast cancer in older women, but the mechanisms are not well understood. We used 18-month-old BALB/c mice injected in the mammary fat pad with syngeneic 4T1 tumor cells as a model of invasive breast cancer. During the tumor progression phase, there was a significant decrease in labeling for F4/80, a marker for mouse macrophages, and CD34, a marker for vascular endothelial cells, in primary tumors from mice that ran higher average distances compared to mice that ran lower average distances (p<=0.05). These observations suggest that immunohistochemistry can be used to monitor stromal cell populations in tumors from old mice under exercise conditions. PMID- 25147647 TI - Antibody-mediated immunity induced by engineered Escherichia coli OMVs carrying heterologous antigens in their lumen. AB - BACKGROUND: Outer membrane vesicles (OMVs) from Gram-negative bacteria are gaining increasing attention as vaccine platform for their built-in adjuvanticity and for their potential use as carriers of heterologous antigens. These 2 properties offer the opportunity to make highly effective, easy to produce multi valent vaccines. OMVs can be loaded with foreign antigens by targeting protein expression either to the outer membrane or to the periplasm of the OMV-producing strain. Periplasmic expression is simple and relatively efficient but leads to the accumulation of recombinant antigens in the lumen of OMVs and the ability of OMVs carrying internalized antigens to induce antigen-specific antibody responses has been only marginally investigated and is considered to be sub-optimal. METHODS: We have systematically analyzed in qualitative and quantitative terms antibody responses induced by OMVs carrying different heterologous antigens in their lumen. Group A Streptococcus (GAS) Slo, SpyCEP, Spy0269 and Group B Streptococcus (GBS) SAM_1372 were fused to the OmpA leader sequence for secretion and expressed in Escherichia coli. OMVs from the recombinant strains were purified and tested for immunogenicity and protective activity. RESULTS: All proteins were incorporated into the OMVs lumen in their native conformation. Upon mice immunization, OMVs induced high functional antibody titers against the recombinant proteins. Furthermore, immunization with Slo-OMVs and SpyCEP-OMVs protected mice against GAS lethal challenge. CONCLUSIONS: The efficiency of antigen delivery to the vesicular lumen via periplasmic expression, and the surprisingly high immunogenicity and protective activity of OMVs carrying internalized recombinant antigens further strengthens the potential of OMVs as vaccine platform. PMID- 25147646 TI - Isolation and characterization of platelet-derived extracellular vesicles. AB - BACKGROUND: Platelet-derived extracellular vesicles (EVs) participate, for example, in haemostasis, immunity and development. Most studies of platelet EVs have targeted microparticles, whereas exosomes and EV characterization under various conditions have been less analyzed. Studies have been hampered by the difficulty in obtaining EVs free from contaminating cells and platelet remnants. Therefore, we optimized an EV isolation protocol and compared the quantity and protein content of EVs induced by different agonists. METHODS: Platelets isolated with iodixanol gradient were activated by thrombin and collagen, lipopolysaccharide (LPS) or Ca(2+) ionophore. Microparticles and exosomes were isolated by differential centrifugations. EVs were quantitated by nanoparticle tracking analysis (NTA) and total protein. Size distributions were determined by NTA and electron microscopy. Proteomics was used to characterize the differentially induced EVs. RESULTS: The main EV populations were 100-250 nm and over 90% were <500 nm irrespective of the activation. However, activation pathways differentially regulated the quantity and the quality of EVs, which also formed constitutively. Thrombogenic activation was the most potent physiological EV-generator. LPS was a weak inducer of EVs, which had a selective protein content from the thrombogenic EVs. Ca(2+) ionophore generated a large population of protein-poor and unselectively packed EVs. By proteomic analysis, EVs were highly heterogeneous after the different activations and between the vesicle subpopulations. CONCLUSIONS: Although platelets constitutively release EVs, vesiculation can be increased, and the activation pathway determines the number and the cargo of the formed EVs. These activation-dependent variations render the use of protein content in sample normalization invalid. Since most platelet EVs are 100-250 nm, only a fraction has been analyzed by previously used methods, for example, flow cytometry. As the EV subpopulations could not be distinguished and large vesicle populations may be lost by differential centrifugation, novel methods are required for the isolation and the differentiation of all EVs. PMID- 25147648 TI - Laboratory to Clinical Investigation of Carbapenem Resistant Acinetobacter baumannii Outbreak in a General Hospital. AB - BACKGROUND: The number of reported cases, infected with carbepenem resistant Acinetobacter baumannii (CRAb) and multi-drug resistant (MDR) Acinetobacter species had gradually increased in most PLA general hospital wards from April to June in 2007. OBJECTIVES: We have described the investigation of an outbreak of CRAb and MDR Acinetobacter in PLA general hospital, Beijing. The prospective and retrospective findings were identified and analyzed to study the infection causes. MATERIALS AND METHODS: A. baumannii samples were collected from the patients and environment in each hospital unit. The onset times were recorded according to their case information. All samples were characterized by genotype and compared using pulsed-field gel electrophoresis (PFGE). The microorganism susceptibility was tested using the in vitro minimal inhibitory concentration (MIC) breakpoints method. RESULTS: A total of 69 A. baumannii strains were successfully isolated from 53 patients. About 89.1% of them were resistant to ampicillin and 89.2% to cefotaxime and 75.4% to all standard antibiotics. PFGE analysis revealed that nine of the isolates had unique clones and the epidemic clone types were A, B and C. CONCLUSIONS: The A. baumannii outbreak, was caused by MDR A. baumannii. The strains had widely spread among 12 departments especially in surgical intensive care unit (SICU), emergency intensive care unit (EICU) and the department of respiratory disease. The outbreak was more likely caused by the A. baumannii infected or carrier patients and EICU was its origin. PMID- 25147649 TI - Genotypic Identification of AmpC beta-Lactamases Production in Gram-Negative Bacilli Isolates. AB - BACKGROUND: AmpC type beta-lactamases are commonly isolated from extended spectrum Cephalosporin-resistant Gram-negative bacteria. Also, resistance appeared in bacterial species not naturally producing AmpC enzymes. Therefore, a standard test for the detection of the plasmid-mediated AmpC enzyme and new breakpoints for extended spectrum Cephalosporins are urgently necessary. OBJECTIVES: To detect plasmid and chromosomal mediated AmpC-beta-lactamases in Gram negative bacteria in community and hospital acquired infections. MATERIALS AND METHODS: 1073 Gram negative clinical isolates were identified by the conventional methods and were screened for AmpC production using Cefoxitin discs. Confirmatory phenotypic identifications were done for the Cefoxitin-resistant isolates using Boronic Acid for combined and double disc synergy tests, Cloxacillin based double disc synergy test, and induction tests. The genotypic identification of plasmid-mediated AmpC was done using multiplex PCR. ESBL production was also screened by discs of Ceftazidime and Cefotaxime with and without Clavulanic Acid (10 MUg). RESULTS: The AmpC-producing isolates among all identified Gram negative bacilli were 5.8% (62/1073) as detected by screening disc diffusion methods, where 72% were positive for AmpC by combined disc method (Cefotetan and Boronic Acid), 56.5% were positive by each of Boronic Acid and Cloxacillin double disc synergy tests, 35.5% were positive by the induction test, and 25.8% were plasmid-mediated AmpC beta-lactamase producers by the multiplex PCR. Plasmid-mediated AmpC genes retrieved, belonged to the families (MOX, FOX, EBC and CIT). ESBL producers were found in 26 (41.9%) isolates, 15 (57%) of which also produced AmpC. Isolates caused hospital acquired infections were (53/62); of which (39/62) were AmpC producers. While only (8/62) of the isolates caused community-acquired infections, were AmpC producers, and (1.6%) (1/62) were non AmpC producer. CONCLUSIONS: The AmpC beta-lactamases detection tests had to be included in the routine microbiology workup of Gram negative bacteria, namely Cefoxitin as a screening test, combined Boronic Acid disc test with Cefotetan, followed by synergy tests and finally by the induction test for phenotypic identifications. Multiplex PCR can successfully detect the plasmid AmpC genes. PMID- 25147650 TI - Incidence and susceptibility pattern of methicillin resistant coagulase-negative staphylococci isolated from a tertiary care hospital of pakistan. AB - BACKGROUND: Methicillin resistant coagulase-negative Staphylococci are resistant organisms causing infections associated with high morbidity and mortality. Methicillin resistant Staphylococcus epidermidis (MRSE), is especially important with respect to admitted patients with indwelling catheters and other installed invasive devices where these organisms are known to be found. As a result, such lifesaving measures may prove fatal from subsequent infection and sepsis by these pathogens. Therefore, to limit such conditions in patients, the spread of MRSE and related organisms in the hospitals have to be effectively controlled. OBJECTIVES: This study was carried out to determine the frequency of methicillin resistant organisms among all isolated coagulase negative Staphylococci (CoNS) and to find effective antibiotics against these microorganisms. PATIENTS AND METHODS: All samples sent to the lab were routinely processed according to standard microbiological procedures and the cultures yielding growth of CoNS were selected for the study. All samples containing CoNS collected over a 2 year period, were included irrespective of patients' age and gender. The antibiogram of the organisms was recorded according to CLSI guidelines and the ratio of methicillin resistant organisms determined. RESULTS: From a total of 299 isolated coagulase negative Staphylococci (CoNS), 40.1% were methicillin resistant. A high proportion of these organisms (more than 50%) were resistant to cephalosporins, aminoglycosides and quinolones while only a small number were found to show resistance to linezolid, minocycline, chloramphenicol and rifampicin. There were no resistant organisms against vancomycin. CONCLUSIONS: A considerable amount of methicillin resistant organisms found among CoNS in our region. The above stated antibiotics would prove effective in limiting these infections. Clinicians should keep these facts in mind while treating their patients. PMID- 25147651 TI - Herpes simplex virus meningitis in children in South East of caspian sea, iran. AB - BACKGROUND: Herpes simplex virus (HSV) is a member of Herpesviridae and a leading cause of human viral diseases. Meningitis occurs as a complication of HSV-1 or HSV-2 primary infection. OBJECTIVES: We aimed to evaluate HSV meningitis in children in Gorgan province, Iran. PATIENTS AND METHODS: Forty-five cerebrospinal fluid samples were taken from children referred with meningitis symptoms. Samples with negative bacterial culture results were tested for viral, biochemical and cytological assays. DNA extraction and PCR were performed. RESULTS: HSV-1 detected in 4 (8.8%) samples without any HSV-2 infections. Cases with positive results had fever and CSF pleocytosis. Vomiting, headache and higher count of WBC were observed in 3, 2 and 3 cases respectively. The cerebrospinal fluid (CSF) glucose and protein levels were normal and 3 cases showed positive C-reactive protein (CRP) results. Also erythrocyte sedimentation rate (ESR) was higher than normal in all positive cases. CONCLUSIONS: Distribution of HSV types in children with meningitis in our area predominantly was type 1 compared with type 2, which has been reported more in other area. PMID- 25147652 TI - Assessment of Biofilm Formation and Resistance to Imipenem and Ciprofloxacin among Clinical Isolates of Acinetobacter baumannii in Tehran. AB - BACKGROUND: Biofilms are communities of bacteria attached to the surfaces in an extracellular polymeric matrix which are associated with many chronic infections in humans. Acinetobacter spp. are emerging as a major cause of nosocomial infections and Acinetobacter baumannii is the predominant species associated with this kind of infections. OBJECTIVES: In the present study, the potential of biofilm formation of clinical isolates, A. baumannii, was assessed by using crystal violet method. Furthermore, susceptibility pattern of these strains to ciprofloxacin and imipenem was determined. METHODS AND MATERIALS: Biofilm formation by 75 A. baumannii isolates was evaluated by using microtiter plate and tube methods and crystal violet staining. Tube method was carried out under static and shaking conditions. Then, the susceptibility of isolates to ciprofloxacin and imipenem was determined. RESULTS: Results showed that in tube method under shaking, 22% of clinical isolates were strong biofilm producers while 23% of them were not able to form biofilms. In this experiment, 18% and 42% of isolates were considered as moderate and weak biofilm-forming strains, respectively. In microtiter plate tests, 18% of strains were strong-biofilm producers and 25% of them were notable biofilm producers. In this assessment, 10% and 47% were considered as moderate and weak biofilm-forming isolates, respectively. The susceptibility tests, using microdilution method, confirmed that 92% of these isolates were resistant and 6.6% were susceptible to ciprofloxacin, although these results for imipenem were 68% and 24%, respectively. CONCLUSIONS: It can be concluded that most of A. baumannii isolates can form biofilm in microtiter plate and tube. The results also verified that most of these isolates were resistant to ciprofloxacin and imipenem. PMID- 25147653 TI - Aflatoxin in raw and salt-roasted nuts (pistachios, peanuts and walnuts) sold in markets of tabriz, iran. AB - BACKGROUND: Nuts are one of the main consumed snacks worldwide and also have an important role among Iranian's food habits. Natural contamination of nuts with aflatoxin is unavoidable and causes a special challenge for nuts safety and quality. OBJECTIVES: The purpose of this research was to study the aflatoxin contamination in commercially-available nuts (pistachio, walnut and peanut) in the markets of Tabriz, Iran. MATERIALS AND METHODS: Sixty two samples of 50 g salt-roasted peanuts and pistachios and 109 samples of 50 g pure pistachios, walnuts and peanuts were collected from different areas of local markets. After the initial preparations, ELISA test was performed for Aflatoxin measurement. RESULTS: Result showed that walnut (90%) and pure pistachio (2.3%) were the most and least contaminated samples, respectively. Mean aflatoxin contamination in the salt-roasted samples (19.88 +/- 19.41 ug/kg) was significantly higher than the pure ones (6.51 +/- 9.4 ug/kg) (P < 0.001). Respectively, 58.6%, 48.4% and 47.6% of salt-roasted pistachios, salt-roasted peanuts and walnut samples had aflatoxin contamination, which were more than the maximum tolerated level of Iran (MTL, 15 ppb). CONCLUSIONS: It was concluded that aflatoxin content of nuts should be monitored regularly to minimize the risk of aflatoxin hazard and ensure the food safety and quality. PMID- 25147654 TI - Effect of Efflux Pump Inhibitor Carbonyl Cyanide 3-Chlorophenylhydrazone on the Minimum Inhibitory Concentration of Ciprofloxacin in Acinetobacter baumannii Clinical Isolates. AB - BACKGROUND: Acinetobacter baumannii is an important human pathogen with increasing notoriety in the recent years, as a causative organism of drug resistant nosocomial infections, particularly in immunocompromised patients hospitalized in burn centers. OBJECTIVES: The aim of this study was to determinate the role of efflux pump(s) in ciprofloxacin resistance of A. baumannii strains isolated from burn patients. MATERIALS AND METHODS: Sixty-five A. baumannii strains were isolated from the burn patients hospitalized in Motahari Burns and Reconstruction Center in Tehran, Iran. Susceptibility test to ciprofloxacin was carried out by disk agar diffusion and agar dilution methods, according to the CLSI guidelines. Activity of the efflux system was evaluated using efflux pump inhibitor carbonyl cyanide 3-chlorophenylhydrazone (CCCP). RESULTS: All Acinetobacter isolates were resistant to ciprofloxacin. The Minimum inhibitory concentration (MIC) range of ciprofloxacin in isolates was 4 to 128 ug/mL or greater. Moreover, susceptibility of strains to ciprofloxacin was highly increased in the presence of efflux pump inhibitor; So that, for 86.1% (56/65) of isolates, CCCP reduced the MIC by 2 to 64 folds. CONCLUSIONS: Our findings are suggestive that efflux-based system may play a role in fluoroquinolone resistance in A. baumannii isolates, affecting hospitalized patients. The ability of Acinetobacter to acquire resistance to these potent antimicrobials by the efflux pump mechanism is a concern. Therefore, new strategies are required in order to eliminate the efflux transport activity from the resistant bacteria causing nosocomial infections and provide more appropriate approaches for treatment and management of troubling infections. PMID- 25147655 TI - In Vitro Anti-Candida Activity of the Hydroalcoholic Extracts of Heracleum persicum Fruit Against Phatogenic Candida Species. AB - BACKGROUND: Nowadays Candida albicans has become resistant to the toxic and expensive commercial anti-Candida drugs. Therefore, investigation for new anti fungal agents is necessary. OBJECTIVES: The purpose of this survey was to investigate the in vitro anti-Candida activity of the hydroalcoholic extracts of Heracleum persicum fruit. MATERIALS AND METHODS: The plant ingredients were extracted using 80% ethanol and the extract was screened against 46 isolated pathogenic Candida species such as C. albicans, C. glabrata and C. tropicalis by agar well diffusion method. RESULTS: The minimum inhibitory concentration (MIC) values at 24 and 48 hours were 0.625 - 20 ug/uL for C. albicans, 0.625 - 40 ug/uL for C. glabrata, and 5.0 - 20 ug/uL for C. tropicalis. CONCLUSIONS: The results of this survey confirmed that tested plant extract had a potential anti-Candida activity. Hence, it is suggested to isolate and identify its active compounds in future. PMID- 25147657 TI - Antibacterial and Antifungal Activity of Holothuria leucospilota Isolated From Persian Gulf and Oman Sea. AB - BACKGROUND: Emergence of antimicrobial resistance toward a number of conventional antibiotics has triggered the search for antimicrobial agents from a variety of sources including the marine environment. OBJECTIVES: The aim of this study was to evaluate the antimicrobial potential of Holothuria leucospilota from Qeshm and Kharg Islands against some selected bacteria and fungi. MATERIALS AND METHODS: In this investigation, sea cucumbers from two coastal cities of Persian Gulf were collected in March and May 2011 and identified by the scale method according to the food and agriculture organization of the United Nations. Antibacterial activity of hydroalcoholic extracts of the body wall, cuvierian organs and coelomic fluid, methanol, chloroform, and n-hexane extracts of the body wall were evaluated by the spot test. In addition, their antifungal activity was assessed by the broth dilution method. RESULTS: The displayed effect was microbiostatic at concentrations of 1000 and 2000 ug/mL rather than microbicidal. The highest activity of hydroalcoholic extracts was exhibited by body wall, cuvierian organs and coelomic fluid against Escherichia coli, Salmonella typhi, Staphylococcus aureus and Pseudomonas aeruginosa; Aspergillus niger, A. fumigatus, A. flavus and A. brasilensis. However, none of the methanol, chloroform and n-haxane extracts showed appreciable effects against Shigella dysenteriae, Proteus vulgaris, Bacillus cereus, S. epidermidis and Candida albicans. Moreover, cuvierian organs did not possess any antifungal potential. CONCLUSIONS: Our data indicated that water-methanol extracts from the body wall of H. leucospilota possess antibacterial and antifungal activity. However, additional and in-depth studies are required to isolate and identify the active component(s). PMID- 25147656 TI - Morphological and Bactericidal Effects of Different Antibiotics on Helicobacter pylori. AB - BACKGROUND: Helicobacter pylori (H. pylori) is a spiral Gram negative bacteria that can transform to the coccoid form in adverse conditions. OBJECTIVES: The aim of this study was to determine the in vitro morphological and bactericidal effects of metronidazole, amoxicillin and clarithromycin on H. pylori. MATERIALS AND METHODS: The standard strain 26695 of H. pylori was cultured on Brucella agar (BA) and the minimum inhibitory concentrations (MICs) of three antibiotics were determined by E-test method. The bacteria were exposed to antibiotics at 1/2 MIC, MIC and 2X MIC concentrations in Brucella broth (BB). Induced coccoid forms were confirmed by Gram staining and light microscopy. The viability of cells as well as the susceptibility of viable coccoids to antibiotics were examined using the flow cytometry method. RESULTS: All of the three antibiotics at sub-MIC induced coccoid forms. The highest rates of coccoids (> 90%) were induced at 0.008 MUg/mL concentration (1/2 MIC) of amoxicillin, 72 hours postexposure. Metronidazole and clarithromycin with 1/2 MIC (0.5 and 0.125 ug/mL respectively) induced lower rates of coccoid forms (60% and 40% respectively). Potent bactericidal effects on coccoids were observed with Metronidazole at 2X MIC and clarithromycin at MIC (0.25 ug/mL) (80 - 90%). Amoxicillin with MIC and 2X MIC had no bactericidal effect on coccoid forms. CONCLUSIONS: Despite the good in vitro bactericidal effect of amoxicillin on spiral forms of H. pylori, this antibiotic has little effect on induced coccoids that may develop after the inappropriate in vivo antibacterial treatment. Hence, for successful therapy, it is essential not only to eradicate the spiral forms, but to eliminate the viable coccoids. PMID- 25147658 TI - Antibacterial effect of silver nanoparticles against four foodborne pathogens. AB - BACKGROUND: There is increased demand for improved disinfection methods due to microorganisms resistant to multiple antimicrobial agents. Numerous types of disinfectants are available with different properties; but the proper disinfectant must be carefully selected for any specific application to obtain the desired antimicrobial effect. OBJECTIVES: Antimicrobial effect of a commercial nanosilver product, NanoCid(r) L2000, against some foodborne pathogens was evaluated. MATERIALS AND METHODS: Minimum inhibitory concentrations (MIC) were determined by monitoring the growth of bacteria at 600 nm, after 24 hours incubation at 35 degrees C. Minimum bactericidal concentrations (MBC) were determined based on 3 log decrease in the viable population of the pathogens after incubation of nutrient agar plates at 35 degrees C for 24 hours. The required exposure time for 3 log reduction in the viable population of the tested pathogens was determined as the minimum exposure time for efficient bactericidal activity. RESULTS: The MIC values of Ag NPs against tested pathogens were in the range of 3.12-6.25 ug/mL. While Listeria monocytogenes showed the MIC value of 6.25 ug/mL, Escherichia coli O157:H7, Salmonella typhimurium and Vibrio parahaemolyticus all showed the MIC values of 3.12 ug/mL. However, all the pathogens showed the same MBC value of 6.25 ug/mL. To obtain an efficient bactericidal activity against E. coli O157:H7 and S. typhimurium, the exposure time should be at least ca. 6 hours., while this time was ca. 5 hours for V. parahaemolyticus and ca. 7 hours for L. monocytogenes. CONCLUSIONS: Silver nanoparticles showed great antibacterial effectiveness on four important foodborne pathogens. Therefore, Ag NPs could be a good alternative for cleaning and disinfection of equipment and surfaces in food-related environments. PMID- 25147659 TI - Mold contamination of untreated and roasted with salt nuts (walnuts, peanuts and pistachios) sold at markets of tabriz, iran. AB - BACKGROUND: Nuts are one of the main consumed snacks worldwide and a significant component of Iranian's diet. Natural contamination of nuts with fungus is unavoidable and is a major challenge to nuts safety and quality. OBJECTIVES: The purpose of this research was to study fungal contamination in commercially available nuts (pistachios, walnuts and peanuts) in the markets of Tabriz, Iran. MATERIALS AND METHODS: 100 samples of 50 gr roasted with salt peanuts and pistachios and 300 samples of 50 gr pure pistachios, walnuts and peanuts were collected from different areas of the local markets. After initial preparation, the samples were cultured on Sabouraud's dextrose agar (SDA). 19 fungal isolates were identified. RESULTS: The results show that Aspergillus niger was the predominant mold among pure (44%) and roasted with salt (14%) nuts (P < 0/001). In addition, percentage of mycotoxigenic fungal contamination was 18% for roasted with salt nuts and 11% for pure samples. CONCLUSIONS: The overall results of the analysed samples showed that the rate of fungal contamination in pure samples was higher than roasted with salt ones (P < 0.005). Results of the current survey could be useful for minimizing fungal contamination and can educate people about the dangers of mold in nuts. PMID- 25147660 TI - Severe falciparum malaria in iran: a very rare case from an endemic region. AB - INTRODUCTION: Malaria is a protozoal disease, transmitted to humans by female Anopheles mosquito bite. Plasmodium falciparum, compared to other kinds of Plasmodium, causes more severe malaria and is associated with a higher mortality rate. Annually, one to three million deaths occur due to malaria, especially by P. falciparum. CASE PRESENTATION: In this report, we introduce an Iranian patient suffering from P. falciparum. Peripheral blood smear for malaria parasites showed severe infection of P. falciparum, with 75 to 85 percent of red blood cells containing one to five parasites per cell. However, the patient revealed a fast response to treatment and a good prognosis, suggesting a high level of relative immunity in the patient. To confirm this hypothesis, we conducted a comparative study by comparing the rate of clinical response to treatment as well as the level of prognosis of our patient with similar patients from different regions around the world. These included some malaria cases (caused by P. falciparum) chosen from endemic and nonendemic regions, such as Africa, South Europe and Canada. DISCUSSION: The findings revealed that generally, patients from endemic regions significantly show a greater response to treatment and also a better prognosis in comparison to the patients from nonendemic regions. These differences can plausibly be attributed to a high level of relative immunity in endemic regions. Consequently, we would strongly support the hypothesis that response to treatment and prognosis of malaria is a matter of patients' living environment circumstances. In other words, people who live in endemic regions acquire a high relative immunity leading to a greater response to treatment and a better prognosis. PMID- 25147661 TI - Construction and Evaluation of a Novel Internal Positive Control (IPC) for Detection of Coxiella burnetii by PCR. AB - BACKGROUND: Due to the limitations of the classical methods to detect Coxiella burnetii, direct diagnosis of the pathogen using PCR techniques is still the preferable approach. However, false negative results owing to the presence of PCR inhibitors are troublesome. OBJECTIVES: In order to identify the inhibitors during PCR assay, an internal positive control (IPC) was designed based on 16SrRNA gene of C. burnetii. MATERIALS AND METHODS: In the current study, the initial and ending parts of the target gene in an external positive control plasmid (pTZ57R/T-16S) amplified using internal primers which had a BglII restriction site on the 5'ends. Both PCR products (fragments 1 and 2) were cloned into pTZ57R/T vector. Following BglII enzyme digestion, the two obtained linear plasmids were ligated. The ligation product was transformed into Escherichia coli Top10 F'. Screening of the desired recombinant clone was carried out using colony PCR. RESULTS: The size of the PCR product was equal to the sum of the first and second fragments. Sequencing confirmed the presence of the desire insert (IPC sequence) in recombinant plasmid. Consequently, the IPC fragment was longer than the target gene while both ends had similar attachments to the same primer pair. CONCLUSIONS: The results showed that direct fusion of the recombinant plasmids containing the initial and ending parts of the target gene are simple and cost effective techniques for increasing the length of the fragment and constructing IPC. PMID- 25147662 TI - Antimicrobial Resistance Patterns and Prevalence of blaPER-1 and blaVEB-1 Genes Among ESBL-producing Pseudomonas aeruginosa Isolates in West of Iran. AB - BACKGROUND: Pseudomonas aeruginosa is a leading cause of nosocomial infections worldwide. Resistance of P. aeruginosa strains to the broad-spectrum cephalosporins may be caused by extended-spectrum beta-lactamases (ESBLs). OBJECTIVES: The aim of this study was to determine the antimicrobial resistance patterns and prevalence of PER-1 and VEB-1 type genes among ESBL producing strains of P. aeruginosa. MATERIAL AND METHODS: A total of 106 P. aeruginosa isolates were collected from two university hospitals in Hamadan, Iran, during a7 month study (2009). The antimicrobial susceptibility of isolates was determined by disc diffusion method and interpreted according to the clinical and laboratory standards institute (CLSI) recommendations. Production of ESBL was determined by combined disk test and presence of PER-1 and VEB-1 type ESBL genes was identified by PCR. RESULTS: The resistance against broad-spectrum cephalosporins and monobactames were: cefepime (97%), cefotaxime (92.5%) ceftazidime (51%), and aztreonam (27%). Ciprofloxacin (91.5%), imipenem (84.9%) and meropenem (82.1%) were the most effective anti-pseudomonas agents in this study. The results revealed that 88.7% of the isolates were multidrug resistant, 58.25% of those were ESBL positive. Sixteen (26.6%), 9 (15%) and 3 (5%) strains among ESBL producing strains contained blaPER-1, blaVEB and blaPER-1-blaVEB, respectively. CONCLUSIONS: This study highlighted the need to establish antimicrobial resistance surveillance networks for P. aeruginosa to determine the appropriate empirical treatment regimens. The high prevalence of multidrug resistance and production of ESBLs in P. aeruginosa isolates confirms the necessity of protocols considering these issues in the hospitals. PMID- 25147664 TI - The Antibacterial Activity of Cassia fistula Organic Extracts. AB - BACKGROUND: Cassia fistula, is a flowering plant and a member of Fabaceae family. Its leaves are compound of 4 - 8 pairs of opposite leaflets. There are many Cassia species around the world which are used in herbal medicine. OBJECTIVES: This study was designed to examine in vitro anti-bacterial activity of methanolic and ethanolic extracts of C. fistula native to Khuzestan, Iran. MATERIALS AND METHODS: The microbial inhibitory effect of methanolic and ethanolic extracts of C. fistula was tested on 3 Gram positive: Bacillus cereus, Staphylococcus aureus and S. epidermidis and 5 Gram negative: Salmonella Typhi, Kelebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis bacterial species using disc diffusion method at various concentrations. The minimum inhibitory and bactericidal concentrations (MIC and MBC) were measured by the tube dilution assay. RESULTS: The extract of C. fistula was effective against B. cereus, S. aureus, S. epidermidis, E. coli and K. pneumoniae. The most susceptible microorganisms to ethanolic and methanolic extracts were E. coli and K. pneumoniae, respectively. Also B. cereus and S. aureus showed the least sensitivity to ethanolic and methanolic extracts, respectively. The MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) of ethanolic extracts against S. aureus, E. coli, S. epidermidis and K. pneumoniae were also determined. CONCLUSIONS: With respect to the obtained results and regarding to the daily increase of the resistant microbial strains to the commercial antibiotics, it can be concluded that these extracts can be proper candidates of antibacterial substance against pathogenic bacterial species especially S. aureus, E. coli, K. pneumoniae and S. epidermidis. PMID- 25147663 TI - The prevalence, etiologic agents and risk factors for urinary tract infection among spinal cord injury patients. AB - BACKGROUND: Urinary tract infections (UTIs) are important causes of morbidity and mortality in patients with spinal cord injury and 22% of patients with acute spinal cord injury develop UTI during the first 50 days. OBJECTIVES: The aim of this study was to determine the prevalence, etiologic agents and risk factors for asymptomatic bacteriuria and symptomatic urinary tract infections in patients with spinal cord injury. PATIENTS AND METHODS: This was a prospective investigation of spinal cord injury patients with asymptomatic bacteriuria and symptomatic urinary tract infections in Baskent University Medical Faculty Ayas Rehabilitation Center and Ankara Physical Therapy and Rehabilitation Center between January 2008 and December 2010. The demographic status, clinical and laboratory findings of 93 patients with spinal cord injury were analyzed in order to determine the risk factors for asymptomatic or symptomatic bacteriuria. RESULTS: Sixty three (67.7%) of 93 patients had asymptomatic bacteriuria and 21 (22.6%) had symptomatic urinary tract infection. Assessment of the frequency of urinary bladder emptying methods revealed that 57 (61.3%) of 93 patients employed permanent catheters and 24 (25.8%) employed clean intermittent catheterization. One hundred and thirty-five (48.0%) of 281 strains isolated form asymptomatic bacteriuria attacks and 16 (66.6%) of 24 strains isolated from symptomatic urinary tract infection attacks, totaling 151 strains, had multidrug resistance (P > 0.05). One hundred (70.4%) of 142 Escherichia coli strains and 19 (34.5%) of 55 Klebsiella spp strains proliferated in patients with asymptomatic bacteriuria; 8 (80%) of 10 E. coli strains and 4 (80%) of 5 Klebsiella spp. strains were multidrug resistant. CONCLUSIONS: The most common infectious episode among spinal cord injury patients was found to be urinary tract infection. E. coli was the most common microorganism isolated from urine samples. Antibiotic use in the previous 2 weeks or 3 months, hospitalization during the last one-year and previous diagnosis of urinary tract infection were the risk factors identified for the development of infections with multi-drug resistant isolates. Urinary catheterization was found to be the only independent risk factor contributing to symptomatic urinary tract infection. PMID- 25147665 TI - Vaginal candidiasis complications on pregnant women. PMID- 25147666 TI - Identification of yeasts and bacteria isolated from Iranian kefir drink. PMID- 25147667 TI - Helicobacter pylori and Serum Magnesium Level in Hemodialysis Patients. PMID- 25147668 TI - Eradication of Pseudomonas aeruginosa Biofilms Using the Combination of n butanolic Cyclamen coum Extract and Ciprofloxacin. AB - BACKGROUND: Biofilm formation is a major pathogenic factor in different bacteria such as Pseudomonas aeruginosa. A number of studies have reported that bacterial biofilms show different levels of antibiotic resistance. In order to re-sensitize the bacterial biofilms to antibiotics, biofilms should be dispersed. OBJECTIVES: In this study, the effect of n-butanolic Cyclamen coum extract in combination with ciprofloxacin was examined on one, three and five day old P. aeruginosa biofilms. The synergistic effect of n-butanolic C. coum extract and ciprofloxacin towards dispersing pre-established P. aeruginosa biofilms was also studied. MATERIALS AND METHODS: The ability of biofilm formation by six different P. aeruginosa strains was confirmed by microtiter plate method and PCR assay for the cupA gene. The extraction of C. coum tubers was achieved by fractionation method using different solvents. The minimum inhibitory concentration (MIC) of n butanolic C. coum extract and ciprofloxacin against planktonic cells was evaluated using agar well diffusion and microdilution methods. The microdilution chequerboard method was used to determine the fractional biofilm eradication concentration index (FBCI), when the combination of n-butanolic C. coum extract and ciprofloxacin were used against P. aeruginosa biofilms. RESULTS: The ability of biofilm formation by P. aeruginosa strains was quantitatively confirmed. The PCR method confirmed the existence of cup A gene (172 bp) in all studied strains. Saponin content of the n-butanolic C. coum extract was 156 ug/mL. The extract revealed antibacterial activity against planktonic cells of P. aeruginosa strains. The results showed that one and three day old biofilms are affected by either ciprofloxacin or n-butanolic C. coum extract. However, n-butanolic C. coum extract in combination with ciprofloxacin was significantly more effective against P. aeruginosa biofilms. CONCLUSIONS: Using n-butanolic C. coum extract in combination with ciprofloxacin offers a novel strategy to control biofilm-based infections caused by P. aeruginosa. PMID- 25147669 TI - Production and Screening of High Yield Avermectin B1b Mutant of Streptomyces avermitilis 41445 Through Mutagenesis. AB - BACKGROUND: Secondary metabolite production from wild strains is very low for economical purpose therefore certain strain improvement strategies are required to achieve hundred times greater yield of metabolites. Most important strain improvement techniques include physical and chemical mutagenesis. Broad spectrum mutagenesis through UV irradiation is the most important and convenient physical method. OBJECTIVES: The present study was conducted for enhanced production of avermectin B1b from Streptomyces avermitilis 41445 by mutagenesis using ultraviolet (UV) radiation, ethidium bromide (EB), and ethyl methanesulfonate (EMS) as mutagens. MATERIALS AND METHODS: S. avermitilis DSM 41445 maintained on yeast extract malt extract glucose medium (YMG) was used as inoculum for SM2 fermentation medium. Spores of S. avermitilis DSM 41445 were exposed to UV radiation for physical broad spectrum mutagenesis and to EMS and EB for chemical mutagenesis. For each mutagen, the lethality rate and mutation rate were calculated along with positive mutation rate. RESULTS: Avermectin B1b-hyper producing mutant, produced using these three different methods, was selected according to the HPLC results. The mutant obtained after 45 minutes of UV radiation to the spores of S. avermitilis 41445, was found to be the best mutant for the enhanced production of avermectin B1b component (254.14 mg/L). Other avermectin B1b-hyper-producing mutants, were obtained from EMS (1 uL/mL) and EB (30 uL/mL) treatments, and yielded 202.63 mg/L and 199.30 mg/L of B1b, respectively. CONCLUSIONS: The hereditary stability analysis of the UV mentioning 45 minutes revealed the UV exposure time for mutants and 3 represented the colony taken from the plate irradiated for 45 minutes mutant showed that the production of avermectin B1b remained constant and no reverse mutation occurred after 15 generations. PMID- 25147670 TI - Correlation of Multi-drug Resistance, Integron and blaESBL Gene Carriage With Genetic Fingerprints of Extended-Spectrum beta-Lactamase Producing Klebsiella pneumoniae. AB - BACKGROUND: Some genetic and phenotypic variables are associated among distinct microbial populations. OBJECTIVES: The associations between multi-drug resistance (MDR) phenotypes, prevalence of antibiotic resistance integrons (ARIs), bla SHV, bla TEM and bla CTX-M gene carriage and genetic fingerprints of random amplified polymorphic DNA (RAPD), confirmed by pulsed field gel electrophoresis (PFGE), were investigated among extended-spectrum beta-lactamases (ESBL)-producing nosocomial isolates of Klebsiella pneumoniae. MATERIALS AND METHODS: Susceptibility of 35 ESBL-producing K. pneumoniae nosocomial isolates to 22 antimicrobial agents was determined. Integron carriage was detected using specific primers for intI1, intI2 and intI3 genes by PCR. RESULTS: All isolates were resistant to piperacillin and susceptible to imipenem. MDR phenotype was observed in 91.4% of the isolates. Class 1 integrons were detected in 21 (60%) and class 2 integrons in 3 (8.57%) of the isolates. Two of the isolates carried both classes and none harbored class 3 integrons. Significant correlations were observed between resistance to aminoglycosides, fluoroquinolones and sulfonamides, and between genotype groups with carriage of ARIs, MDR phenotype and bla SHV gene carriage. ARI carriage was also significantly associated with MDR phenotype. CONCLUSIONS: Our findings suggest the possible co-carriage of some bla SHV genes and ARIs on the same plasmids harboring the MDR genes. Possible role of integrons in dissemination of ESBL-encoding bla SHV genes among ESBL producing K. pneumoniae nosocomial isolates may be inferred. PMID- 25147671 TI - Characterization of AmpC, CTX-M and MBLs types of beta-lactamases in clinical isolates of Klebsiella pneumoniae and Escherichia coli producing Extended Spectrum beta-lactamases in Kerman, Iran. AB - BACKGROUND: Extended spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases enzyme are major sources of resistance to beta-lactam antibiotics especially in Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae. Increasing frequency of the co-existence of ESBLs with AmpC-beta-lactamases in bacteria is a serious threat for treating bacterial infections. OBJECTIVES: The aim of this study was to determine the presence of AmpC and CTX-M types of beta-lactamases in clinical isolates of E. coli and K. pneumoniae producing ESBLs. MATERIALS AND METHODS: Resistance to different antibiotics was determined using the standard disk diffusion method. ESBLs, MBLs and AmpC-beta-lactamases were detected by the combination double disk test (CDDT) method and polymerase chain reaction (PCR) was used to determine bla CTX -M genes in the ESBLs and AmpC positive isolates. RESULTS: The prevalence of ESBLs and AmpC-beta-lactamase producer isolates was 181 (43.8%) and 133 (37.2%), respectively. The prevalence of bla CTX -M among isolates was 61 (14.7%). CONCLUSIONS: Outbreak of isolates co-expressing AmpC beta-lactamases and ESBLs can cause serious problems in the future, regarding the treatment of infections caused by these common enteric pathogens. PMID- 25147672 TI - Biodegradation of hard keratins by two bacillus strains. AB - BACKGROUND: Extensive quantities of keratinic by-products are disposed annually by animal-processing industry, causing a mounting ecological problem due to extreme resilience of these materials to enzymatic breakdown. There is a growing trend to apply cheap and environment-friendly methods to recycle keratinic wastes. Soil bacteria of profound keratinolytic potential, especially spore forming rods from the genus Bacillus, play a significant role in keratinase mediated biodegradation of keratins, therefore could be effective in hastening their biodegradation. Keratin hydrolysis in microbial cultures is one of the most promising techniques not only to utilize this protein but also to obtain valuable by products. OBJECTIVES: The study was undertaken to investigate the biodegradation process of various keratinic materials by two Bacillus strains. MATERIALS AND METHODS: Two keratinolytic strains, Bacillus cereus and B. polymyxa, were subject to cultures in the presence of several keratinic appendages, like chicken feathers, barbs and rachea of ostrich feathers, pig bristle, lamb wool, human hair and stratum corneum of epidermis, as main nutrient sources. Bacterial ability to decompose these waste materials was evaluated, at the background of keratinase and protease biosynthesis, in brief four-day cultures. Keratinolytic activity was measured on soluble keratin preparation and proteases were assayed on casein. Additionally, amounts of liberated proteins, amino acids and thiols were evaluated. Residual keratin weight was tested afterwards. RESULTS: Both tested strains proved to be more adapted for fast biodegradation of feather beta-keratins than hair-type alpha-keratins. B. cereus revealed its significant proteolytic potential, especially on whole chicken feathers (230 PU) and stratum corneum (180 PU), but also on separated barbs and rachea, which appeared to be moderate protease inducers. Keratinolytic activity of B. cereus was comparable on most substrates and maximum level obtained was 11 KU. B. polymyxa was found to be a better producer of keratinases, up to 32 KU on chicken feathers and 14 KU on both fractions of ostrich feathers. Its proteolytic activity was mostly revealed on stratum corneum and human hair. Stratum corneum was extensively degraded by both bacterial strains up to 99% - 87%, chicken feathers 47-56%, ostrich barbs and rachea, 28% and 35% at maximum, respectively. Keratin fibres of structures like human hair, lamb wool and pig bristle remained highly resilient to this short microbiological treatment, however certain extent of keratinase induction was also observed. CONCLUSIONS: The obtained results prove that keratinolytic potential of both tested bacterial strains could be applied mainly in biodegradation of feathers, however, B. cereus and B. polymyxa differed in terms of keratinase and protease production on each of the substrates. Biodegradation of highly resilient structures like hair or pig bristle requires further analysis of process conditions. PMID- 25147673 TI - Comparison of Culture and PCR Methods for Diagnosis of Mycobacterium tuberculosis in Different Clinical Specimens. AB - BACKGROUND: Tuberculosis remains a global epidemic, especially in developing countries, including Iran. Rapid diagnosis of active Mycobacterium tuberculosis infection plays a critical role in controlling the spread of tuberculosis. Conventional methods may take up to several weeks or longer to produce results. In addition to multiplicity of steps involved in conventional detection, including isolation, identification and drug susceptibility testing, the slow growth rate of M. tuberculosis is also responsible for this lengthy time. OBJECTIVES: The aim of this study was to compare the polymerase chain reaction (PCR) and culture methods for the detection of M. tuberculosis in different clinical specimens. MATERIALS AND METHODS: This study was performed on different samples (urine, gastric aspirate, bronchoalveolar lavage, pleural fluid, cerebrospinal fluid, ascetic fluid and joint fluid specimens) of tuberculosis suspected patients. M. tuberculosis DNA was extracted directly from different samples using two different protocols. Next, PCR was performed using three sets of specific primers to detect members of Mycobacterium genus, M. tuberculosis complex and non-tuberculosis Mycobacteria. The results were then compared with that of the culture method, which is considered as the gold standard method. RESULTS: The concordance rate between the three sets of primers was calculated and IS6110/buffer PCR method showed good agreement with the LJ culture method (kappa = 0.627, P < 0.0001). The sensitivity of IS6110/buffer PCR was 58.33%, with specificity of 77.78%; the positive and negative predictive values were 100% and 78.26%, respectively. Buffer method for DNA extraction was proved to give a higher accuracy to PCR in comparison with the boiling method. CONCLUSIONS: PCR method is a valuable, cost-effective and alternative tool for quick diagnosis of active tuberculosis in different clinical specimens. PMID- 25147674 TI - Determination of Vancomycin Resistant Enterococcus faecium Diversity in Tehran Sewage Using Plasmid Profile, Biochemical Fingerprinting and Antibiotic Resistance. AB - BACKGROUND: Sewage treatment plants are considered to be the hotspots for antibiotic resistance transfer among bacterial species. Many fecal bacteria including Enterococci circulate and are exposed to antibiotic residues in this environment. Being as one of the most common cause of nosocomial infections, special concerns have risen worldwide about the rate and characteristics of Enterococci (especially, isolates with high resistance against glycopeptides) which are available in raw sewages. OBJECTIVES: Study on the vancomycin Resistant E. faecium diversity in Tehran sewage by plasmid profile, biochemical fingerprinting and antibiotic resistance. MATERIALS AND METHODS: Forty isolates recovered from an urban sewage treatment plant were studied during 2009- 2010. The antibiotic resistance of isolates against 7 antibiotics was examined by disk diffusion method. Extraction of plasmid DNA was performed and identification of van genotype (vanA and vanB) was done by PCR. Biochemical fingerprinting was done by the use of Phene-Plate system (PhP). RESULTS: All isolates were found to be resistant to erythromycin, ampicillin and ciprofloxacin. The PCR analyses showed that all E. faecium isolates harbored vanA gene and 5 (13%) isolates harbored vanA and vanB concomitantly. By plasmid profiling the VRE isolates differentiated into 11 types. PhP showed that VRE isolates were grouped into 23 biochemical types. CONCLUSIONS: The combination of plasmid profiling and PhP techniques revealed the presence of diverse population of VRE in sewage treatment plant in Tehran. Furthermore, the results showed that the PhP technique is a reliable method in determining the VRE clonal diversity. PMID- 25147675 TI - Th1 Platform Immune Responses Against Leishmania major Induced by Thiol-Specific Antioxidant-Based DNA Vaccines. AB - BACKGROUND: The Thiol-specific antioxidant (TSA) is an antigen of Leishmania major which is believed to be the most promising molecule as a vaccine candidate against leishmaniasis. OBJECTIVES: In this study, we investigated the protective efficacy of TSA-based DNA vaccine against L. major infection. MATERIALS AND METHODS: Recombinant plasmid construction TSA (pcTSA) was prepared and transfected into eukaryotic cells and expression was confirmed with western blot and RT-PCR. The mice were assigned to six different groups and DNA immunization was performed with 100 ug intramuscular recombinant plasmid with a two-week interval. Cytokines and lymphocyte proliferation assay, antibody responses and determination of parasite burden were performed following immunization and the challenging infection with L. major. RESULTS: The antibody and IFN-gamma titers were higher in pcTSA + AlPO4 group the immunized mice with pcTSA alone, but there was no statistically significant difference between the two groups. Additionally the IL-4 titer was not statistically different between the groups following immunization and challenge. After infection with L. major promastigotes, the immunized mice with pcTSA and the one immunized with both pcTSA + AlPO4 presented a considerable reduction in diameter of lesion but there was no statistical difference between the two groups. The immunized mice had significantly lower parasite loads. No significant differences were observed between the two vaccinated groups. However the highest reduction in parasite burden was observed in the group immunized with pcDNA + AlPO4. No significant differences were observed in survival rate of the immunized mice after the challenge with L. major. CONCLUSIONS: In conclusion, TSA-based DNA vaccine induced Th1 platform immune response and aluminum phosphate could improve the efficacy of these vaccines with induction of humoral and cellular immune responses against L. major infection. There were no significant differences observed between pcTSA and pcTSA + AlPO4 groups. PMID- 25147676 TI - Evaluation of Ciprofloxacin (gyrA, parC Genes) and Tetracycline (tetB Gene) Resistance in Nosocomial Acinetobacter baumannii Infections. AB - BACKGROUND: Acinetobacter baumannii plays an important role in some types of nosocomial infections as an opportunist microorganism which increases levels of resistance to antibacterial drugs and disinfectants. OBJECTIVES: The aim of this study was to determine the resistance and sensitivity of A. baumannii to different antibiotics and evaluate the minimal inhibitory concentration (MIC) for Ciprofloxacin and Tetracycline; in addition to Surfanios, Citron and Aniosyme DD1 disinfectants, and also to detect the presence of gyrA, parC and tetB gene bands in the isolates. MATERIALS AND METHODS: In this study, 65 A. baumannii isolates were collected from the hospitalized patients in NIOC hospital (National Iranian Oil Company hospital) of Tehran, Iran during 2010-2011. The pattern of sensitivity to antibiotics was determined using CSLI disk diffusion and MIC methods. Furthermore, resistance of isolates to the common disinfectants (Surfanios Citron and Aniosyme DD1) was determined in different hospital wards. Presence of gyrA, parC and tetB gene bands was also detected by PCR method. RESULTS: Frequency of Acinetobacter resistance to Amikacin, Ciprofloxacin, co Trimoxazole, Ceftazidime and Ceftriaxone was 100% in the isolates reviewed in this study. The frequency of resistance to Gentamicin and Tetracycline were 86.1% in the isolates. The MIC of Ciprofloxacin in all (100%) of isolates was 32-64 MUg/mL which showed the resistance to Ciprofloxacin In 86.1% of cases the Gentamicin and Tetracycline MIC were >= 16 MUg/mL and in 13.9% of isolates the Gentamicin and Tetracycline MIC were 4 MUg/mL, these results showed the resistance and sensitivity to the Gentamicin and Tetracycline, respectively. Additionally, all (100%) of the A. baumannii isolates were resistant to disinfectant concentrations, which were used with the methods recommended by manufacturers (0.5%). In 100% of the isolates parC and gyrA genes bands were detected, and tetB gene was also detected in 86.1% of Tetracycline resistant isolates. CONCLUSIONS: Due to the high resistance of A. baumannii isolates to most antibiotics in our study and also its high resistance to the common disinfectants usually used in hospitals, it seems that more attentions should be paid for applying disinfectants. Since most of the isolates were collected from tracheal and sputum samples (46%), it seems that respiratory tract is the most t prevalent site of infection among Acinetobacter infections. Therefore, disinfecting the respiratory tract related equipment and instruments by using proper disinfectants seems to be an appropriate way to prevent these infections. PMID- 25147677 TI - Down Regulation of ackA-pta Pathway in Escherichia coli BL21 (DE3): A Step Toward Optimized Recombinant Protein Expression System. AB - BACKGROUND: One of the most important problems in production of recombinant protein is to attain over-expression of the target gene and high cell density. In such conditions, the secondary metabolites of bacteria become toxic for the medium and cause cells to die. One of these aforementioned metabolites is acetate, which enormously accumulated in the medium, so that both cell and protein yields are affected. OBJECTIVES: To overcome this problem, several strategies applied. In this research we used antisense RNA strategy, where the transcription of phosphotransacetylase (PTA) and acetate kinase (ACK), two acetate pathway key enzymes, could be controlled, which led to reduced acetate production. MATERIALS AND METHODS: In order to achieve this, recombinant plasmid harboring antisense sequences targeting both of pta and ackA was assembled, after transfecting to the cells, its effects on the cell growth and acetate accumulation in the minimal media was assessed and compared with the control, the plasmid without antisense cassette, in presence and absence of IPTG in Escherichia coli BL21 (DE3). RESULTS: It was observed that the mentioned strategy partially affect the growth and amount of excreted acetate in comparison with the control. In addition it was found that high down-regulation of the acetate production pathway reduces the growth rate of E. coli BL21 (DE3). CONCLUSIONS: The study principally proved the importance of this strategy in acetate excretion control. PMID- 25147678 TI - Evaluating the Efficacy of Achillea millefolium and Thymus vulgaris Extracts Against Newcastle Disease Virus in Ovo. AB - BACKGROUND: Nowadays natural products such as pure compounds and plant extract scan provide unlimited opportunities for new antiviral drugs. Newcastle disease virus (NDV) is one of the most important viral diseases in poultry industry. Vaccination could provide protection against NDV outbreaks, but it is not sufficient because infections by NDVs have remained frequent around the world. OBJECTIVES: The current research aimed to study Achillea millefolium and Thymus vulgaris antiviral activity against Newcastle disease virus (NDV). MATERIALS AND METHODS: The antiviral activity of the plants was measured by the reduction assay of viral titer, and explained by inhibition percentage (IP). RESULTS: Inhibition percentage was determined as 10 (1.75), which indicated the ability of the extracts to reduce the viral potency by more than 56 folds. CONCLUSIONS: Both plants were found effective against Newcastle disease virus. PMID- 25147679 TI - Transfer of Herb-Resistance Plasmid From Escherichia coli to Staphylococcus aureus Residing in the Human Urinary Tract. AB - BACKGROUND: Plasmid transfer among bacteria provides a means for dissemination of resistance. Plasmid Analysis has made it possible to track plasmids that induce resistance in bacterial population. OBJECTIVES: To screen the presence of herb resistance plasmid in Escherichia coli strains and determine the transferability of this resistance plasmid directly from E. coli to the Gram-positive, Staphylococcus aureus. MATERIALS AND METHODS: The donor strain E. coli CP9 and recipient strain S. aureus RN450RF were isolated from UTI patients. E. coli CP9 was highly resistant to herbal concoction. Isolates of S. aureus RN450RF were fully susceptible. Total plasmid DNA was prepared and transferred into E. coli DH5alpha. Transconjugants were selected on agar plates containing serial dilutions of herbal concoction. Resistance plasmid was transferred to susceptible S. aureus RN450RFin triple replicas. The mating experiments were repeated twice. RESULTS: The identified 45 kb herb-resistance plasmid could be transferred from E. coli CP9 isolates to E. coli DH5alpha. As a consequence E. coli DH5alpha transconjugant MIC increased from 0.0125 g/mL to 0.25 g/mL. The plasmid was easily transferred from E. coli CP9 strain to S. aureus RN450RF with a mean transfer rate of 1*10(-2) transconjugants/recipient. The E. coli donor and the S. aureus RN450RF transconjugant contained a plasmid of the same size, which was absent in the recipient before mating. Susceptibility testing showed that the S. aureus RN450RF transconjugant was resistant to herbal concoction. CONCLUSIONS: E. coli herb-resistance plasmid can replicate and be expressed in S. aureus. PMID- 25147680 TI - The Prevalence Rate of Helicobacter pylori Infection in, Chronic Otitis Media With Effusion Patients. AB - BACKGROUND: Otitis media with effusion (OME) is a common disease in children. Viral or bacterial infections, allergy, adenoids, functional abnormalities of the Eustachian tube, and gastroesophageal reflux might have a possible role in the pathogenesis of OME. However, the exact pathogenesis of OME is still unsettled. OBJECTIVES: The purpose of this study was to compare Helicobacter pylori prevalence rates in the nasopharynx of pediatric patients with and without OME. PATIENTS AND METHODS: Eighty-four patients (50 males and 34 females) who were subjected to adenoidectomy and myringotomy were included in the study group. Ninety-one patients (48 males and 43 females) who had only adenoidectomy were selected as the control group. Detection of H. pylori was done by polymerase chain reaction (PCR). RESULTS: Adenoid samples were positive for H. pylori in 21 (25%) patients in study group and 18 (19.8%) patients in control group. In the study group, 36 (42.8%) effusion samples (otitis media) of the patients were positive for H. pylori. In an analysis that compared H. pylori-negative and positive children, the odds ratio (OR) for the occurrence of H. pylori was 1.35 (95% CI, 0.66 - 2.71). The association of age with H. pylori positivity decreased for 1-5 years age group, (1.09; 95% CI, 0.39 - 3.05) but increased for the 6-10 years group (OR, 1.48; 95% CI, 0.61-3.58). Furthermore, the association of sex with H. pylori positivity decreased for the male group (OR, 1.21; 95% CI, 0.50 - 2.91), but increased in the female group (OR, 1.44; 95% CI, 0.51-0.4.05). CONCLUSIONS: Heavy colonization of H. pylori in adenoid tissue and middle ear might have a role in pathogenesis of this infection. For OME cases resistant to medical treatment, it might be meaningful to evaluate the patient for H. pylori. PMID- 25147681 TI - Isolation of Vibrio cholera El Tor Inaba From Lemna minor and Eichhornia crassipens Roots in Veracruz, Mexico. AB - BACKGROUND: During epidemic periods, the strain Vibrio cholera El Tor has been isolated from the aquatic macrophyte roots of Eichhornia crassipens and Lemna minor, suggesting that aquatic plants could be environmental reservoirs through either a non-specific association or a commensalism relationship. Therefore, it is important to understand V. cholera reservoirs in order to establish prevention strategies against this pathogen. OBJECTIVES: Our interest was to determine whether V. cholera could be isolated and typified from L. minor and E. crassipens roots. MATERIALS AND METHODS: From 2004 to 2005, plants were collected from various ecological niches and the roots were used to isolate V. cholera. Standard bacteriological, biochemical and serological tests were used for its typification. RESULTS: In five out of the nine ecological niches explored, we collected either L. minor or E. crassipens, as these specimens cohabited only in two niches. V. cholera was isolated from both L. minor and E. crassipens roots. The isolated V. cholera showed the same biochemical characteristics as the pure V. cholera strain which was used as a control. The isolated V. cholera corresponded to V. cholera O1 El Tor Inaba, which is the same serotype related to the last outbreak in Mexico. CONCLUSIONS: For first time V. cholera El Tor Inaba has been isolated several years after the last emergence of cholera in Mexico. A viable and cultivable V. cholera strain, sourced from freshwater niches in E. crassipens and L. minor roots, suggests the importance of these plants as a permanent aquatic reservoir for these organisms. The monitoring of E. crassipens and L. minor is the responsibility of health institutions in order to evaluate the ongoing risks. PMID- 25147682 TI - Bactericidal Effect of Silver Nanoparticles on Intramacrophage Brucella abortus 544. AB - BACKGROUND: Brucellosis is an infectious disease that is caused by Brucella spp. As Brucella spp. are intramacrophage pathogens, the treatment of this infection is very difficult. On the other hand, due to the side effects of the brucellosis treatment regime, it is necessary to find new antimicrobial agents against it. OBJECTIVES: The aim of this study was to investigate the antimicrobial effect of silver nanoparticles against Brucella abortus 544 in the intramacrophage condition. MATERIALS AND METHODS: The antimicrobial effect of silver nanoparticles was determined by an agar well diffusion method. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of silver nanoparticles against B. abortus 544 were determined by a broth macrodilution method. The effect of time on the antimicrobial activity of silver nanoparticles was analyzed. The effect of silver nanoparticles on the intramacrophage survival of B. abortus 544 was studied on mice peritoneal macrophages. RESULTS: The well diffusion agar study showed that silver nanoparticles have an antimicrobial effect on B. abortus 544. The MIC and MBC of silver nanoparticles against B. abortus 544 were; 6 ppm and 8 ppm, respectively. The silver nanoparticles showed antibacterial effects within 40 minutes. The results of the macrophage culture indicated that silver nanoparticles have antibacterial activity against intramacrophage B. abortus 544, and the highest efficiency was observed at a concentration of 8-10 ppm of silver nanoparticles. CONCLUSIONS: The results showed that silver nanoparticles have an antimicrobial effect against intramacrophage B. abortus 544. PMID- 25147683 TI - Bacterial sepsis: challenges of diagnosis and treatment in a teaching hospital southwest of iran. AB - BACKGROUND: Management of bacterial sepsis as a common cause of hospitalization and a life threatening clinical syndrome is a challenge. In previous studies, incorrect diagnosis of sepsis and unnecessary treatment have been frequently reported. OBJECTIVES: The aim of this study was to evaluate the diagnosis and treatment of cases with a primary diagnosis of sepsis. PATIENTS AND METHODS: Of 410 medical files of patients with primary diagnosis of bacterial sepsis, 187 fulfilled our criteria and were enrolled in the study. The study was conducted in Razi Hospital of Ahvaz, southwest Iran, from 2009 to 2011. Data included demographic characteristics, underlying disease, clinical symptoms, laboratory and imaging findings, administrated antibacterial drugs, and nurses and doctors analyzed notes. For evaluation of the diagnosis, patients were divided to two groups, sepsis group and pseudosepsis group, and for evaluation of the treatment, patients were categorized in appropriate and inappropriate treatment groups and compared using SSPS software version 16 by chi-square and fisher exact tests. P values less than 0.05 were considered significant. RESULTS: Out of 187 cases, 61 were in the intensive care unit (ICU), 98 in the infectious disease ward, and 28 in the internal medicine ward. Correct diagnosis of sepsis in the ICU, internal and infectious diseases wards were made in 16 (26.2%), 4 (14.3%) and 71 (72.4%) cases, respectively. Appropriate treatments for sepsis in the ICU, internal and infectious wards were applied in 12 (19.7%), 3 (10.7%) and 61 (78.2%) cases, respectively. Ninety-one patients (48.6%) were diagnosed correctly (true sepsis) and 76 (40.6%) were treated with proper regimes. CONCLUSIONS: Inappropriate and unnecessary use of antibiotics by patients with preliminary diagnosis of sepsis in our hospital, similar to other parts of the world, was high. PMID- 25147684 TI - Characterization of Variations in PB2, NS1, M, Neuraminidase and Hemagglutinin of Influenza A (H3N2) Viruses in Iran. AB - BACKGROUND: In the influenza A viruses, neuraminidase (NA), hemagglutinin (HA), PB2, NS1 and M are responsible for the disease pathogenicity. The mechanism of pathogenicity differs among these viruses. Binding of host proteases by the viral NA, sequence of HA in the cleavage and receptor-binding sites, number of oligosaccharide side chains of HA, shortening of NA, and substitutions in PB2, NS1 and M genes, all have been suggested as molecular correlates of pathogenicity of influenza viruses. OBJECTIVES: The goal of this study was to find the alterations in genes, which might be responsible in the virus pathogenesis. MATERIALS AND METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and sequencing of HA, NA, PB2, NS and M genes were performed. RESULTS: In the receptor binding site of HA, Ile-226, Pro-227, Ser-228, and Asp-190 were found. Arg was in the cleavage site of all viruses and 11-12 N-linked glycosylation sites were found. In NS1, Asp-92 and Ala-149 were detected and Lys-627 was found in PB2 of all viruses in this study. Val-15, Thr-139 and Ala-218 of M1 and Val 28, Leu-54 and His-57 were found in M2 gene. At residue 146 of NA, there was N linked glycosylation, and Ile-222 was found in the enzyme active site. CONCLUSIONS: The changes found in these five genes, compared to other studies, suggest that viruses studied in this research had the ability to bind to Neu Acalpha2,6 Gal linkage and had low pathogenicity. It is important to mention that these changes were at the amino acid level and studies need to be performed on animals to investigate the significance of these findings. PMID- 25147685 TI - Improvement of Biodesulfurization Rate of Alginate Immobilized Rhodococcus erythropolis R1. AB - BACKGROUND: Sulfur oxides released from the burning of oil causes severe environmental pollution. The sulfur can be removed via the 4S pathway in biodesulfurization (BDS). Immobilization approaches have been developed to prevent cell contamination of oil during the BDS process. OBJECTIVES: The encapsulation of Rhodococcus erythropolis R1 in calcium alginate beads was studied in order to enhance conversion of dibenzothiophene (DBT) to 2-hydroxy biphenyl (2-HBP) as the final product. Also the effect of different factors on the BDS process was investigated. MATERIALS AND METHODS: Calcium alginate capsules were prepared using peristaltic pumps with different needle sizes to control the beads sizes. Scanning electron microscopy and flow cytometry methods were used to study the distribution and viability of encapsulated cells, respectively. Two non-ionic surfactants and also nano Y-Al2O3were used with the ratio of 0.5% (v/v) and 1:5 (v/v) respectively to investigate their BDS efficiency. In addition, the effect of different bead sizes and different concentrations of sodium alginate in BDS activity was studied. RESULTS: The 2% (w/v) sodium alginate beads with 1.5mm size were found to be the optimum for beads stability and efficient 2-HBP production. The viability of encapsulated cells decreased by 12% after 20 h of desulfurization, compared to free cells. Adding the non-ionic surfactants markedly enhanced the rate of BDS, because of increasing mass transfer of DBT to the gel matrix. In addition, Span 80 was more effective than Tween 80. The nanoY-Al2O3 particles could increase BDS rate by up to two-folds greater than that of the control beads. CONCLUSIONS: The nano Y Al2O3 can improve the immobilized biocatalyst for excellent efficiency of DBT desulfurization. Also the BDS activity can be enhanced by setting the other explained factors at optimum levels. PMID- 25147686 TI - Synergistic Effects of Bismuth Thiols and Various Antibiotics Against Pseudomonas aeruginosa Biofilm. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen that takes advantages of some weaknesses in the immune system to initiate an infection. Biofilms of P. aeruginosa can cause chronic opportunistic infections in immunocompromised and elderly patients. This bacterium is considered as a model organism to study antibiotic resistance as well as biofilm formation. In the biofilm structures, bacteria are protected from many harmful environmental factors such as fluctuations in the level of oxygen and nutrients, and the alterations of pH as well as sensitivity to antibiotics. Decreased permeability of biofilms is one of the important reasons of antimicrobial resistance in bacteria. OBJECTIVES: In this study the anti-biofilm activity of bismuth thiols in combination with ciprofloxacin, imipenem and ceftazidime against the P. aeruginosa biofilm was investigated. MATERIALS AND METHODS: Checkerboard method was used to test the susceptibility of biofilms against various antimicrobial combinations. The biofilm formation was measured by 2,3-bis (2-methoxy-4-nitro-5 sulfo-phenyl)-2H-tetrazolium-5-carboxanilide (XTT) colorimetric assay. The fractional bio-film inhibitory concentration was reported for each agent. RESULTS: The combination of bismuth ethanedithiol with ciprofloxacin showed synergistic inhibitory effect on the P. aeruginosa biofilm formation. The combination of bismuth ethanedithiol ciprofloxacin, ceftazidime and imipenem showed synergistic inhibitory effects on the biofilm formation. Furthermore, the combination of bismuth ethanedithiol, imipenem and ceftazidime did not show any synergistic inhibitory effect on biofilm formation. CONCLUSIONS: Our studies show that using appropriate concentrations of bismuth thiols in combination with various antibiotics can act synergistically against P. aeruginosa biofilm formation. PMID- 25147687 TI - The probable role of cytomegalovirus in acute myocardial infarction. AB - BACKGROUND: Coronary artery disease (CAD) is the most common cause of death worldwide and many studies have been performed on reduction of its prevalence. OBJECTIVES: This case control study was designed to investigate the presence of Cytomegaloviruses, Chlamydia pneumoniae and Helicobacter pylori in atherosclerotic plaques of cadaveric coronary endothelium of patients with and without acute myocardial infarction. PATIENTS AND METHODS: Sixty cadavers in two equal groups were analyzed. Acute myocardial infarction group included cadavers with acute myocardial infarction and atherosclerotic plaque. The non- acute myocardial infarction group included those with innocent atherosclerotic plaques in autopsy, expired due to other causes. Specimens from coronary vessels' atherosclerotic plaque were taken and studied by polymerase chain reaction for Cytomegaloviruses, C. pneumoniae and H. pylori. RESULTS: Cadavers of 26 males and 34 females underwent autopsy procedures. Their mean age at the time of death was 48.17 +/- 18.74 years. Unknown causes (20%), hanging (20%), head trauma (16.7%) and multiple traumas (13.3%) were the most common causes of death in the non- acute myocardial infarction group. PCR test results were negative for C. pneumoniae and H. pylori in all cadavers of both groups. Nine cadavers from the acute myocardial infarction group and one from the non- acute myocardial infarction group showed positive PCR results for Cytomegaloviruses (30% and 3.33%, respectively). There was a significant difference between the two groups regarding Cytomegaloviruses positivity in coronary artery plaques (P < 0.01, odd ratio: 12.42, 95% CI: 10.46 to 15.73). CONCLUSIONS: A significant proportion of coronary atherosclerotic plaques in cadavers with confirmed acute myocardial infarction were detected to be infected with Cytomegaloviruses while no infections of C. pneumoniae and H. pylori were detected.Coronary artery disease (CAD) is the most common cause of death worldwide and many studies have been performed on reduction of its prevalence. PMID- 25147688 TI - Urine PCR evaluation to diagnose pulmonary tuberculosis. AB - BACKGROUND: Culture and specific staining (including Zeil-Nelson and fluorescent methods) are standard measures for the diagnosis of tuberculosis (TB). These methods are time-consuming and sometimes have a low level of accuracy. In addition, in some cases obtaining samples for smear and culture involves invasive procedures; while in other cases there is no suitable sample for evaluation. Therefore, there is a need for faster and more accurate diagnostic methods. OBJECTIVES: The current study investigated the diagnostic value of tuberculosis polymerase chain reaction (TB-PCR) of urine in the diagnosis of pulmonary tuberculosis (PTB). PATIENTS AND METHODS: This case-control study included; 77 proven pulmonary tuberculosis cases (according to the national TB protocol), and 30 subjects who were completely healthy. The urine samples (50 mL) were mixed with 0.5 mL Ethylene diamine tetraacetic acid. DNA extraction and PCR testing were performed on all blood samples using SI 6110 primers. Mycobacterium tuberculosis was also cultivated in the sputum and urine samples of the patients. RESULTS: Results of the current study indicated that 48 (62.3%) patients out of 77 had a positive sputum culture. Urine cultures and acid-fast smears were negative. Urine PCR-TB was positive in 48.0% (37/77) of the patients. The specific TBPCR complex was positive in 56.2% (27/48) of the positive cultures and 34.4% (10/29) of the negative culture PTB patients. The control group had negative urine PCR (sensitivity 56.2% and specificity 100%). CONCLUSIONS: With regard to the ease of urine sample preparation and the 100% specificity the PCR method, performing urine PCR could be used as a diagnostic aid in PTB cases obtaining sputum samples is problematic. PMID- 25147689 TI - Survival of Normal and Chlorine-Stressed Pathogenic and Non-Pathogenic Vibrio parahaemolyticus Under Adverse Conditions. AB - BACKGROUND: Vibrio parahaemolyticus is an important human pathogen which can cause gastroenteritis when consumed in raw or partially-cooked seafood. The pathogenesis of V. parahaemolyticus is based on the presence of virulence factors: the thermostable direct hemolysin (TDH) and TDH-related hemolysin (TRH), encoded by the tdh and trh genes, respectively. OBJECTIVES: The present study aimed to evaluate the survival of normal and chlorine-stressed cells of pathogenic and non-pathogenic V. parahaemolyticus under adverse conditions. MATERIALS AND METHODS: Normal and chlorine-stressed cells of pathogenic and non pathogenic V. parahaemolyticus were subjected to environmental stresses such as low storage temperature (4 degrees C and -18 degrees C), high incubation temperature (50 degrees C) and high NaCl content (20%). Viable counts were then made at various time intervals by surface plating on TSA-2.0% NaCl, and the survival rates of the cells were determined and compared. RESULTS: Findings of the current study revealed that the normal cells of pathogenic and non-pathogenic V. parahaemolyticus, as well as the chlorine-stressed cells of both strains behave similarly under adverse conditions. In addition, chlorine stress increased the susceptibility of pathogenic and non-pathogenic V. parahaemolyticus to incubation at 4 degrees C, and the presence of high NaCl content in the medium. However, chlorine stress did not significantly affect the thermal tolerance of pathogenic and non-pathogenic V. parahaemolyticus, and the susceptibility to incubation at -18 degrees C. CONCLUSIONS: Chlorine-stressed cells of V. parahaemolyticus were more susceptible to adverse conditions than the non stressed ones. Pathogenic and non-pathogenic strains showed the same survival characteristics under the adverse conditions. These results should be considered in the development of food preservation measures. PMID- 25147690 TI - A Molecular Biological and Biochemical Investigation on Mycobacterium tuberculosis MutT Protein. AB - BACKGROUND: Mycobacterium tuberculosis is a vicious microbe co-existing with the infected host. This pathogen exploited opportunities to spread during periods of urbanization and social upheaval, and got retreated with improved hygiene. OBJECTIVES: This investigation was designed to clone and characterize M. tuberculosis mutT gene, a homologue of a DNA repair protein in Escherichia coli. The aim was to depict the possible role of this homologue in the virulent microbe. MATERIALS AND METHODS: A DNA fragment of the mutT gene was amplified with PCR from the genomic DNA of strain H37Rv M. tuberculosis. The expression vector was transformed into E. coli strains BL21 (DE3) and MK602 (DE3) (mutT-). The protein activity assay was performed by biochemical methods. RESULTS: M. tuberculosis MutT shares 23% identity with the E. coli MutT protein. The mutT gene DNA fragment was subcloned into the expression vector pET28a(+) and the recombinant plasmid was overexpressed in E. coli. Purified and refolded M. tuberculosis MutT possesses a dGTPase activity, which is one of the most well known preference nucleotidase activities of MutT in E. coli. This study also showed that the dGTPase activity of M. tuberculosis MutT was enhanced by magnesium and inhibited by Ni(2+) or EDTA. Endogenous MutT protein in M. tuberculosis lysate displayed a smear pattern in the Western blot, suggesting instability of this protein in the bacteria similar to the important proteins, such as P53 protein, tightly regulated by protein degradation. CONCLUSIONS: The cloned M. tuberculosis mutT gene and MutT protein were characterized. M. tuberculosis MutT has a dGTPase activity, which is one of the most well-known preference nucleotidase activities of MutT in E. coli. These findings provide further understanding about the vicious bacterium. PMID- 25147691 TI - Shedding Rates and SeroPrevalence of Brucella melitensis in Lactating Goats of Shahrekord, Iran. AB - BACKGROUND: Brucellosis remains a major worldwide zoonosis. Caprine brucellosis is a significant problem for both public health and animal production. Brucella melitensis causes disease in goats, sheep, humans, and occasionally cattle. Transmission is by ingestion or contact with infected materials, vaginal discharge, or milk. OBJECTIVES: The current study aimed to determine the rate of B. melitensis seropositives and its probable shedding in lactating goats from flocks in Shahrekord district, Iran. MATERIALS AND METHODS: In the current study, 1080 samples of milk, blood and vaginal swabs of 360 lactating goats (three samples from each animal) were randomly collected from 12 flocks in Shahrekord district. Serums from blood samples were examined by Rose Bengal plate (RBT) test and the titre of positives determined by tube agglutination test (TAT). Vaginal swab and milk (cream and sediment) samples were cultured on Brucella agar. Brucella spp. suspected pure cultures were incubated in the same conditions and then examined by Modified Zeil-Nelson (MZN) staining, oxidase and catalase tests. Positive isolates were examined by PCR. RESULTS: Out of 360 serum samples, 50 (13.9%) were positive by RBT, and six (1/66%) were positive by TAT. Culturing of milk and vaginal samples lead to isolation of 12 (3.33%) and 10 (2.77%) Brucella spp. suspected colonies, respectively. The PCR examinations of these isolates showed that ten (2.77%) milk and 6 vaginal swab samples (1.66%) belonged to B. melitensis species. Eight goats (2.22%) had positive results in RBT, culture and PCR examinations, simultaneously. CONCLUSIONS: The regional distribution of caprine brucellosis and shedding of B. melitensis through vaginal secretions and milk secretions of lactating goats indicated that 50% and 83.33% of the goat flocks contained vaginal and milk shedders, respectively. PMID- 25147692 TI - Fungal Prosthetic Valve Endocarditis by Candida parapsilosis: A Case Report. AB - INTRODUCTION: Fungal prosthetic valve endocarditis (PVE) is rare but serious complication of valve replacement surgery. Candida species, particularly Candida albicans is the most common isolated pathogen in fungal PVE (1-6%of cases). CASE PRESENTATION: We describe a 35-year-old woman who underwent mechanical mitral valve replacement about 3 years ago. She was admitted with neurological symptoms and later with dyspnea and hypotension. Transesophageal echocardiography showed large and mobile prosthetic valve vegetation. She underwent mitral valve surgery. The explanted valve and vegetation revealed lots of budding yeasts and the isolated yeast was identified as C. parapsilosis. Amphotericin B and broad spectrum antibiotic were started immediately. Unfortunately, the patient died two days after surgery, due to sepsis probably related to the candidemia. CONCLUSIONS: Fungal endocarditis is uncommon infection, but it is a serious problem in patients with prosthetic valve. Fungal PVE can occur years after the surgery, thus long-term follow-up is essential. PMID- 25147694 TI - A retrospective analysis of acute gastroenteritis agents in children admitted to a university hospital pediatric emergency unit. AB - BACKGROUND: Acute gastroenteritis is responsible observed in all age groups, especially infants and children. The etiology and clinical course of acute gastroenteritis may vary with age and etiological agents. In developing countries, the morbidity and mortality associated with infectious diarrhea is higher in children younger than five-years-of-age. OBJECTIVES: The aim of this study was to determine the prevalence and seasonal distribution of the major agents of acute gastroenteritis in children who were admitted to a Turkish university hospital pediatric emergency unit during 2009. PATIENTS AND METHODS: Seasonal distribution within a one year period and quantitative distribution were analyzed with demographic data and laboratory findings. A total of 644 subjects were enrolled in the study, with a mean age of 4.14 years. Pathogens were detected in 183 (28.4%) stool samples in children less than 16 years, admitted with acute gastroenteritis. RESULTS: Pathogens were detected in 184 (28.4%) stool samples. The age distributions of the cases were 0 - 24 months (n = 59), 2 - 5 years (n = 100), and > 5 years (n = 25). The detection rate of rotavirus, norovirus and adenovirus were; 12.7% (75/588), 9.8% (51/520) and 4.9% (28/575), respectively. Bacterial agents were detected in 36 cases. The main agent was norovirus in the 0 - 24 months group (n = 25, 42.4%), and rotavirus for ages 2 - 5 years (n = 43, 43%) and > 5 years. On the monthly distribution, cases of rotavirus were found to be more frequent in the first four months of the year. DISCUSSION: Viruses were the major pathogens in all age groups. Norovirus was the leading pathogen in the first two years. For the age groups 2 - 5 years and 6 - 16 years, rotavirus was the major pathogen. PMID- 25147693 TI - Hepatitis B virus genotyping among chronic hepatitis B individuals with resistance to Lamivudine in shahrekord, iran. AB - BACKGROUND: Hepatitis B infection, caused by hepatitis B Virus (HBV), is one of the major global public health problems. Hepatitis B Virus genotypes appear to show varying geographic distribution with possible pathogenic and therapeutic differences. Knowledge of HBV genotypes is very important for clinical treatment. Lamivudine is a nucleoside analogue that is clinically used to treat chronic hepatitis B infection. However, the main problem with the application of lamivudine is the development of viral resistance to the treatment with this anti viral drug. Besides, it has been suggested that lamivudine -resistant HBV may be genotype dependent. However, HBV genotype distribution and the biological relevance in this region are poorly understood. OBJECTIVES: The current study aimed to determine hepatitis B genotypes and their correlation with lamivudine- resistant HBV frequency among patients with chronic hepatitis B from Shahrekord, Iran. METHODS AND MATERIALS: Hepatitis B virus DNA was detected by conventional PCR in some of the serum samples obtained from HBsAg-positive Chronic Hepatitis B (CHB) patients who were referred to Health Centers of Shahrekord for routine monitoring of the disease. Subsequently, using real-time PCR, the DNA samples were used for genotyping and analysis of resistance to lamivudine. RESULTS: The DNA was detected in 23 out of 116 (19.82%) of the studied samples. Genotypes D and C were found in 17 out of 23 (73.9%), and in 6 out of 23 (26.1%) of the samples, respectively. To the authors' best knowledge, the current study is the first report on isolation of Genotype C from Iran. Two out of 17 (11.76%), and 6 out of 6 (100%) of genotypes D and C were resistant to lamivudine, respectively. Resistance to this drug was significantly different between genotypes C and D (P <0.001). CONCLUSIONS: In addition to genotype D, other lamivudine resistant hepatitis B genotypes might be distributed in Iran. PMID- 25147695 TI - mec-A-mediated Resistance in Staphylococcus aureus in a Referral Hospital, Tehran, Iran. AB - BACKGROUND: The emerge of rapid and accurate detection of Meticillin-Resistant Staphylococcus aureus (MRSA) has been highlighted. OBJECTIVES: The current study evaluated the prevalence of mec-A gene in biological specimens of various medical wards, in order to determine any possible relationship. PATIENTS AND METHODS: Using traditional culture methods, 250 isolates were detected. The prevalence of mec-A mediated resistance was evaluated by PCR method. RESULTS: Among 98 isolates (39.2%) with resistant inhibition zones, 92 isolates carried mec-A gene and were considered as MRSA. Significantly higher rate of MRSA was observed in the specimens from emergency department and intensive care unit (P value < 0.001). Although, the prevalence of MRSA was higher in patients with history of previous hospital admission within the past three months (P = 0.006), but only one case with the same history was hospitalized in the emergency ward that was among the wards with the highest rate of MRSA. CONCLUSIONS: The study findings show that, although there is higher rate of MRSA infection in patients with history of hospitalization, but even in cases without any history of medical admission, more detailed questions emphasizing on receiving any recent health care should be asked in a referral hospital, in order to determine the true community-acquired MRSA. PMID- 25147697 TI - Some Virulence Factors of Staphylococci Isolated From Wound and Skin Infections in Shahrekord, IR Iran. AB - BACKGROUND: Staphylococci release a large number of enzymes. Some of these, such as coagulase, beta- lactamase, hemolysins and biofilms are considered indices of pathogenicity. OBJECTIVES: The aim of the current study was based on the isolation and identification of Staphylococcus aureus and coagulase negative Staphylococci (CNS) strains from various skin lesions and examining their biofilms, beta- lactamase, hemolysins production and antibiotic resistance pattern. MATERIALS AND METHODS: Sixty one infected wounds and 39 skin infections samples were collected and examined. After the culture and identification, examination for production of hemolysins, beta- lactamase, biofilm and susceptibility toward 9 antimicrobials was performed. RESULTS: Out of 75 isolated Staphylococci, sixty (80%) were biofilm producers. Two overall prevalence of 28.5% and 100% of beta-lactamase production were recorded for isolated S. aureus and CNS, respectively. Twenty out of 49 (40.8%), the same number of alpha- and beta- hemolytic S. aureus, were isolated while six (12.24%) were ? -hemolysin producers. Twenty two of Twenty six (84.6%) isolates of CNS, were hemolysin producers that all were ? type. The S. aureus isolates from wound infections, show a high sensitivity pattern to all examined antibiotics, this sensitivity pattern for isolates from skin dermatitis is relatively low, though. CONCLUSIONS: High percentage of hemolysins, biofilm and beta lactamase production by isolated Staphylococci, suggests an important role of these virulence factors in the pathogenesis of isolated Staphylococci from dermatitis lesions. The S. aureus isolates from wound infections, show a high sensitivity pattern to all examined antibiotics. Only ciprofloxacin was found to be active against all isolates from dedermatitis lesions. PMID- 25147696 TI - Molecular Characterization of Cryptosporidium spp. Isolated From Immunocompromised Patients and Children. AB - BACKGROUND: Cryptosporidium is known to be one of the most important causes of diarrhea in children and immunocompromised patients. Genotype characterization of Cryptosporidium species in each region would help in the treatment of this disease, as well as to locate the source of infection and to prevent the disease. OBJECTIVES: This current research was conducted in order to analyze the molecular characterization of isolated Cryptosporidium spp. in the Southwest of Iran. MATERIALS AND METHODS: In this survey, 390 fecal samples were collected from immunocompromised individuals and children under five-years-of-age. Parasitic infection was evaluated using wet mount preparation, formalin ether, a modified acid fast staining method and microscopic examination. Finally, a PCR-RFLP assay was performed on the extracted DNA collected from fecal samples that were positive for Cryptosporidium by the acid fast method. RESULTS: Among the 390 fecal samples, 16 cases (4.1%) were infected with Cryptosporidium. Molecular and genotype characterization found the following protozoan species; 11 Cryptosporidium parvum (68.8%), 4 C. hominis (25%), and one case of C. meleagridis (6.2%). CONCLUSIONS: The present study emphasized the public health importance of Cryptosporidium spp. in the study area. In addition, it seems that zoonotic species are the most important causes of infection in the region. As far as we are aware this the first report of a C. meleagridis infection in Iran. PMID- 25147698 TI - Prevalence of yersinia species in traditional and commercial dairy products in isfahan province, iran. AB - BACKGROUND: Yersinia species, especially Yersinia enterocolitica, are considered as the most prevalent milk-borne pathogens. Several serological and molecular techniques have been developed for rapid and safe diagnosis of yersiniosis. OBJECTIVES: This study was carried out to assess the prevalence rate of Yersinia species, especially Y. enterocolitica, in milk and dairy products in Isfahan province, Iran. MATERIALS AND METHODS: A total of 285 commercial and traditional dairy products as well as 267 pasteurized and raw milk samples were collected during one year. The samples were studied by culturing and the positive-culture samples were investigated using PCR techniques. RESULTS: The results of culture showed that 52 (9.42%) and 28 (5.07%) of the total 552 milk and dairy samples were positive for presences of Yersinia species and Y. enterocolitica, respectively. Totally, 24 of 28 Y. enterocolitica isolates by culture were positive in PCR test (4.59%). Raw cow milk and traditional cheese had the highest prevalence of Yersinia species and Y. enterocolitica, respectively. There were no positive results for pasteurized cow milk, raw camel milk, commercial ice cream, commercial cheese, yoghurt, Doogh, butter and curd. Yersinia species and Y. enterocolitica had the highest prevalence in autumn (15.15% and 10.6%, respectively). Significant differences regarding P < 0.05 were observed between the presences of Yersinia species and Y. enterocolitica in various samples and seasons. CONCLUSIONS: Sanitation and pasteurization are the best ways to increase the microbial quality and particularly decrease the load of Yersinia species. The ability of Yersinia species to growth in Doogh, yoghurt, curd and butter is very low. PMID- 25147699 TI - Prevalence of Salmonella spp. in Packed and Unpacked Red Meat and Chicken in South of Tehran. AB - BACKGROUND: Despite of the advances in infectious diseases prevention and food technology, food-borne diseases are considered major problems in developed and developing countries. Meat plays a key role in transferring zoonotic diseases to human. OBJECTIVES: This study was conducted in south of Tehran, Iran, to investigate the prevalence rate of Salmonella spp. in packed and unpacked red meat and chicken. MATERIALS AND METHODS: A total of 379 packed and unpacked samples including 189 red meat and 190 chicken samples were collected randomly. From each sample, 25 g was separated and treated with 225 mL of buffered peptone water, homogenized and incubated at 37 degrees C for 24 hours. Samples were enriched using Rappaport-Vassiliadis broth and then streaked onto Hektoen enteric agar. RESULTS: Totally, 86 out of 190 chicken and 38 out of 189 red meat samples were contaminated with Salmonella spp. The most isolated serotypes were Salmonella thompson (67.7%), S. heaardt (6.5%), S. enteritidis (4.8%), and S. veyle (4%), respectively. In general, the rate of chicken contamination was higher than meat, as 43.3% of packed and 46% of unpacked chicken samples were contaminated. CONCLUSIONS: These results confirmed the pervious findings, stating that proper packaging of meat products can effectively decreases the rate of microbial contaminations. PMID- 25147700 TI - Prevalence and Mortality of Influenza A (H1N1) Virus Among Patients With Acute Respiratory Infection in Southwest Iran. AB - BACKGROUND: Khuzestan and other parts of Iran were involved with Influenza A (H1N1) pandemic in 2009. OBJECTIVES: The aim of this study was to describe the prevalence and mortality of H1N1 in Behbahan, a city in Khuzestan, Southwest of Iran. PATIENTS AND METHODS: The study population consisted of cases of influenza, hospitalized or referred to the city health centers. Diagnosis of H1N1 virus infection was based on rapid antigen testing (RT-PCR) of nasopharyngeal swabs. Data extracted from epidemiological survey forms, including demographic and clinical characteristics, laboratory results, risk factors and underlying diseases, medications, and treatment outcomes of patients were analyzed using SPSS 16 software by using Pearson chi-square test. RESULTS: From a total of 318 patients, 180 (56.6%) were male and 138 (43.4%) female. Total number of patients with positive H1N1 tests was 167 (52.5%) with a male: female ratio of 1.2:1. Of total 318 admitted patients, 173 (96.1%) males and 135 (97.8%) females recovered and 10 people (7 (3.9%) males and 3 (2.3%) females) died, among which, three had positive test results for H1N1. The most prevalent signs and symptoms were: fever in 308 (96%) patients, cough in 278 (86.6%), lower respiratory symptoms in 208 (64.8%), gastrointestinal symptoms in 90 (28%), respiratory distress in 45 (13.7), and flu-like symptoms in 65 (20.2%) patients. CONCLUSIONS: Prevalence rate of H1N1 infection in the study region was higher compared to other part of Iran; but, close to the expected rate. The H1N1-associated mortality rate was lower than the reported rates in Iran and other parts of the world. PMID- 25147701 TI - Vancomycin and oxacillin co-resistance of commensal staphylococci. AB - BACKGROUND: Many disease conditions including Staphylococcal infections are becoming increasingly difficult to treat in South Africa due to the surge of vancomycin-oxacillin resistant strains. How widespread this phenomenon is in commensal isolates in the Nkonkobe municipality in the Eastern Cape Province of South Africa is not known, and considering the high level of immunocompromised individuals in the province, this study couldn't have come at a better time. OBJECTIVES: The objective of this study is to evaluate the prevalence of vancomycin and oxacillin co-resistance in methicillin-resistant commensal staphylococci in Nkonkobe municipality, South Africa as part of our larger study on the surveillance of reservoirs of antibiotic resistance in South Africa. MATERIALS AND METHODS: Staphylococcus species were isolated from domestic animals of Nkonkobe municipality, in the Eastern Cape Province of South Africa. The isolates were evaluated for antibiotic susceptibility against a panel of several relevant antibiotics. Specific primer sets were also used for the polymerase chain reaction assay to detect the presence of mecA gene as well as vanA and vanB genes in the genome of resistant Staphylococcus species. RESULTS: A total of 120 Staphylococcus isolates were screened, out of which, 32 (26%) were susceptible to both methicillin and vancomycin, while 12 (10%) had co-resistance to the antibiotics, which is still on the high side, both clinically and epidemiologically. Gentamicin (an aminoglycoside) had a relatively high potency against the isolates with 107 (89.17%) of the bacteria being susceptible to it, while 10 (8.33%) were resistant. On the other hand, erythromycin (a macrolide) was active against 72 (60%) of the isolates, while 5 (4.17%) and 74 (61.67%) of them yielded intermediate and resistant responses, respectively. Similarly, 51 (42.5%) of the isolates were susceptible to rifampicin, while 1 (0.83%) and 17 (14.17%) were intermediate and resistant, respectively. CONCLUSIONS: Ten percent of the isolates were positive for mecA gene among the vancomycin-oxacillin resistant strains, while van gene was not detected in any of the isolates. The data obtained would be useful in clinical control of resistant staphylococcal strains. PMID- 25147702 TI - Morphological, biochemical and molecular characterization of twelve nitrogen fixing bacteria and their response to various zinc concentration. AB - BACKGROUND: Zinc is an essential micronutrient used in the form of zinc sulfate in fertilizers in the agriculture production system. Nitrogen-fixing microorganisms are also of considerable value in promoting soil fertility. OBJECTIVES: This study aimed to investigate the degree of sensitivity to varying concentrations of zinc, in the form of ZnSO4, in different strains of Azotobacter chroococcum in a laboratory environment. MATERIALS AND METHODS: To isolate A. chroococcum strains, soil samples were collected from wheat, corn and asparagus rhizospheres and cultured in media lacking nitrogen at 30C for 48 hours. Strains were identified based on morphological and biochemical characteristics. The presence of the nitrogenase enzyme system was confirmed by testing for the presence of the nifH gene using PCR analysis. The minimum inhibitory concentration (MIC) and optimal zinc concentration for the growth of each strain was determined. RESULTS: A total of 12 bacterial strains were isolated from six different soil samples. A. chroococcum strains were morphologically and biochemically characterized. The presence of the nifH gene was confirmed in all the strains. MIC and the optimal zinc concentration for bacterial growth were 50 ppm and 20 ppm, respectively. CONCLUSIONS: It was concluded that increasing the concentration of zinc in the agricultural soil is harmful to beneficial microorganisms and reduces the soil fertility. A 20-ppm zinc concentration in soil is suggested to be optimal. PMID- 25147703 TI - Therapeutic Effect of Hedera helix Alcoholic Extract Against Cutaneous Leishmaniasis Caused by Leishmania major in Balb/c Mice. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is common and endemic in many areas of Iran, caused by species of a protozoan parasite belonging to the genus Leishmania. There is not any effective vaccine against leishmaniasis; so, therapy is important for prevention and separation of disease. Herbal extract for treatment of CL is cost-effective, applicable topically to lesions, and can avoid the development of drug resistance. OBJECTIVES: The aim of this study was to evaluate the in vivo activity of an alcoholic extract of Hedera helix (a native Iranian plant) on the experimental ulcer of zoonotic CL in Balb/c mice. MATERIALS AND METHODS: At least 5x l0(6) promastigotes of Leishmania major (MHOM/64/IR/ER75) were inoculated subcutaneously in the tail base of Balb/c mice. Fifty six infected mice were distributed in four groups, two groups (16 mice for 20% alcoholic extract of H. helix and 13 for 70% extract) were used as experimental groups, one (15 mice) as placebo control (Control A), and one (12 mice) as negative control. Treatment effects of two concentrations were determined by comparison of placebo and nontreated groups via measuring the size of skin lesions and the number of parasitologically positive and negative mice after the therapy period. RESULTS: This study showed that the main lesion size did not decrease significantly, or the small lesions did not completely disappear after treatment by H. helix alcoholic extract. Amastigotes counts (mean +/- SD) of the skin lesions decreased in control A and 20% concentration groups, but in negative control and 70% concentration groups the number of parasites did not reduce. CONCLUSIONS: The present study did not support the in vivo antileishmanial effect of H. helix extract. We recommend further studies using major components of H. helix, especially hederasaponin (saponin K10), to investigate the antileishmanial effect of this plant on L. major. PMID- 25147704 TI - Comparison of Genital Chlamydia trachomatis Infection Incidence Between Women With Infertility and Healthy Women in Iran Using PCR and Immunofluorescence Methods. AB - BACKGROUND: For a long time, infertility has been one of the most sequels in medical sciences with microbial agents as one group of its causes. The possible etiological role of Chlamydia trachomatis in infertility was suggested years ago, but it has not yet been proved completely. To decrease the severe involvements of C. trachomatis infections, screening by efficient diagnostic methods are necessary. OBJECTIVES: In this study we attempted to determine the incidence of C. trachomatis in infertile women and compared this with healthy women. MATERIALS AND METHODS: This case-control study was performed on 150 infertile women with unknown causes and without physiological deficiency for infertility. The control group consisted of 200 fertile safe and impregnated women. Presence of C. trachomatis in the two groups was examined by direct and indirect immunofluorescence tests and PCR. RESULTS: C. trachomatis was detected by direct immunofluorescence method in 23 (15.3%) infertile women compared and 7 (3.5%) healthy controls. Using indirect immunofluorescence tests, a positive test titer of 1:16 as well as the above results were detected in 34 (22.6%) of the infertile cases and 9 (4.5%) of the controls. C. trachomatis was detected by PCR method in 48 (32%) infertile women and 13 (8.7%) among the controls. CONCLUSIONS: The results of our study suggest that there is a significant association between C. trachomatis infection and female infertility. PMID- 25147705 TI - Statins and postoperative infections: a randomized clinical trial. AB - BACKGROUND: Observational studies, rather than randomized trials, revealed that statins might be associated with other benefits. OBJECTIVES: The present study aimed at evaluating the preventive effects of lovastatin when used as a prophylactic agent for early and late infective complications after surgery. PATIENTS AND METHODS: A total of 149 patients undergoing elective intracranial and spinal surgeries, were enrolled in a double- blind randomized clinical trial in the department of neurosurgery of a teaching hospital. An amount of 20 mg lovastatin and the same dose of placebo, one day before the operation and three days after the surgery, were used for cases and controls, respectively. The patients were evaluated for local and systemic infections during hospitalization and 10, 30, 60 and 90 days after discharge. RESULTS: A total of 149 patients, 78 men and 71 women with a mean age of 40.3 +/- 16.5, were assigned to prophylactic protocols. 46 and 103 patients were in the case and control groups, respectively. Eight episodes of infection were detected, including six bacterial meningitis and two episodes of hospital- acquired pneumonia. All of the patients with documented postoperative infections were part of the placebo group, however, there were no significant statistical differences between the groups (P = 0.059). CONCLUSIONS: In spite of the differences between the two groups, the results did not significantly support the preventive effect of statins in postoperative infections. PMID- 25147706 TI - Electrophoretic Patterns of Toxoplasma gondii Excreted/Secreted Antigens and Their Role in Induction of the Humoral Immune Response. AB - BACKGROUND: Toxoplasma gondii is an obligatory intracellular protozoan parasite on which studies are pending regarding production of vaccine. To date, the production of human vaccine has not been successful where approximately one third of the world's population is thought to be infected with T. gondii. OBJECTIVES: The present study was designed to compare the electrophoretic patterns of T. gondii excreted/secreted antigens (ESAs) and determine their role in the stimulation of the humoral immune response. MATERIALS AND METHODS: T. gondii ESAs were prepared from cell cultures (albino rat fibroblast) and cell-free mediums (RPMI-1640). Next, the SDS-PAGE technique was used for comparing molecular weights of the antigens. Forty C57BL/6 mice were divided randomly into four groups (n = 10). Immunization was performed subcutaneously at an interval of 2 weeks in two groups by injecting 100 ug of each of the above-mentioned antigens. Two groups, as negative control, also received fibroblast lysate proteins or adjuvant separately. All of the groups were then challenged with the T. gondii RH strain. Serum samples were collected from all mice and measured by immunoblotting technique for detection of immunogenic antigens. RESULTS: The electrophoretic mobility of the prepared antigens/proteins from cell culture, cell-free media, Fibroblast Lysate Proteins and Toxoplasma Lysate Antigens (TLA) showed 13, 12, 8 and 8 bands, respectively. The case groups, in challenge with T. gondii (RH strain), showed more survival prolongation than the control groups. Furthermore, the survival period was identical for both case groups with a tendency for slightly higher survival of mice receiving ESA from cell-free medium. Analysis of sera by immunoblotting also revealed one band of 65 KDa in sera from both case groups. CONCLUSIONS: We suggest that this band be extracted and its amino acids sequence determined to produce Synthetic Polypeptide for immunization studies. PMID- 25147708 TI - Cloning, Expression, and Purification of Recombinant Lysostaphin From Staphylococcus simulans. AB - BACKGROUND: Staphylococcus aureus is one of the most common causes of nosocomial infections and its resistance to antibiotics is a global concern. Lysostaphin is an antimicrobial agent belonging to a major class of antimicrobial peptides and proteins known as the bacteriocins. It exhibits a high degree of anti staphylococcal bacteriolytic activity. OBJECTIVES: In this study, high level of recombinant mature lysostaphin in Escherichia coli was produced by using pET32a expression vector. MATERIALS AND METHODS: The S. simulans gene encoding lysostaphin was extracted, amplified by polymerase chain reaction (PCR), and sub cloned in prokaryotic expression vector pET32a. E. coli BL21 (DE3) plysS were transformed with pET32a-lys and gene expression was induced by IPTG. The expressed protein was purified by affinity-chromatography using (Ni-NTA) resin. RESULTS: PCR and sequencing results confirmed the successful cloning of the target gene into the vector. The expression of protein was induced by IPTG and high concentration of the recombinant protein was obtained via the purification process by affinity-chromatography. CONCLUSIONS: Our data showed that the recombinant mature lysostaphin protein produced by pET32a vector in E. coli system was very efficient. PMID- 25147707 TI - Identification of leishmania isolates from healing and nonhealing cutaneous leishmaniasis patients using internal transcribed spacer region PCR. AB - BACKGROUND: Cutaneous Leishmaniasis (CL) is a parasitic disease in most parts of Iran, especially in the Isfahan province. The most common form of CL is a self healing lesion but in rare situations, infection might develop to non-healing forms. Clinical symptoms and treatment process might be influenced by several agents such as host immune response and parasite strains. In this study, the isolates which caused healing and nonhealing forms of CL in Isfahan were characterized by internal transcribed spacer (ITS) polymerase chain reaction (PCR) technique. OBJECTIVES: The aim of this study was to identify Leishmania species isolated from healing and non-healing CLs using PCR method. PATIENTS AND METHODS: Thirty patients resident in Isfahan province, with healing or non healing form of CL were entered into this study. After DNA extraction, the identification of Leishmania isolates was done by ITS1-PCR method. RESULTS: Leishmania major was found as the predominant species (100%) in both healing and non-healing forms of CL. CONCLUSIONS: It seems that there is no difference between Leishmania species in healing and non-healing forms of CL. In order to recognize the reason of long lasting lesions in non-healing patients, the study about parasite strains and immune factors at the molecular level mostly in nonhealing patient is recommended. PMID- 25147709 TI - Detection of Helicobacter pylori in Various Types of Vegetables and Salads. AB - BACKGROUND: There is a possibility for the presence of Helicobacter pylori in vegetables due to their close contact with polluted water, soil and feces. OBJECTIVES: This study was carried out to detect the presence of H. pylori in vegetables and salads in Iran. MATERIALS AND METHODS: In total, 460 vegetable and salad samples were collected and transferred immediately to the laboratory. All samples were cultured and tested for the presence of H. pylori using the Polymerase Chain Reaction technique. RESULTS: The results showed that 44 of 460 samples (9.56%) were positive for H. pylori using the culture method. The Polymerase Chain Reaction technique showed that 50 of 460 samples (10.86%) were positive for H. pylori. Un-washed leek, traditional salad, un-washed basil and un washed lettuce were the most commonly contaminated samples. The presence of the bacteria in various vegetables was statistically significant (P < 0.05). CONCLUSIONS: Vegetables are a new source of H. pylori and accurate washing of vegetables improves such contaminations. PMID- 25147710 TI - Investigation of Class I Integron in Salmonella infantis and Its Association With Drug Resistance. AB - BACKGROUND: Infection with non-typhoid Salmonella (NTS) is one of the most important health problems all over the world. Antimicrobial drug resistance is increasing among Salmonella infantis species. OBJECTIVES: The aim of this study was to investigate the frequency of presence of class 1 integrons in S. infantis species as well as its association with drug resistance. MATERIALS AND METHODS: This cross-sectional study was performed on 50 S. infantis isolated strains, collected from chicken samples between 2009-2011. These strains were identified by standard biochemical tests and serology. Antibiotic susceptibility profiles and minimum inhibitory concentration determination for 14 antibacterial agents were performed using micro dilution and disk diffusion methods. The detection of class 1 integron was performed by the PCR method. The demographic and microbiological data for the integron positive and negative isolates were compared by SPSS software. RESULTS: Eighteen out of 50 (36%) of isolated S. infantis species had intl gene. The isolated bacteria were sensitive to cefotaxime and ciprofloxacin (100%). Also isolates were resistant to nalidixic acid, tetracycline and streptomycin. All isolate with class 1 integron were multidrug resistant. CONCLUSIONS: The result of this study showed that due to increased level of drug resistance in S. infantis and the presence of class 1 integron in these strains, resistance can be transferred to other food borne pathogens. PMID- 25147711 TI - Biofilm Formation by Staphylococcus epidermidis on Foldable and Rigid Intraocular Lenses. AB - BACKGROUND: Biofilm formation of Staphylococcus epidermidis is a major etiological factor of inducing device-related infections. OBJECTIVES: The ability of biofilm formation by the S. epidermidis was assessed in vitro on two brands of foldable (hydrophilic) and two brands of rigid (hydrophobic) intraocular lens materials in order to investigate the role of lens material in postoperative endophthalmitis. MATERIALS AND METHODS: To ensure reproducibility of biofilm formation on intraocular lenses, two strains of S. epidermidis and three quantification methods were performed. The S. epidermidis strains, DSMZ3270 (biofilm-producer) and ATCC12228 (non-biofilm-producer) were applied. Organisms were cultivated on disks of different brands of foldable hydrophilic Intra Ocular Lens (IOL) made of acrylic (Didar, Iran; (A) and Omni, India; (B)), and rigid hydrophobic IOL made of polymethyl methacrylate (PMMA; Didar, Iran; (C) and Hexavision, France; (D)). Biofilms were stained with crystal violet (CV) dye, which is an index of biofilm formation. The bacterial population was counted after biofilm homogenization. Scanning electron microscopy (SEM) was performed to examine the extent of biofilm formation. RESULTS: Adherence of DSMZ3270 strain on both types of foldable and rigid IOLs, was significantly more than ATCC12228 (P < 0.001-0.05 and, P < 0.01-0.05, respectively). The bacterial populations between the lenses were significantly different (P < 0.05). Subsequent studies demonstrated significant differences between brands of foldable and PMMA IOLs. According to statistical analyses the incubation time influenced the biofilm formation on both types of IOLs which meant that by increasing incubation time, the biofilm formation increased. According to the SEM pictures, biofilm seems to be lysed at 72 hours. CONCLUSIONS: These data demonstrated that the attachment of bacteria to hydrophilic acrylic IOLs was more than hydrophobic PMMA ones independent of the brand. According to these results the bacterial strain might have more hydrophilic properties. Augmenting the biomass of biofilm by passing of time demonstrated the key role of time in biofilm formation on the IOL surfaces. The differences between IOL brands in the biofilm formation indicated the influence of design parameters for IOLs. PMID- 25147712 TI - Antimicrobial and Genotoxicity Effects of Zero-valent Iron Nanoparticles. AB - BACKGROUND: In a world of nanotechnology, the first concern is the potential environmental impact of nanoparticles. An efficient way to estimate nanotoxicity is to monitor the responses of bacteria exposed to these particles. OBJECTIVES: The current study explored the antimicrobial properties of nZVI (zero-valent Iron nanoparticles) on the Gram-negative bacterial systems Erwinia amylovora, Xanthomonas oryzae and the Gram-positive bacterial systems Bacillus cereus and Streptomyces spp. The genotoxicity potential of nZVI was also assayed. MATERIALS AND METHODS: THE TOXICITY OF NZVI WAS TESTED BY TWO DIFFERENT METHODS: Growing bacteria in liquid (broth dilution) and agar media (challenge test) containing different nZVI concentrations for 24-72 hours. The genotoxicity of nZVI was assessed using the preincubation version of the Ames test. RESULTS: The lowest concentrations of nZVI that inhibited the visible growth (MIC) of E. amylovora, X. oryzae, B. cereus and Streptomyces spp. were 625, 550, 1250 and 1280 ppm, respectively. The minimum bactericidal concentration (MBC) for E. amylovora and X. oryzae were 10,000 and 5,000 ppm of nZVI, respectively. MBC was not observed for the Gram positive bacteria. No bacteriostatic and bactericidal effects were observed for oxidized nZVI. Mutant frequency did not increase according to the vehicle control at the concentrations assayed, indicating a lack of mutagenicity associated with nZVI. CONCLUSIONS: nZVI nanoparticles are not mutagenic at low concentrations, therefore they can be used without detrimental effects on soil bacteria. PMID- 25147713 TI - Hepatitis B virus DNA level Among the Seropositive Afghan Immigrants, Southern Iran. AB - BACKGROUND: Diagnosis and control programs for infectious diseases among immigrants are the most important aspects of epidemiological studies for both origin and destination countries. Data about hepatitis B virus (HBV) infection among the Afghan immigrants in Iran is limited. OBJECTIVES: To the best of HBV treatment and prevention in Afghan immigrants in Iran, the present study was conducted to determine the virus DNA level, and the frequency of respective hepatitis B risk factors among the respective seropositive patients in Fars province, southern Iran. PATIENTS AND METHODS: A total of 64 HBsAg positive Afghan immigrants including 47 (73.4%) men and 17 (26.6%) women, with ages ranging between 15 and 74 years (mean +/- standard deviation: 37.69 +/- 15.02 years) participated in this study. From those, whole blood sample were collected and DNAs were extracted from the sera and analyzed by TaqMan real-time PCR assay with a set of primers and probe amplified core protein region of HBV genome. RESULTS: HBV DNA was detected in a total of 51/64 (79.7 %) serum samples; 37 (72.5%) male and 14 (27.5%) female. The copy number of HBV DNA ranged from 5 * 10(2) to 8.49 * 10(8) copies/mL in the serum samples; median 3.8 * 10(4) copies/mL. Demographic data and risk factors were also evaluated. The comparison of viral loads between the age groups and sex indicated no significant correlation (P > 0.05). However, the serum HBV DNA level significantly decreased in the treated patient group (P = 0.03). There was no significant difference in medicine usage between the two sexes in the study population (P > 0.05). CONCLUSIONS: Considering the results, determining the HBV DNA load and evaluation of treatment response can help to reduce the costs of diagnosis and treatment procedures in such patients, as well as, decreasing the risk of HBV transmission in immigrant Afghan population. Moreover, HBV screening strategies in country border entrances among immigrant should be performed. Moreover, free vaccination and treatment programs, and improving the level of HBV knowledge among Afghan immigrants in Iran is highly recommended. PMID- 25147714 TI - Pyelonephritis Caused Solely by Escherichia hermanii. AB - INTRODUCTION: In contrast with Escherichia coli, the association of E. hermanii with urinary tract infections has not been described. CASE PRESENTATION: In this case, E. hermanii was the sole isolate recovered from urine specimens of a pyelonephritis patient. The organism was found to be susceptible to piperacillin tazobactam, ceftazidime, cefazolin, cefixime, aztreonam, gentamicin, tobramycin, imipenem, meropenem and amikacin, and resistant to amoxicillin. Antibiotic treatment was initiated with oral cefixime (400 mg every 24 hours). The symptoms were relieved within 72 hours after therapy. A urine sample was taken seven days after antibiotic therapy. E. hermanii was no longer isolated. DISCUSSION: The present case demonstrates that the uropathogenic E. hermanii clone can cause destruction of the kidneys. During asymptomatic bacteriuria or cystitis, the bacteria remain in the urinary tract. Even when pyelonephritis develops, inflammatory response of the host is still restricted to the urinary tract. These signs mean that uropathogenic E. hermanii may be not very virulent. PMID- 25147716 TI - Effects of onion juice on the normal flora of eyelids and conjunctiva in an animal model. AB - BACKGROUND: Traditional medicine/complementary alternative medicine may suggest new ideas to modern medicine in order to face new challenges however these concepts should be acknowledged based on experimental studies. OBJECTIVES: We aimed to study the effects of onion (Allium cepa) juice on the normal flora of conjunctiva and eye lids, and to follow the histopathology changes of conjunctiva in an animal study. MATERIALS AND METHODS: Twenty-four rabbits were randomly classified into three equal groups. Groups 1, 2 and 3 received fresh red onion juice, as an eye drop, into the right eye twice daily for; one week, one month, and two months, respectively. Microbiological sampling by sterile swabs was performed before and after the intervention. Cultural characteristics, including the growth rate and the kind of organisms, are reported. At the end of the study, pathological samples were collected from the inferior fornix. RESULTS: After the intervention, the number of positive cultures in the samples, collected from both the conjunctiva and eyelid, had decreased. Group 3 demonstrated the lowest amount of growth after the administration of the onion juice and the bacterial isolation rates from each organism had decreased. All pathological samples revealed some degree of inflammation. There was no evidence of metaplasia or dysplasia. There was no significant difference between the growth rates of organisms in the experimental groups using statistical analysis. CONCLUSIONS: According to our experiment, onion has an inhibitory effect on the growth of normal eye flora; although the duration of onion juice instillation did not show any significant effect on the group results. Hence, this finding is an initiating point for further investigations into the antimicrobial properties of this herb to treat common eye infections, including conjunctivitis and blepharitis. PMID- 25147715 TI - Epidemiology of hepatitis e virus infection in patients on chronic hemodialysis. AB - BACKGROUND: Many studies have been done on the epidemiology of Hepatitis E on general population, but the data among patients with end stage renal disease (ESRD) are few and give conflicting results. OBJECTIVES: The aim of this study was to investigate the prevalence of hepatitis E virus (HEV) infection and its relationship in ESRD patients undergoing maintenance hemodialysis (HD). PATIENTS AND METHODS: This cross-sectional study was carried out on ESRD patients treated with HD in Imam Khomeini Hospital, Ahvaz city, Southwest of Iran. Blood sampling of patients was collected immediately before the dialysis session and the serum were evaluated for anti-HEV IgG titers by enzyme-linked immunosorbent assays. The statistical package for social sciences (SPSS) version 15 software was used for data analysis. RESULTS: Out of 47 ESRD patients, 27 were male (57.4%) and 20 were female (42.6%), with mean age of 55.27 +/- 8.1 years. The prevalence of anti-HEV antibody was 10.6 % (five patients, four male and one female). The mean age of HEV positive and negative patients were 58 +/- 5.52 and 53.82 +/- 15.55 years, respectively without any significant difference (P = 0.058). There also was no significant association between HEV and gender (P = 0.28). The mean time of HD in HEV positive and negative patients were 1224.2 and 1168.5 days, respectively with no significant association (P = 0.88). In addition, there also was no association between HEV and HCV (P = 0.61). CONCLUSIONS: According to the present study, the prevalence of anti-HEV IgG antibody was 10.63 % among chronic HD patients and there was no association between HEV, age, gender, duration of HD and HCV antibody titer. PMID- 25147717 TI - Effect of Polyvinyl Alcohol (PVA) Containing Artemether in Treatment of Cutaneous Leishmaniasis Caused by Leishmania major in BALB/c Mice. AB - BACKGROUND: Polyvinyl alcohol (PVA) is one of the well-known polymers, which has been used in numerous biomedical applications because of its good biocompatibility. OBJECTIVES: Due to problems made by the therapeutics already used for leishmaniasis, the aim of this study was to evaluate the effect of PVA containing artemether in treating cutaneous leishmaniasis in BALB/c mice. MATERIALS AND METHODS: Aqueous solution of PVA was prepared by mixing with Double Distilled Water. After preparation of PVA, 4.33 mg of each drug (main drug artemether and control drug 14% glucantime) was added to 100 g of prepared PVA honey solution. The solution was incubated at 37 degrees C and the release of artemether was evaluated by measuring absorbance at 260 nm wave length. In this study for treatment of mice lesion, we used PVA containing artemether and glucantime and this method was compared with ointment treatment. RESULTS: Mean diameters of lesions in mice treated with artemether were smaller than the control group and the differences were significant (P < 0.05). The mean lesion size of mice treated with PVA containing artemether in comparison with the group treated with ointment of artemether were smaller and the differences were significant (P < 0.05). CONCLUSIONS: PVA containing artemether is a new method for treatment of cutaneous leishmaniasis and according to the obtained results, artemether is an appropriate and effective drug, especially when used with PVA as a lesion dressing; thus we suggest that this method can be applied for the treatment of cutaneous leishmaniasis. PMID- 25147718 TI - Allelic Forms of Merozoite Surface Protein-3 in Plasmodium falciparum Isolates From Southeast of Iran. AB - BACKGROUND: Genetic diversity has provided Plasmodium falciparum with the potential capacity of avoiding the immune response, and possibly supported the natural selection of drug or vaccine-resistant parasites. Merozoite surface protein-3 (MSP-3) has been used to develop vaccines and investigate the genetic diversity regarding P. falciparum malaria in Iran. OBJECTIVES: The main goal of this study was to analyze the polymorphic antigen MSP-3 genes across southeast of Iran among four different districts, to identify the differences in the allele frequency and genetic diversity. MATERIALS AND METHODS: Nested polymerase chain reaction amplification was used to determine polymorphisms of N-terminal region of the MSP-3 gene. A total of 85 microscopically positive P. falciparum infected individuals from southeast of Iran were included in this study. RESULTS: Of the 85 confirmed P. falciparum samples obtained from four different districts, 72 were successfully scored for MSP-3.The MSP-3 allele classes (K1 and 3D7 types) showed comparable prevalence in all districts. Overall frequencies of K1 and 3D7 allele classes were 94.5 % for both. CONCLUSIONS: Since no study has yet looked at the extent of P. falciparum MSP-3 in this geographic region, these data can be helpful to support development of a vaccine based on MSP-3 against malaria. There should be a comparative analysis in different seasonal peaks to indicate the allelic polymorphism of MSP-3 over a period. PMID- 25147719 TI - The rise of staphylococcal super antigens in psoriatic patients: a case-control study. AB - BACKGROUND: Staphylococcus aureus, the major virulence factor of hospital and community acquired infections, secretes numerous exotoxins (super antigens), which may affect immunological and inflammatory status in psoriatic skin lesion. OBJECTIVES: This study is designed to compare the S. aureus super antigens level in sera of psoriatic patients with normal cases (nevus). PATIENTS AND METHODS: A case control study was performed in dermatology ward of Rasoul Hospital in Tehran, IR Iran (2008 - 2010). Staphylococcal super antigens (Entrotoxin A, B, D and TSST1) were measured in serum of 41 psoriatic patients and 28 normal persons (Nevus) by ELISA. Chi square values (CI 95%, P value < 0.05) were calculated for all categorical variables. RESULTS: In this study 63.4% (26) of cases were male, 36.6% (15) were female. Age ranged from 4 months to 64 years old, with a mean age of 33.7 +/- 15.4 years. Type of skin disease in cases: 20% (8) were inflicted by the Gutate form of the disease; 59% (23) with chronic plaque psoriasis (CPP), 7.7% (3) with erythrodermic and 12.8% (5) had other types of the disease (plaque, pustular, inverse). TSST (toxic shock syndrome toxin) was detected in 47% (20/41) of cases and in 6% (1/28) of the controls with a significant difference. (P value = 0.000) Entrotoxins (A, B, D) were detected in the sera of 48.8% (21/41) of cases; and only 6 %( 1/21) of controls, showed significant differences (P value = 0.000) positive TSST was more common in spring, and correlates with CPP type of psoriasis, but not related to patient's gender and age. CONCLUSIONS: In this study, S. aureus were 25 times more in psoriatic patients. Super antigens should be first detected in the serum samples; if negative, the skin lesions should be examined by PCR especially in chronic types of disease. Adding the antibiotics against S. aureus to other conventional treatments might be helpful. It has a more important and significant role in children with acuteinfection. PMID- 25147720 TI - Genetic elements associated with antimicrobial resistance among intestinal bacteria. AB - BACKGROUND: Integrons are the major reasons of multidrug resistance (MDR) among enteropathogenic bacteria. Occurrence of horizontal gene transfer between integron-carrying microorganisms and other enteric bacteria may increase the rate of emergence of integron-associated antibiotic resistance. OBJECTIVES: The objective of this study was to investigate class 1 integrons among members of enteropathogenic bacteria isolated from patients in Iran. MATERIALS AND METHODS: A total of 120 enteropathogenic bacterial isolates from diarrhoeal patients were included in this study. Identities of the isolates were investigated by biochemical tests and confirmed by genus or species specific PCRs. Antimicrobial susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Presence of class 1 integron among the isolates was investigated using primers specific for the integrase gene conserved region. RESULTS: The result of this study showed the highest resistance to trimethoprim and cotrimoxazole, especially in enteropathogenic Escherichia coli (EPEC) (100%), Shigella sonnei (93.7%) and Vibrio cholerae (95%). The results showed that 16 (57.1%) of the 28 EPEC, 9 (25%) of the 36 Salmonella enterica, 32 of the 13 (40.6%) Sh. sonnei, and only 1 (4.2%) of the 24 V. cholerae isolate harbored class 1 integron. CONCLUSIONS: The data obtained in the present study suggested that class 1 integrons are widely distributed among members of Enterobacteriaceae. The resistance patterns of our E. coli, S. sonnei, and S. enterica isolates were nearly identical, suggesting the same genetic elements involved in attainment of multi-drug resistance. PMID- 25147721 TI - Detection of human papillomavirus in chronic cervicitis, cervical adenocarcinoma, intraepithelial neoplasia and squamus cell carcinoma. AB - BACKGROUND: Cervical cancer is the second most common cancer in women worldwide. Recent studies show that human papillomavirus (HPV) DNA is present in all cervical carcinomas and in some cervicitis cases, with some geographical variation in viral subtypes. Therefore determination of the presence of HPV in the general population of each region can help reveal the role of these viruses in tumors. OBJECTIVES: This study aimed to estimate the frequency of infection with HPV in cervicitis, cervical adenocarcinoma, intraepithelial neoplasia and squamus cell carcinoma samples from the Isfahan Province, Iran. PATIENTS AND METHODS: One hundred and twenty two formalin fixed paraffin embedded tissue samples of crevicitis cases and different cervix tumors including cervical intraepithelial neoplasia (CIN) (I, II, III), squamus cell carcinoma (SCC) and adenocarcinoma were collected from histopathological files of Al-Zahra Hospital in Isfahan. Data about histopathological changes were collected by reexamination of the hematoxylin and eosin stained sections. DNA was extracted and subjected to Nested PCR using consensus primers, MY09/MY11 and GP5+/GP6+, designed for amplification of a conserved region of the genome coding for L1 protein. RESULTS: In total 74.5% of the tested samples were positive for HPV. Amongst the tested tumors 8 out of 20 (40%) of CIN (I, II, III), 5 out of 21 (23.8%) of adenocarcinoma cases and 78 out of 79 chronic cervicitis cases were positive for HPV. CONCLUSIONS: The rate of different carcinomas and also the rate of HPV infection in each case were lower than other reports from different countries. This could be correlated with the social behavior of women in the area, where they mostly have only one partner throughout their life, and also the rate of smoking behavior of women in the studied population. On the other hand the rate of HPV infection in chronic cervicitis cases was much higher than cases reported by previous studies. This necessitates more attention to the role of human papillomaviruses in the their induction in the studied area. PMID- 25147722 TI - The Association of Virulence Determinants of Uropathogenic Escherichia coli With Antibiotic Resistance. AB - BACKGROUND: The emergence of antimicrobial resistant strains of Escherichia coli has raised considerable interest in understanding the diversity and epidemiology of E. coli infections in humans. Virulence factors of E. coli determine the specific infections caused by this microorganism. OBJECTIVES: This study aimed to determine the prevalence of eight E. coli virulence factors and their association with antimicrobial resistance in bacteria isolated from patients with urinary tract infections (UTI). PATIENTS AND METHODS: One thousand patients with UTI were enrolled in this cross-sectional study. Antimicrobial susceptibility was examined by disc diffusion method according to CLSI guidelines. After DNA extraction, the materials were probed by PCR for eight virulence factors genes, namely fimH, hly, iucC, ibeA, sfa/foc, neuC, papC, and afa genes. RESULTS: The frequency of virulence factors papC, afa, sfa/foc, fimH, hly, neuC, ibeA, and iucC were 53.3%, 51.7%, 53.3%, 56.7%, 23.3%, 31.7%, 20%, and 73.3%, respectively. In addition, there was a high degree resistance to cotrimoxazole and nalidixic acid while a high degree of susceptibility to nitrofurantoin was detected. There was a statistically significant association between fimH gene and resistance to ciprofloxacin (P = 0.006), nalidixic acid (P = 0.025), and cotrimoxazole (P = 0.02). Such associations were found between ibeA gene and amikacin (P = 0.02) and cotrimoxazole (P = 0.02) as well as between afa gene and gentamycin (P = 0.05). CONCLUSIONS: The results showed that E. coli isolated from patients with UTI had eight virulence factors with high frequencies. Moreover, these results alleged a direct connection between virulence factors and antimicrobial resistance in E. coli. PMID- 25147723 TI - Application of Pulsed Field Gel Electrophoresis for Study of Genetic Diversity in Mycobacterium tuberculosis Strains Isolated From Tuberculosis Patients. AB - BACKGROUND: Mycobacterium tuberculosis genotyping can effectively improve tuberculosis (TB) control programs by controlling disease transmission. Pulsed field gel electrophoresis (PFGE) is a particularly powerful tool for determination of clonal identity of bacteria providing information for understanding and controlling the spread of disease. OBJECTIVES: The aim of present study was to investigate the genetic diversity of M. tuberculosis strains in Khuzestan province by the PFGE technique. PATIENTS AND METHODS: In total, 80 M. tuberculosis positive cultures were obtained from tuberculosis patients. PFGE was performed on 60 PCR-confirmed isolates by using DraI and XbaI restriction enzymes according to standard protocols. Plugs containing digested DNA were then loaded on agarose gels and run using contour-clamped homogenous electric fields. RESULTS: Fifty distinct DNA banding patterns were obtained by digestion of DNA with DraI and 38 DNA banding patterns by digestion with XbaI restriction enzymes. The patterns comprised of 17 different clusters in which cluster I was the major one, containing six strains. Three clusters contained three strains each and the 13 remaining clusters comprised of two strains each. Digestion with DraI yielded 15-20 DNA fragments with 50-485 kb size, while digestion by XbaI produced DNA fragments with a size smaller than 50-242 kb. CONCLUSIONS: Despite the ability of PFGE for study of genetic diversity of many mycobacterial species and it being considered as a robust and useful tool, in this study we only found a 15% epidemiological relationship amongst the isolates. Thus, for higher discrimination of genotypic clusters among M. tuberculosis clinical isolates, the application of more sophisticated complementary techniques is required. PMID- 25147724 TI - Seroprevalence of Anti-Toxoplasma gondii Antibodies Among Pregnant Woman in South Khuzestan, Iran. AB - BACKGROUND: Acute toxoplasmosis may lead to congenital toxoplasmosis with fetal complications outcome during pregnancy. Anti- Toxoplasma gondii antibody seroprevalence is unclear in pregnant women of south of Khuzestan province, since limited data about T. gondii seroepidemiology has been published in pregnant women of this area (Abadan, Shadegan, Khoramshar). OBJECTIVES: The aim of this study was to clarify the status of T. gondii seroprevalence in pregnant women of south of Khuzestan province. MATERIALS AND METHODS: In this cross-sectional study, 501 full-term pregnant women were included. This study was carried out in Taleghani teaching hospital for six 6 months from May to October 2011. Informed consents signed by the patients were obtained. Blood IgG and IgM were measured using ELISA technique. The data was analyzed by SPSS 13 (Chicago, IL, USA). Chi square test was used for comparison. RESULTS: The participants' age range was 15 to 45 years (average: 27.4 +/- 13). Of the 501 pregnant women, 70.65 % (n = 354) were seronegative for T. gondii IgG and IgM antibodies. There were statistical relationships between IgG seroprevalence and age, as well as IgG seroprevalence and cat holding. CONCLUSIONS: There was high percentage of seronegative (70.65 %) IgG and IgM antibodies in full-term pregnant women. They were susceptible to acute toxoplasmosis; thus, prenatal screening was recommend in our province after cost-beneficial analyses. PMID- 25147725 TI - Protein analytical assays for diagnosing, monitoring, and choosing treatment for cancer patients. AB - Cancer treatment is often hindered by inadequate methods for diagnosing the disease or insufficient predictive capacity regarding therapeutic efficacy. Targeted cancer treatments, including Bcr-Abl and EGFR kinase inhibitors, have increased survival for some cancer patients but are ineffective in other patients. In addition, many patients who initially respond to targeted inhibitor therapy develop resistance during the course of treatment. Molecular analysis of cancer cells has emerged as a means to tailor treatment to particular patients. While DNA analysis can provide important diagnostic information, protein analysis is particularly valuable because proteins are more direct mediators of normal and diseased cellular processes. In this review article, we discuss current and emerging protein assays for improving cancer treatment, including trends toward assay miniaturization and measurement of protein activity. PMID- 25147726 TI - When Proteins Start to Make Sense: Fine-tuning Aminoglycosides for PTC Suppression Therapy. AB - Aminoglycosides (AGs) are highly potent antibacterial agents, which are known to exert their deleterious effects on bacterial cells by interfering with the translation process, leading to aberrant protein synthesis that usually results in cell death. Nearly 45 years ago, AGs were shown to induce read-through activity in prokaryotic systems by selectively encoding tRNA molecules at premature termination codon (PTC) positions; resulting in the generation of full length functional proteins. However, only in the last 20 years this ability has been demonstrated in eukaryotic systems, highlighting their potential as therapeutic agents to treat PTC induced genetic disorders. Despite the great potential, AGs use in these manners is quite restricted due to relatively high toxicity values observed upon their administration. Over the last few years several synthetic derivatives were developed to overcome some of the enhanced toxicity issues, while in parallel showed significantly improved PTC suppression activity in various in-vitro, ex-vivo and in-vivo models of a variety of different diseases models underling by PTC mutations. Although these derivatives hold great promise to serve as therapeutic candidates they also demonstrate the necessity to further understand the molecular mechanisms of which AGs confer their biological activity in eukaryotic cells for further rational drug design. Recent achievements in structural research shed light on AGs mechanism of action and opened a new avenue in the development of new and improved therapeutic derivatives. The following manuscript highlights these accomplishments and summarizes their contributions to the state of art rational drug design. PMID- 25147727 TI - Strategies to balance covalent and non-covalent biomolecule attachment within collagen-GAG biomaterials. AB - Strategies to integrate instructive biomolecular signals into a biomaterial are becoming increasingly complex and bioinspired. While a large majority of reports still use repeated treatments with soluble factors, this approach can be prohibitively costly and difficult to translate in vivo for applications where spatial control over signal presentation is necessary. Recent efforts have explored the use of covalent immobilization of biomolecules to the biomaterial, via both bulk (ubiquitous) as well as spatially-selective light-based crosslinking, as a means to both enhance stability and bioactivity. However, little is known about how processing conditions during immobilization impact the degree of unintended non-covalent interactions, or fouling, that takes place between the biomaterial and the biomolecule of interest. Here we demonstrate the impact of processing conditions for bulk carbodiimide (EDC) and photolithography based benzophenone (BP) crosslinking on specific attachment vs. fouling of a model protein (Concanavalin A, ConA) within collagen-glycosaminoglycan (CG) scaffolds. Collagen source significantly impacts the selectivity of biomolecule immobilization. EDC crosslinking intensity and ligand concentration significantly impacted selective immobilization. For benzophenone photoimmobilization we observed that increased UV exposure time leads to increased ConA immobilization. Immobilization efficiency for both EDC and BP strategies was maximal at physiological pH. Increasing ligand concentration during immobilization process led to enhanced immobilization for EDC chemistry, no impact on BP immobilization, but significant increases in non-specific fouling. Given recent efforts to covalently immobilize biomolecules to a biomaterial surface to enhance bioactivity, improved understanding of the impact of crosslinking conditions on selective attachment versus non-specific fouling will inform the design of instructive biomaterials for applications across tissue engineering. PMID- 25147728 TI - A simple material model to generate epidermal and dermal layers in vitro for skin regeneration. AB - There is an urgent need for a rationally-designed, cellularized skin graft capable of reproducing the micro-environmental cues necessary to promote skin healing and regeneration. To address this need, we developed a composite scaffold, namely, CA/C-PEG, composing of a porous chitosan-alginate (CA) structure impregnated with a thermally reversible chitosan-poly(ethylene glycol) (C-PEG) gel to incorporate skin cells as a bi-layered skin equivalent. Fibroblasts were encapsulated in C-PEG to simulate the dermal layer while the keratinocytes were seeded on the top of CA/C-PEG composite scaffold to mimic the epidermal layer. The CA scaffold provided mechanical support for the C-PEG gel and the C-PEG gel physically segregated the keratinocytes from fibroblasts in the construct. Three different tissue culture micro-environments were tested: CA scaffolds without C-PEG cultured in cell culture medium without air-liquid interface (-gel-interface), CA scaffolds impregnated with C-PEG and cultured in cell culture medium without air-liquid interface (-gel-interface), and CA scaffolds impregnated with C-PEG cultured in cell culture medium with air-liquid interface (-gel- interface). We found that the presence of C-PEG increased the cellular proliferation rates of both keratinocytes and fibroblasts, and the air liquid interface induced keratinocyte maturation. This CA/C-PEG composite scaffold design is able to recapitulate micro-environments relevant to skin tissue engineering, and may be a useful tool for future skin tissue engineering applications. PMID- 25147729 TI - Modern Multicomponent Reactions for better Drug Syntheses** AB - Multicomponent reaction (MCR) technology is now widely recognized for its impact on drug discovery projects and is strongly endorsed by industry as well as academia. However, still relatively few products based on MCRs are marketed or under development. This provides tremendous opportunities for organic chemists to shorten synthetic pathways thus reducing the cost-of-goods considerably. A recent example of the HCV drug Telaprevir is highlighted where introduction of two MCRs could lead to a shortening of the synthesis route by more than 50%. PMID- 25147730 TI - Value of a mobile information system to improve quality of care by community health workers. AB - INTRODUCTION: We will be unable to achieve sustained impact on health outcomes with community health worker (CHW)-based interventions unless we bridge the gap between small scale efficacy studies and large scale interventions. Effective strategies to support the management of CHWs are central to bridging the gap. Mobile phones are broadly available, particularly in low and middle income countries (LAMIC's), where the penetration rate approaches 100%. In this article we describe how mobile phones may be combined with mobile web-based technology to assist in the management of CHWs in two projects in South Africa. METHODS: This paper is a descriptive one, drawing lessons from two Randomised Controlled Trials (RCT's), outlining how a mobile phone information system can be utilized to enhance the quality of health interventions. We organized our comprehensive management and supervision system around a previously published management framework. The system is composed of mobile phones utilized by CHWs and a web based interface utilized by CHW supervisors. Computerized algorithms were designed with intervention and assessment protocols to aid in the real-time supervision and management of CHWs. RESULTS: CHWs used mobile phones to initiate intervention visits and trigger content to be delivered during the course of intervention visits. Supervisors used the web-based interface for real-time monitoring of the location, timing, and content of intervention visits. Additional real-time support was provided through direct support calls in the event of crises in the field. CONCLUSION: Mobile phone-based information system platforms offer significant opportunities to improve CHW-delivered interventions. The extent to which these efficiency gains can be translated into realized health gains for communities is yet to be tested. PMID- 25147731 TI - Emphysematous pyelonephritis in a diabetic patient with obstructed kidney. AB - Emphysematous pyelonephritis (EPN) is an acute, rare, inflammatory disease, which typically occurs in patients who suffer from diabetes mellitus. We report the case of a patient who was admitted to the Department of Urology with septic signs, in whom, after performing computed tomography, the diagnosis of EPN was established. The patient underwent organ-preserving treatment, which consisted of pyelolithotomy with nephrostomy, and the insertion of a double J catheter into the left ureter. The importance of the classification of EPN is also discussed. The need for individualized procedures is highlighted. PMID- 25147732 TI - Role of Intravitreal Antivascular Endothelial Growth Factor Injections for Choroidal Neovascularization due to Choroidal Osteoma. AB - We treated 26 eyes of 25 young patients having a mean age of 30 years with intravitreal vascular endothelial growth factor (VEGF) inhibitor for choroidal new vessel (CNV) formation overlying choroidal osteoma over a mean follow-up of 26 months. Mean number of injections was 2.4 at 6 months, 3.2 at 12 months, and 5.5 at 24 months. CNV was subfoveal in 14 eyes, juxtafoveal in 5, extrafoveal in 5, and peripapillary in 2. By paired comparison, mean decrease from baseline was 119.7 microns at 6 months (n = 15; P = 0.001), 105.3 microns at 1 year (n = 10; P = 0.03), and 157.6 microns at 2 years (n = 7; P = 0.08). BCVA improved by 3.3 lines at 6 months after therapy (n = 26; P < 0.001), 2.8 lines (n = 20; P = 0.01) at 1 year, and 3.1 lines (n = 13; P = 0.049) at 2 years. We conclude that intravitreal anti-VEGF injections improve vision in majority of eyes with CNV from choroidal osteoma. PMID- 25147733 TI - Effectiveness of a cognitive behavioral therapy for dysfunctional eating among patients admitted for bariatric surgery: a randomized controlled trial. AB - OBJECTIVE: To examine whether cognitive behavioral therapy (CBT) alleviates dysfunctional eating (DE) patterns and symptoms of anxiety and depression in morbidly obese patients planned for bariatric surgery. DESIGN AND METHODS: A total of 98 (68 females) patients with a mean (SD) age of 43 (10) years and BMI 43.5 (4.9) kg/m(2) were randomly assigned to a CBT-group or a control group receiving usual care (i.e., nutritional support and education). The CBT-group received ten weekly intervention sessions. DE, anxiety, and depression were assessed by the TFEQ R-21 and HADS, respectively. RESULTS: Compared with controls, the CBT-patients showed significantly less DE, affective symptoms, and a larger weight loss at follow-up. The effect sizes were large (DE-cognitive restraint, g = -.92, P <= .001; DE-uncontrolled eating, g = -.90, P <= .001), moderate (HADS-depression, g = -.73, P <= .001; DE-emotional eating, g = -.67, P <= .001; HADS-anxiety, g = -.62, P = .003), and low (BMI, g = -.24, P = .004). CONCLUSION: This study supports the use of CBT in helping patients preparing for bariatric surgery to reduce DE and to improve mental health. This clinical trial is registered with NCT01403558. PMID- 25147735 TI - Reliability of a Fully Automated Interpretation of gamma -H2AX Foci in Lymphocytes of Moderately Trained Subjects under Resting Conditions. AB - Background. Analysis of gamma-H2AX foci is a promising approach to evaluate exercise-induced DNA damage. However, baseline levels and day-to-day variability of gamma-H2AX foci have not been investigated in healthy subjects at rest. Methods. Blood was taken from eight moderately trained healthy males (29 +/- 3 yrs, 1.84 +/- 0.03 m, and 85 +/- 6 kg) at two separate days (M1/M2) after 24-hour exercise cessation. Number of gamma-H2AX foci per 100 lymphocytes (N), number of foci per affected lymphocyte (NAL), percentage of affected lymphocytes (PAL), and diameter (D) of gamma-H2AX foci were analyzed (mean +/- SD). Differences between M1 and M2 were analyzed using paired t-tests (alpha = 0.05). Day-to-day variability was evaluated by calculating the coefficients of variation (CV%), bias, and limits of agreement (LoA). Results. There were no statistically significant differences between M1 (N: 7.6 +/- 4.4, NAL: 1.2 +/- 0.2, PAL: 5.9 +/ 2.6%, and D: 0.63 +/- 0.07) and M2 (N: 8.4 +/- 4.6, NAL: 1.3 +/- 0.1, PAL: 6.9 +/- 4.2%, and D: 0.66 +/- 0.06). CV was calculated to be 98.5% (N), 88.9% (PAL), 11.3% (NAL), and 8.0% (D). Bias (LoA) was 0.75 (-15.2/13.7), -0.02 (-0.36/0.33), 1.0 (-11.9/9.9), and -0.04 (-0.16/0.09), respectively. Conclusions. Background level in healthy subjects is approximately 0.07 to 0.09 gamma-H2AX foci/cell. NAL and D are reliable measures. PMID- 25147734 TI - The weight-inclusive versus weight-normative approach to health: evaluating the evidence for prioritizing well-being over weight loss. AB - Using an ethical lens, this review evaluates two methods of working within patient care and public health: the weight-normative approach (emphasis on weight and weight loss when defining health and well-being) and the weight-inclusive approach (emphasis on viewing health and well-being as multifaceted while directing efforts toward improving health access and reducing weight stigma). Data reveal that the weight-normative approach is not effective for most people because of high rates of weight regain and cycling from weight loss interventions, which are linked to adverse health and well-being. Its predominant focus on weight may also foster stigma in health care and society, and data show that weight stigma is also linked to adverse health and well-being. In contrast, data support a weight-inclusive approach, which is included in models such as Health at Every Size for improving physical (e.g., blood pressure), behavioral (e.g., binge eating), and psychological (e.g., depression) indices, as well as acceptability of public health messages. Therefore, the weight-inclusive approach upholds nonmaleficience and beneficience, whereas the weight-normative approach does not. We offer a theoretical framework that organizes the research included in this review and discuss how it can guide research efforts and help health professionals intervene with their patients and community. PMID- 25147736 TI - The Danish Symptom Cohort: Questionnaire and Feasibility in the Nationwide Study on Symptom Experience and Healthcare-Seeking among 100 000 Individuals. AB - Introduction. In order to develop strategies to prevent delay in diagnosis, it is important to gain knowledge of symptoms and healthcare-seeking processes in the population. This paper describes a combined survey and register-based study with (1) focus on development of a questionnaire concerning experience of symptoms and subsequent consequences and (2) feasibility of the study. Methods. The study is a nationwide cohort study of 100 000 individuals randomly selected from the Danish general population. A comprehensive questionnaire concerning experience of symptoms and subsequent consequences was developed. The methodological framework for the development included defining the domains to be measured, identification of previous items, scales and questionnaires in the literature, and pilot and field testing. Results. A total of five domains and 16 subdomains were defined covering the area of symptom experience, symptom characteristics, reaction in response to symptom experience, external factors, and personality characteristics with potential influence on the symptom experience. In total, 49 706 questionnaires were completed, yielding a response rate of 52.2%. Conclusion. We developed a comprehensive questionnaire used in a large combined survey and register-based study concerning experience of symptoms and subsequent consequences of symptom experiences. We succeeded in conducting a large survey providing the groundwork for The Danish Symptom Cohort. PMID- 25147737 TI - Factors affecting mortality in elderly patients hospitalized for nonmalignant reasons. AB - Elderly population is hospitalized more frequently than young people, and they suffer from more severe diseases that are difficult to diagnose and treat. The present study aimed to investigate the factors affecting mortality in elderly patients hospitalized for nonmalignant reasons. Demographic data, reason for hospitalization, comorbidities, duration of hospital stay, and results of routine blood testing at the time of first hospitalization were obtained from the hospital records of the patients, who were over 65 years of age and hospitalized primarily for nonmalignant reasons. The mean age of 1012 patients included in the study was 77.8 +/- 7.6. The most common reason for hospitalization was diabetes mellitus (18.3%). Of the patients, 90.3% had at least a single comorbidity. Whilst 927 (91.6%) of the hospitalized patients were discharged, 85 (8.4%) died. Comparison of the characteristics of the discharged and dead groups revealed that the dead group was older and had higher rates of poor general status and comorbidity. Differences were observed between the discharged and dead groups in most of the laboratory parameters. Hypoalbuminemia, hypertriglyceridemia, hypopotassemia, hypernatremia, hyperuricemia, and high TSH level were the predictors of mortality. In order to meet the health necessities of the elderly population, it is necessary to well define the patient profiles and to identify the risk factors. PMID- 25147738 TI - Cytotoxic Effects of Newly Synthesized Palladium(II) Complexes of Diethyldithiocarbamate on Gastrointestinal Cancer Cell Lines. AB - As a part of a drug development program to discover novel therapeutic and more effective palladium (Pd) based anticancer drugs, a series of water-soluble Pd complexes have been synthesized by interaction between [Pd (phen)(H2O)2(NO3)2] and alkylenebisdithiocarbamate(al-bis-dtc) disodium salts. This study was undertaken to examine the possible cytotoxic effect of three novel complexes (0.125-64 ug/mL) on human gastric carcinoma (AGS), esophageal squamous cell carcinoma (Kyse-30), and hepatocellular carcinoma (HepG2) cell lines. The cytotoxicity was examined using cell proliferation and acridine orange/ethidium bromide (AO/EB) assay. In order to examine the effects of new Pd(II) complexes on cell cycle status, we performed cell cycle analysis. The complexes were found to have completely lethal effects on the cell lines, and the half maximal inhibitory concentration (IC50) values obtained for the cell lines were much lower in comparison with cisplatin. We demonstrated that the three new Pd(II) complexes are able to induce G2/M phase arrest in AGS and HepG2; in addition, the Pd(II) complexes caused an S phase arrest in Kyse-30 cell line. Our results indicate that newly synthesized Pd(II) complexes may provide a novel class of chemopreventive compounds for anticancer therapy. PMID- 25147740 TI - Neurological disorders related neuronal network impairment: function and mechanism. PMID- 25147741 TI - Tracheal Intubation through the I-gel for Emergency Cesarean Section in a Patient with Multidrug Hypersensitivity: A New Technique. AB - 31-year-old female with hypersensitivity to local anesthetics and neuromuscular blocking agents presented for emergency Cesarean section. We successfully performed I-gel-assisted tracheal intubation without using neuromuscular blockers. We believe this method would be helpful in selected situations. PMID- 25147739 TI - Molecular regulation of bone marrow metastasis in prostate and breast cancer. AB - Metastasis is a multistep process, which refers to the ability to leave a primary tumor through circulation toward the distant tissue and form a secondary tumor. Bone is a common site of metastasis, in which osteolytic and osteoblastic metastasis are observed. Signaling pathways, chemokines, growth factors, adhesion molecules, and cellular interactions as well as miRNAs have been known to play an important role in the development of bone metastasis. These factors provide an appropriate environment (soil) for growth and survival of metastatic tumor cells (seed) in bone marrow microenvironment. Recognition of these factors and determination of their individual roles in the development of metastasis and disruption of cellular interactions can provide important therapeutic targets for treatment of these patients, which can also be used as prognostic and diagnostic biomarkers. Thus, in this paper, we have attempted to highlight the molecular regulation of bone marrow metastasis in prostate and breast cancers. PMID- 25147742 TI - A shocking complication of a pneumothorax: chest tube-induced arrhythmias and review of the literature. AB - We describe a patient with a recent chest tube insertion leading to atrial fibrillation with rapid ventricular rate that led to multiple inappropriate internal cardiac defibrillator (ICD) shocks. This is the first reported case of this occurring in a patient with an ICD leading to inappropriate shocks. Our elderly patient with emphysema presented with a spontaneous pneumothorax and developed rapid atrial fibrillation following emergency tube thoracostomy. The patient had a single lead ICD and received multiple inappropriate shocks for the rapid ventricular rate in the therapy zone. Although medical treatment helped stabilize the patient, resolution of the atrial fibrillation occurred only after the chest tube was removed. In a patient with a chest tube or other intrathoracic catheters, maintaining a high index of suspicion that chest tube insertions can cause secondary life threatening cardiovascular complications needs to be considered. In such patients, removal of the device proves to be the most prudent treatment action. PMID- 25147743 TI - Mechanical ventilation weaning in inclusion body myositis: feasibility of isokinetic inspiratory muscle training as an adjunct therapy. AB - Inclusion body myositis is a rare myopathy associated with a high rate of respiratory complications. This condition usually requires prolonged mechanical ventilation and prolonged intensive care stay. The unsuccessful weaning is mainly related to respiratory muscle weakness that does not promptly respond to immunosuppressive therapy. We are reporting a case of a patient in whom the use of an inspiratory muscle-training program which started after a two-week period of mechanical ventilation was associated with a successful weaning in one week and hospital discharge after 2 subsequent weeks. PMID- 25147744 TI - Five canalled and three-rooted primary second mandibular molar. AB - A thorough knowledge of root canal anatomy and its variation is necessary for successful completion of root canal procedures. Morphological variations such as additional root canals in human deciduous dentition are rare. A mandibular second primary molar with more than four canals is an interesting example of anatomic variations, especially when three of these canals are located in the distal root. This case shows a rare anatomic configuration and points out the importance of looking for additional canals. PMID- 25147745 TI - Mandibular atrophy and genial spines enlargement on cone beam computed tomography. AB - Purpose. The aim of this paper is to report a case in which the cone beam computed tomography (CBCT) was important for the confirmation of the presence of mandibular atrophy and genial spines enlargement. Case Description. A 76-year-old female patient was referred for the assessment due to the complaint of chronic trauma in the anterior region of the floor of the mouth, which had been present for 2 months. CBCT images showed severe resorption of alveolar ridge and genial spines enlargement (5.5 mm * 12 mm). Conclusion. Accurate imaging assessment with the aid of 3D reconstructions allows the elimination of image superimposition and, therefore, plays an important role in the depiction of anatomical and pathological conditions, such as genial spines enlargement. PMID- 25147746 TI - Lasers in esthetic dentistry: soft tissue photobiomodulation, hard tissue decontamination, and ceramics conditioning. AB - The increasing concern and the search for conservative dental treatments have resulted in the development of several new technologies. Low and high power lasers can be cited as one of these new technologies. Low power lasers act at cellular level leading to pain reduction, modulation of inflammation, and improvement of tissue healing. High power lasers act by increasing temperature and have the potential to promote microbial reduction and ablation of hard and soft tissues. The clinical application of both low and high power lasers requires specific knowledge concerning laser interaction with biological tissues, so that the correct irradiation protocol can be established. The present case report describes the clinical steps of two metal-ceramic crowns development in a 60-year old patient. Three different laser wavelengths were applied throughout the treatment with different purposes: Nd:YAG laser (1,064 nm) for dentin decontamination, diode (660 nm) for soft tissue biomodulation, and Er:YAG laser (2,940 nm) for inner ceramic surface conditioning. Lasers were successfully applied in the present case report as coadjutant in the treatment. This coadjutant technology can be a potential tool to assist treatment to reach the final success. PMID- 25147747 TI - Predictors of middle school students' interest in participating in an incentive based tobacco prevention and cessation program in connecticut. AB - Behavioral incentives have been used to encourage smoking cessation in older adolescents, but the acceptability of incentives to promote a smoke-free lifestyle in younger adolescents is unknown. To inform the development of novel, effective, school-based interventions for youth, we assessed middle school students' interest in participating in an incentive-based tobacco abstinence program. We surveyed 988 students (grades 6-8) attending three Connecticut middle schools to determine whether interest in program participation varied as a function of (1) intrapersonal factors (i.e., demographic characteristics (sex, age, race), smoking history, and trait impulsivity) and/or (2) aspects of program design (i.e., prize type, value, and reward frequency). Primary analyses were conducted using multiple regression. A majority of students (61.8%) reported interest in program participation. Interest did not vary by gender, smoking risk status, or offering cash prizes. However, younger students, non-Caucasian students, behaviorally impulsive students, and students with higher levels of self-regulation were more likely to report interest. Inexpensive awards (e.g., video games) offered monthly motivated program interest. In sum, middle school students reported high levels of interest in an incentive-based program to encourage a tobacco-free lifestyle. These formative data can inform the design of effective, incentive-based smoking cessation and prevention programs in middle schools. PMID- 25147748 TI - Differential network analyses of Alzheimer's disease identify early events in Alzheimer's disease pathology. AB - In late-onset Alzheimer's disease (AD), multiple brain regions are not affected simultaneously. Comparing the gene expression of the affected regions to identify the differences in the biological processes perturbed can lead to greater insight into AD pathogenesis and early characteristics. We identified differentially expressed (DE) genes from single cell microarray data of four AD affected brain regions: entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC), and middle temporal gyrus (MTG). We organized the DE genes in the four brain regions into region-specific gene coexpression networks. Differential neighborhood analyses in the coexpression networks were performed to identify genes with low topological overlap (TO) of their direct neighbors. The low TO genes were used to characterize the biological differences between two regions. Our analyses show that increased oxidative stress, along with alterations in lipid metabolism in neurons, may be some of the very early events occurring in AD pathology. Cellular defense mechanisms try to intervene but fail, finally resulting in AD pathology as the disease progresses. Furthermore, disease annotation of the low TO genes in two independent protein interaction networks has resulted in association between cancer, diabetes, renal diseases, and cardiovascular diseases. PMID- 25147749 TI - Conservation and variability of synaptonemal complex proteins in phylogenesis of eukaryotes. AB - The problems of the origin and evolution of meiosis include the enigmatic variability of the synaptonemal complexes (SCs) which, being morphology similar, consist of different proteins in different eukaryotic phyla. Using bioinformatics methods, we monitored all available eukaryotic proteomes to find proteins similar to known SC proteins of model organisms. We found proteins similar to SC lateral element (LE) proteins and possessing the HORMA domain in the majority of the eukaryotic taxa and assume them the most ancient among all SC proteins. Vertebrate LE proteins SYCP2, SYCP3, and SC65 proved to have related proteins in many invertebrate taxa. Proteins of SC central space are most evolutionarily variable. It means that different protein-protein interactions can exist to connect LEs. Proteins similar to the known SC proteins were not found in Euglenophyta, Chrysophyta, Charophyta, Xanthophyta, Dinoflagellata, and primitive Coelomata. We conclude that different proteins whose common feature is the presence of domains with a certain conformation are involved in the formation of the SC in different eukaryotic phyla. This permits a targeted search for orthologs of the SC proteins using phylogenetic trees. Here we consider example of phylogenetic trees for protozoans, fungi, algae, mosses, and flowering plants. PMID- 25147750 TI - Forecasting malaria cases using climatic factors in delhi, India: a time series analysis. AB - Background. Malaria still remains a public health problem in developing countries and changing environmental and climatic factors pose the biggest challenge in fighting against the scourge of malaria. Therefore, the study was designed to forecast malaria cases using climatic factors as predictors in Delhi, India. Methods. The total number of monthly cases of malaria slide positives occurring from January 2006 to December 2013 was taken from the register maintained at the malaria clinic at Rural Health Training Centre (RHTC), Najafgarh, Delhi. Climatic data of monthly mean rainfall, relative humidity, and mean maximum temperature were taken from Regional Meteorological Centre, Delhi. Expert modeler of SPSS ver. 21 was used for analyzing the time series data. Results. Autoregressive integrated moving average, ARIMA (0,1,1) (0,1,0)(12), was the best fit model and it could explain 72.5% variability in the time series data. Rainfall (P value = 0.004) and relative humidity (P value = 0.001) were found to be significant predictors for malaria transmission in the study area. Seasonal adjusted factor (SAF) for malaria cases shows peak during the months of August and September. Conclusion. ARIMA models of time series analysis is a simple and reliable tool for producing reliable forecasts for malaria in Delhi, India. PMID- 25147751 TI - Role of matrix metalloproteinase activity in the neurovascular protective effects of Angiotensin antagonism. AB - Background and Purpose. Oxidative stress and matrix metalloproteinase (MMP) activity have been identified as key mediators of early vascular damage after ischemic stroke. Somewhat surprisingly, the angiotensin II type 1 receptor (AT1) blocker, candesartan, has been shown to acutely increase MMP activity while providing neurovascular protection. We aimed to determine the contribution of MMP and nitrative stress to the effects of angiotensin blockade in experimental stroke. Methods. Wistar rats (n = 9-14/group; a total of 99) were treated in a factorial design with candesartan 1 mg/kg IV, alone or in combination with either a peroxynitrite decomposition catalyst, FeTPPs, 30 mg/kg IP or GM6001 50 mg/kg IP (MMP inhibitor). Neurological deficit, infarct, size and hemorrhagic transformation (HT) were measured after 3 h of middle cerebral artery occlusion (MCAO) and 21 h of reperfusion. MMP activity and nitrotyrosine expression were also measured. Results. Candesartan reduced infarct size and HT when administered alone (P = 0.0011) and in combination with FeTPPs (P = 0.0016). GM6001 did not significantly affect HT when administered alone, but the combination with candesartan caused increased HT (P < 0.0001) and worsened neurologic score (P = 0.028). Conclusions. Acute administration of candesartan reduces injury after stroke despite increasing MMP activity, likely by an antioxidant mechanism. PMID- 25147752 TI - The adverse effect of spasticity on 3-month poststroke outcome using a population based model. AB - Several devices and medications have been used to address poststroke spasticity. Yet, spasticity's impact on outcomes remains controversial. Using data from a cohort of 460 ischemic stroke patients, we previously published a validated multivariable regression model for predicting 3-month modified Rankin Score (mRS) as an indicator of functional outcome. Here, we tested whether including spasticity improved model fit and estimated the effect spasticity had on the outcome. Spasticity was defined by a positive response to the question "Did you have spasticity following your stroke?" on direct interview at 3 months from stroke onset. Patients who had expired by 90 days (n = 30) or did not have spasticity data available (n = 102) were excluded. Spasticity affected the 3 month functional status (beta = 0.420, 95 CI = 0.194 to 0.645) after accounting for age, diabetes, leukoaraiosis, and retrospective NIHSS. Using spasticity as a covariable, the model's R (2) changed from 0.599 to 0.622. In our model, the presence of spasticity in the cohort was associated with a worsened 3-month mRS by an average of 0.4 after adjusting for known covariables. This significant adverse effect on functional outcomes adds predictive value beyond previously established factors. PMID- 25147753 TI - Differences in Plantar Flexor Fascicle Length and Pennation Angle between Healthy and Poststroke Individuals and Implications for Poststroke Plantar Flexor Force Contributions. AB - Poststroke plantar flexor muscle weakness has been attributed to muscle atrophy and impaired activation, which cannot collectively explain the limitations in force-generating capability of the entire muscle group. It is of interest whether changes in poststroke plantar flexor muscle fascicle length and pennation angle influence the individual force-generating capability and whether plantar flexor weakness is due to uniform changes in individual muscle force contributions. Fascicle lengths and pennation angles for the soleus, medial, and lateral gastrocnemius were measured using ultrasound and compared between ten hemiparetic poststroke subjects and ten healthy controls. Physiological cross-sectional areas and force contributions to poststroke plantar flexor torque were estimated for each muscle. No statistical differences were observed for any muscle fascicle lengths or for the lateral gastrocnemius and soleus pennation angles between paretic, nonparetic, and healthy limbs. There was a significant decrease (P < 0.05) in the paretic medial gastrocnemius pennation angle compared to both nonparetic and healthy limbs. Physiological cross-sectional areas and force contributions were smaller on the paretic side. Additionally, bilateral muscle contributions to plantar flexor torque remained the same. While the architecture of each individual plantar flexor muscle is affected differently after stroke, the relative contribution of each muscle remains the same. PMID- 25147754 TI - Re-assessment of YAP1 and MCR1 contributions to inhibitor tolerance in robust engineered Saccharomyces cerevisiae fermenting undetoxified lignocellulosic hydrolysate. AB - Development of robust yeast strains that can efficiently ferment lignocellulose based feedstocks is one of the requirements for achieving economically feasible bioethanol production processes. With this goal, several genes have been identified as promising candidates to confer improved tolerance to S. cerevisiae. In most of the cases, however, the evaluation of the genetic modification was performed only in laboratory strains, that is, in strains that are known to be quite sensitive to various types of stresses. In the present study, we evaluated the effects of overexpressing genes encoding the transcription factor (YAP1) and the mitochondrial NADH-cytochrome b5 reductase (MCR1), either alone or in combination, in an already robust and xylose-consuming industrial strain of S. cerevisiae and evaluated the effect during the fermentation of undiluted and undetoxified spruce hydrolysate. Overexpression of either gene resulted in faster hexose catabolism, but no cumulative effect was observed with the simultaneous overexpression. The improved phenotype of MCR1 overexpression appeared to be related, at least in part, to a faster furaldehyde reduction capacity, indicating that this reductase may have a wider substrate range than previously reported. Unexpectedly a decreased xylose fermentation rate was also observed in YAP1 overexpressing strains and possible reasons behind this phenotype are discussed. PMID- 25147756 TI - Association of Mitochondrial Dysfunction and Fatigue: A Review of the Literature. AB - Fatigue is often described by patients as a lack of energy, mental or physical tiredness, diminished endurance, and prolonged recovery after physical activity. Etiologic mechanisms underlying fatigue are not well understood; however, fatigue is a hallmark symptom of mitochondrial disease, making mitochondrial dysfunction a putative biological mechanism for fatigue. Therefore, this review examined studies that investigated the association of markers of mitochondrial dysfunction with fatigue and proposes possible research directions to enhance understanding of the role of mitochondrial dysfunction in fatigue. A thorough search using PubMed, Scopus, Web of Science, and Embase databases returned 1,220 articles. After application of inclusion and exclusion criteria, a total of 25 articles meeting eligibility criteria were selected for full review. Dysfunctions in the mitochondrial structure, mitochondrial function (mitochondrial enzymes and oxidative/nitrosative stress), mitochondrial energy metabolism (ATP production and fatty acid metabolism), immune response, and genetics were investigated as potential contributors to fatigue. Carnitine was the most investigated mitochondrial function marker. Dysfunctional levels were reported in all the studies investigating carnitine; however, the specific type of carnitine that was dysfunctional varied. Genetic profiles were the second most studied mitochondrial parameter. Six common pathways were proposed: metabolism, energy production, protein transport, mitochondrial morphology, central nervous system dysfunction and post-viral infection. Coenzyme Q10 was the most commonly investigated mitochondrial enzyme. Low levels of Coenzyme Q10 were consistently associated with fatigue. Potential targets for further investigation were identified as well as gaps in the current literature. PMID- 25147755 TI - Current Neural and Behavioral Dimensional Constructs across Mood Disorders. AB - Our understanding of the underlying neurobiology for mood disorders is still limited. We present an integrated model for conceptualizing and understanding mood disorders drawing upon a broad literature pertinent to mood disorders. The integrated model of emotion processing and regulation incorporates the linguistic constructs of the Research Domain Criteria (RDoC) initiative. In particular, we focus on the Positive Valence domain/circuit (PVC), highlighting recent reward research and the Negative Valence domain/circuit (NVC), highlighting rumination. Furthermore, we also illustrate the Cognitive Control and Problem Solving (CCaPS) circuit, which is heavily involved in emotion regulation, as well as the default mode network (DMN) and interactions between circuits. We conclude by proposing methods for addressing challenges in the developmental study of mood disorders including using high-risk design that incorporates risk for many disorders. PMID- 25147757 TI - Activation of the Notch1 Stem Cell Signaling Pathway during Routine Cell Line Subculture. PMID- 25147758 TI - Reasoning has become a luxury. PMID- 25147759 TI - Trafficking GRK2: Cellular and Metabolic consequences of GRK2 subcellular localization. AB - G protein coupled receptor kinase 2 (GRK2) has a key role in cellular function by regulating different intracellular mechanisms in a kinase dependent or independent manner. In this review we have dealt with the recently discovered roles of GRK2 in the regulation of cell metabolism. In particular, we have focused on recent findings about the mitochondrial role of GRK2 in the regulation of energy metabolism. Few findings exist about this topic that all concur to identify a mitochondrial localization of GRK2, leading to the rising of the following question: is GRK2 detrimental or advantageous for mitochondrial function? By the review of available literature, a new concept arises about GRK2 role into the cell,which is that of a stress protein acutely activated by cellular stress whose specific subcellular localization, in particular mitochondrial localization, results in compensatory metabolic responses. Thus, the possibility to regulate GRK2 trafficking within the cell is a promising strategy to regulate the adaptative effects of the kinase on cell metabolism. PMID- 25147760 TI - Anandamide inhibits breast tumor-induced angiogenesis. AB - Breast cancer is one of the most frequently diagnosed malignancies and a leading cause of cancer death in women. Great advances in the treatment of primary tumors have led to a significant increment in the overall survival rates, however recurrence and metastatic disease, the underlying cause of death, are still a medical challenge. Breast cancer is highly dependent on neovascularization to progress. In the last years several anti-angiogenic drugs have been developed and administered to patients in combination with chemotherapeutic drugs. Collected preclinical evidence has proposed the endocannabinoid system as a potential target in cancer. The endocannabinoid anandamide has been reported to affect breast cancer growth at multiple levels, by inhibiting proliferation, migration and invasiveness in vitro and in vivo and by directly inhibiting angiogenesis. Aim of the present work is to investigate if anandamide is able to affect the proangiogenic phenotype of the highly invasive and metastatic breast cancer cells MDA-MB-231. We found that following anandamide treatment, MDAMB-231 cells lose their ability to stimulate endothelial cells proliferation in vitro, due to a significant inhibition of all the pro-angiogenic factors produced by these cells. This finding adds another piece of evidence to the anti-tumor efficacy of anandamide in breast cancer. PMID- 25147761 TI - Spontaneous muscle haematomas: management of 10 cases. AB - This is a retrospective study about the treatment of spontaneous muscle haematomas (SMH) that are an uncommon disease that occurs especially in elderly patients with acquired coagulopathy. We report the management of 10 cases admitted to our Emergency Surgical Unit (ESU) between March 2011 and October 2012. For this analysis we have considered some parameters such as age, drug history, current symptoms, location of the haematoma, cause, and imaging examination. Our attention focused on: clinical presentation, differential diagnosis, diagnostic imaging techniques and treatments. PMID- 25147762 TI - Designing in-vitro systems to simulate the in-vivo permeability of drugs. AB - In this work an engineering approach, consisting in an experimental procedure and a model to derive the data, was presented and applied to improve the testing methods of pharmaceuticals. The permeability of several active molecules have been evaluated across a synthetic membrane. The permeability of these drugs measured through the artificial membrane were successfully correlated to their in vivo permeability. The relationship with in-vivo permeability was derived, and then a rule to design systems to simulate the intestinal absorption was proposed to reduce the need for expensive and ethical problematic in-vivo measurements. PMID- 25147763 TI - An evaluation of coronary atherosclerosis using coronary CT in subjects with asymptomatic carotid lesions. AB - The evaluation of coronary lesions in patients with asymptomatic carotid plaque represents a very promising line of research to assess cardiovascular risk and the possible implementation of a more aggressive prevention therapy. METHODS: In this study we enrolled 102 patients with intermediate to high cardiovascular risk but no history of coronary artery disease. The first group, consisting of 51 patients, underwent a Coronary CT scan (CCT-group) as well as carotid ultrasonography. The second group, also consisting of 51 patients, underwent coronary angiography (CA) and carotid ultrasonography. RESULTS: The absence of a statistically significant difference between the involvement of both coronary and carotid sites, assessed by CCT and CA, confirms the role of coronary CT as a useful method in the preclinical evaluation of cardiovascular risk. In the CCT group, the correlation between atherosclerosis of carotid artery and coronary disease, as well as between the mean carotid intimal medial thickness and the number of involved coronary vessels, and between the maximum values of carotid plaque and the presence of coronary artery stenosis > 50%, were statistically significant. The Agatson calcium score was also statistically associated with carotid plaque size. CONCLUSION: The imaging biomarkers have a key role in the evaluation of subclinical atherosclerotic disease. Moreover, carotid ultrasound examination and a CT-scan of coronary arteries, in a particular sub-group of patients with intermediate to high cardiovascular risk, can play a crucial role to assess the preventive therapeutic strategies. PMID- 25147765 TI - Resveratrol exerts no effect on inflammatory response and delayed onset muscle soreness after a marathon in male athletes.: A randomised, double-blind, placebo controlled pilot feasibility study. AB - OBJECTIVE: We investigated whether the inflammatory response and delayed onset of muscle soreness after a marathon are altered by resveratrol, a natural polyphenolic flavonoid antioxidant. DESIGN: Double blind placebo-controlled randomised pilot study. SETTING: London Marathon. PARTICIPANTS: Marathon race participants. INTERVENTIONS: 7 healthy male athletes were randomised to receive Resveratrol (600 mg Resveratrol daily for 7 days immediately before the marathon) or a placebo. MAIN OUTCOME MEASUREMENTS: Blood samples taken 48 hours before and 18-32 hours after the marathon were analysed for white blood cell count (WBC) and C-reactive protein (CRP). A VAS score was taken at the same times as the blood samples to assess delayed onset muscle soreness. RESULTS: There were no significant differences between the two groups in terms of changes occurring between pre- and post- tests for WBC, CRP or VAS. CONCLUSIONS: There were no differences in immune response or delayed onset muscle soreness between resveratrol and placebo after a marathon. Further investigations are needed with longer treatment time and higher doses, analysing additional parameters such interleukins for a possible effect of resveratrol on the inflammatory response due to extensive exercise. To avoid a type II error, 17 subjects in each group would be required. PMID- 25147764 TI - Molecular biology of gliomas: present and future challenges. AB - Malignant brain tumours are one of the most relevant causes of morbidity and mortality across a wide range of individuals. Malignant glioma is the most common intra axial tumor in the adult. Many researches on this theme brought advances in the knowledge of gliomas biology and pathogenesis and to the development of new agents for targeted molecular therapy. Recent studies focused on either tumor metabolism analysis or epigenetic regulation in the pathogenesis or maintenance of brain tumors. This Review summarizes these developments analyzing molecular pathology and possible further developments for targeted therapies. PMID- 25147766 TI - Lifestyle and eating habits in a business community. AB - PURPOSE: The present study verified, using a validated questionnaire, the presence of unhealthy aspects of lifestyle and chronic degenerative conditions in a working community. METHODS: A cohort from a working community in Italy was investigated using of the INRAN (Istituto Nazionale di Ricerca per gli Alimenti e Nutrizione) questionnaire dedicated to the eating habits and Physical Activity Stages of Change. RESULTS: Most of the 93 subjects (56 females and 37 males, aged 42.0+/-0.7) recruited reported low levels of physical activity (70 subjects). Slightly more than 50% of the subjects undertook physical activity more than once a week, while 13% did it only once. Food intolerances were reported by 7 subjects (8%), with a high consumption of fruits, cereals and dairy products, low consumption of fish and alcohol, and meat consumption in the normal range. There was a high satisfaction in general quality of life. CONCLUSION: Questionnaire investigations play a role to identify the presence of degenerative chronic conditions in working communities. The self-reported perception of quality of life does not necessarily agree with the lifestyle habits found. Awareness of this aspect could be helpful to plan lifestyle interventions and promote healthy living habits. PMID- 25147767 TI - Assessment of the Effectiveness of Extracorporeal Shock Wave Therapy (ESWT) For Soft Tissue Injuries (ASSERT): An Online Database Protocol. AB - BACKGROUND: Soft tissue injuries and tendinopathies account for large numbers of chronic musculoskeletal disorders. Extracorporeal shockwave therapy (ESWT) is popular, and effective in the management of chronic tendon conditions in the elbow, shoulder, and pain at and around the heel. METHODS/DESIGN: Ethical approval was granted from the South East London Research Ethics Committee to implement a database for the Assessment of Effectiveness of Extracorporeal Shock Wave Therapy for Soft Tissue Injuries (ASSERT) to prospectively collect information on the effectiveness of ESWT across the UK. All participants will give informed consent. All clinicians follow a standardised method of administration of the ESWT. The primary outcome measures are validated outcome measures specific to the condition being treated. A Visual Analogue Score for pain and the EuroQol will be completed alongside the condition specific outcome tool at baseline, 3, 6, 12 and 24 months post treatment. DISCUSSION: The development of the ASSERT database will enable the evaluation of the effectiveness of ESWT for patients suffering from chronic conditions (plantar fasciopathy, tennis elbow, Achilles tendinopathy, greater trochanter pain syndrome and patellar tendinopathy). The results will aid the clinicians in the decision making process when managing these patients. PMID- 25147768 TI - Osteitis pubis: can early return to elite competition be contemplated? AB - BACKGROUND AND PURPOSE: In elite athletes, osteitis pubis is a common painful degenerative process of the pubic symphysis and surrounding soft tissues and tendons. We report the diagnostic pathway and the rehabilitation protocol of six elite athletes with osteitis pubis in three different sports, and compare protocol stages and time to return to competition. METHODS: 6 athletes (2 soccer, 2 basketball, 2 rugby players) were diagnosed with osteitis pubis stage III and IV according to Rodriguez classification using standard clinical and imaging criteria. After performing a baseline lumbo-pelvic assessment, the rehabilitation protocol described by Verrall was adapted to each individual athlete. RESULTS: The length of time for each stage of the protocol was as follows; Stage 1 (rest from sport) was 26 +/- 5 days, Stage 2 (to achieve pain free running), 18 +/- 5 days, Stage 3 (squad training) 63 +/- 7, Stage 4 (return to competition) 86 +/- 15. Soccer players took longer to return to competition than basketball and rugby players. No recurrences were reported at 2 year follow-up. CONCLUSION: The protocol presented ensures a safe return to elite athletes. The time from diagnosis to full recovery is longer in football players, and seems to increase with age. PMID- 25147769 TI - Bioethical issues of preventing hereditary diseases with late onset in the Sakha Republic (Yakutia). AB - BACKGROUND: Prenatal diagnosis of congenital and hereditary diseases is a priority for the development of medical technologies in Russia. However, there are not many published research results on bioethical issues of prenatal DNA testing. OBJECTIVE: The main goal of the article is to describe some of the bioethical aspects of prenatal DNA diagnosis of hereditary diseases with late onset in genetic counselling practice in the Sakha Republic (Yakutia) - a far north-eastern region of Russia. METHODS: The methods used in the research are genetic counselling, invasive chorionic villus biopsy procedures, molecular diagnosis, social and demographic characteristics of patients. RESULTS: In 10 years, 48 (76%) pregnant women from families tainted with hereditary spinocerebellar ataxia type 1 and 15 pregnant women from families with myotonic dystrophy have applied for medical and genetic counselling in order to undergo prenatal DNA testing. The average number of applications is 7-8 per year. There are differences in prenatal genetic counselling approaches. CONCLUSION: It is necessary to develop differentiated ethical approaches depending on the mode of inheritance, age of manifestation, and clinical polymorphism of hereditary disease. PMID- 25147770 TI - Obesity and obesity-associated cardiometabolic risk factors in indigenous Nenets women from the rural Nenets Autonomous Area and Russian women from Arkhangelsk city. AB - BACKGROUND: The prevalence of obesity and obesity-related conditions varies by population groups. Indigenous women of the circumpolar north are believed to be at high risk of obesity. OBJECTIVE: We studied, first the obesity prevalence in indigenous Arctic women, Nenets, compared to urban Russian women. Second, the association between obesity and cardiometabolic risk factors in the combined group of Nenets and Russian women. Third, ethnic differences in the association between obesity and cardiometabolic risk factors. DESIGN: Cross-sectional study performed in 2008-2009. SUBJECTS: 93 Nenets women, aged 19-77 (the indigenous village, the Nenets Autonomous Area) and 132 Russian women, aged 21-72 (Arkhangelsk city). Obesity was defined as body mass index (BMI)>=30 kg/m(2), waist circumference (WC)>=88 cm and or waist-to-hip ratio (WHR)>=0.85%. We assessed associations between obesity and cardiometabolic risk factors by linear and logistic regression models that included covariates of ethnicity, age, smoking and physical activity. We also tested for interaction between obesity measurements and ethnicity. RESULTS: Prevalence of obesity estimated through BMI, WC and WHR were 42.5, 45.3 and 41.9% in Nenets and 34.4, 46.4 and 29.5% in Russians, respectively, with no differences found. BMI, WC and WHR associated positively with triglycerides, fasting insulin and Homeostasis Model Assessment of Insulin Resistance index. In addition, BMI and WC correlated negatively with high-density lipoprotein cholesterol and positively with systolic blood pressure and apolipoprotein B/apoliporotein A-I ratio. WC explained significant variation in fasting glucose (FG) level. BMI predicted type 2 diabetes history. FG level associated strongly with ethnicity and was found to be higher in Russians. CONCLUSIONS: We found no differences in prevalence of obesity between Nenets and Russian females. Obesity was associated with cardiometabolic risk factors independently of ethnicity in the sample studied. There was no link between obesity measurements and ethnicity. PMID- 25147771 TI - Paediatric trauma on the Last Frontier: an 11-year review of injury mechanisms, high-risk injury patterns and outcomes in Alaskan children. AB - BACKGROUND: Paediatric trauma system development in Alaska is complicated by a vast geographic coverage area, wide regional variations in environment and culture, and a lack of available published data. OBJECTIVE: To provide a detailed description of paediatric trauma mechanisms, high-risk injury patterns and outcomes in Alaska. DESIGN: This retrospective study included all children aged 17 years or younger in the State of Alaska Trauma Registry database admitted with traumatic injury between 2001 and 2011. Each injury record was reviewed individually and assigned a mechanism based on Centers for Disease Control E codes. Geographic definitions were based on existing Emergency Medical Services regions. Mechanisms were compared by geographic region, patient demographics, injury characteristics and outcome. Subgroup analysis of fatal injuries was performed to identify causes of death. RESULTS: Of 5,547 patients meeting inclusion criteria, the most common mechanisms of injury were falls (39%), motor vehicle collisions (10%) and all-terrain vehicle (ATV) accidents (9%). The overall case fatality rate was 2%. Mechanisms with the greatest risk of death were gunshot wounds (21%), pedestrians struck by motorized vehicles (9%) and motor vehicle collisions (5%). These 3 mechanisms accounted for 15% of injuries but 60% of deaths in the overall cohort. Injury patterns involving combined central nervous system (CNS) and torso injuries were unusual but especially lethal, occurring in 3% of patients but carrying a case fatality rate of 18%. Although the distribution of mechanisms was generally similar for each geographic region, ATV and snowmobile injuries were significantly more common in remote areas (23% remote vs. 7% non-remote, p < 0.0001). CONCLUSIONS: Mechanisms of paediatric trauma in Alaska have widely varying impacts on outcome and show some variation by region. Highest-risk mechanisms include gunshot wounds and motorized vehicle-related accidents. Prevention efforts should give special attention to CNS injury prevention, ATV and snowmobile safety in remote areas, and optimization of management of multisystem trauma. Further studies should investigate predictors of outcome in greater detail. PMID- 25147772 TI - Development of a strategic plan for food security and safety in the Inuvialuit Settlement Region, Canada. AB - BACKGROUND: Current social and environmental changes in the Arctic challenge the health and well-being of its residents. Developing evidence-informed adaptive measures in response to these changes is a priority for communities, governments and researchers. OBJECTIVES: To develop strategic planning to promote food security and food safety in the Inuvialuit Settlement Region (ISR), Northwest Territories (NWT), Canada. DESIGN: A qualitative study using group discussions during a workshop. METHODS: A regional workshop gathered Inuit organizations and community representatives, university-based researchers from the Inuit Health Survey (IHS) and NWT governmental organizations. Discussions were structured around the findings from the IHS. For each key area, programs and activities were identified and prioritized by group discussion and voting. RESULTS: The working group developed a vision for future research and intervention, which is to empower communities to promote health, well-being and environmental sustainability in the ISR. The group elaborated missions for the region that address the following issues: (a) capacity building within communities; (b) promotion of the use of traditional foods to address food security; (c) research to better understand the linkages between diseases and contaminants in traditional foods, market foods and lifestyle choices; (d) and promotion of affordable housing. Five programs to address each key area were developed as follows: harvest support and traditional food sharing; education and promotion; governance and policy; research; and housing. Concrete activities were identified to guide future research and intervention projects. CONCLUSIONS: The results of the planning workshop provide a blueprint for future research and intervention projects. PMID- 25147773 TI - Application of the queuing analytic theory in emergency department. PMID- 25147775 TI - Doubt About Prediction Role of S100B Protein in Brain Death. PMID- 25147774 TI - Epidemiology of patients with multiple trauma and the quality of their prehospital respiration management in kashan, iran: six months assessment. AB - BACKGROUND: Respiration management is an important and critical issue in prehospital transportation phase of multiple trauma patients. However, the quality of this important care has not been assessed in Iran Emergency Medical Services' (EMS). OBJECTIVES: This study was conducted to investigate the quality of prehospital respiration management in patients with multiple trauma, referred to the Shahid Beheshti Trauma Center, Kashan, Iran. PATIENTS AND METHODS: This cross-sectional study was conducted in the first six months of 2013. All the 400 patients with multiple trauma, transferred by EMS to the Shahid Beheshti Medical Center, were recruited. The study instrument was a checklist, which was completed through observation. Descriptive statistics were presented. RESULTS: Out of all included individuals, 301 were males (75.2%) and 99 were females (24.8%). The most common mechanism of trauma was traffic accident (87.25%). Furthermore, 71.7% of the patients were injured in head and neck and chest areas. The quality of consciousness monitoring and airway management was desirable in 95% of the cases. However, the quality of monitoring patients' respiration was only desirable in 42% of the cases. Only 18.6% of the patients received oxygen therapy during prehospital transportation. CONCLUSIONS: The quality of monitoring patients' respiration and oxygen therapy was undesirable in most patients with multiple trauma. Therefore, the EMS workers should be retrained to apply proper respiration management in patients with multiple trauma. PMID- 25147776 TI - Diabetic foot due to anaphylactic shock: a case report. AB - INTRODUCTION: Diabetic foot is a clinical disorder, which is commonly seen in patients with diabetes mellitus. It is also the major cause of below knee amputation in the world. There are many underlying causes such as neuropathic, ischemic, and infectious causes for diabetic foot. Local or systemic complications may develop after snake bite. CASE PRESENTATION: We reported a very rare case, involving a 78-year-old male admitted to the Emergency Department, who developed anaphylactic shock and diabetic foot after the snake bite. CONCLUSIONS: Reviewing the literature, this is the second reported case of snake bite associated with diabetic foot. PMID- 25147777 TI - Quality of life among veterans with chronic spinal cord injury and related variables. AB - BACKGROUND: In recent decades, the incidence of spinal cord injuries has increased. In a systemic review on epidemiology of traumatic spinal cord injury in developing countries reported 25.5/million cases per year. OBJECTIVES: To assess the quality of life (QOL) of the veterans among Iran-Iraq war with chronic spinal cord injuries (SCI) and to evaluate long-term impressions of SCI on their quality of life. PATIENTS AND METHODS: Fifty-two veterans, all male, with chronic spinal cord injury from Iran-Iraq war (1980-1988) were interviewed and examined. The mean age of veterans at the time of interview was 49.3 years (38 to 80 years). Veterans were assessed by using a 36-item short-form (SF-36), hospital anxiety and depression scale (HADS) and the Barthel index. The presence or absence of pressure sores and spasticity were documented as well. RESULTS: The mean age of veterans at the time of study was 49.3 years. Pearson's correlation test showed that depression and anxiety have a reverse association with mental component summary (MCS) scale and physical component summary (PCS) scale scores, respectively. Regression analysis showed a negative effect of depression and pressure sore on PCS. Moreover, no association was found between the duration of injury and age with quality of life. CONCLUSIONS: Lower QOL was found among veterans with chronic SCI. More researches on health-related quality of life (HRQOL) are needed to give us a better understanding of changes in life of patients with SCI and the ways to improve them. PMID- 25147778 TI - Readability of patient education materials on the american association for surgery of trauma website. AB - BACKGROUND: Because the quality of information on the Internet is of dubious worth, many patients seek out reliable expert sources. As per the American Medical Association (AMA) and the National Institutes of Health (NIH) recommendations, readability of patient education materials should not exceed a sixth-grade reading level. The average reading skill of U.S. adults is at the eighth-grade level. OBJECTIVES: This study evaluates whether a recognized source of expert content, the American Association for Surgery of Trauma (AAST) website's patient education materials, recommended readability guidelines for medical information. MATERIALS AND METHODS: Using the well-validated Flesch Kincaid formula to analyze grade level readability, we evaluated the readability of all 16 of the publicly-accessible entries within the patient education section of the AAST website. RESULTS: Mean +/- SD grade level readability was 10.9 +/- 1.8 for all the articles. All but one of the articles had a readability score above the sixth-grade level. Readability of the articles exceeded the maximum recommended level by an average of 4.9 grade levels (95% confidence interval, 4.0 5.8; P < 0.0001). Readability of the articles exceeded the eighth-grade level by an average of 2.9 grade levels (95% confidence interval, 2.0-3.8; P < 0.0001). Only one of the articles had a readability score below the eighth-grade level. CONCLUSIONS: The AAST's online patient education materials may be of limited utility to many patients, as the readability of the information exceeds the average reading skill level of adults in the U.S. Lack of patient comprehension represents a discrepancy that is not in accordance with the goals of the AAST's objectives for its patient education efforts. PMID- 25147779 TI - Burn Patients Infected With Metallo-Beta-Lactamase-Producing Pseudomonas aeruginosa: Multidrug-Resistant Strains. AB - BACKGROUND: Metallo-beta-lactamase (MBL) producing Pseudomonas aeruginosa in the burn patients is a leading cause of morbidity and mortality and remains a serious health concern among the clinicians. OBJECTIVES: The aim of this study was to detect MBL-producing P. aeruginosa in burn patients and determine multidrug resistant (MDR) strains, and respective resistance patterns. PATIENTS AND METHODS: In this cross-sectional study, 270 strains of P. aeruginosa were isolated from the burn patients referred to Ghotbeddin Burn Hospital, Shiraz, Iran. Among them, 55 MBL-producing P. aeruginosa strains were isolated from 55 patients hospitalized in burn unit. Minimum inhibitory concentrations (MICs) and MBLs were determined by the E-test method. RESULTS: Of the 55 burn cases, 29 (53%) were females and 26 (47%) males. Injured burn patients' ages ranged from 16 to 87 years, with maximum number of cases in the age group of 16 to 36 years (n, 40; 72.7%). Overall, 32 cases were accidental (60%), and 22 were suicidal burns (40%). Of the 55 burn patients, 17 cases were expired (30%). All deaths were due to chemical exposures. In antibiotic susceptibility testing by E-test method, ceftazidime was the most effective one and 35 isolates (63.5%) were resistant to all the 11 tested antibiotics. CONCLUSIONS: Routine microbiological surveillance and careful in vitro testing of antibiotics prior to prescription and strict adherence to hospital antibiotic policy may help to prevent, treat, and control MDR and pandrug-resistant (PDR) P. aeruginosa strains in burn units. PMID- 25147780 TI - The Serum Lead level in Patients With Retained Lead Pellets. AB - BACKGROUND: Patients, who survived from shotgun injuries, often have some retained lead pellets in their bodies. Several cases of lead toxicity have been reported regarding these patients. OBJECTIVES: This study seeks to compare the serum lead level in patients who have retained lead pellets in their bodies with the control group. PATIENTS AND METHODS: In this case-control study, we gathered the serum lead levels of 25 patients with some retained lead pellets in their bodies due to shotgun and 25 volunteers without similar lead exposure and compared them in view of the age, gender, and living place. RESULTS: While the mean serum lead level in both groups was lower than the standard level (i.e. 40 ug/dL) , the mean +/- SD of serum lead level were 29 +/- 12.8 ug/dL and 25.3 +/- 6.4 ug/dL in the case and control groups, respectively without any significant difference (P = 0. 30) . However, a positive relationship was seen between serum lead level, and the number of retained lead pellets (r = 0.447, P = 0. 025) . CONCLUSIONS: Although extensive surgery to remove the lead pellets is not recommended in patients injured with shotguns, those with many retained lead pellets in their bodies should be considered at risk for lead poisoning and monitored carefully. PMID- 25147781 TI - Ocular trauma: an overview. PMID- 25147782 TI - Targeting Glutathione S-transferase M4 in Ewing sarcoma. AB - Ewing sarcoma is a malignant pediatric bone and soft tissue tumor. Although the 5 year survival rate of localized disease approaches 75%, the prognosis of metastatic and/or therapy-resistant disease remains dismal despite the wide use of aggressive therapeutic strategies. We previously reported that high expression of glutathione S-transferase M4 (GSTM4) in primary tumors correlates with poor patient outcomes. GSTM4 is required for oncogenic transformation and mediates resistance to chemotherapeutic drugs in Ewing sarcoma cells. Here, we performed RNA-sequencing analyses of Ewing sarcoma cells and combined our results with publicly available datasets to demonstrate that GSTM4 is a major GST specifically expressed in Ewing sarcoma. Pharmacological inhibition of GSTM4 activity using a pan GST inhibitor, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX), significantly limited cellular proliferation and oncogenic transformation of Ewing sarcoma cells. Moreover, combined use of NBDHEX and etoposide synergistically increased cytotoxicity, suggesting a role for GSTM4 as an inhibitor of apoptosis. Mechanistic studies revealed that GSTM4 limits apoptosis owing to its ability to interact with Apoptosis Signal-regulating Kinase 1 (ASK1) and inhibit signaling via the c-Jun N-terminal Kinase axis. To exploit our observation that GSTM4 expression is specifically up-regulated in Ewing sarcoma, we tested the effect of a GSTM4-activated anti-cancer agent, O(2)-(2,4 dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate or JS K, on tumor growth and survival. We found that JS-K robustly decreased Ewing sarcoma cell viability and xenograft tumor growth and improved overall survival of xenograft mice. Our data suggest that GSTM4 is a novel therapeutic target for the treatment of high GSTM4-expressing Ewing sarcoma. Strategies that combine standard chemotherapy with agents that inhibit GSTM4, that are activated by GSTM4, or that block GSTM4/ASK1 interactions, can potentially be more specific and/or efficacious than standard therapeutic approaches. PMID- 25147783 TI - Genetic Associations with Plasma B12, B6, and Folate Levels in an Ischemic Stroke Population from the Vitamin Intervention for Stroke Prevention (VISP) Trial. AB - BACKGROUND: B vitamins play an important role in homocysteine metabolism, with vitamin deficiencies resulting in increased levels of homocysteine and increased risk for stroke. We performed a genome-wide association study (GWAS) in 2,100 stroke patients from the Vitamin Intervention for Stroke Prevention (VISP) trial, a clinical trial designed to determine whether the daily intake of high-dose folic acid, vitamins B6, and B12 reduce recurrent cerebral infarction. METHODS: Extensive quality control (QC) measures resulted in a total of 737,081 SNPs for analysis. Genome-wide association analyses for baseline quantitative measures of folate, Vitamins B12, and B6 were completed using linear regression approaches, implemented in PLINK. RESULTS: Six associations met or exceeded genome-wide significance (P <= 5 * 10(-08)). For baseline Vitamin B12, the strongest association was observed with a non-synonymous SNP (nsSNP) located in the CUBN gene (P = 1.76 * 10(-13)). Two additional CUBN intronic SNPs demonstrated strong associations with B12 (P = 2.92 * 10(-10) and 4.11 * 10(-10)), while a second nsSNP, located in the TCN1 gene, also reached genome-wide significance (P = 5.14 * 10(-11)). For baseline measures of Vitamin B6, we identified genome-wide significant associations for SNPs at the ALPL locus (rs1697421; P = 7.06 * 10( 10) and rs1780316; P = 2.25 * 10(-08)). In addition to the six genome-wide significant associations, nine SNPs (two for Vitamin B6, six for Vitamin B12, and one for folate measures) provided suggestive evidence for association (P <= 10( 07)). CONCLUSION: Our GWAS study has identified six genome-wide significant associations, nine suggestive associations, and successfully replicated 5 of 16 SNPs previously reported to be associated with measures of B vitamins. The six genome-wide significant associations are located in gene regions that have shown previous associations with measures of B vitamins; however, four of the nine suggestive associations represent novel finding and warrant further investigation in additional populations. PMID- 25147784 TI - Characterization of a GHF45 cellulase, AkEG21, from the common sea hare Aplysia kurodai. AB - The common sea hare Aplysia kurodai is known to be a good source for the enzymes degrading seaweed polysaccharides. Recently four cellulases, i.e., 95, 66, 45, and 21 kDa enzymes, were isolated from A. kurodai (Tsuji et al., 2013). The former three cellulases were regarded as glycosyl-hydrolase-family 9 (GHF9) enzymes, while the 21 kDa cellulase was suggested to be a GHF45 enzyme. The 21 kDa cellulase was significantly heat stable, and appeared to be advantageous in performing heterogeneous expression and protein-engineering study. In the present study, we determined some enzymatic properties of the 21 kDa cellulase and cloned its cDNA to provide the basis for the protein engineering study of this cellulase. The purified 21 kDa enzyme, termed AkEG21 in the present study, hydrolyzed carboxymethyl cellulose with an optimal pH and temperature at 4.5 and 40 degrees C, respectively. AkEG21 was considerably heat-stable, i.e., it was not inactivated by the incubation at 55 degrees C for 30 min. AkEG21 degraded phosphoric-acid-swollen cellulose producing cellotriose and cellobiose as major end products but hardly degraded oligosaccharides smaller than tetrasaccharide. This indicated that AkEG21 is an endolytic beta-1,4-glucanase (EC 3.2.1.4). A cDNA of 1013 bp encoding AkEG21 was amplified by PCR and the amino-acid sequence of 197 residues was deduced. The sequence comprised the initiation Met, the putative signal peptide of 16 residues for secretion and the catalytic domain of 180 residues, which lined from the N-terminus in this order. The sequence of the catalytic domain showed 47-62% amino-acid identities to those of GHF45 cellulases reported in other mollusks. Both the catalytic residues and the N-glycosylation residues known in other GHF45 cellulases were conserved in AkEG21. Phylogenetic analysis for the amino-acid sequences suggested the close relation between AkEG21 and fungal GHF45 cellulases. PMID- 25147786 TI - Drug-related genomics in cancer and immunological diseases. PMID- 25147785 TI - Immunological and technical considerations in application of alginate-based microencapsulation systems. AB - Islets encapsulated in immunoprotective microcapsules are being proposed as an alternative for insulin therapy for treatment of type 1 diabetes. Many materials for producing microcapsules have been proposed but only alginate does currently qualify as ready for clinical application. However, many different alginate-based capsule systems do exist. A pitfall in the field is that these systems are applied without a targeted strategy with varying degrees of success as a consequence. In the current review, the different properties of alginate-based systems are reviewed in view of future application in humans. The use of allogeneic and xenogeneic islet sources are discussed with acknowledging the different degrees of immune protection the encapsulation system should supply. Also issues such as oxygen supply and the role of danger associated molecular patterns (DAMPS) in immune activation are being reviewed. A common property of the encapsulation systems is that alginates for medical application should have an extreme high degree of purity and lack pathogen-associated molecular patterns (PAMPs) to avoid activation of the recipient's immune system. Up to now, non inflammatory alginates are only produced on a lab-scale and are not yet commercially available. This is a major pitfall on the route to human application. Also the lack of predictive pre-clinical models is a burden. The principle differences between relevant innate and adaptive immune responses in humans and other species are reviewed. Especially, the extreme differences between the immune system of non-human primates and humans are cumbersome as non human primates may not be predictive of the immune responses in humans, as opposed to the popular belief of regulatory agencies. Current insight is that although the technology is versatile major research efforts are required for identifying the mechanical, immunological, and physico-chemical requirements that alginate-based capsules should meet for successful human application. PMID- 25147788 TI - 1,3,4-oxadiazole derivatives: synthesis, characterization, antimicrobial potential, and computational studies. AB - We report the synthesis and biological assessment of 1,3,4-oxadiazole substituted 24 derivatives as novel, potential antibacterial agents. The structures of the newly synthesized derivatives were established by the combined practice of UV, IR, (1)H NMR, (13)C NMR, and mass spectrometry. Further these synthesized derivatives were subjected to antibacterial activity against all the selected microbial strains in comparison with amoxicillin and cefixime. The antibacterial activity of synthesized derivatives was correlated with their physicochemical and structural properties by QSAR analysis using computer assisted multiple regression analysis and four sound predictive models were generated with good R(2), R(adj)(2), and Fischer statistic. The derivatives with potent antibacterial activity were subjected to molecular docking studies to investigate the interactions between the active derivatives and amino acid residues existing in the active site of peptide deformylase to assess their antibacterial potential as peptide deformylase inhibitor. PMID- 25147789 TI - A hadoop-based method to predict potential effective drug combination. AB - Combination drugs that impact multiple targets simultaneously are promising candidates for combating complex diseases due to their improved efficacy and reduced side effects. However, exhaustive screening of all possible drug combinations is extremely time-consuming and impractical. Here, we present a novel Hadoop-based approach to predict drug combinations by taking advantage of the MapReduce programming model, which leads to an improvement of scalability of the prediction algorithm. By integrating the gene expression data of multiple drugs, we constructed data preprocessing and the support vector machines and naive Bayesian classifiers on Hadoop for prediction of drug combinations. The experimental results suggest that our Hadoop-based model achieves much higher efficiency in the big data processing steps with satisfactory performance. We believed that our proposed approach can help accelerate the prediction of potential effective drugs with the increasing of the combination number at an exponential rate in future. The source code and datasets are available upon request. PMID- 25147787 TI - N-acyl homoserine lactone-mediated quorum sensing with special reference to use of quorum quenching bacteria in membrane biofouling control. AB - Membrane biofouling remains a severe problem to be addressed in wastewater treatment systems affecting reactor performance and economy. The finding that many wastewater bacteria rely on N-acyl homoserine lactone-mediated quorum sensing to synchronize their activities essential for biofilm formations; the quenching bacterial quorum sensing suggests a promising approach for control of membrane biofouling. A variety of quorum quenching compounds of both synthetic and natural origin have been identified and found effective in inhibition of membrane biofouling with much less environmental impact than traditional antimicrobials. Work over the past few years has demonstrated that enzymatic quorum quenching mechanisms are widely conserved in several prokaryotic organisms and can be utilized as a potent tool for inhibition of membrane biofouling. Such naturally occurring bacterial quorum quenching mechanisms also play important roles in microbe-microbe interactions and have been used to develop sustainable nonantibiotic antifouling strategies. Advances in membrane fabrication and bacteria entrapment techniques have allowed the implication of such quorum quenching bacteria for better design of membrane bioreactor with improved antibiofouling efficacies. In view of this, the present paper is designed to review and discuss the recent developments in control of membrane biofouling with special emphasis on quorum quenching bacteria that are applied in membrane bioreactors. PMID- 25147791 TI - Peptide-ligand binding modeling of siRNA with cell-penetrating peptides. AB - The binding affinity of a series of cell-penetrating peptides (CPP) was modeled through docking and making use of the number of intermolecular hydrogen bonds, lipophilic contacts, and the number of sp3 molecular orbital hybridization carbons. The new ranking of the peptides is consistent with the experimentally determined efficiency in the downregulation of luciferase activity, which includes the peptides' ability to bind and deliver the siRNA into the cell. The predicted structures of the complexes of peptides to siRNA were stable throughout 10 ns long, explicit water molecular dynamics simulations. The stability and binding affinity of peptide-siRNA complexes was related to the sidechains and modifications of the CPPs, with the stearyl and quinoline groups improving affinity and stability. The reranking of the peptides docked to siRNA, together with explicit water molecular dynamics simulations, appears to be well suited to describe and predict the interaction of CPPs with siRNA. PMID- 25147790 TI - Heat shock proteins at the crossroads between cancer and Alzheimer's disease. AB - Heat shock proteins 70 and heat shock proteins 90 (Hsp70/90) have been implicated in many crucial steps of carcinogenesis: stabilizing oncogenic proteins, inhibiting programmed cell death and replicative senescence, induction of tumor angiogenesis, and activation of the invasion and metastasis. Plenty of cancer related proteins have the ability of regulating the expression of Hsp70/90 through heat shock factor 1. Cancer and Alzheimer's disease (AD) have plenty of overlapping regions in molecular genetics and cell biology associated with Hsp70/90. The Hsp70, as a protein stabilizer, has a cellular protection against neurodegeneration of the central nervous system, while Hsp90 promote neurodegenerative disorders indirectly through regulating the expression of Hsp70 and other chaperones. All these make existing anticancer drugs target Hsp70/90 which might be used in AD therapy. PMID- 25147792 TI - The N-terminal domain of human DNA helicase Rtel1 contains a redox active iron sulfur cluster. AB - Human telomere length regulator Rtel1 is a superfamily II DNA helicase and is essential for maintaining proper length of telomeres in chromosomes. Here we report that the N-terminal domain of human Rtel1 (RtelN) expressed in Escherichia coli cells produces a protein that contains a redox active iron-sulfur cluster with the redox midpoint potential of -248 +/- 10 mV (pH 8.0). The iron-sulfur cluster in RtelN is sensitive to hydrogen peroxide and nitric oxide, indicating that reactive oxygen/nitrogen species may modulate the DNA helicase activity of Rtel1 via modification of its iron-sulfur cluster. Purified RtelN retains a weak binding affinity for the single-stranded (ss) and double-stranded (ds) DNA in vitro. However, modification of the iron-sulfur cluster by hydrogen peroxide or nitric oxide does not significantly affect the DNA binding activity of RtelN, suggesting that the iron-sulfur cluster is not directly involved in the DNA interaction in the N-terminal domain of Rtel1. PMID- 25147794 TI - The evolution of legislation in the field of Medically Assisted Reproduction and embryo stem cell research in European union members. AB - Medically Assisted Reproduction (MAR), involving in vitro fertilisation (IVF), and research on embryos have created expectation to many people affected by infertility; at the same time it has generated a surplus of laws and ethical and social debates. Undoubtedly, MAR represents a rather new medical field and constant developments in medicine and new opportunities continue to defy the attempt to respond to those questions. In this paper, the authors reviewed the current legislation in the 28 EU member states trying to evaluate the different legislation paths adopted over the last 15 years and highlighting those EU countries with no specific legislation in place and MAR is covered by a general health Law and those countries in which there are no laws in this field but only "guidelines." The second aim of this work has been to compare MAR legislation and embryo research in EU countries, which derive from different origins ranging from an extremely prohibitive approach versus a liberal one, going through a cautious regulatory approach. PMID- 25147793 TI - New perspectives on antiacne plant drugs: contribution to modern therapeutics. AB - Acne is a common but serious skin disease, which affects approximately 80% adolescents and young adults in 11-30 age group. 42.5% of men and 50.9% of women continue to suffer from this disease into their twenties. Bacterial resistance is now at the alarming stage due to the irrational use of antibiotics. Hence, search for new lead molecule/bioactive and rational delivery of the existing drug (for better therapeutic effect) to the site of action is the need of the hour. Plants and plant-derived products have been an integral part of health care system since time immemorial. Therefore, plants that are currently used for the treatment of acne and those with a high potential are summarized in the present review. Most active plant extracts, namely, P. granatum, M. alba, A. anomala, and M. aquifolium exhibit minimum inhibitory concentration (MIC) in the range of 4-50 ug/mL against P. acnes, while aromatic oils of C. obovoides, C. natsudaidai, C. japonica, and C. nardus possess MICs 0.005-0.6 MUL/mL and phytomolecules such as rhodomyrtone, pulsaquinone, hydropulsaquinone, honokiol, magnolol, xanthohumol lupulones, chebulagic acid and rhinacanthin-C show MIC in the range of 0.5-12.5 MUg/mL. Novel drug delivery strategies of important plant leads in the treatment of acne have also been discussed. PMID- 25147795 TI - miRNA transcriptome of hypertrophic skeletal muscle with overexpressed myostatin propeptide. AB - MicroRNAs (miRNAs) play an imperative role in cell proliferation, differentiation, and cell metabolism through regulation of gene expression. Skeletal muscle hypertrophy that results from myostatin depression by its propeptide provides an interesting model to understand how miRNA transcriptome is involved in myostatin-based fiber hypertrophy. This study employed Solexa deep sequencing followed by Q-PCR methods to analyze miRNA transcriptome of skeletal muscle of myostatin propeptide transgenic mice in comparison with their littermate controls. A total of 461 mature known and 69 novel miRNAs were reported from this study. Fifty-seven miRNAs were expressed differentially between transgenic and littermate controls, of which most abundant miRNAs, miR 133a and 378a, were significantly differentially expressed. Expression profiling was validated on 8 known and 2 novel miRNAs. The miRNA targets prediction and pathway analysis showed that FST, SMAD3, TGFBR1, and AcvR1a genes play a vital role in skeletal muscle hypertrophy in the myostatin propeptide transgenic mice. It is predicted that miR-101 targeted to TGFBR1 and SMAD3, miR-425 to TGFBR2 and FST, and miR-199a to AcvR2a and TGF-beta genes. In conclusion, the study offers initial miRNA profiling and methodology of miRNA targets prediction for myostatin based hypertrophy. These differentially expressed miRNAs are proposed as candidate miRNAs for skeletal muscle hypertrophy. PMID- 25147796 TI - Tattoo-associated skin reaction: the importance of an early diagnosis and proper treatment. AB - Tattoo is going to be a very common practice especially among young people and we are witnessing a gradual increase of numerous potential complications to tattoo placement which are often seen by physicians, but generally unknown to the public. The most common skin reactions to tattoo include a transient acute inflammatory reaction due to trauma of the skin with needles and medical complications such as superficial and deep local infections, systemic infections, allergic contact dermatitis, photodermatitis, granulomatous and lichenoid reactions, and skin diseases localized on tattooed area (eczema, psoriasis, lichen, and morphea). Next to these inflammatory skin reactions we have to consider also the possibility of the development of cutaneous conditions such as pseudolymphomatous reactions and pseudoepitheliomatous hyperplasia. The aim of this study is to underline the importance of an early diagnosis by performing a histological examination especially when we are in front of suspected papulonodular lesions arising from a tattoo, followed by a proper treatment, since cutaneous neoplastic evolution is known to be a rare but possible complication. PMID- 25147797 TI - Differences in cytotoxic, genotoxic, and inflammatory response of bronchial and alveolar human lung epithelial cells to pristine and COOH-functionalized multiwalled carbon nanotubes. AB - Functionalized MWCNTs are used in many commercial and biomedical applications, but their potential health effects are not well defined. We investigated and compared cytotoxic, genotoxic/oxidative, and inflammatory effects of pristine and carboxyl MWCNTs exposing human respiratory (A549 and BEAS-2B) cells to 1-40 MUg/mL of CNTs for 24 h. Both MWCNTs induced low viability reduction (by WST1 assay) in A549 cells and only MWCNTs-COOH caused high viability reduction in BEAS 2B cells reaching 28.5% viability at 40 MUg/mL. Both CNTs induced membrane damage (by LDH assay) with higher effects in BEAS-2B cells at the highest concentrations reaching 20% cytotoxicity at 40 MUg/mL. DNA damage (by Fpg-comet assay) was induced by pristine MWCNTs in A549 cells and by both MWCNTs in BEAS-2B cells reaching for MWCNTs-COOH a tail moment of 22.2 at 40 MUg/mL versus 10.2 of unexposed cells. Increases of IL-6 and IL-8 release (by ELISA) were detected in A549 cells exposed to MWCNTs-COOH from 10 MUg/mL while IL-8 increased in BEAS-2B cells exposed to pristine MWCNTs at 20 and 40 MUg/mL. The results show higher cytogenotoxicity of MWCNTs-COOH in bronchial and of pristine MWCNTs in alveolar cells. Different inflammatory response was also found. The findings suggest the use of in vitro models with different end points and cells to study CNT toxicity. PMID- 25147798 TI - Hemodynamic indexes derived from computed tomography angiography to predict pulmonary embolism related mortality. AB - Pulmonary embolism (PE) induces an acute increase in the right ventricle afterload that can lead to right-ventricular dysfunction (RVD) and eventually to circulatory collapse. Hemodynamic status and presence of RVD are important determinants of adverse outcomes in acute PE. Technologic progress allows computed tomography angiography (CTA) to give more information than accurate diagnosis of PE. It may also provide an insight into hemodynamics and right ventricular function. Proximal localization of emboli, reflux of contrast medium to the hepatic veins, and right-to-left short-axis ventricular diameter ratio seem to be the most relevant CTA predictors of 30-day mortality. These elements require little postprocessing time, an advantage in the emergency room. We herein review the prognostic value of RVD and other CTA mortality predictors for patients with acute PE. PMID- 25147799 TI - The emerging use of in vivo optical imaging in the study of neurodegenerative diseases. AB - The detection and subsequent quantification of photons emitted from living tissues, using highly sensitive charged-couple device (CCD) cameras, have enabled investigators to noninvasively examine the intricate dynamics of molecular reactions in wide assortment of experimental animals under basal and pathophysiological conditions. Nevertheless, extrapolation of this in vivo optical imaging technology to the study of the mammalian brain and related neurodegenerative conditions is still in its infancy. In this review, we introduce the reader to the emerging use of in vivo optical imaging in the study of neurodegenerative diseases. We highlight the current instrumentation that is available and reporter molecules (fluorescent and bioluminescent) that are commonly used. Moreover, we examine how in vivo optical imaging using transgenic reporter mice has provided new insights into Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Prion disease, and neuronal damage arising from excitotoxicity and inflammation. Furthermore, we also touch upon studies that have utilized these technologies for the development of therapeutic strategies for neurodegenerative conditions that afflict humans. PMID- 25147800 TI - Fibrinogen alpha chain precursor and apolipoprotein A-I in urine as biomarkers for noninvasive diagnosis of calcium oxalate nephrolithiasis: a proteomics study. AB - Calcium oxalate nephrolithiasis is the most common urological disease, but noninvasive and convenient methods of diagnosis are rarely available. OBJECTIVE: The present study aimed to identify potential urine biomarkers for noninvasive diagnosis of CaOx nephrolithiasis. METHODOLOGY: Urine samples from 72 patients with CaOx nephrolithiasis and 30 healthy controls were collected and proteomics analysis was performed using matrix-assisted laser desorption/ionization-time of flight-mass spectrometer (MALDI-TOF-MS). RESULTS: Thirteen proteins/peptides displayed statistically significant differences. The peptides of m/z 1207.23 and 2773.86 were selected by the genetic algorithm (GA) to build a possible diagnostic model. The area under the curve of m/z 1207.23 and 2773.86 was 0.936 and 0.987, respectively. The diagnostic model in distinguishing patients and healthy subjects showed 100% sensitivity and specificity. The peak at m/z 2773.86 was identified as fibrinogen alpha chain (FGA) with the sequence G.EGDFLAEGGGVR.G, and the peak at m/z 2773.86 was identified as apolipoprotein A I (apoA-I) with the sequence L.PVLESFKVSFLSALEEYTKKLNTQ. CONCLUSION: The study results strongly suggested that urinary FGA and apoA-I are highly sensitive and specific biomarkers for noninvasive diagnosis of CaOx nephrolithiasis. PMID- 25147801 TI - Diagnostic and prognostic value of soluble syndecan-1 in pleural malignancies. AB - BACKGROUND: The distinction between malignant and benign pleural effusions is a diagnostic challenge today and measuring soluble biomarkers could add to the diagnostic accuracy. Syndecan-1 is a proteoglycan involved in various cellular functions and is cleaved from the cell surface in a regulated manner. The shed fragment, which can be recovered in effusion supernatant and in serum, retains its binding capacities, but often with different functions and signalling properties than the cell-bound form. AIM: This study aimed to investigate the diagnostic and prognostic value of soluble syndecan-1 in pleural effusions and sera from patients with pleural malignancies. STUDY DESIGN: Using two cohorts of patients, we assessed the diagnostic and prognostic value of soluble syndecan-1 in pleural effusions and sera, using enzyme-linked immunosorbent assays. RESULTS: In pleural effusions, syndecan-1 distinguished malignant and benign diseases, with an odds ratio of 8.59 (95% CI 3.67 to 20.09). Furthermore, syndecan-1 in pleural effusions predicted a survival difference for patients with pleural metastatic disease and malignant mesothelioma of 11.2 and 9.2 months, respectively. However, no such effects were seen when syndecan-1 was measured in serum. CONCLUSION: Soluble syndecan-1 is a promising candidate biomarker for the cytopathological diagnosis and prognostication of malignant pleural effusions. PMID- 25147802 TI - An intelligent system for identifying acetylated lysine on histones and nonhistone proteins. AB - Lysine acetylation is an important and ubiquitous posttranslational modification conserved in prokaryotes and eukaryotes. This process, which is dynamically and temporally regulated by histone acetyltransferases and deacetylases, is crucial for numerous essential biological processes such as transcriptional regulation, cellular signaling, and stress response. Since the experimental identification of lysine acetylation sites within proteins is time-consuming and laboratory intensive, several computational approaches have been developed to identify candidates for experimental validation. In this work, acetylated protein data collected from UniProtKB were categorized into histone or nonhistone proteins. Support vector machines (SVMs) were applied to build predictive models by using amino acid pair composition (AAPC) as a feature in a histone model. We combined BLOSUM62 and AAPC features in a nonhistone model. Furthermore, using maximal dependence decomposition (MDD) clustering can enhance the performance of the model on a fivefold cross-validation evaluation to yield a sensitivity of 0.863, specificity of 0.885, accuracy of 0.880, and MCC of 0.706. Additionally, the proposed method is evaluated using independent test sets resulting in a predictive accuracy of 74%. This indicates that the performance of our method is comparable with that of other acetylation prediction methods. PMID- 25147803 TI - Sequence alignment tools: one parallel pattern to rule them all? AB - In this paper, we advocate high-level programming methodology for next generation sequencers (NGS) alignment tools for both productivity and absolute performance. We analyse the problem of parallel alignment and review the parallelisation strategies of the most popular alignment tools, which can all be abstracted to a single parallel paradigm. We compare these tools to their porting onto the FastFlow pattern-based programming framework, which provides programmers with high-level parallel patterns. By using a high-level approach, programmers are liberated from all complex aspects of parallel programming, such as synchronisation protocols, and task scheduling, gaining more possibility for seamless performance tuning. In this work, we show some use cases in which, by using a high-level approach for parallelising NGS tools, it is possible to obtain comparable or even better absolute performance for all used datasets. PMID- 25147804 TI - Update in pathogenesis and prospective in treatment of necrotizing enterocolitis. AB - Necrotizing enterocolitis (NEC) is among the most common and devastating diseases in neonates and, despite the significant advances in neonatal clinical and basic science investigations, its etiology is largely understood, specific treatment strategies are lacking, and morbidity and mortality remain high. Improvements in the understanding of pathogenesis of NEC may have therapeutic consequences. Pharmacologic inhibition of toll-like receptor signaling, the use of novel nutritional strategies, and microflora modulation may represent novel promising approaches to the prevention and treatment of NEC. This review, starting from the recent acquisitions in the pathogenic mechanisms of NEC, focuses on current and possible therapeutic perspectives. PMID- 25147805 TI - Innervation of a prefabricated flap: a new experimental model. AB - INTRODUCTION: Flap innervation by neoaxonogenesis is a promising field of investigation. The authors evaluated the possibility of innervating an acellular collagen scaffold as component of a potential prefabricated flap. MATERIALS AND METHODS: Collagen matrix sheets were implanted around the femoral bundle of a murine model to produce two flaps on proximal and distal nerve stumps based on a flow-through model. After thirty days, nerve regeneration and integration into the collagen matrix were evaluated. The specimens were microscopically analyzed to study Schwann cell colonization and axonal integration with the matrix. Axonal count and density were assessed and statistically evaluated. RESULTS: Qualitative structural and ultrastructural evaluation indicated integration, with axonal fibers merged within the collagen matrix, along with a newly formed vascular network on the proximal flap. Wallerian degeneration occurred inside the distal chamber. Axonal count and density did not show statistically significant differences between the nerve inside the proximal flap and the control side. CONCLUSIONS: Innervation of an acellular matrix can be obtained by direct nerve stump implantation. The flow-through system was relatively easy to build and reliable to provide adequate blood supply. The collagen scaffold may be a promising support or further studies of preinnervated microsurgical flaps. PMID- 25147806 TI - Randomized controlled trial of strain-specific probiotic formulation (Renadyl) in dialysis patients. AB - BACKGROUND: Primary goal of this randomized, double-blind, placebo-controlled crossover study of Renadyl in end-stage renal disease patients was to assess the safety and efficacy of Renadyl measured through improvement in quality of life or reduction in levels of known uremic toxins. Secondary goal was to investigate the effects on several biomarkers of inflammation and oxidative stress. METHODS: Two 2-month treatment periods separated by 2-month washout and crossover, with physical examinations, venous blood testing, and quality of life questionnaires completed at each visit. Data were analyzed with SAS V9.2. RESULTS: 22 subjects (79%) completed the study. Observed trends were as follows (none reaching statistical significance): decline in WBC count (-0.51 * 10(9)/L, P = 0.057) and reductions in levels of C-reactive protein (-8.61 mg/L, P = 0.071) and total indoxyl glucuronide (-0.11 mg%, P = 0.058). No statistically significant changes were observed in other uremic toxin levels or measures of QOL. CONCLUSIONS: Renadyl appeared to be safe to administer to ESRD patients on hemodialysis. Stability in QOL assessment is an encouraging result for a patient cohort in such advanced stage of kidney disease. Efficacy could not be confirmed definitively, primarily due to small sample size and low statistical power-further studies are warranted. PMID- 25147807 TI - The parameters of transcutaneous electrical nerve stimulation are critical to its regenerative effects when applied just after a sciatic crush lesion in mice. AB - We investigated the effect of two frequencies of transcutaneous electrical nerve stimulation (TENS) applied immediately after lesion on peripheral nerve regeneration after a mouse sciatic crush injury. The animals were anesthetized and subjected to crushing of the right sciatic nerve and then separated into three groups: nontreated, Low-TENS (4 Hz), and High-TENS (100 Hz). The animals of Low- and High-TENS groups were stimulated for 2 h immediately after the surgical procedure, while the nontreated group was only positioned for the same period. After five weeks the animals were euthanized, and the nerves dissected bilaterally for histological and histomorphometric analysis. Histological assessment by light and electron microscopy showed that High-TENS and nontreated nerves had a similar profile, with extensive signs of degeneration. Conversely, Low-TENS led to increased regeneration, displaying histological aspects similar to control nerves. High-TENS also led to decreased density of fibers in the range of 6-12 MUm diameter and decreased fiber diameter and myelin area in the range of 0-2 MUm diameter. These findings suggest that High-TENS applied just after a peripheral nerve crush may be deleterious for regeneration, whereas Low-TENS may increase nerve regeneration capacity. PMID- 25147808 TI - Resveratrol, a natural antioxidant, has a protective effect on liver injury induced by inorganic arsenic exposure. AB - Resveratrol (Rev) can ameliorate cytotoxic chemotherapy-induced toxicity and oxidative stress. Arsenic trioxide (As2O3) is a known cytotoxic environmental toxicant and a potent chemotherapeutic agent. However, the mechanisms by which resveratrol protects the liver against the cytotoxic effects of As2O3 are not known. Therefore, in the present study we investigated the mechanisms involved in the action of resveratrol using a cat model in which hepatotoxicity was induced by means of As2O3 treatment. We found that pretreatment with resveratrol, administered using a clinically comparable dose regimen, reversed changes in As2O3-induced morphological and liver parameters and resulted in a significant improvement in hepatic function. Resveratrol treatment also improved the activities of antioxidant enzymes and attenuated As2O3-induced increases in reactive oxygen species and malondialdehyde production. In addition, resveratrol attenuated the As2O3-induced reduction in the ratio of reduced glutathione to oxidized glutathione and the retention of arsenic in liver tissue. These findings provide a better understanding of the mechanisms whereby resveratrol modulates As2O3-induced changes in liver function and tissue morphology. They also provide a stronger rationale for the clinical utilization of resveratrol for the reduction of As2O3-induced hepatotoxicity. PMID- 25147809 TI - Platelet concentration in platelet-rich plasma affects tenocyte behavior in vitro. AB - Since tendon injuries and tendinopathy are a growing problem, sometimes requiring surgery, new strategies that improve conservative therapies are needed. Platelet rich plasma (PRP) seems to be a good candidate by virtue of its high content of growth factors, most of which are involved in tendon healing. This study aimed to evaluate if different concentrations of platelets in PRP have different effects on the biological features of normal human tenocytes that are usually required during tendon healing. The different platelet concentrations tested (up to 5 * 10(6) plt/uL) stimulated differently tenocytes behavior; intermediate concentrations (0.5 * 10(6), 1 * 10(6) plt/uL) strongly induced all tested processes (proliferation, migration, collagen, and MMPs production) if compared to untreated cells; on the contrary, the highest concentration had inhibitory effects on proliferation and strongly reduced migration abilities and overall collagen production but, at the same time, induced increasing MMP production, which could be counterproductive because excessive proteolysis could impair tendon mechanical stability. Thus, these in vitro data strongly suggest the need for a compromise between extremely high and low platelet concentrations to obtain an optimal global effect when inducing in vivo tendon healing. PMID- 25147810 TI - Mechanical models of the dynamics of vitreous substitutes. AB - We discuss some aspects of the fluid dynamics of vitreous substitutes in the vitreous chamber, focussing on the flow induced by rotations of the eye bulb. We use simple, yet not trivial, theoretical models to highlight mechanical concepts that are relevant to understand the dynamics of vitreous substitutes and also to identify ideal properties for vitreous replacement fluids. We first recall results by previous authors, showing that the maximum shear stress on the retina grows with increasing viscosity of the fluid up to a saturation value. We then investigate how the wall shear stress changes if a thin layer of aqueous humour is present in the vitreous chamber, separating the retina from the vitreous replacement fluid. The theoretical predictions show that the existence of a thin layer of aqueous is sufficient to substantially decrease the shear stress on the retina. We finally discuss a theoretical model that predicts the stability conditions of the interface between the aqueous and a vitreous substitute. We discuss the implications of this model to understand the mechanisms leading to the formation of emulsion in the vitreous chamber, showing that instability of the interface is possible in a range of parameters relevant for the human eye. PMID- 25147811 TI - Newborn screening for sickle cell disease: technical and legal aspects of a German pilot study with 38,220 participants. AB - Sickle cell disease (SCD) does not occur in the indigenous German population, but with the increasing number of immigrants from countries at high risk for hemoglobinopathies, the question emerges whether or not a newborn screening program (NBS) for SCD disease should be initiated in Germany anyhow. We have recently shown that in Berlin, a city with a very large immigrant population, the incidence of SCD is considerable, but our findings are insufficient to make a decision for the country as a whole. In this paper we will show that a large body of epidemiological data can be generated in a relatively short period of time, with a very high degree of precision and at relatively little expense--a result that might motivate other working groups to start such a pilot project locally. We examined previously collected dried blood cards that were up to six months old, using high performance liquid chromatography (HPLC) as first method and capillary electrophoresis (CE) as second method. A single, part-time laboratory technician processed 38,220 samples in a period of 162 working days. The total costs per sample including all incidentals (as well as labor costs) were EUR 1.44. PMID- 25147813 TI - Biomedical data integration, modeling, and simulation in the era of big data and translational medicine. PMID- 25147812 TI - Cationic polyene phospholipids as DNA carriers for ocular gene therapy. AB - Recent success in the treatment of congenital blindness demonstrates the potential of ocular gene therapy as a therapeutic approach. The eye is a good target due to its small size, minimal diffusion of therapeutic agent to the systemic circulation, and low immune and inflammatory responses. Currently, most approaches are based on viral vectors, but efforts continue towards the synthesis and evaluation of new nonviral carriers to improve nucleic acid delivery. Our objective is to evaluate the efficiency of novel cationic retinoic and carotenoic glycol phospholipids, designated C20-18, C20-20, and C30-20, to deliver DNA to human retinal pigmented epithelium (RPE) cells. Liposomes were produced by solvent evaporation of ethanolic mixtures of the polyene compounds and coformulated with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or cholesterol (Chol). Addition of DNA to the liposomes formed lipoplexes, which were characterized for binding, size, biocompatibility, and transgene efficiency. Lipoplex formulations of suitable size and biocompatibility were assayed for DNA delivery, both qualitatively and quantitatively, using RPE cells and a GFP encoding plasmid. The retinoic lipoplex formulation with DOPE revealed a transfection efficiency comparable to the known lipid references 3beta-[N-(N',N' dimethylaminoethane)-carbamoyl]-cholesterol (DC-Chol) and 1,2-dioleoyl-sn-glycero 3-ethylphosphocholine (EPC) and GeneJuice. The results demonstrate that cationic polyene phospholipids have potential as DNA carriers for ocular gene therapy. PMID- 25147814 TI - Tailored PVA/ECM scaffolds for cartilage regeneration. AB - Articular cartilage lesions are a particular challenge for regenerative medicine due to cartilage low self-ability repair in case of damage. Hence, a significant goal of musculoskeletal tissue engineering is the development of suitable structures in virtue of their matrix composition and biomechanical properties. The objective of our study was to design in vitro a supporting structure for autologous chondrocyte growth. We realized a biohybrid composite scaffold combining a novel and nonspecific extracellular matrix (ECM), which is decellularized Wharton's jelly ECM, with the biomechanical properties of the synthetic hydrogel polyvinyl alcohol (PVA). Wharton's jelly ECM was tested for its ability in promoting scaffold colonization by chondrocytes and compared with polyvinyl alcohol itself and the more specific decellularized cartilage matrix. Our preliminary evidences highlighted the chance of using Wharton's jelly ECM in combination with PVA hydrogels as an innovative and easily available scaffold for cartilage restoration. PMID- 25147815 TI - Inhibition of MMP-2 expression with siRNA increases baseline cardiomyocyte contractility and protects against simulated ischemic reperfusion injury. AB - Matrix metalloproteinases (MMPs) significantly contribute to ischemia reperfusion (I/R) injury, namely, by the degradation of contractile proteins. However, due to the experimental models adopted and lack of isoform specificity of MMP inhibitors, the cellular source and identity of the MMP(s) involved in I/R injury remain to be elucidated. Using isolated adult rat cardiomyocytes, subjected to chemically induced I/R-like injury, we show that specific inhibition of MMP-2 expression and activity using MMP-2 siRNA significantly protected cardiomyocyte contractility from I/R-like injury. This was also associated with increased expression of myosin light chains 1 and 2 (MLC1/2) in comparison to scramble siRNA transfection. Moreover, the positive effect of MMP-2 siRNA transfection on cardiomyocyte contractility and MLC1/2 expression levels was also observed under control conditions, suggesting an important additional role for MMP-2 in physiological sarcomeric protein turnover. This study clearly demonstrates that intracellular expression of MMP-2 plays a significant role in sarcomeric protein turnover, such as MLC1 and MLC2, under aerobic (physiological) conditions. In addition, this study identifies intracellular/autocrine, cardiomyocyte-produced MMP-2, rather than paracrine/extracellular, as responsible for the degradation of MLC1/2 and consequent contractile dysfunction in cardiomyocytes subjected to I/R injury. PMID- 25147817 TI - Repeated batch fermentation biotechnology for the biosynthesis of lipid and gamma linolenic acid by Cunninghamella bainieri 2A1. AB - The biosynthesis of biomedical products including lipid and gamma-linolenic acid (GLA) by Cunninghamella bainieri 2A1 was studied in repeated batch fermentation. Three key process variables, namely, glucose concentration, ammonium tartrate concentration, and harvesting time, were optimized using response surface methodology. Repeated batch fermentation was carried out by the cultivation of Cunninghamella bainieri 2A1 in nitrogen-limited medium with various nitrogen concentration (1-4 g/L) and glucose concentration (20-40 g/L) at three time intervals (12 h, 24 h, and 48 h). Experimental results showed that the highest lipid concentration of 6.2 g/L and the highest GLA concentration of 0.4 g/L were obtained in optimum conditions, where 20.2 g/L glucose, 2.12 g/L ammonium tartrate, and 48 h harvesting time were utilized. Statistical results showed that the interaction between glucose and ammonium tartrate concentration had highly significant effects on lipid and GLA biosynthesis (P < 0.01). Moreover, harvesting time had a significant interaction effect with glucose and ammonium tartrate concentration on lipid production (P < 0.05). PMID- 25147816 TI - Accumulation of extracellular hyaluronan by hyaluronan synthase 3 promotes tumor growth and modulates the pancreatic cancer microenvironment. AB - Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic beta-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and beta-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth. PMID- 25147818 TI - Human umbilical cord perivascular cells exhibited enhanced migration capacity towards hepatocellular carcinoma in comparison with bone marrow mesenchymal stromal cells: a role for autocrine motility factor receptor. AB - Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. Unfortunately, the incidence and mortality associated with HCC are increasing. Therefore, new therapeutic strategies are urgently needed and the use of mesenchymal stromal cells (MSCs) as carrier of therapeutic genes is emerging as a promising option. Different sources of MSCs are being studied for cell therapy and bone marrow-derived cells are the most extensively explored; however, birth associated-tissues represent a very promising source. The aim of this work was to compare the in vitro and in vivo migration capacity between bone marrow MSCs (BM-MSCs) and human umbilical cord perivascular cells (HUCPVCs) towards HCC. We observed that HUCPVCs presented higher in vitro and in vivo migration towards factors released by HCC. The expression of autocrine motility factor (AMF) receptor, genes related with the availability of the receptor on the cell surface (caveolin-1 and -2) and metalloproteinase 3, induced by the receptor activation and important for cell migration, was increased in HUCPVCs. The chemotactic response towards recombinant AMF was increased in HUCPVCs compared to BM-MSCs, and its inhibition in the conditioned medium from HCC induced higher decrease in HUCPVC migration than in BM-MSC. Our results indicate that HUCPVCs could be a useful cellular source to deliver therapeutic genes to HCC. PMID- 25147819 TI - The effect of rilonacept versus placebo on health-related quality of life in patients with poorly controlled familial Mediterranean fever. AB - OBJECTIVE: To examine the effect of rilonacept on the health-related quality of life (HRQoL) in patients with poorly controlled familial Mediterranean fever (FMF). METHODS: As part of a randomized, double-blinded trial comparing rilonacept and placebo for the treatment of FMF, patients/parents completed the modified Child Health Questionnaire (CHQ) at baseline, and at the start and end of each of 4 treatment courses, 2 each with rilonacept and placebo. RESULTS: Fourteen subjects were randomized; mean age was 24.4 +/- 11.8 years. At baseline the physical HRQoL score was significantly less (24.2 +/- 49.5) but the psychosocial score was similar to the population norm (49.5 +/- 10.0). There were significant improvements in most HRQoL concepts after rilonacept but not placebo. Significant differences between rilonacept and placebo were found in the physical (33.7 +/- 16.4 versus 23.7 +/- 14.5, P = 0.021) but not psychosocial scores (51.4 +/- 10.3 versus 49.8 +/- 12.4, P = 0.42). The physical HRQoL was significantly impacted by the treatment effect and patient global assessment. CONCLUSION: Treatment with rilonacept had a beneficial effect on the physical HRQoL in patients with poorly controlled FMF and was also significantly related to the patient global assessment. This trial is registered with ClinicalTrials.gov Identifier NCT00582907. PMID- 25147820 TI - Morphometric analysis of connective tissue sheaths of sural nerve in diabetic and nondiabetic patients. AB - One of the most common complications of diabetes mellitus is diabetic neuropathy. It may be provoked by metabolic and/or vascular factors, and depending on duration of disease, various layers of nerve may be affected. Our aim was to investigate influence of diabetes on the epineurial, perineurial, and endoneurial connective tissue sheaths. The study included 15 samples of sural nerve divided into three groups: diabetic group, peripheral vascular disease group, and control group. After morphological analysis, morphometric parameters were determined for each case using ImageJ software. Compared to the control group, the diabetic cases had significantly higher perineurial index (P < 0.05) and endoneurial connective tissue percentage (P < 0.01). The diabetic group showed significantly higher epineurial area (P < 0.01), as well as percentage of endoneurial connective tissue (P < 0.01), in relation to the peripheral vascular disease group. It is obvious that hyperglycemia and ischemia present in diabetes lead to substantial changes in connective tissue sheaths of nerve, particularly in peri- and endoneurium. Perineurial thickening and significant endoneurial fibrosis may impair the balance of endoneurial homeostasis and regenerative ability of the nerve fibers. Future investigations should focus on studying the components of extracellular matrix of connective tissue sheaths in diabetic nerves. PMID- 25147821 TI - Decreased gastric motility in type II diabetic patients. AB - BACKGROUND: To differentiate gastric motility and sensation between type II diabetic patients and controls and explore different expressions of gastric motility peptides. METHODS: Eleven type II diabetic patients and health volunteers of similar age and body mass index were invited. All underwent transabdominal ultrasound for gastric motility and visual analogue scales. Blood samples were taken for glucose and plasma peptides (ghrelin, motilin, and glucagon-like peptides-1) by ELISA method. RESULTS: Gastric emptying was significantly slower in diabetic patients than controls (T50: 46.3 (28.0-52.3) min versus 20.8 (9.6-22.8) min, P <= 0.05) and less antral contractions in type II diabetic patients were observed (P = 0.02). Fundus dimensions did not differ. There were a trend for less changes in gastrointestinal sensations in type II diabetic patients especially abdomen fullness, hunger, and abdominal discomfort. Although the serum peptides between the two groups were similar a trend for less serum GLP-1 in type II diabetic patients was observed (P = 0.098). CONCLUSION: Type II diabetic patients have delayed gastric emptying and less antral contractions than controls. The observation that there were lower serum GLP-1 in type II diabetic patients could offer a clue to suggest that delayed gastric emptying in diabetic patients is not mainly influenced by GLP-1. PMID- 25147822 TI - Childhood renal tumor: a report from a Chinese Children's Cancer Group. AB - Here we investigated the establishment of multicenter cooperative treatment groups in China, as well as radiotherapy compliance and effectiveness among children with renal tumors. Medical records were reviewed for 316 children with renal tumors diagnosed by a multicenter cooperative group from 14 hospitals in China from 1998 to 2012. Median patient age was 29.5 months (range, 2-173 months old), and male-to-female ratio was 1.4 : 1. After a median follow-up of 22 months (range, 1-177 months), five-year event-free survival rates were 72% overall; 76.1% for favorable histology (251 cases); 59% for unfavorable histology (27 cases); and 91%, 75%, 71%, 53%, and 48.5%, respectively for Stages I, II, III, IV, and V. Following standardized criteria, radiation therapy was indicated for 153 patients, among whom five-year event-free survival was 72.8% for the 95 who received radiation and 24% for the 58 patients who did not. Our results are reasonable but can be further improved and show the feasibility of a multicenter cooperative group model for childhood renal tumor treatment in China. Radiation therapy is important for stage III and IV patients but remains difficult to implement in some parts of China. Government management departments and medical professionals must pay attention to this situation. This clinical trial is registered with ChiCTR-PRCH-14004372. PMID- 25147823 TI - Frequency of TGF- beta and IFN- gamma genotype as risk factors for acute kidney injury and death in intensive care unit patients. AB - Genetic variations in TGF-beta and IFN-gamma may interfere with proinflammatory cytokine production and, consequently, may be involved with inflammatory diseases, as acute kidney injury (AKI). We considered that genetic polymorphisms of these cytokines may have a crucial role in the outcome of critically ill patients. To investigate whether the genetic polymorphisms of rs1800470 (codon 10 T/C), rs1800471 (codon 25 C/G) from the TGF-beta, and rs2430561 (+874 T/A) from IFN-gamma may be a risk factor for ICU patients to the development of AKI and/or death. In a prospective nested case-control study, were included 139 ICU patients who developed AKI, 164 ICU patients without AKI, and 244 healthy individuals. We observed a higher frequency to T/A genotype for IFN-gamma (intermediate producer phenotype) and higher frequency of TT GG and TC GG genotype (high producer) for TGF-beta polymorphism in overall population. However, these polymorphisms have not been shown as a predictor of risk for AKI and death. We found an increased prevalence of high and intermediate producer phenotypes from TGF-beta and IFN gamma, respectively, in patients in ICU setting. However, the studied genetic polymorphism of the TGF-beta and IFN-gamma was not associated as a risk factor for AKI or death in our population. PMID- 25147824 TI - Biotechnological applications derived from microorganisms of the Atacama Desert. AB - The Atacama Desert in Chile is well known for being the driest and oldest desert on Earth. For these same reasons, it is also considered a good analog model of the planet Mars. Only a few decades ago, it was thought that this was a sterile place, but in the past years fascinating adaptations have been reported in the members of the three domains of life: low water availability, high UV radiation, high salinity, and other environmental stresses. However, the biotechnological applications derived from the basic understanding and characterization of these species, with the notable exception of copper bioleaching, are still in its infancy, thus offering an immense potential for future development. PMID- 25147825 TI - Studying the complex expression dependences between sets of coexpressed genes. AB - Organisms simplify the orchestration of gene expression by coregulating genes whose products function together in the cell. The use of clustering methods to obtain sets of coexpressed genes from expression arrays is very common; nevertheless there are no appropriate tools to study the expression networks among these sets of coexpressed genes. The aim of the developed tools is to allow studying the complex expression dependences that exist between sets of coexpressed genes. For this purpose, we start detecting the nonlinear expression relationships between pairs of genes, plus the coexpressed genes. Next, we form networks among sets of coexpressed genes that maintain nonlinear expression dependences between all of them. The expression relationship between the sets of coexpressed genes is defined by the expression relationship between the skeletons of these sets, where this skeleton represents the coexpressed genes with a well defined nonlinear expression relationship with the skeleton of the other sets. As a result, we can study the nonlinear expression relationships between a target gene and other sets of coexpressed genes, or start the study from the skeleton of the sets, to study the complex relationships of activation and deactivation between the sets of coexpressed genes that carry out the different cellular processes present in the expression experiments. PMID- 25147826 TI - Immobilization of murine anti-BMP-2 monoclonal antibody on various biomaterials for bone tissue engineering. AB - Biomaterials are widely used as scaffolds for tissue engineering. We have developed a strategy for bone tissue engineering that entails application of immobilized anti-BMP-2 monoclonal antibodies (mAbs) to capture endogenous BMPs in vivo and promote antibody-mediated osseous regeneration (AMOR). The purpose of the current study was to compare the efficacy of immobilization of a specific murine anti-BMP-2 mAb on three different types of biomaterials and to evaluate their suitability as scaffolds for AMOR. Anti-BMP-2 mAb or isotype control mAb was immobilized on titanium (Ti) microbeads, alginate hydrogel, and ACS. The treated biomaterials were surgically implanted in rat critical-sized calvarial defects. After 8 weeks, de novo bone formation was assessed using micro-CT and histomorphometric analyses. Results showed de novo bone regeneration with all three scaffolds with immobilized anti-BMP-2 mAb, but not isotype control mAb. Ti microbeads showed the highest volume of bone regeneration, followed by ACS. Alginate showed the lowest volume of bone. Localization of BMP-2, -4, and -7 antigens was detected on all 3 scaffolds with immobilized anti-BMP-2 mAb implanted in calvarial defects. Altogether, these data suggested a potential mechanism for bone regeneration through entrapment of endogenous BMP-2, -4, and 7 proteins leading to bone formation using different types of scaffolds via AMOR. PMID- 25147828 TI - Antiviral action of synthetic stigmasterol derivatives on herpes simplex virus replication in nervous cells in vitro. AB - Polyfunctionalized stigmasterol derivatives, (22S,23S)-22,23-dihydroxystigmast-4 en-3-one (compound 1) and (22S,23S)-3beta-bromo-5alpha,22,23-trihydroxystigmastan 6-one (compound 2), inhibit herpes simplex virus type 1 (HSV-1) replication and spreading in human epithelial cells derived from ocular tissues. Both compounds reduce the incidence and severity of lesions in a murine model of herpetic stromal keratitis when administered in different treatment modalities. Since encephalitis caused by HSV-1 is another immunopathology of viral origin, we evaluate here the antiviral effect of both compounds on HSV-1 infected nervous cell lines as well as their anti-inflammatory action. We found that both stigmasterol derivatives presented low cytotoxicity in the three nervous cell lines assayed. Regarding the antiviral activity, in all cases both compounds prevented HSV-1 multiplication when added after infection, as well as virus propagation. Additionally, both compounds were able to hinder interleukin-6 and Interferon-gamma secretion induced by HSV-1 infection in Neuro-2a cells. We conclude that compounds 1 and 2 have exerted a dual antiviral and anti inflammatory effect in HSV-1 infected nervous cell lines, which makes them interesting molecules to be further studied. PMID- 25147827 TI - Upregulation of pluripotency markers in adipose tissue-derived stem cells by miR 302 and leukemia inhibitory factor. AB - The expression pattern of pluripotency markers in adipose tissue-derived stem cells (ADSCs) is a subject of controversy. Moreover, there is no data about the signaling molecules that regulate these markers in ADSCs. In the present study, we studied the roles of leukemia inhibitory factor (LIF) and miR-302 in this regard. Freshly isolated mouse ADSCs expressed hematopoietic, mesenchymal, and pluripotency markers. One day after plating, ADSCs expressed OCT4 and Sox2 proteins. After three passages, the expression of hematopoietic and pluripotency markers decreased, while the expression of mesenchymal stem cell markers exhibited a striking rise. Both supplementation of culture media with LIF and transfection of the ADSCs with miR-302 family upregulated the expression levels of OCT4, Nanog, and Sox2 mRNAs. These findings showed that mouse adipose tissue contains a population of cells with molecular resemblance to embryonic stem cells, and LIF and miR-302 family positively affect the expression of pluripotency markers. PMID- 25147829 TI - Pregnancy differentially regulates the collagens types I and III in left ventricle from rat heart. AB - The pathologic cardiac remodeling has been widely documented; however, the physiological cardiac remodeling induced by pregnancy and its reversion in postpartum are poorly understood. In the present study we investigated the changes in collagen I (Col I) and collagen III (Col III) mRNA and protein levels in left ventricle from rat heart during pregnancy and postpartum. Col I and Col III mRNA expression in left ventricle samples during pregnancy and postpartum were analyzed by using quantitative PCR. Data obtained from gene expression show that Col I and Col III in left ventricle are upregulated during pregnancy with reversion in postpartum. In contrast to gene expression, the protein expression evaluated by western blot showed that Col I is downregulated and Col III is upregulated in left ventricle during pregnancy. In conclusion, the pregnancy differentially regulates collagens types I and III in heart; this finding could be an important molecular mechanism that regulates the ventricular stiffness in response to blood volume overload present during pregnancy which is reversed in postpartum. PMID- 25147830 TI - Applying the maternal near miss approach for the evaluation of quality of obstetric care: a worked example from a Multicenter Surveillance Study. AB - OBJECTIVE: To assess quality of care of women with severe maternal morbidity and to identify associated factors. METHOD: This is a national multicenter cross sectional study performing surveillance for severe maternal morbidity, using the World Health Organization criteria. The expected number of maternal deaths was calculated with the maternal severity index (MSI) based on the severity of complication, and the standardized mortality ratio (SMR) for each center was estimated. Analyses on the adequacy of care were performed. RESULTS: 17 hospitals were classified as providing adequate and 10 as nonadequate care. Besides almost twofold increase in maternal mortality ratio, the main factors associated with nonadequate performance were geographic difficulty in accessing health services (P < 0.001), delays related to quality of medical care (P = 0.012), absence of blood derivatives (P = 0.013), difficulties of communication between health services (P = 0.004), and any delay during the whole process (P = 0.039). CONCLUSIONS: This is an example of how evaluation of the performance of health services is possible, using a benchmarking tool specific to Obstetrics. In this study the MSI was a useful tool for identifying differences in maternal mortality ratios and factors associated with nonadequate performance of care. PMID- 25147832 TI - A service based adaptive U-learning system using UX. AB - In recent years, traditional development techniques for e-learning systems have been changing to become more convenient and efficient. One new technology in the development of application systems includes both cloud and ubiquitous computing. Cloud computing can support learning system processes by using services while ubiquitous computing can provide system operation and management via a high performance technical process and network. In the cloud computing environment, a learning service application can provide a business module or process to the user via the internet. This research focuses on providing the learning material and processes of courses by learning units using the services in a ubiquitous computing environment. And we also investigate functions that support users' tailored materials according to their learning style. That is, we analyzed the user's data and their characteristics in accordance with their user experience. We subsequently applied the learning process to fit on their learning performance and preferences. Finally, we demonstrate how the proposed system outperforms learning effects to learners better than existing techniques. PMID- 25147831 TI - Immunomodulation by gut microbiota: role of Toll-like receptor expressed by T cells. AB - A close relationship exists between gut microbiota and immune responses. An imbalance of this relationship can determine local and systemic immune diseases. In fact the immune system plays an essential role in maintaining the homeostasis with the microbiota that normally resides in the gut, while, at the same time, the gut microbiota influences the immune system, modulating number and function of effector and regulatory T cells. To achieve this aim, mutual regulation between immune system and microbiota is achieved through several mechanisms, including the engagement of toll-like receptors (TLRs), pathogen-specific receptors expressed on numerous cell types. TLRs are able to recognize ligands from commensal or pathogen microbiota to maintain the tolerance or trigger the immune response. In this review, we summarize the latest evidences about the role of TLRs expressed in adaptive T cells, to understand how the immune system promotes intestinal homeostasis, fights invasion by pathogens, and is modulated by the intestinal microbiota. PMID- 25147833 TI - Apoptosis-inducing effect of three medicinal plants on oral cancer cells KB and ORL-48. AB - Brucea javanica, Azadirachta indica, and Typhonium flagelliforme are medicinal plants commonly used to treat conditions associated with tumour formation. This study aimed to determine the antiproliferative activity of these plants extracts on KB and ORL-48 oral cancer cell lines and to suggest their mode of cell death. The concentration producing 50% cell inhibition (IC50) was determined and the activity was examined under an inverted microscope. Immunohistochemistry fluorescent staining method (TUNEL) was performed to indicate the mechanism of cell death and the fragmented DNA band pattern produced was obtained for verification. Compared to Azadirachta sp. and Typhonium sp., the antiproliferative activity of Brucea sp. extract was the most potent on both KB and ORL-48 cells with IC50 of 24.37 +/- 1.75 and 6.67 +/- 1.15 ug/mL, respectively. Signs of cell attrition were observed 24 hr after treatment. Green fluorescent spots indicating cell death by apoptosis were observed in images of both cells following treatment with all the three extracts. DNA fragments harvested from Brucea-treated cells produced bands in a ladder pattern suggesting the apoptotic effect of the extract. It is thus concluded that Brucea sp. extract exhibited cytotoxic activity on ORL-48 cells and their action mechanism is via apoptosis. PMID- 25147834 TI - A novel concept acquisition approach based on formal contexts. AB - As an important tool for data analysis and knowledge processing, formal concept analysis (FCA) has been applied to many fields. In this paper, we introduce a new method to find all formal concepts based on formal contexts. The amount of intents calculation is reduced by the method. And the corresponding algorithm of our approach is proposed. The main theorems and the corresponding algorithm are examined by examples, respectively. At last, several real-life databases are analyzed to demonstrate the application of the proposed approach. Experimental results show that the proposed approach is simple and effective. PMID- 25147835 TI - Response of soil CO2 emission and summer maize yield to plant density and straw mulching in the North China Plain. AB - Demand for food security and the current global warming situation make high and strict demands on the North China Plain for both food production and the inhibition of agricultural carbon emissions. To explore the most effective way to decrease soil CO2 emissions and maintain high grain yield, studies were conducted during the 2012 and 2013 summer maize growing seasons to assess the effects of wheat straw mulching on the soil CO2 emissions and grain yield of summer maize by adding 0 and 0.6 kg m(-2) to fields with plant densities of 100,000, 75,000, and 55,000 plants ha(-1). The study indicated that straw mulching had some positive effects on summer maize grain yield by improving the 1000-kernel weight. Meanwhile, straw mulching effectively controlled the soil respiration rate and cumulative CO2 emission flux, particularly in fields planted at a density of 75,000 plants ha(-1), which achieved maximum grain yield and minimum carbon emission per unit yield. In addition, soil microbial biomass and microbial activity were significantly higher in mulching treatments than in nonmulching treatments. Consequently, summer maize with straw mulching at 75,000 plants ha( 1) is an environmentally friendly option in the North China Plain. PMID- 25147837 TI - Dynamics of a delayed model for the transmission of malicious objects in computer network. AB - An SEIQRS model for the transmission of malicious objects in computer network with two delays is investigated in this paper. We show that possible combination of the two delays can affect the stability of the model and make the model bifurcate periodic solutions under some certain conditions. For further investigation, properties of the periodic solutions are studied by using the normal form method and center manifold theory. Finally, some numerical simulations are given to justify the theoretical results. PMID- 25147836 TI - Phytochemical profiles and antioxidant and antimicrobial activities of the leaves of Zanthoxylum bungeanum. AB - The ethanol crude extracts (ECE) and their subfractions from Zanthoxylum bungeanum leaves were prepared and their phytochemical profiles and antioxidant and antimicrobial activities were investigated. Moreover, the effective HPLC procedure for simultaneous quantification of twelve compounds in Z. bungeanum leaves was established. The correlation between the phytochemicals and antioxidant activity was also discussed. The ethyl acetate fraction (EAF) had the highest total phenolic (97.29 mmol GAE/100 g) and flavonoid content (67.93 mmol QE/100 g), while the greatest total alkaloid content (4.39 mmol GAE/100 g) was observed in the chloroform fraction (CF). Twelve compounds were quantified by RP HPLC assay. EAF exhibited the highest content of quercitrin, kaempferol-3 rhamnoside, quercetin, sesamin, and nitidine chloride (125.21, 54.95, 24.36, 26.24, and 0.20 mg/g); acetone fraction (AF) contained the highest content of chlorogenic acid, rutin, hyperoside, and trifolin (5.87, 29.94, 98.33, and 31.24 mg/g), while kaempferol-3-rhamnoside, xanthyletin, and sesamin were rich in CF. EAF and AF exhibited significant DPPH, ABTS radical scavenging abilities and reducing power (FRAP), whereas CF exhibited significant antifungal activity. Moreover, EAF also showed stronger antibacterial activity. In conclusion, Z. bungeanum leaves have health benefits when consumed and could be served as an accessible source for production of functional food ingredients and medicinal exploration. PMID- 25147838 TI - Slope stability analysis using limit equilibrium method in nonlinear criterion. AB - In slope stability analysis, the limit equilibrium method is usually used to calculate the safety factor of slope based on Mohr-Coulomb criterion. However, Mohr-Coulomb criterion is restricted to the description of rock mass. To overcome its shortcomings, this paper combined Hoek-Brown criterion and limit equilibrium method and proposed an equation for calculating the safety factor of slope with limit equilibrium method in Hoek-Brown criterion through equivalent cohesive strength and the friction angle. Moreover, this paper investigates the impact of Hoek-Brown parameters on the safety factor of slope, which reveals that there is linear relation between equivalent cohesive strength and weakening factor D. However, there are nonlinear relations between equivalent cohesive strength and Geological Strength Index (GSI), the uniaxial compressive strength of intact rock sigma ci , and the parameter of intact rock m i . There is nonlinear relation between the friction angle and all Hoek-Brown parameters. With the increase of D, the safety factor of slope F decreases linearly; with the increase of GSI, F increases nonlinearly; when sigma ci is relatively small, the relation between F and sigma ci is nonlinear, but when sigma ci is relatively large, the relation is linear; with the increase of m i , F decreases first and then increases. PMID- 25147839 TI - Prescribed burning and clear-cutting effects on understory vegetation in a Pinus canariensis stand (Gran Canaria). AB - Prescribed fires are a powerful tool for reducing fire hazards by decreasing amounts of fuel. The main objective is to analyze the effects of prescribed burning on the understory vegetation composition as well as on the soil characteristics of a reforested stand of Pinus canariensis. The study attempts to identify the effects of the preburning treatment of cutting understory vegetation on the floristic parameters of the vegetation community. This study was carried out for two years following a prescribed fire in a Canarian pine stand. Cutting and burning treatment affected species composition and increased diversity. Burnt and cut plots were characterized by a diverse array of herbaceous species and by a lower abundance of Teline microphylla (endemic legume), although burning apparently induced its germination. Cut treatment was more consistently differentiated from the control plots than burnt treatment. Soil K decreased after both treatments, pH slightly decreased after cutting, while P and Ca increased after fire. From an ecological point of view, prescribed burning is a better management practice than cutting the woody species of the understory. However, long-term studies would be necessary to evaluate the effects of fire intensity, season and frequency in which the prescribed burning is applied. PMID- 25147840 TI - Secure access control and large scale robust representation for online multimedia event detection. AB - We developed an online multimedia event detection (MED) system. However, there are a secure access control issue and a large scale robust representation issue when we want to integrate traditional event detection algorithms into the online environment. For the first issue, we proposed a tree proxy-based and service oriented access control (TPSAC) model based on the traditional role based access control model. Verification experiments were conducted on the CloudSim simulation platform, and the results showed that the TPSAC model is suitable for the access control of dynamic online environments. For the second issue, inspired by the object-bank scene descriptor, we proposed a 1000-object-bank (1000OBK) event descriptor. Feature vectors of the 1000OBK were extracted from response pyramids of 1000 generic object detectors which were trained on standard annotated image datasets, such as the ImageNet dataset. A spatial bag of words tiling approach was then adopted to encode these feature vectors for bridging the gap between the objects and events. Furthermore, we performed experiments in the context of event classification on the challenging TRECVID MED 2012 dataset, and the results showed that the robust 1000OBK event descriptor outperforms the state-of-the-art approaches. PMID- 25147842 TI - Hyperbolic cross truncations for stochastic Fourier cosine series. AB - Based on our decomposition of stochastic processes and our asymptotic representations of Fourier cosine coefficients, we deduce an asymptotic formula of approximation errors of hyperbolic cross truncations for bivariate stochastic Fourier cosine series. Moreover we propose a kind of Fourier cosine expansions with polynomials factors such that the corresponding Fourier cosine coefficients decay very fast. Although our research is in the setting of stochastic processes, our results are also new for deterministic functions. PMID- 25147841 TI - Effects of nonsurgical periodontal therapy on clinical response, microbiological profile, and glycemic control in Malaysian subjects with type 1 diabetes. AB - The association between diabetes mellitus and chronic periodontal disease has long been established. Most of the researches linking these two very common chronic diseases were based on type 2 diabetes mellitus and chronic periodontal disease. However, this study was conducted to investigate the association between type 1 diabetes and chronic periodontal disease in Malaysian subjects. Forty-one Malaysian subjects, of which 20 subjects were type 1 diabetics and with chronic periodontal disease (test group) and 21 subjects with only chronic periodontal disease (control group), were included in the study. Periodontal parameters and plaque samples for microbiological evaluation were done at baseline, 2 and 3 months after nonsurgical periodontal therapy. Blood samples were taken from only the test group and evaluated for HbA1c at baseline and 3 months after periodontal therapy. There were no statistically significant difference in periodontal parameters between groups (P>0.05) and no significant improvement in the level of HbA1c in the test group. Microbiological studies indicated that there were significant reductions in the levels of the tested pathogens in both groups. The results of our study were similar to the findings of several other studies that had been done previously. PMID- 25147843 TI - Influence of microsprinkler irrigation amount on water, soil, and pH profiles in a coastal saline soil. AB - Microsprinkler irrigation is a potential method to alleviate soil salinization. After conducting a homogeneous, highly saline, clayey, and coastal soil from the Bohai Gulf in northern China in a column experiment, the results show that the depth of the wetting front increased as the water amount applied increased, low salinity and low-SAR enlarged after irrigation and water redistribution, and the soil pH increased with an increase in irrigation amount. We concluded that a water amount of 207 mm could be used to reclaim the coastal saline soil in northern China. PMID- 25147844 TI - A full ranking for decision making units using ideal and anti-ideal points in DEA. AB - We propose a procedure for ranking decision making units in data envelopment analysis, based on ideal and anti-ideal points in the production possibility set. Moreover, a model has been introduced to compute the performance of a decision making unit for these two points through using common set of weights. One of the best privileges of this method is that we can make ranking for all decision making units by solving only three programs, and also solving these programs is not related to numbers of decision making units. One of the other advantages of this procedure is to rank all the extreme and nonextreme efficient decision making units. In other words, the suggested ranking method tends to seek a set of common weights for all units to make them fully ranked. Finally, it was applied for different sets holding real data, and then it can be compared with other procedures. PMID- 25147845 TI - The study on stage financing model of IT project investment. AB - Stage financing is the basic operation of venture capital investment. In investment, usually venture capitalists use different strategies to obtain the maximum returns. Due to its advantages to reduce the information asymmetry and agency cost, stage financing is widely used by venture capitalists. Although considerable attentions are devoted to stage financing, very little is known about the risk aversion strategies of IT projects. This paper mainly addresses the problem of risk aversion of venture capital investment in IT projects. Based on the analysis of characteristics of venture capital investment of IT projects, this paper introduces a real option pricing model to measure the value brought by the stage financing strategy and design a risk aversion model for IT projects. Because real option pricing method regards investment activity as contingent decision, it helps to make judgment on the management flexibility of IT projects and then make a more reasonable evaluation about the IT programs. Lastly by being applied to a real case, it further illustrates the effectiveness and feasibility of the model. PMID- 25147846 TI - A community detection algorithm based on topology potential and spectral clustering. AB - Community detection is of great value for complex networks in understanding their inherent law and predicting their behavior. Spectral clustering algorithms have been successfully applied in community detection. This kind of methods has two inadequacies: one is that the input matrixes they used cannot provide sufficient structural information for community detection and the other is that they cannot necessarily derive the proper community number from the ladder distribution of eigenvector elements. In order to solve these problems, this paper puts forward a novel community detection algorithm based on topology potential and spectral clustering. The new algorithm constructs the normalized Laplacian matrix with nodes' topology potential, which contains rich structural information of the network. In addition, the new algorithm can automatically get the optimal community number from the local maximum potential nodes. Experiments results showed that the new algorithm gave excellent performance on artificial networks and real world networks and outperforms other community detection methods. PMID- 25147847 TI - delta-Cut decision-theoretic rough set approach: model and attribute reductions. AB - Decision-theoretic rough set is a quite useful rough set by introducing the decision cost into probabilistic approximations of the target. However, Yao's decision-theoretic rough set is based on the classical indiscernibility relation; such a relation may be too strict in many applications. To solve this problem, a delta-cut decision-theoretic rough set is proposed, which is based on the delta cut quantitative indiscernibility relation. Furthermore, with respect to criterions of decision-monotonicity and cost decreasing, two different algorithms are designed to compute reducts, respectively. The comparisons between these two algorithms show us the following: (1) with respect to the original data set, the reducts based on decision-monotonicity criterion can generate more rules supported by the lower approximation region and less rules supported by the boundary region, and it follows that the uncertainty which comes from boundary region can be decreased; (2) with respect to the reducts based on decision monotonicity criterion, the reducts based on cost minimum criterion can obtain the lowest decision costs and the largest approximation qualities. This study suggests potential application areas and new research trends concerning rough set theory. PMID- 25147848 TI - Theoretical modeling of intensity noise in InGaN semiconductor lasers. AB - This paper introduces modeling and simulation of the noise properties of the blue violet InGaN laser diodes. The noise is described in terms of the spectral properties of the relative intensity noise (RIN). We examine the validity of the present noise modeling by comparing the simulated results with the experimental measurements available in literature. We also compare the obtained noise results with those of AlGaAs lasers. Also, we examine the influence of gain suppression on the quantum RIN. In addition, we examine the changes in the RIN level when describing the gain suppression by the case of inhomogeneous spectral broadening. The results show that RIN of the InGaN laser is nearly 9 dB higher than that of the AlGaAs laser. PMID- 25147849 TI - Narrow-gap semiconductors and low-dimensional structures for optoelectronic applications. PMID- 25147850 TI - A cuckoo search algorithm for multimodal optimization. AB - Interest in multimodal optimization is expanding rapidly, since many practical engineering problems demand the localization of multiple optima within a search space. On the other hand, the cuckoo search (CS) algorithm is a simple and effective global optimization algorithm which can not be directly applied to solve multimodal optimization problems. This paper proposes a new multimodal optimization algorithm called the multimodal cuckoo search (MCS). Under MCS, the original CS is enhanced with multimodal capacities by means of (1) the incorporation of a memory mechanism to efficiently register potential local optima according to their fitness value and the distance to other potential solutions, (2) the modification of the original CS individual selection strategy to accelerate the detection process of new local minima, and (3) the inclusion of a depuration procedure to cyclically eliminate duplicated memory elements. The performance of the proposed approach is compared to several state-of-the-art multimodal optimization algorithms considering a benchmark suite of fourteen multimodal problems. Experimental results indicate that the proposed strategy is capable of providing better and even a more consistent performance over existing well-known multimodal algorithms for the majority of test problems yet avoiding any serious computational deterioration. PMID- 25147852 TI - Optimization of reflux conditions for total flavonoid and total phenolic extraction and enhanced antioxidant capacity in Pandan (Pandanus amaryllifolius Roxb.) using response surface methodology. AB - Response surface methodology was applied to optimization of the conditions for reflux extraction of Pandan (Pandanus amaryllifolius Roxb.) in order to achieve a high content of total flavonoids (TF), total phenolics (TP), and high antioxidant capacity (AC) in the extracts. Central composite experimental design with three factors and three levels was employed to consider the effects of the operation parameters, including the methanol concentration (MC, 40%-80%), extraction temperature (ET, 40-70 degrees C), and liquid-to-solid ratio (LS ratio, 20-40 mL/g) on the properties of the extracts. Response surface plots showed that increasing these operation parameters induced the responses significantly. The TF content and AC could be maximized when the extraction conditions (MC, ET, and LS ratio) were 78.8%, 69.5 degrees C, and 32.4 mL/g, respectively, whereas the TP content was optimal when these variables were 75.1%, 70 degrees C, and 31.8 mL/g, respectively. Under these optimum conditions, the experimental TF and TP content and AC were 1.78, 6.601 mg/g DW, and 87.38%, respectively. The optimized model was validated by a comparison of the predicted and experimental values. The experimental values were found to be in agreement with the predicted values, indicating the suitability of the model for optimizing the conditions for the reflux extraction of Pandan. PMID- 25147853 TI - A novel prediction method about single components of analog circuits based on complex field modeling. AB - Few researches pay attention to prediction about analog circuits. The few methods lack the correlation with circuit analysis during extracting and calculating features so that FI (fault indicator) calculation often lack rationality, thus affecting prognostic performance. To solve the above problem, this paper proposes a novel prediction method about single components of analog circuits based on complex field modeling. Aiming at the feature that faults of single components hold the largest number in analog circuits, the method starts with circuit structure, analyzes transfer function of circuits, and implements complex field modeling. Then, by an established parameter scanning model related to complex field, it analyzes the relationship between parameter variation and degeneration of single components in the model in order to obtain a more reasonable FI feature set via calculation. According to the obtained FI feature set, it establishes a novel model about degeneration trend of analog circuits' single components. At last, it uses particle filter (PF) to update parameters for the model and predicts remaining useful performance (RUP) of analog circuits' single components. Since calculation about the FI feature set is more reasonable, accuracy of prediction is improved to some extent. Finally, the foregoing conclusions are verified by experiments. PMID- 25147851 TI - Effect of codon optimisation on the production of recombinant fish growth hormone in Pichia pastoris. AB - This study was established to test the hypothesis of whether the codon optimization of fish growth hormone gene (FGH) based on P. pastoris preferred codon will improve the quantity of secreted rFGH in culture supernatant that can directly be used as fish feed supplements. The optimized FGH coding sequence (oFGH) and native sequence (nFGH) of giant grouper fish (Epinephelus lanceolatus) were cloned into P. pastoris expression vector (pPICZalphaA) downstream of alcohol oxidase gene (AOX1) for efficient induction of extracellular rFGH by adding 1% of absolute methanol. The results showed that recombinant P. pastoris was able to produce 2.80 +/- 0.27 mg of oFGH compared to 1.75 +/- 0.25 of nFGH in one litre of culture supernatant. The total body weight of tiger grouper fingerlings fed with oFGH increased significantly at third (P < 0.05) and fourth weeks (P < 0.01) of four-week experiment period compared to those fed with nFGH. Both oFGH and nFGH significantly enhanced the final biomass and fish survival percentage. In conclusion, codon optimization of FGH fragment was useful to increase rFGH quantity in the culture supernatant of P. pastoris that can be directly used as fish feed supplements. Further studies are still required for large scale production of rFGH and practical application in aquaculture production. PMID- 25147854 TI - A value and ambiguity-based ranking method of trapezoidal intuitionistic fuzzy numbers and application to decision making. AB - The aim of this paper is to develop a method for ranking trapezoidal intuitionistic fuzzy numbers (TrIFNs) in the process of decision making in the intuitionistic fuzzy environment. Firstly, the concept of TrIFNs is introduced. Arithmetic operations and cut sets over TrIFNs are investigated. Then, the values and ambiguities of the membership degree and the nonmembership degree for TrIFNs are defined as well as the value-index and ambiguity-index. Finally, a value and ambiguity-based ranking method is developed and applied to solve multiattribute decision making problems in which the ratings of alternatives on attributes are expressed using TrIFNs. A numerical example is examined to demonstrate the implementation process and applicability of the method proposed in this paper. Furthermore, comparison analysis of the proposed method is conducted to show its advantages over other similar methods. PMID- 25147856 TI - A novel approach for blast-induced flyrock prediction based on imperialist competitive algorithm and artificial neural network. AB - Flyrock is one of the major disturbances induced by blasting which may cause severe damage to nearby structures. This phenomenon has to be precisely predicted and subsequently controlled through the changing in the blast design to minimize potential risk of blasting. The scope of this study is to predict flyrock induced by blasting through a novel approach based on the combination of imperialist competitive algorithm (ICA) and artificial neural network (ANN). For this purpose, the parameters of 113 blasting operations were accurately recorded and flyrock distances were measured for each operation. By applying the sensitivity analysis, maximum charge per delay and powder factor were determined as the most influential parameters on flyrock. In the light of this analysis, two new empirical predictors were developed to predict flyrock distance. For a comparison purpose, a predeveloped backpropagation (BP) ANN was developed and the results were compared with those of the proposed ICA-ANN model and empirical predictors. The results clearly showed the superiority of the proposed ICA-ANN model in comparison with the proposed BP-ANN model and empirical approaches. PMID- 25147855 TI - Wide distribution of virulence genes among Enterococcus faecium and Enterococcus faecalis clinical isolates. AB - Enterococcus, a Gram-positive facultative anaerobic cocci belonging to the lactic acid bacteria of the phylum Firmicutes, is known to be able to resist a wide range of hostile conditions such as different pH levels, high concentration of NaCl (6.5%), and the extended temperatures between 5( degrees )C and 65( degrees )C. Despite being the third most common nosocomial pathogen, our understanding on its virulence factors is still poorly understood. The current study was aimed to determine the prevalence of different virulence genes in Enterococcus faecalis and Enterococcus faecium. For this purpose, 79 clinical isolates of Malaysian enterococci were evaluated for the presence of virulence genes. pilB, fms8, efaAfm, and sgrA genes are prevalent in all clinical isolates. In conclusion, the pathogenicity of E. faecalis and E. faecium could be associated with different virulence factors and these genes are widely distributed among the enterococcal species. PMID- 25147857 TI - Bioconversion of high concentrations of hydrogen sulfide to elemental sulfur in airlift bioreactor. AB - Several bioreactor systems are used for biological treatment of hydrogen sulfide. Among these, airlift bioreactors are promising for the bioconversion of hydrogen sulfide into elemental sulfur. The performance of airlift bioreactors is not adequately understood, particularly when directly fed with hydrogen sulfide gas. The objective of this paper is to investigate the performance of an airlift bioreactor fed with high concentrations of H2S with special emphasis on the effect of pH in combination with other factors such as H2S loading rate, oxygen availability, and sulfide accumulation. H2S inlet concentrations between 1,008 ppm and 31,215 ppm were applied and elimination capacities up to 113 g H2S m(-3) h(-1) were achieved in the airlift bioreactor under investigation at a pH range 6.5-8.5. Acidic pH values reduced the elimination capacity. Elemental sulfur recovery up to 95% was achieved under oxygen limited conditions (DO < 0.2 mg/L) and at higher pH values. The sulfur oxidizing bacteria in the bioreactor tolerated accumulated dissolved sulfide concentrations >500 mg/L at pH values 8.0 8.5, and near 100% removal efficiency was achieved. Overall, the resident microorganisms in the studied airlift bioreactor favored pH values in the alkaline range. The bioreactor performance in terms of elimination capacity and sulfur recovery was better at pH range 8-8.5. PMID- 25147858 TI - Models and frameworks: a synergistic association for developing component-based applications. AB - The use of frameworks and components has been shown to be effective in improving software productivity and quality. However, the results in terms of reuse and standardization show a dearth of portability either of designs or of component based implementations. This paper, which is based on the model driven software development paradigm, presents an approach that separates the description of component-based applications from their possible implementations for different platforms. This separation is supported by automatic integration of the code obtained from the input models into frameworks implemented using object-oriented technology. Thus, the approach combines the benefits of modeling applications from a higher level of abstraction than objects, with the higher levels of code reuse provided by frameworks. In order to illustrate the benefits of the proposed approach, two representative case studies that use both an existing framework and an ad hoc framework, are described. Finally, our approach is compared with other alternatives in terms of the cost of software development. PMID- 25147859 TI - Null steering of adaptive beamforming using linear constraint minimum variance assisted by particle swarm optimization, dynamic mutated artificial immune system, and gravitational search algorithm. AB - Linear constraint minimum variance (LCMV) is one of the adaptive beamforming techniques that is commonly applied to cancel interfering signals and steer or produce a strong beam to the desired signal through its computed weight vectors. However, weights computed by LCMV usually are not able to form the radiation beam towards the target user precisely and not good enough to reduce the interference by placing null at the interference sources. It is difficult to improve and optimize the LCMV beamforming technique through conventional empirical approach. To provide a solution to this problem, artificial intelligence (AI) technique is explored in order to enhance the LCMV beamforming ability. In this paper, particle swarm optimization (PSO), dynamic mutated artificial immune system (DM AIS), and gravitational search algorithm (GSA) are incorporated into the existing LCMV technique in order to improve the weights of LCMV. The simulation result demonstrates that received signal to interference and noise ratio (SINR) of target user can be significantly improved by the integration of PSO, DM-AIS, and GSA in LCMV through the suppression of interference in undesired direction. Furthermore, the proposed GSA can be applied as a more effective technique in LCMV beamforming optimization as compared to the PSO technique. The algorithms were implemented using Matlab program. PMID- 25147860 TI - The coral reefs optimization algorithm: a novel metaheuristic for efficiently solving optimization problems. AB - This paper presents a novel bioinspired algorithm to tackle complex optimization problems: the coral reefs optimization (CRO) algorithm. The CRO algorithm artificially simulates a coral reef, where different corals (namely, solutions to the optimization problem considered) grow and reproduce in coral colonies, fighting by choking out other corals for space in the reef. This fight for space, along with the specific characteristics of the corals' reproduction, produces a robust metaheuristic algorithm shown to be powerful for solving hard optimization problems. In this research the CRO algorithm is tested in several continuous and discrete benchmark problems, as well as in practical application scenarios (i.e., optimum mobile network deployment and off-shore wind farm design). The obtained results confirm the excellent performance of the proposed algorithm and open line of research for further application of the algorithm to real-world problems. PMID- 25147861 TI - Scheduling jobs and a variable maintenance on a single machine with common due date assignment. AB - We investigate a common due-date assignment scheduling problem with a variable maintenance on a single machine. The goal is to minimize the total earliness, tardiness, and due-date cost. We derive some properties on an optimal solution for our problem. For a special case with identical jobs we propose an optimal polynomial time algorithm followed by a numerical example. PMID- 25147863 TI - On Thompson's conjecture for alternating groups A p+3. AB - Let G be a group. Denote by pi(G) the set of prime divisors of |G|. Let GK(G) be the graph with vertex set pi(G) such that two primes p and q in pi(G) are joined by an edge if G has an element of order p . q. We set s(G) to denote the number of connected components of the prime graph GK(G). Denote by N(G) the set of nonidentity orders of conjugacy classes of elements in G. Alavi and Daneshkhah proved that the groups, A n where n = p, p + 1, p + 2 with s(G) >= 2, are characterized by N(G). As a development of these topics, we will prove that if G is a finite group with trivial center and N(G) = N(A p+3) with p + 2 composite, then G is isomorphic to A p+3. PMID- 25147862 TI - Vitamin C protected human retinal pigmented epithelium from oxidant injury depending on regulating SIRT1. AB - The purpose was to investigate the protective effects of Vitamin C (Vit C) and the regulatory mechanism between Vit C and sirtuin 1 (SIRT1) in PREs during oxidative stress as Vit C and SIRT1 exerted famous effects as antioxidants. We found that moderate Vit C (100 uM) prevented ARPE-19 cells from damages induced by H2O2, including increasing viability, reducing apoptosis, and attenuating intracellular ROS levels. But lower and higher concentration of Vit C had no effects. Further results indicated that Vit C caused the dysregulation of some stress responses factors (SIRT1, p53 and FOXO3) in ARPE-19 cells response to H2O2. Moreover we found that SIRT1 activator resveratrol (SRV) stimulated significantly the protective effects of moderate Vit C, provided the property of antioxidative stress for the lower and higher concentration of Vit C in ARPE-19 cells as well. Consistently, nicotinamide (NA) relieved the protective functions of moderate Vit C. Interestingly, data also revealed the dysregulation of p53 and FOXO3 was dependent on the regulation of SIRT1 rather than Vit C. Summarily, the protective effect of Vit C against oxidative stress was involved in regulation of SIRT1. It suggested that combined application of Vit C and RSV might be a promising therapeutic method for AMD. PMID- 25147864 TI - A user authentication scheme using physiological and behavioral biometrics for multitouch devices. AB - With the rapid growth of mobile network, tablets and smart phones have become sorts of keys to access personal secured services in our daily life. People use these devices to manage personal finances, shop on the Internet, and even pay at vending machines. Besides, it also helps us get connected with friends and business partners through social network applications, which were widely used as personal identifications in both real and virtual societies. However, these devices use inherently weak authentication mechanism, based upon passwords and PINs that is not changed all the time. Although forcing users to change password periodically can enhance the security level, it may also be considered annoyances for users. Biometric technologies are straightforward because of the simple authentication process. However, most of the traditional biometrics methodologies require diverse equipment to acquire biometric information, which may be expensive and not portable. This paper proposes a multibiometric user authentication scheme with both physiological and behavioral biometrics. Only simple rotations with fingers on multitouch devices are required to enhance the security level without annoyances for users. In addition, the user credential is replaceable to prevent from the privacy leakage. PMID- 25147865 TI - Effect of cosolutes on the sorption of phenanthrene onto mineral surface of river sediments and kaolinite. AB - Sorption of phenanthrene onto the natural sediment with low organic carbon content (OC%), organic-free sediment, and kaolinite was investigated through isotherm experiments. Effects of cosolutes (pyrene, 4-n-nonyphenol (NP), and humic acid (HA)) on phenanthrene sorption were also studied by comparing apparent solid-water distribution coefficients (K d (app)) of phenanthrene. Two addition sequences, including "cosolute added prior to phenanthrene" and "cosolute and phenanthrene added simultaneously," were adopted. The Freundlich model fits phenanthrene sorption on all 3 sorbents well. The sorption coefficients on these sorbents were similar, suggesting that mineral surface plays an important role in the sorption of hydrophobic organic contaminants on low OC% sediments. Cosolutes could affect phenanthrene sorption on the sorbents, which depended on their properties, concentrations, and addition sequences. Pyrene inhibited phenanthrene sorption. Sorbed NP inhibited phenanthrene sorption at low levels and promoted sorption at high levels. Similar to NP, effect of HA on phenanthrene sorption onto the natural sediment depended on its concentrations, whereas, for the organic-free sediment and kaolinite, preloading of HA at high levels led to an enhancement in phenanthrene K d (app) while no obvious effect was observed at low HA levels; dissolved HA could inhibit phenanthrene sorption on the two sorbents. PMID- 25147866 TI - User localization in complex environments by multimodal combination of GPS, WiFi, RFID, and pedometer technologies. AB - Many user localization technologies and methods have been proposed for either indoor or outdoor environments. However, each technology has its own drawbacks. Recently, many researches and designs have been proposed to build a combination of multiple localization technologies system which can provide higher precision results and solve the limitation in each localization technology alone. In this paper, a conceptual design of a general localization platform using combination of multiple localization technologies is introduced. The combination is realized by dividing spaces into grid points. To demonstrate this platform, a system with GPS, RFID, WiFi, and pedometer technologies is established. Experiment results show that the accuracy and availability are improved in comparison with each technology individually. PMID- 25147867 TI - Information filtering via biased random walk on coupled social network. AB - The recommender systems have advanced a great deal in the past two decades. However, most researchers focus their attentions on mining the similarities among users or objects in recommender systems and overlook the social influence which plays an important role in users' purchase process. In this paper, we design a biased random walk algorithm on coupled social networks which gives recommendation results based on both social interests and users' preference. Numerical analyses on two real data sets, Epinions and Friendfeed, demonstrate the improvement of recommendation performance by taking social interests into account, and experimental results show that our algorithm can alleviate the user cold-start problem more effectively compared with the mass diffusion and user based collaborative filtering methods. PMID- 25147868 TI - A partition-based active contour model incorporating local information for image segmentation. AB - Active contour models are always designed on the assumption that images are approximated by regions with piecewise-constant intensities. This assumption, however, cannot be satisfied when describing intensity inhomogeneous images which frequently occur in real world images and induced considerable difficulties in image segmentation. A milder assumption that the image is statistically homogeneous within different local regions may better suit real world images. By taking local image information into consideration, an enhanced active contour model is proposed to overcome difficulties caused by intensity inhomogeneity. In addition, according to curve evolution theory, only the region near contour boundaries is supposed to be evolved in each iteration. We try to detect the regions near contour boundaries adaptively for satisfying the requirement of curve evolution theory. In the proposed method, pixels within a selected region near contour boundaries have the opportunity to be updated in each iteration, which enables the contour to be evolved gradually. Experimental results on synthetic and real world images demonstrate the advantages of the proposed model when dealing with intensity inhomogeneity images. PMID- 25147869 TI - Stress-strain relationship of Ca(OH)2-activated Hwangtoh concrete. AB - This study examined the stress-strain behavior of 10 calcium hydroxide (Ca(OH)2) activated Hwangtoh concrete mixes. The volumetric ratio of the coarse aggregate (V agg) and the water-to-binder (W/B) ratio were selected as the main test variables. Two W/B ratios (25% and 40%) were used and the value of V agg varied between 0% and 40.0%, and 0% and 46.5% for W/B ratios of 25% and 40%, respectively. The test results demonstrated that the slope of the ascending branch of the stress-strain curve of Ca(OH)2-activated Hwangtoh concrete was smaller, and it displayed a steeper drop in stress in the descending branch, compared with those of ordinary Portland cement (OPC) concrete with the same compressive strength. This trend was more pronounced with the increase in the W/B ratio and decrease in V agg. Based on the experimental observations, a simple and rational stress-strain model was established mathematically. Furthermore, the modulus of elasticity and strain at peak stress of the Ca(OH)2-activated Hwangtoh concrete were formulated as a function of its compressive strength and V agg. The proposed stress-strain model predicted the actual behavior accurately, whereas the previous models formulated using OPC concrete data were limited in their applicability to Ca(OH)2-activated Hwangtoh concrete. PMID- 25147870 TI - Stimulatory effects of gamma irradiation on phytochemical properties, mitotic behaviour, and nutritional composition of sainfoin (Onobrychis viciifolia Scop.). AB - Sainfoin (Onobrychis viciifolia Scop. Syn. Onobrychis sativa L.) is a bloat-safe forage crop with high levels of tannins, which is renowned for its medicinal qualities in grazing animals. Mutagenesis technique was applied to investigate the influence of gamma irradiation at 30, 60, 90, and 120 Gy on mitotic behavior, in vitro growth factors, phytochemical and nutritional constituents of sainfoin. Although a percentage of plant necrosis and non-growing seed were enhanced by irradiation increment, the germination speed was significantly decreased. It was observed that gamma irradiated seeds had higher value of crude protein and dry matter digestibility compared to control seeds. Toxicity of copper was reduced in sainfoin irradiated seeds at different doses of gamma rays. Anthocyanin content also decreased in inverse proportion to irradiation intensity. Accumulation of phenolic and flavonoid compounds was enhanced by gamma irradiation exposure in leaf cells. HPLC profiles differed in peak areas of the two important alkaloids, Berberine and Sanguinarine, in 120 Gy irradiated seeds compared to control seeds. There were positive correlations between irradiation dose and some abnormality divisions such as laggard chromosome, micronucleus, binucleated cells, chromosome bridge, and cytomixis. In reality, radiocytological evaluation was proven to be essential in deducing the effectiveness of gamma irradiation to induce somaclonal variation in sainfoin. PMID- 25147871 TI - Neural network L1 adaptive control of MIMO systems with nonlinear uncertainty. AB - An indirect adaptive controller is developed for a class of multiple-input multiple-output (MIMO) nonlinear systems with unknown uncertainties. This control system is comprised of an L 1 adaptive controller and an auxiliary neural network (NN) compensation controller. The L 1 adaptive controller has guaranteed transient response in addition to stable tracking. In this architecture, a low pass filter is adopted to guarantee fast adaptive rate without generating high frequency oscillations in control signals. The auxiliary compensation controller is designed to approximate the unknown nonlinear functions by MIMO RBF neural networks to suppress the influence of uncertainties. NN weights are tuned on-line with no prior training and the project operator ensures the weights bounded. The global stability of the closed-system is derived based on the Lyapunov function. Numerical simulations of an MIMO system coupled with nonlinear uncertainties are used to illustrate the practical potential of our theoretical results. PMID- 25147872 TI - Ecological effects of roads on the plant diversity of coastal wetland in the Yellow River Delta. AB - The 26 sample sites in 7 study plots adjacent to asphalt road and earth road in coastal wetland in the Yellow River Delta were selected to quantify plant diversity using quadrat sampling method in plant bloom phase of July and August 2012. The indice of beta T and Jaccard's coefficient were applied to evaluate the species diversity. The results showed that the plant diversities and alien plants were high in the range of 0-20 m to the road verge. There were more exotics and halophytes in plots of asphalt roadside than that of earth roadside. However, proportion of halophytes in habitats of asphalt roadsides was lower than that of earth roadside. By comparing beta-diversity, there were more common species in the asphalt roadsides than that in the earth roadsides. The similarity of plant communities in studied plots of asphalt roadsides and earth roadsides increased with increasing the distance to road verge. The effect range of roads for plant diversity in study region was about 20 m to road verge. Our results indicate that the construction and maintenance of roads in wetland could increase the plant species diversities of communities and risk of alien species invasion. PMID- 25147873 TI - Effects of different regulatory methods on improvement of greenhouse saline soils, tomato quality, and yield. AB - To identify effective regulatory methods scheduling with the compromise between the soil desalination and the improvement of tomato quality and yield, a 3-year field experiment was conducted to evaluate and compare the effect of straw mulching and soil structure conditioner and water-retaining agent on greenhouse saline soils, tomato quality, and yield. A higher salt removing rate of 80.72% in plough layer with straw mulching was obtained based on the observation of salt mass fraction in 0 ~ 20 cm soil layer before and after the experiment. Salts were also found to move gradually to the deeper soil layer with time. Straw mulching enhanced the content of soil organic matter significantly and was conductive to reserve soil available N, P, and K, while available P and K in soils of plough layer with soil structure conditioner decreased obviously; thus a greater usage of P fertilizer and K fertilizer was needed when applying soil structure conditioner. Considering the evaluation indexes including tomato quality, yield, and desalination effects of different regulatory methods, straw mulching was recommended as the main regulatory method to improve greenhouse saline soils in south China. Soil structure conditioner was the suboptimal method, which could be applied in concert with straw mulching. PMID- 25147874 TI - Multi-Kernel Classification for Integration of Clinical and Imaging Data: Application to Prediction of Cognitive Decline in Older Adults. AB - Diagnosis of neurologic and neuropsychiatric disorders typically involves considerable assessment including clinical observation, neuroimaging, and biological and neuropsychological measurements. While it is reasonable to expect that the integration of neuroimaging data and complementary non-imaging measures is likely to improve early diagnosis on individual basis, due to technical challenges associated with the task of combining different data types, medical image pattern recognition analysis has been largely focusing solely on neuroimaging evaluations. In this paper, we explore the potential of integrating neuroimaging and clinical information within a pattern classification framework, and propose that the multi-kernel learning (MKL) paradigm may be suitable for building a multimodal classifier of a disorder, as well as for automatic identification of the relevance of each information type. We apply our approach to the problem of detecting cognitive decline in healthy older adults from single visit evaluations, and show that the performance of a classifier can be improved when nouroimaging and clinical evaluations are used simultaneously within a MKL based classification framework. PMID- 25147875 TI - Additional Article Notification: Comparison between generations of foams and single vertical films--single and mixed surfactant systems. AB - The purpose of this article is to compare experiments carried out with single vertical foam films and with foams. We focus on the generation of films and foams and measure (i) the quantity of water entrained and (ii) the stability of the systems. The surfactants we used are C12E6, b-C12G2 and their 1 : 1 mixture because those systems are very well characterised in the literature and are known to stabilise foams with very different properties. We show that the quantity of water uptake in foams and single vertical films scales in the same way with the velocity of generation. However, the different surfactant solutions have different foamabilities, whereas the films they stabilise have exactly the same thickness. Moreover, the foamability of a C12E6 solution is much lower than that of a b-C12G2 solution or of a solution of the 1 : 1 mixture. This is due to the rapid rupture of the C12E6 foam films during foam generation. Surprisingly, the isolated films have exactly the same lifetime for all the surfactant solutions. We conclude that, though drawing a correlation between films and foams is tempting, the results obtained do not allow correlating of film and foam stability during the generation process. The only difference we observed between the single films stabilised by the different solutions is the stability of their respective black films. We thus suggest that the stability of black films during foam generation plays an important role which should be explored further in future work. PMID- 25147876 TI - Plasma-based ambient sampling/ionization/transmission integrated source for mass spectrometry. AB - Better sensitivity and interface of ambient sampling/ionization mass spectrometry remain a challenge. Herein, a novel, plasma-based, ambient sampling/ionization/transmission (PASIT) integrated source in a pin-to-funnel configuration was developed for the sensitive analysis of complex samples. With the funnel sleeve directly affected by direct-current discharge plasma, PASIT combines the ability to sample/ionize analyte molecules and then efficiently collect/transport charged mass species under atmospheric pressure and consequently shows an improved sensitivity. The integrated source enhances the signal intensity by more than 2 orders of magnitude compared with the previous pin-to-plate plasma source without significant background addition. A surface limit of detection (LOD) of 130 fmol mm-(2) (S/N = 3) has been achieved for clenbuterol on filter paper with an argon carrier gas. Demonstrated applications include the direct determination of active ingredients from drugs and symbolic compounds from natural plants and cholesterol from mouse brain tissue sections. PMID- 25147877 TI - Porous organic ligands (POLs) for synthesizing highly efficient heterogeneous catalysts. AB - We reported a universal route for synthesizing porous organic ligands (POLs) via solvothermal polymerization. The POLs were obtained quantitatively, showing high surface area, large pore volume, hierarchical porosity, and superior stability. The POL bearing a triphenylphosphine supported rhodium catalyst (Rh/POL-PPh3) exhibits high activity and excellent recyclability in 1-octene hydroformylation. PMID- 25147878 TI - Thermally-stable resistive switching with a large ON/OFF ratio achieved in poly(triphenylamine). AB - Thermally stable poly(triphenylamine) (PTPA) synthesized by an oxidative coupling reaction is used as the functional layer in memory devices, which exhibit non volatile bistable resistive switching behavior with a large ON/OFF ratio over 5 * 10(8), a long retention time exceeding 8 * 10(3) s and a wide working temperature range of 30-390 K. PMID- 25147881 TI - [Macroglossia as a bone marrow disorder manifestation]. PMID- 25147879 TI - Branch retinal vein occlusion and vitreovascular traction: a preliminary spectral domain OCT case-control study. AB - OBJECTIVE: Branch retinal vein occlusion (BRVO) typically occurs at an arteriovenous (AV) crossing site. Although the pathogenesis is unclear, vitreovascular traction might have a significant role in some BRVO cases. The purpose of present study was to determine the incidence of vitreoretinal traction at the obstruction site in patients diagnosed with BRVO. METHODS: In this prospective observational case-control study, 32 consecutive BRVO patients were studied with spectral-domain optical coherence tomography (SD-OCT) to detect the presence of vitreovascular traction or vitreous adherence at the occlusion site. RESULTS: SD-OCT directed to the occlusion site revealed a vitreovascular traction at this point in eight eyes (25 %). Fourteen eyes (43.75 %) were associated with an adherence of posterior hyaloids without signs of retinal traction, whereas ten eyes (31.25 %) had neither vitreoretinal adherence nor vitreous traction. Regarding either the same vessel segment of the fellow eye, none of the cases revealed vitreovascular traction in the correspondent AV crossing site; 12 cases (37.5 %) presented vitreoretinal adherence; and the remaining 20 cases (62.5 %) showed neither traction nor adhesion. Thus, vitreovascular traction in the occlusion site was significantly associated with BRVO (p = 0.024, chi-squared test). B-scan ultrasonography showed that the posterior vitreous cortex remains more frequently attached in eyes with BRVO compared to unaffected fellow eyes (p = 0.041, chi-squared test). CONCLUSIONS: A common firm vitreous adhesion at the obstruction site is reported herein, pointing out the possible role of vitreovascular traction in the etiology of some cases of BRVO. Likewise, although not all BRVO cases can be explained by this pathogenic mechanism, an attached posterior vitreous cortex might be a cofactor in the origin of this entity. PMID- 25147882 TI - Response. PMID- 25147883 TI - Featuring... Susanna Tornroth-Horsefield: winner of the FEBS Letters 2014 FEBS Letters Young Group Leader Award. PMID- 25147884 TI - Treatments for idiopathic pulmonary fibrosis. PMID- 25147885 TI - Biomedical science: Houston has lift-off. PMID- 25147886 TI - [Jose M. Canadell Carafi (Barcelona 1923-Pamplona 2014)]. PMID- 25147887 TI - Core competencies in human milk and breastfeeding: policy and practice implications for nurses. PMID- 25147888 TI - What if? PMID- 25147889 TI - Three alternative ways to treat VMS failed. PMID- 25147890 TI - Summary analysis of 2014 survey of National Influenza Centres in the WHO Global Influenza Surveillance and Response System. PMID- 25147891 TI - Recurrent venous thromboembolism in estrogen users. PMID- 25147892 TI - Fibromyalgia and menopause: any link? PMID- 25147893 TI - Routine calcium and vitamin D supplementation: the end of the story? PMID- 25147894 TI - Incomplete periacetabular acetabuloplasty--reply. PMID- 25147895 TI - [Mobile telephone in the hospital: so far an underestimated source of pathogen transmission]. PMID- 25147896 TI - Revenue cycle technology: key factors for choosing a solution. PMID- 25147897 TI - Acquisition and affiliation strategies highlights from HFMA's Value Project research. PMID- 25147898 TI - Costs of treating patients before transfer to long-term care, 2010-12. PMID- 25147899 TI - Join our uncertainty and loss conference. Sign up now. PMID- 25147900 TI - The politics of birth. PMID- 25147901 TI - Merger concerns. PMID- 25147903 TI - All change. PMID- 25147904 TI - [The results of intravitreal bevacizumab in subretinal neovascularisation in angioid streaks]. AB - PURPOSE: To assess the anatomical and functional results after intravitreal bevacizumab administration in choroidal neovascularization (CNV) due to angioid streaks; To assess the safety and results stability; METHODS: Prospective, nonrandomized, interventional case study on choroidal neovascularization due to angioid streaks treated with intravitreal bevacizumab (AVASTIN). Intravitreal injection was repeated, if needed, at 4-6 weeks until leakage stopped. In all cases fluorescein angiograms and Spectral 3D OCTs were performed. Visual acuity was measured with ETDRS optotype. Cases were followed-up at least 6 months. Statistical analysis was performed using ANOVA and Wilcoxon tests. RESULTS: 8 cases with CNV associated to angioid streaks were evaluated between January 2007 and January 2013. Mean age of patients in the study was 52,36 +/- 4,33 years (ranging 42-64 years). The mean number of intravitreal injections was 4.64 +/- 0,42 (ranging between 3-8 injections). Mean visual acuity improved significantly in all cases after 3 intravitreal injections with a gain of more than 15 letters in 6 out of 8 cases (75%). OCT confirmed reduced depth of lesion and also a reduced lesion volume after treatment. No major local or systemic side-effects were noted. At 6 months follow-up the CNV reoccurred in 5 out of 8 cases (62.5%) requiring additional treatment. 3 out of 8 cases finally lost more than 5 letters due to subretinal fibrosis. CONCLUSIONS: These results confirm the efficacy and safety of intravitreal bevacizumab in controlling the CNV due to angioid streaks. High recurrence rate and quick lesion progression to subretinal fibrosis might be responsible for long-term poor functional results in this type of CNVs. More cases are needed for validation. PMID- 25147905 TI - Interview with Jill Jarecki, PhD. PMID- 25147907 TI - L-type Ca2+ channel responses to bay k 8644 in stem cell-derived cardiomyocytes are unusually dependent on holding potential and charge carrier. AB - Human stem cell-derived cardiomyocytes provide a cellular model for the study of electrophysiology in the human heart and are finding a niche in the field of safety pharmacology for predicting proarrhythmia. The cardiac L-type Ca2+ channel is an important target for some of these safety studies. However, the pharmacology of this channel in these cells is altered compared to native cardiac tissue, specifically in its sensitivity to the Ca2+ channel activator S-(-)-Bay K 8644. Using patch clamp electrophysiology, we examined the effects of S-(-)-Bay K 8644 in three separate stem cell-derived cardiomyocyte cell lines under various conditions in an effort to detect more typical responses to the drug. S-(-)-Bay K 8644 failed to produce characteristically large increases in current when cells were held at -40 mV and Ca2+ was used as the charge carrier, although high affinity binding and the effects of the antagonist isomer, R-(+)-Bay K 8644, were intact. Dephosphorylation of the channel with acetylcholine failed to restore the sensitivity of the channel to the drug. Only when the holding potential was shifted to a more hyperpolarized (-60 mV) level, and external Ca2+ was replaced by Ba2+, could large increases in current amplitude be observed. Even under these conditions, increases in current amplitude varied dramatically between different cell lines and channel kinetics following drug addition were generally atypical. The results indicate that the pharmacology of S-(-)-Bay K 8644 in stem cell derived cardiomyocytes varies by cell type, is unusually dependent on holding potential and charge carrier, and is different from that observed in primary human heart cells. PMID- 25147908 TI - A comparison of assay performance between the calcium mobilization and the dynamic mass redistribution technologies for the human urotensin receptor. AB - The popular screening method for urotensin (UT) receptor antagonists is to measure the intracellular calcium concentration with a calcium-sensitive fluorescent dye. This assay format has an inherent limitation on the problem related to the fluorescence interference as it involves fluorescent dyes. In the present study, a label-free assay for the screening of UT receptor antagonists was developed by using dynamic mass redistribution (DMR) assay based on label free optical biosensor. The addition of urotensin II (UII) stimulated a DMR profile to HEK293 cells stably expressing the human UT receptor (HEK293UT cells) but not on parental cells. The EC50 value of UII in label-free assay was 4.58 nM, which is very similar to that in conventional calcium mobilization assay (4.15 nM). Compared with the calcium mobilization assay for UII (Z' factor, 0.77), the current label-free assay presented improved Z' factor (0.81), with a relatively similar S/B ratio (28.0 and 25.6, respectively). The known high-affinity UT receptor antagonists, SB657510, GSK562590, and urantide, exhibited comparable IC50 values but rather less potent in the DMR assay than in calcium mobilization. Our DMR assay was able to present various functional responses, including inverse agonism in SB657510 and GSK1562590 as well as partial agonism in urantide. Moreover, the DMR assay exerted the stable antagonist window upon the minimal agonist stimulus. These results suggest that the label-free cell-based UT receptor assay can be applicable to evaluate the various functional activities of UT receptor-related drug candidates. PMID- 25147910 TI - Acute liver failure. PMID- 25147909 TI - Electrospun superhydrophobic membranes with unique structures for membrane distillation. AB - With modest temperature demand, low operating pressure, and high solute rejection, membrane distillation (MD) is an attractive option for desalination, waste treatment, and food and pharmaceutical processing. However, large-scale practical applications of MD are still hindered by the absence of effective membranes with high hydrophobicity, high porosity, and adequate mechanical strength, which are important properties for MD permeation fluxes, stable long term performance, and effective packing in modules without damage. This study describes novel design strategies for highly robust superhydrophobic dual-layer membranes for MD via electrospinning. One of the newly developed membranes comprises a durable and ultrathin 3-dimensional (3D) superhydrophobic skin and porous nanofibrous support whereas another was fabricated by electrospinning 3D superhydrophobic layers on a nonwoven support. These membranes exhibit superhydrophobicity toward distilled water, salty water, oil-in-water emulsion, and beverages, which enables them to be used not only for desalination but also for other processes. The superhydrophobic dual-layer membrane #3S-N with nanofibrous support has a competitive permeation flux of 24.6 +/- 1.2 kg m(-2) h( 1) in MD (feed and permeate temperate were set as 333 and 293 K, respectively) due to the higher porosity of the nanofibrous scaffold. Meanwhile, the membranes with the nonwoven support exhibit greater mechanical strength due to this support combined with better long-term performance because of the thicker 3D superhydrophobic layers. The morphology, pore size, porosity, mechanical properties, and liquid enter pressure of water of these superhydrophobic composite membranes with two different structures are reported and compared with commercial polyvinylidene fluoride membranes. PMID- 25147911 TI - The entry-level physical therapist: a case for COMFORT communication training. AB - Entry-level physical therapists provide clinical care for patients with functional mobility limitations. Their care spans the continuum of settings, disease processes, and diagnoses. Although effective communication skills are required to conduct physical therapy work, there is limited instruction provided in physical therapy education and students receive little exposure to seriously or chronically ill patients. The goal of this study was to assess the effects of communication training for the entry-level physical therapist facing palliative and end-of-life communication with patients/families. A pre-post survey design and narrative writing were used to assess the effect of the COMFORT communication training curriculum provided to doctorally trained, graduating physical therapists. The study demonstrated decreased student apprehension about communicating with dying patients and their families, and a comparison of mean scores reflecting the students' communication knowledge, confidence, and behaviors increased in a positive direction. As students became more willing to communicate, they were also more adept at integrating task and relational messages, as well as assimilating emotional support messages for patients and families. This study shows promise for the feasibility and utilization of the COMFORT curriculum for entry-level physical therapists. Further research should address the integration of COMFORT earlier into physical therapy education, as well as assess evidence of COMFORT communication skills in the clinical context. PMID- 25147906 TI - Assays for the identification and prioritization of drug candidates for spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder resulting in degeneration of alpha-motor neurons of the anterior horn and proximal muscle weakness. It is the leading cause of genetic mortality in children younger than 2 years. It affects ~1 in 11,000 live births. In 95% of cases, SMA is caused by homozygous deletion of the SMN1 gene. In addition, all patients possess at least one copy of an almost identical gene called SMN2. A single point mutation in exon 7 of the SMN2 gene results in the production of low levels of full-length survival of motor neuron (SMN) protein at amounts insufficient to compensate for the loss of the SMN1 gene. Although no drug treatments are available for SMA, a number of drug discovery and development programs are ongoing, with several currently in clinical trials. This review describes the assays used to identify candidate drugs for SMA that modulate SMN2 gene expression by various means. Specifically, it discusses the use of high throughput screening to identify candidate molecules from primary screens, as well as the technical aspects of a number of widely used secondary assays to assess SMN messenger ribonucleic acid (mRNA) and protein expression, localization, and function. Finally, it describes the process of iterative drug optimization utilized during preclinical SMA drug development to identify clinical candidates for testing in human clinical trials. PMID- 25147912 TI - Factors contributing to decline in foodborne disease outbreak reports, United States. AB - The number of foodborne disease outbreaks reported in the United States declined substantially in 2009, when the surveillance system transitioned from reporting only foodborne disease outbreaks to reporting all enteric disease outbreaks. A 2013 survey found that some outbreaks that would have been previously reported as foodborne are now reported as having other transmission modes. PMID- 25147913 TI - X-ray crystal structure of teicoplanin A2-2 bound to a catalytic peptide sequence via the carrier protein strategy. AB - We report the X-ray crystal structure of a site-selective peptide catalyst moiety and teicoplanin A2-2 complex. The expressed protein ligation technique was used to couple T4 lysozyme (T4L) and a synthetic peptide catalyst responsible for the selective phosphorylation of the N-acetylglucosamine sugar in a teicoplanin A2-2 derivative. The T4L-Pmh-dPro-Aib-dAla-dAla construct was crystallized in the presence of teicoplanin A2-2. The resulting 2.3 A resolution protein-peptide teicoplanin complex crystal structure revealed that the nucleophilic nitrogen of N-methylimidazole in the Pmh residue is in closer proximity (7.6 A) to the N acetylglucosamine than the two other sugar rings present in teicoplanin (9.3 and 20.3 A, respectively). This molecular arrangement is consistent with the observed selectivity afforded by the peptide-based catalyst when it is applied to a site selective phosphorylation reaction involving a teicoplanin A2-2 derivative. PMID- 25147914 TI - Characteristic DNA methylation profiles in peripheral blood monocytes are associated with inflammatory phenotypes of asthma. AB - Epigenetic changes including DNA methylation caused by environmental exposures may contribute to the heterogeneous inflammatory response in asthma. Here we investigate alterations in DNA methylation of purified blood monocytes that are associated with inflammatory phenotypes of asthma. Peripheral blood was collected from adults with eosinophilic asthma (EA; n = 21), paucigranulocytic asthma (PGA; n = 22), neutrophilic asthma (NA; n = 9), and healthy controls (n = 10). Blood monocytes were isolated using ficoll density gradient and immuno-magnetic cell separation. Bisulfite converted genomic DNA was hybridized to Illumina Infinium Methylation27 arrays and analyzed for differential methylation using R/Bioconductor packages; networks of gene interactions were identified using the STRING database. Compared with healthy controls, differentially methylated CpG loci were identified in EA (n = 413), PGA (n = 495), and NA (n = 89). We found that 223, 237, and 72 loci were significantly hypermethylated in EA, PGA, and NA, respectively. Nine genes were common to all three phenotypes and showed increased methylation in asthma. Three pathway networks were identified in EA, involved in purine metabolism, calcium signaling, and ECM-receptor interaction. In PGA, two networks were identified, involved in neuroactive ligand-receptor interaction and ubiquitin mediated proteolysis. In NA, one network was identified involving sFRP1 as a key node, over representing the Wnt signaling pathway. We have identified characteristic alterations in DNA methylation that are associated with inflammatory phenotypes of asthma and may contribute to the disease mechanisms. This network-based characterization may help in the development of epigenetic biomarkers and therapeutic targets for asthma. PMID- 25147915 TI - A pilot examination of the genome-wide DNA methylation signatures of subjects entering and exiting short-term alcohol dependence treatment programs. AB - Alcoholism has a profound impact on millions of people throughout the world. However, the ability to determine if a patient needs treatment is hindered by reliance on self-reporting and the clinician's capability to monitor the patient's response to treatment is challenged by the lack of reliable biomarkers. Using a genome-wide approach, we have previously shown that chronic alcohol use is associated with methylation changes in DNA from human cell lines. In this pilot study, we now examine DNA methylation in peripheral mononuclear cell DNA gathered from subjects as they enter and leave short-term alcohol treatment. When compared with abstinent controls, subjects with heavy alcohol use show widespread changes in DNA methylation that have a tendency to reverse with abstinence. Pathway analysis demonstrates that these changes map to gene networks involved in apoptosis. There is no significant overlap of the alcohol signature with the methylation signature previously derived for smoking. We conclude that DNA methylation may have future clinical utility in assessing acute alcohol use status and monitoring treatment response. PMID- 25147916 TI - Human factors and pathways essential for mediating epigenetic gene silencing. AB - Cellular identity in both normal and disease processes is determined by programmed epigenetic activation or silencing of specific gene subsets. Here, we have used human cells harboring epigenetically silent GFP-reporter genes to perform a genome-wide siRNA knockdown screen for the identification of cellular factors that are required to maintain epigenetic gene silencing. This unbiased screen interrogated 21,121 genes, and we identified and validated a set of 128 protein factors. This set showed enrichment for functional categories, and protein-protein interactions. Among this set were known epigenetic silencing factors, factors with no previously identified role in epigenetic gene silencing, as well as unstudied factors. The set included non-nuclear factors, for example, components of the integrin-adhesome. A key finding was that the E1 and E2 enzymes of the small ubiquitin-like modifier (SUMO) pathway (SAE1, SAE2/UBA2, UBC9/UBE2I) are essential for maintenance of epigenetic silencing. This work provides the first genome-wide functional view of human factors that mediate epigenetic gene silencing. The screen output identifies novel epigenetic factors, networks, and mechanisms, and provides a set of candidate targets for epigenetic therapy and cellular reprogramming. PMID- 25147917 TI - DPPA3 prevents cytosine hydroxymethylation of the maternal pronucleus and is required for normal development in bovine embryos. AB - Dppa3 has been described in mice as an important maternal factor contributed by the oocyte that participates in protecting the maternal genome from oxidation of methylated cytosines (5mC) to hydroxymethylated cytosines (5hmC). Dppa3 is also required for normal mouse preimplantation development. This gene is poorly conserved across mammalian species, with less than 32% of protein sequence shared between mouse, cow and human. RNA-seq analysis of bovine oocytes and preimplantation embryos revealed that DPPA3 transcripts are some of the most highly abundant mRNAs in the oocyte, and their levels gradually decrease toward the time of embryonic genome activation (EGA). Knockdown of DPPA3 by injection of siRNA in germinal vesicle (GV) stage oocytes was used to assess its role in epigenetic remodeling and embryo development. DPPA3 knockdown resulted in increased intensity of 5hmC staining in the maternal pronucleus (PN), demonstrating a role for this factor in the asymmetric remodeling of the maternal and paternal PN in bovine zygotes. Also, DPPA3 knockdown decreased the developmental competence of parthenogenetic and in vitro fertilized embryos. Finally, DPPA3 knockdown embryos that reached the blastocyst stage had significantly fewer ICM cells as compared with control embryos. We conclude that DPPA3 is a maternal factor important for correct epigenetic remodeling and normal embryonic development in cattle, indicating that the role of DPPA3 during early development is conserved between species. PMID- 25147918 TI - Highly conserved ENY2/Sus1 protein binds to Drosophila CTCF and is required for barrier activity. AB - Chromatin insulators affect interactions between promoters and enhancers/silencers and function as barriers for the spreading of repressive chromatin. Drosophila insulator protein dCTCF marks active promoters and boundaries of many histone H3K27 trimethylation domains associated with repressed chromatin. In particular, dCTCF binds to such boundaries between the parasegment specific regulatory domains of the Bithorax complex. Here we demonstrate that the evolutionarily conserved protein ENY2 is recruited to the zinc-finger domain of dCTCF and is required for the barrier activity of dCTCF-dependent insulators in transgenic lines. Inactivation of ENY2 by RNAi in BG3 cells leads to the spreading of H3K27 trimethylation and Pc protein at several dCTCF boundaries. The results suggest that evolutionarily conserved ENY2 is responsible for barrier activity mediated by the dCTCF protein. PMID- 25147919 TI - RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia. AB - Aberrant DNA methylation at specific genetic loci is a key molecular feature of juvenile myelomonocytic leukemia (JMML) with poor prognosis. Using quantitative high-resolution mass spectrometry, we identified RASA4 isoform 2, which maps to chromosome 7 and encodes a member of the GAP1 family of GTPase-activating proteins for small G proteins, as a recurrent target of isoform-specific DNA hypermethylation in JMML (51% of 125 patients analyzed). RASA4 isoform 2 promoter methylation correlated with clinical parameters predicting poor prognosis (older age, elevated fetal hemoglobin), with higher risk of relapse after hematopoietic stem cell transplantation, and with PTPN11 mutation. The level of isoform 2 methylation increased in relapsed cases after transplantation. Interestingly, most JMML cases with monosomy 7 exhibited hypermethylation on the remaining RASA4 allele. The results corroborate the significance of epigenetic modifications in the phenotype of aggressive JMML. PMID- 25147920 TI - A CRISPR-based approach for proteomic analysis of a single genomic locus. AB - Any given chromosomal activity (e.g., transcription) is governed predominantly by the local epiproteome. However, defining local epiproteomes has been limited by a lack of effective technologies to isolate discrete sections of chromatin and to identify with precision specific proteins and histone posttranslational modifications (PTMs). We report the use of the Cas9 and guide RNA (gRNA) components of the CRISPR system for gRNA-directed purification of a discrete section of chromatin. Quantitative mass spectrometry provides for unambiguous identification of proteins and histone PTMs specifically associated with the enriched chromatin. This CRISPR-based Chromatin Affinity Purification with Mass Spectrometry (CRISPR-ChAP-MS) approach revealed changes in the local epiproteome of a promoter during activation of transcription. CRISPR-ChAP-MS thus has broad applications for discovering molecular components and dynamic regulation of any in vivo activity at a given chromosomal location. PMID- 25147921 TI - Promoter hypermethylation using 24-gene array in early head and neck cancer: better outcome in oral than in oropharyngeal cancer. AB - Silencing of tumor suppressor genes (TSGs) by DNA promoter hypermethylation is an early event in carcinogenesis and a potential target for personalized cancer treatment. In head and neck cancer, little is known about the role of promoter hypermethylation in survival. Using methylation specific multiplex ligation dependent probe amplification (MS-MLPA) we investigated the role of promoter hypermethylation of 24 well-described genes (some of which are classic TSGs), which are frequently methylated in different cancer types, in 166 HPV-negative early oral squamous cell carcinomas (OSCC), and 51 HPV-negative early oropharyngeal squamous cell carcinomas (OPSCC) in relation to clinicopathological features and survival. Early OSCC showed frequent promoter hypermethylation in RARB (31% of cases), CHFR (20%), CDH13 (13%), DAPK1 (12%), and APC (10%). More hypermethylation (>= 2 genes) independently correlated with improved disease specific survival (hazard ratio 0.17, P = 0.014) in early OSCC and could therefore be used as prognostic biomarker. Early OPSCCs showed more hypermethylation of CDH13 (58%), TP73 (14%), and total hypermethylated genes. Hypermethylation of two or more genes has a significantly different effect on survival in OPSCC compared with OSCC, with a trend toward worse instead of better survival. This could have a biological explanation, which deserves further investigation and could possibly lead to more stratified treatment in the future. PMID- 25147922 TI - Genome-wide DNA methylation profiling in rheumatoid arthritis identifies disease associated methylation changes that are distinct to individual T- and B lymphocyte populations. AB - Changes to the DNA methylome have been described in patients with rheumatoid arthritis (RA). In previous work, we reported genome-wide methylation differences in T-lymphocyte and B-lymphocyte populations from healthy individuals. Now, using HumanMethylation450 BeadChips to interrogate genome-wide DNA methylation, we have determined disease-associated methylation changes in blood-derived T- and B lymphocyte populations from 12 female patients with seropositive established RA, relative to 12 matched healthy individuals. Array data were analyzed using NIMBL software and bisulfite pyrosequencing was used to validate array candidates. Genome-wide DNA methylation, determined by analysis of LINE-1 sequences, revealed higher methylation in B-lymphocytes compared with T-lymphocytes (P <= 0.01), which is consistent with our findings in healthy individuals. Moreover, loci specific methylation differences that distinguished T-lymphocytes from B lymphocytes in healthy individuals were also apparent in RA patients. However, disease-associated methylation differences were also identified in RA. In these cases, we identified 509 and 252 CpGs in RA-derived T- and B-lymphocytes, respectively, that showed significant changes in methylation compared with their cognate healthy counterparts. Moreover, this included a restricted set of 32 CpGs in T-lymphocytes and 20 CpGs in B-lymphocytes (representing 15 and 10 genes, respectively, and including two, MGMT and CCS, that were common to both cell types) that displayed more substantial changes in methylation. These changes, apparent as hyper- or hypo-methylation, were independently confirmed by pyrosequencing analysis. Validation by pyrosequencing also revealed additional sites in some candidate genes that also displayed altered methylation in RA. In this first study of genome-wide DNA methylation in individual T- and B-lymphocyte populations in RA patients, we report disease-associated methylation changes that are distinct to each cell type and which support a role for discrete epigenetic regulation in this disease. PMID- 25147924 TI - Traditional medicine and childcare in Western Africa: mothers' knowledge, folk illnesses, and patterns of healthcare-seeking behavior. AB - BACKGROUND: In spite of the strong role of traditional medicine in childcare in the pluralistic healthcare system in Western Africa, little information is known on mothers' domestic plant knowledge. Identifying local perspectives and treatments of children's illnesses, including folk illnesses, is essential to having a comprehensive understanding of how mothers make healthcare treatment decisions. We aimed to identify which infant illnesses Beninese and Gabonese mothers knew to treat with medicinal plants and for which illnesses they sought biomedical care or traditional healers. METHODS: We conducted 81 questionnaires with mothers in Benin and Gabon and made 800 botanical specimens of cited medicinal plants. We calculated the number of species cited per illness and the proportion of participants knowledgeable on at least one herbal remedy per illness. Using qualitative data, we described folk illnesses in each country and summarized responses on preferences for each of the three healthcare options. RESULTS: Participants from both countries were most knowledgeable on plants to treat respiratory illnesses, malaria, diarrhea, and intestinal ailments. Mothers also frequently mentioned the use of plants to encourage children to walk early, monitor the closure of fontanels, and apply herbal enemas. Major folk illnesses were atita and ka in Benin and la rate and fesses rouges in Gabon. Traditional healers were reported to have specialized knowledge of cultural bound illnesses. Malaria was frequently cited as an illness for which mothers would directly seek biomedical treatment. CONCLUSION: Mothers largely saw the three systems as complementary, seamlessly switching between different healing options until a remedy was found. Folk illnesses were found to give insight into local treatments and may reveal important neglected diseases. Due to high reported levels of knowledge on treating top statistical causes of infant mortality and folk illnesses, mothers' medicinal plant knowledge should be included in the analysis of healthcare-seeking behavior for childcare. PMID- 25147925 TI - In silico approach to study adaptive divergence in nucleotide composition of the 16S rRNA gene among bacteria thriving under different temperature regimes. AB - Bacteria exist in a wide range of habitats ranging from psychrophilic through mesophilic to thermophilic. These different habitats have distinct environmental restriction for their existence. These microorganisms evolve themselves to survive in a specific habitat through the phenotypic and genotypic changes. In the bacterial domain, in silico analysis of 16S rRNA gene sequences using Mega 5.2 software by computing nucleotide composition, and evaluating their significance by statistical analysis using analysis of variance through Statistical Package for the Social Sciences (SPSS) version 16.0, revealed the habitat-specific bias in the occurrence of four types of nucleosides (A, T, C, and G) in the 16S rRNA gene. This hypothesis is also supported by Duncan's multiple range significance test at p=0.05 and also by the clustering of bacterial species of the same habitat group in the neighbor-joining tree of 150 different bacterial species of different psychrophilic, mesophilic, and thermophilic habitats (50 from each). The results on the probability of substitution (transition and transversion) in 16S rRNA gene sequences suggest that there is a habitat-specific selection pressure that possibly happens at the level of replication and repair process that results in a decreasing frequency of occurrence of adenine and thymine in the order psychrophilic>mesophilic>thermophilic species, and in an increasing frequency of occurrence of cytosine and guanine in the order psychrophilic700 fmol/g initial wet weight were seen in hypothalamic, thalamic and septal regions, while the lowest level of binding <300 fmol/g initial wet weight was in the mediolateral medulla. 125I-SI Ang II binding was substantially higher by an average of 85% in wild-type mouse brains compared to neurolysin knockout brains, suggesting the presence of an additional non-AT1, non-AT2, non-neurolysin Ang II binding site in the mouse brain. Binding of 125I SI Ang II to neurolysin in the presence of PCMB was highest in hypothalamic and ventral cortical brain regions, but broadly distributed across all regions surveyed. Non-AT1, non-AT2, non-neurolysin binding was also highest in the hypothalamus but had a different distribution than neurolysin. There was a significant reduction in AT2 receptor binding in the neurolysin knockout brain and a trend towards decreased AT1 receptor binding. In the neurolysin knockout brains, the size of the lateral ventricles was increased by 56% and the size of the mid forebrain (-2.72 to +1.48 relative to Bregma) was increased by 12%. These results confirm the identity of neurolysin as a novel Ang II binding site, suggesting that neurolysin may play a significant role in opposing the pathophysiological actions of the brain RAS and influencing brain morphology. PMID- 25147933 TI - Understanding the role alpha7 nicotinic receptors play in dopamine efflux in nucleus accumbens. AB - Neuronal nicotinic acetylcholine receptors (NNRs) of the alpha7 subtype have been shown to contribute to the release of dopamine in the nucleus accumbens. The site of action and the underlying mechanism, however, are unclear. Here we applied a circuit modeling approach, supported by electrochemical in vivo recordings, to clarify this issue. Modeling revealed two potential mechanisms for the drop in accumbal dopamine efflux evoked by the selective alpha7 partial agonist TC-7020. TC-7020 could desensitize alpha7 NNRs located predominantly on dopamine neurons or glutamatergic afferents to them or, alternatively, activate alpha7 NNRs located on the glutamatergic afferents to GABAergic interneurons in the ventral tegmental area. Only the model based on desensitization, however, was able to explain the neutralizing effect of coapplied PNU-120596, a positive allosteric modulator. According to our results, the most likely sites of action are the preterminal alpha7 NNRs controlling glutamate release from cortical afferents to the nucleus accumbens. These findings offer a rationale for the further investigation of alpha7 NNR agonists as therapy for diseases associated with enhanced mesolimbic dopaminergic tone, such as schizophrenia and addiction. PMID- 25147935 TI - A Case of Orbital Metastasis of Uterine Leiomyosarcoma With Intracranial Extension Presenting With Proptosis. AB - A 57-year-old woman presented with protrusion of the OS 2 months in duration and decreased vision 1 month in duration. The patient was diagnosed with uterine leiomyosarcoma approximately 3 years before presentation. Lung and liver metastases were diagnosed by biopsy 1 year prior to this visit. CT revealed a solid mass with central necrosis in the left lateral orbit that resulted in orbital shifting, bony destruction, and intracranial extension. The diagnosis was left orbital metastatic leiomyosarcoma, and the patient died 2 months after receiving the diagnosis. PMID- 25147936 TI - Possible association between dysfunction of vitamin D binding protein (GC Globulin) and migraine attacks. AB - To identify the genetic causality of migraine and acute, severe melalgia, we performed a linkage analysis and exome sequencing in a family with four affected individuals. We identified a variant (R21L) in exon 2 of the GC globulin gene, which is involved in the transportation of vitamin D metabolites and acts as a chemotaxic factor; this variant was co-segregated within the family. To investigate the relationship between GC globulin and melalgia, we investigated the cytokine levels in serum samples from the patients and control subjects using a cytokine antibody array. GC globulin can bind to both MCP-1 and RANTES in human serum but has a higher affinity to MCP-1. In cell culture systems, MCP-1 was able to bind to overexpressed wild-type GC globulin but not to the GC globulin variant, and the GC globulin binding affinity to MCP-1 was significantly lower in sera from the patients than in sera from control subjects. A higher concentration of MCP-1 was also observed in sera from the patients. Thus, the dysfunctional GC globulin affected cytokine release, especially the release of MCP-1, and MCP-1 might play important roles in melalgia and migraine. PMID- 25147940 TI - Expanding access to non-traditional vaccines: a perspective from Indonesia. AB - In addition to the use of traditional vaccines in the National Immunization Program, the introduction: of additional vaccines in Indonesia appears to be important to further reduce rates of childhood mortality. However, it typically takes at least two decades for additional vaccines to be introduced into the National Immunization Program since decisions to introduce additional vaccines must be supported with clear strategies to guarantee the supply of affordable vaccines, financial sustainability and long-term commitments. PMID- 25147937 TI - Selenite enhances immune response against Pseudomonas aeruginosa PA14 via SKN-1 in Caenorhabditis elegans. AB - BACKGROUND: Selenium (Se) is an important nutrient that carries out many biological processes including maintaining optimal immune function. Here, inorganic selenite (Se(IV)) was evaluated for its pathogen resistance and potential-associated factors in Caenorhabditis elegans. The immune effects of Se(IV) were investigated by examining the responses of C. elegans to Pseudomonas aerugonisa PA14 strain. PRINCIPAL FINDINGS: Se(IV)-treated C. elegans showed increased survival under PA14 infection compared with untreated controls. The significant pathogen resistance of Se(IV) on C. elegans might not be attributed to the effects of Se(IV) on PA14 as Se(IV) showed no effect on bacterial quorum sensing and virulence factors of PA14. This study showed that Se(IV) enhanced the expression of a gene pivotal for the innate immunity in C. elegans. The study found that the pathogen-resistant phenotypes contributed by Se(IV) was absent from the skn-1 mutant worms. Moreover, Se(IV) influenced the subcellular distribution of SKN-1/Nrf in C. elegans upon PA14 infection. Furthermore, Se(IV) increased mRNA levels of SKN-1 target genes (gst-4 and gcs-1). CONCLUSIONS: This study found evidence of Se(IV) protecting C. elegans against P. aeruginosa PA14 infection by exerting effects on the innate immunity of C. elegans that is likely mediated via regulation of a SKN-1-dependent signaling pathway. PMID- 25147938 TI - Changes in cecal microbiota and mucosal gene expression revealed new aspects of epizootic rabbit enteropathy. AB - Epizootic Rabbit Enteropathy (ERE) is a severe disease of unknown aetiology that mainly affects post-weaning animals. Its incidence can be prevented by antibiotic treatment suggesting that bacterial elements are crucial for the development of the disease. Microbial dynamics and host responses during the disease were studied. Cecal microbiota was characterized in three rabbit groups (ERE-affected, healthy and healthy pretreated with antibiotics), followed by transcriptional analysis of cytokines and mucins in the cecal mucosa and vermix by q-rtPCR. In healthy animals, cecal microbiota with or without antibiotic pretreatment was very similar and dominated by Alistipes and Ruminococcus. Proportions of both genera decreased in ERE rabbits whereas Bacteroides, Akkermansia and Rikenella increased, as well as Clostridium, gamma-Proteobacteria and other opportunistic and pathogenic species. The ERE group displayed remarkable dysbiosis and reduced taxonomic diversity. Transcription rate of mucins and inflammatory cytokines was very high in ERE rabbits, except IL-2, and its analysis revealed the existence of two clearly different gene expression patterns corresponding to Inflammatory and (mucin) Secretory Profiles. Furthermore, these profiles were associated to different bacterial species, suggesting that they may correspond to different stages of the disease. Other data obtained in this work reinforced the notion that ERE morbidity and mortality is possibly caused by an overgrowth of different pathogens in the gut of animals whose immune defence mechanisms seem not to be adequately responding. PMID- 25147941 TI - Deforestation and benthic indicators: how much vegetation cover is needed to sustain healthy Andean streams? AB - Deforestation in the tropical Andes is affecting ecological conditions of streams, and determination of how much forest should be retained is a pressing task for conservation, restoration and management strategies. We calculated and analyzed eight benthic metrics (structural, compositional and water quality indices) and a physical-chemical composite index with gradients of vegetation cover to assess the effects of deforestation on macroinvertebrate communities and water quality of 23 streams in southern Ecuadorian Andes. Using a geographical information system (GIS), we quantified vegetation cover at three spatial scales: the entire catchment, the riparian buffer of 30 m width extending the entire stream length, and the local scale defined for a stream reach of 100 m in length and similar buffer width. Macroinvertebrate and water quality metrics had the strongest relationships with vegetation cover at catchment and riparian scales, while vegetation cover did not show any association with the macroinvertebrate metrics at local scale. At catchment scale, the water quality metrics indicate that ecological condition of Andean streams is good when vegetation cover is over 70%. Further, macroinvertebrate community assemblages were more diverse and related in catchments largely covered by native vegetation (>70%). Our results suggest that retaining an important quantity of native vegetation cover within the catchments and a linkage between headwater and riparian forests help to maintain and improve stream biodiversity and water quality in Andean streams affected by deforestation. This research proposes that a strong regulation focused to the management of riparian buffers can be successful when decision making is addressed to conservation/restoration of Andean catchments. PMID- 25147942 TI - Surface survival and internalization of salmonella through natural cracks on developing cantaloupe fruits, alone or in the presence of the melon wilt pathogen Erwinia tracheiphila. AB - Outbreaks of foodborne illness attributed to the consumption of Salmonella tainted cantaloupe have occurred repeatedly, but understanding of the ecology of Salmonella on cantaloupe fruit surfaces is limited. We investigated the interactions between Salmonella enterica Poona, the plant pathogenic bacterium Erwinia tracheiphila, and cantaloupe fruit. Fruit surfaces were inoculated at the natural cracking stage by spreading S. enterica and E. tracheiphila, 20 ul at 107 cfu/ml, independently or together, over a 2*2 cm rind area containing a crack. Microbial and microscopic analyses were performed at 0, 9 and 24 days post inoculation (DPI). Even at 24 DPI (fruit maturity) S. enterica was detected on 14% and 40% of the fruit inoculated with S. enterica alone and the two-pathogen mixture, respectively. However, the population of S. enterica declined gradually after initial inoculation. E. tracheiphila, inoculated alone or together with Salmonella, caused watersoaked lesions on cantaloupe fruit; but we could not conclude in this study that S. enterica survival on the fruit surface was enhanced by the presence of those lesions. Of fruit inoculated with E. tracheiphila alone and sampled at 24 DPI, 61% had watersoaked lesions on the surface. In nearly half of those symptomatic fruits the watersoaking extended into the sub-rind mesocarp, and E. tracheiphila was recovered from that tissue in 50% of the symptomatic fruit. In this work, E. tracheiphila internalized through natural cracks on developing fruits. S. enterica was never detected in the fruit interior (ca. 2-3 mm below rind surface) under the limited conditions of our experiments, but the possibility that it, or other human pathogens that contaminate fresh produce, might also do so should be investigated under a wider range of conditions and produce types. PMID- 25147943 TI - Purification and characterization of Plantaricin ZJ5, a new bacteriocin produced by Lactobacillus plantarum ZJ5. AB - The aim of this study is to investigate the antimicrobial potential of Lactobacillus plantarum ZJ5, a strain isolated from fermented mustard with a broad range of inhibitory activity against both Gram-positive and Gram-negative bacteria. Here we present the peptide plantaricin ZJ5 (PZJ5), which is an extreme pH and heat-stable. However, it can be digested by pepsin and proteinase K. This peptide has strong activity against Staphylococcus aureus. PZJ5 has been purified using a multi-step process, including ammonium sulfate precipitation, cation exchange chromatography, hydrophobic interactions and reverse-phase chromatography. The molecular mass of the peptide was found to be 2572.9 Da using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The primary structure of this peptide was determined using amino acid sequencing and DNA sequencing, and these analyses revealed that the DNA sequence translated as a 44-residue precursor containing a 22-amino-acid N terminal extension that was of the double-glycine type. The bacteriocin sequence exhibited no homology with known bacteriocins when compared with those available in the database, indicating that it was a new class IId bacteriocin. PZJ5 from a food-borne strain may be useful as a promising probiotic candidate. PMID- 25147944 TI - Spectroscopic and permeation studies of phospholipid bilayers supported by a soft hydrogel scaffold. AB - Polarized attenuated total reflection infrared (ATR-IR) spectroscopy, fluorescence microscopy, and fluorescence spectroscopy were used to characterize a lipid coating composed of 70 mol % 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 30 mol % cholesterol, supported on a spherical hydrogel scaffold. The fluorescence microscopy images show an association between the lipid coating and the hydrogel scaffold. Fluorescence permeability measurements revealed that the phospholipid coating acts as a permeability barrier, exhibiting characteristics of a lamellar bilayer coating structure. Variable evanescent wave penetration depth ATR-IR spectroscopy studies validated the determination of quantitative molecular orientation information for a lipid coating supported on a spherical scaffold. These polarized ATR-IR studies measured an average DMPC acyl chain tilt angle of ~21-25 degrees , with respect to the surface normal. PMID- 25147945 TI - CSF biomarkers and neuropsychological profiles in patients with cerebral small vessel disease. AB - Despite existing criteria, differential diagnosis of Vascular Dementia (VD) and Alzheimer's disease (AD) remains difficult. The aim of this study is to figure out cognitive and biomarker profiles that may help to distinguish between VD, AD and AD + Cerebral Small Vessel Disease (CSVD). We examined a cohort of patients with CSVD (n = 92). After stratification of cognitive impaired patients (n = 59) using the standard CSF beta-amyloid 42/40 ratio cut-off point of 0.975, we obtained two groups which differed with respect to several features: 32 patients with normal beta-amyloid 42/40 ratio (>0.975) showed markedly impaired blood brain-barrier function as indicated by an elevated albumin ratio (median 8.35). They also differed in cognitive profiles when compared to 27 patients with AD typical beta-amyloid ratio and normal albumin ratio. We also enrolled an additional group of patients with AD (no significant CSVD on MRI, n = 27) which showed no impairment of the blood-brain-barrier. We showed a negative correlation between the albumin ratio and executive cognitive function (p = 0.016) and a negative correlation between memory function and typical AD markers like Tau (p = 0.004) and p181-Tau (p = 0.023) in our cohort. We suppose that the group of patients with normal beta-amyloid ratio represents VD while patients in the other groups represent AD+CSVD and pure AD. Our results support the idea that a dysfunction of the blood-brain-barrier might be contributing factor in the development of cognitive decline in CSVD as it seems to be of more importance than the severity of white matter lesions. PMID- 25147947 TI - Advantages and limitations of the Five Domains model for assessing welfare impacts associated with vertebrate pest control. AB - Many pest control activities have the potential to impact negatively on the welfare of animals, and animal welfare is an important consideration in the development, implementation and evaluation of ethically defensible vertebrate pest control. Thus, reliable and accurate methods for assessing welfare impacts are required. The Five Domains model provides a systematic method for identifying potential or actual welfare impacts associated with an event or situation in four physical or functional domains (nutrition, environment, health or functional status, behaviour) and one mental domain (overall mental or affective state). Here we evaluate the advantages and limitations of the Five Domains model for this purpose and illustrate them using specific examples from a recent assessment of the welfare impacts of poisons used to lethally control possums in New Zealand. The model has a number of advantages which include the following: the systematic identification of a wide range of impacts associated with a variety of control tools; the production of relative rankings of tools in terms of their welfare impacts; the easy incorporation of new information into assessments; and the highlighting of additional information needed. For example, a recent analysis of sodium fluoroacetate (1080) poisoning in possums revealed the need for more information on the period from the onset of clinical signs to the point at which consciousness is lost, as well as on the level of consciousness during or after the occurrence of muscle spasms and seizures. The model is also valuable because it clearly separates physical or functional and affective impacts, encourages more comprehensive consideration of negative affective experiences than has occurred in the past, and allows development and evaluation of targeted mitigation strategies. Caution must be used in interpreting and applying the outputs of the model, most importantly because relative rankings or grades are fundamentally qualitative in nature. Certain domains are more useful for evaluating impacts associated with slower/longer-acting tools than for faster acting methods, and it may be easier to identify impacts in some domains than others. Overall, we conclude that the Five Domains model advances evaluation of the animal welfare impacts of vertebrate pest control methods, provided users are cognisant of its limitations. PMID- 25147946 TI - Genomic characterization of a circovirus associated with fatal hemorrhagic enteritis in dog, Italy. AB - Dog circovirus (DogCV) was identified in an outbreak of enteritis in pups in Italy. The disease was observed in 6 young dachshunds pups of a litter from a breeding kennel and caused the death of 2 dogs. Upon full-genome analysis, the virus detected in one of the dead pups (strain Bari/411-13) was closely related to DogCVs that have been recently isolated in the USA. The present study, if corroborated by further reports, could represent a useful contribution to the knowledge of the pathogenic potential of DogCV and its association with enteritis in dogs. PMID- 25147949 TI - Short-term dispersal response of an endangered Australian lizard varies with time of year. AB - Dispersal is an important component in the demography of animal populations. Many animals show seasonal changes in their tendency to disperse, reflecting changes in resource availability, mating opportunities, or in population age structure at the time when new offspring enter the population. Understanding when and why dispersal occurs can be important for the management of endangered species. The pygmy bluetongue lizard is an endangered Australian species that occupies and defends single burrow refuges for extended periods of time, rarely moving far from the burrow entrance. However, previous pitfall trapping data have suggested movement of adult males in spring and of juveniles in autumn of each year. In the current study we compared behaviours of adult lizards each month, over the spring summer activity period over two consecutive field seasons, to provide deeper understanding of the seasonal dispersal pattern. We released adult pygmy bluetongue lizards into a central area, provided with artificial burrows, within large enclosures, and monitored the behaviour and movements of the released lizards over a four day period. There was a consistent decline in time spent basking, amount of movement around burrow entrances, and rates of dispersal from the central release area from early spring to late summer. Results could be relevant to understanding and managing natural populations and for any translocation attempts of this endangered lizard species. PMID- 25147950 TI - The increased risk for autoimmune diseases in patients with eating disorders. AB - OBJECTIVE: Research suggests autoimmune processes to be involved in psychiatric disorders. We aimed to address the prevalence and incidence of autoimmune diseases in a large Finnish patient cohort with anorexia nervosa, bulimia nervosa, and binge eating disorder. METHODS: Patients (N = 2342) treated at the Eating Disorder Unit of Helsinki University Central Hospital between 1995 and 2010 were compared with general population controls (N = 9368) matched for age, sex, and place of residence. Data of 30 autoimmune diseases from the Hospital Discharge Register from 1969 to 2010 were analyzed using conditional and Poisson regression models. RESULTS: Of patients, 8.9% vs. 5.4% of control individuals had been diagnosed with one or more autoimmune disease (OR 1.7, 95% CI 1.5-2.0, P<0.001). The increase in endocrinological diseases (OR 2.4, 95% CI 1.8-3.2, P<0.001) was explained by type 1 diabetes, whereas Crohn's disease contributed most to the risk of gastroenterological diseases (OR 1.8, 95% CI 1.4-2.5, P<0.001). Higher prevalence of autoimmune diseases among patients with eating disorders was not exclusively due to endocrinological and gastroenterological diseases; when the two categories were excluded, the increase in prevalence was seen in the patients both before the onset of the eating disorder treatment (OR 1.5, 95% CI 1.1-2.1, P = 0.02) and at the end of the follow-up (OR 1.4, 95% CI 1.1-1.8, P = 0.01). CONCLUSIONS: We observed an association between eating disorders and several autoimmune diseases with different genetic backgrounds. Our findings support the link between immune-mediated mechanisms and development of eating disorders. Future studies are needed to further explore the risk of autoimmune diseases and immunological mechanisms in individuals with eating disorders and their family members. PMID- 25147951 TI - Cartilage-specific ablation of site-1 protease in mice results in the endoplasmic reticulum entrapment of type IIb procollagen and down-regulation of cholesterol and lipid homeostasis. AB - The proprotein convertase site-1 protease (S1P) converts latent ER-membrane bound transcription factors SREBPs and ATF6 to their active forms. SREBPs are involved in cholesterol and fatty acid homeostasis whereas ATF6 is involved in unfolded protein response pathways (UPR). Cartilage-specific ablation of S1P in mice (S1Pcko) results in abnormal cartilage devoid of type II collagen protein (Col II). S1Pcko mice also lack endochondral bone development. To analyze S1Pcko cartilage we performed double-labeled immunofluorescence studies for matrix proteins that demonstrated that type IIB procollagen is trapped inside the ER in S1Pcko chondrocytes. This retention is specific to type IIB procollagen; other cartilage proteins such as type IIA procollagen, cartilage oligomeric matrix protein (COMP) and aggrecan are not affected. The S1Pcko cartilage thus exhibits COMP-, aggrecan-, and type IIA procollagen-derived matrices but is characterized by the absence of a type IIB procollagen-derived matrix. To understand the molecular reason behind S1Pcko phenotypes we performed genome-wide transcriptional profiling of cartilage isolated from S1Pcko and wild type littermates. While the UPR pathways are unaffected, the SREBPs-directed cholesterol and fatty acid pathways are significantly down-regulated in S1Pcko chondrocytes, with maximal down-regulation of the stearoyl-CoA desaturase-1 (Scd1) gene. However, mouse models that lack Scd1 or exhibit reduction in lipid homeostasis do not suffer from the ER retention of Col II or lack endochondral bone. These studies indicate an indispensable role for S1P in type IIB procollagen trafficking from the ER. This role appears not to be related to lipid pathways or other current known functions of S1P and is likely dependent on additional, yet unknown, S1P substrates in chondrocytes. PMID- 25147955 TI - Nanoscale structural modulation and enhanced room-temperature multiferroic properties. AB - Availability of a single-phase multiferroic material functional at room temperature poses a big challenge, although it is very important to both fundamental physics and application development. Recently, layered Aurivillius oxide materials, one of the most promising candidates, have attracted considerable interest. In this work, we investigated the nanoscale structural evolution of the six-layer Bi7Fe(3-x)Co(x)Ti3O21 when substituting excessive Co. Nanoscale structural modulation (NSM) occurred at the boundaries when changing the material gradually from the originally designed six-layer nanoscale architecture down to five and then four, when increasing the Co content, inducing a previously unidentified analogous morphotropic transformation (AMT) effect. The AMT's net contribution to the enhanced intrinsic multiferroic properties at room temperature was confirmed by quantifying and deducting the contribution from the existing impurity phase using derivative thermo-magneto-gravimetry measurements (DTMG). Significantly, this new AMT effect may be caused by a possible coupling contribution from co-existing NSM phases, indicating a potential method for realizing multiferroic materials that function at room temperature. PMID- 25147953 TI - RecA protein plays a role in the chemotactic response and chemoreceptor clustering of Salmonella enterica. AB - The RecA protein is the main bacterial recombinase and the activator of the SOS system. In Escherichia coli and Salmonella enterica sv. Typhimurium, RecA is also essential for swarming, a flagellar-driven surface translocation mechanism widespread among bacteria. In this work, the direct interaction between RecA and the CheW coupling protein was confirmed, and the motility and chemotactic phenotype of a S. Typhimurium DeltarecA mutant was characterized through microfluidics, optical trapping, and quantitative capillary assays. The results demonstrate the tight association of RecA with the chemotaxis pathway and also its involvement in polar chemoreceptor cluster formation. RecA is therefore necessary for standard flagellar rotation switching, implying its essential role not only in swarming motility but also in the normal chemotactic response of S. Typhimurium. PMID- 25147956 TI - Stabilization of the potent odorant 2-acetyl-1-pyrroline and structural analogues by complexation with zinc halides. AB - 2-Acetyl-1-pyrroline (2AP) and the structurally similar compounds 6-acetyl 2,3,4,5-tetrahydropyridine (ATHP, along with its tautomer 6-acetyl-1,2,3,4 tetrahydropyridine), 2-propionyl-1-pyrroline (2PP), and 2-acetyl-2-thiazoline (2A2T) are well-known potent odorants in various food products. However, due to the highly unstable nature of these compounds, especially 2AP and ATHP, they are scarcely used commercially in flavor formulations. A novel and attractive method for the stabilization of these potent odorants in dry powder form is presented. Coordination of 2AP, ATHP, 2PP, and 2A2T to zinc ions (ZnI2, ZnBr2, or ZnCl2) resulted in the formation in high yields of stable crystalline complexes, which upon hydration release the free odorant. Infrared spectroscopy was used to study the coordination complexes. 2AP contains donor atoms, which coordinate (with covalent character) through both the heterocyclic nitrogen and carbonyl oxygen atoms to the zinc ion. This is also the case for ATHP and 2PP, but not for 2A2T, because the sulfur group in 2A2T provides a third possible donor site. Stability studies showed that the 2AP-ZnI2 complex (with 14% loading) maintained >94% retention of 2AP after 3 months of storage at ambient temperature in a dry environment. Meanwhile, the ATHP-ZnI2 complex was similarly stable and retained 89% of the ATHP after 3 months of storage. This stabilization technology may enable the commercial use of this powerful aroma compound as a flavoring agent. PMID- 25147954 TI - Strong effects of genetic and lifestyle factors on biomarker variation and use of personalized cutoffs. AB - Ideal biomarkers used for disease diagnosis should display deviating levels in affected individuals only and be robust to factors unrelated to the disease. Here we show the impact of genetic, clinical and lifestyle factors on circulating levels of 92 protein biomarkers for cancer and inflammation, using a population based cohort of 1,005 individuals. For 75% of the biomarkers, the levels are significantly heritable and genome-wide association studies identifies 16 novel loci and replicate 2 previously known loci with strong effects on one or several of the biomarkers with P-values down to 4.4 * 10(-58). Integrative analysis attributes as much as 56.3% of the observed variance to non-disease factors. We propose that information on the biomarker-specific profile of major genetic, clinical and lifestyle factors should be used to establish personalized clinical cutoffs, and that this would increase the sensitivity of using biomarkers for prediction of clinical end points. PMID- 25147957 TI - Expedient preparation of nazlinine and a small library of indole alkaloids using flow electrochemistry as an enabling technology. AB - An expedient synthesis of the indole alkaloid nazlinine is reported. Judicious choice of flow electrochemistry as an enabling technology has permitted the rapid generation of a small library of unnatural relatives of this biologically active molecule. Furthermore, by conducting the key electrochemical Shono oxidation in a flow cell, the loading of electrolyte can be significantly reduced to 20 mol % while maintaining a stable, broadly applicable process. PMID- 25147952 TI - Phosphorylation site dynamics of early T-cell receptor signaling. AB - In adaptive immune responses, T-cell receptor (TCR) signaling impacts multiple cellular processes and results in T-cell differentiation, proliferation, and cytokine production. Although individual protein-protein interactions and phosphorylation events have been studied extensively, we lack a systems-level understanding of how these components cooperate to control signaling dynamics, especially during the crucial first seconds of stimulation. Here, we used quantitative proteomics to characterize reshaping of the T-cell phosphoproteome in response to TCR/CD28 co-stimulation, and found that diverse dynamic patterns emerge within seconds. We detected phosphorylation dynamics as early as 5 s and observed widespread regulation of key TCR signaling proteins by 30 s. Development of a computational model pointed to the presence of novel regulatory mechanisms controlling phosphorylation of sites with central roles in TCR signaling. The model was used to generate predictions suggesting unexpected roles for the phosphatase PTPN6 (SHP-1) and shortcut recruitment of the actin regulator WAS. Predictions were validated experimentally. This integration of proteomics and modeling illustrates a novel, generalizable framework for solidifying quantitative understanding of a signaling network and for elucidating missing links. PMID- 25147958 TI - Transport in disordered monolayer MoS2 nanoflakes--evidence for inhomogeneous charge transport. AB - We study charge transport in a monolayer MoS2 nanoflake over a wide range of carrier density, temperature and electric bias. We find that the transport is best described by a percolating picture in which the disorder breaks translational invariance, breaking the system up into a series of puddles, rather than previous pictures in which the disorder is treated as homogeneous and uniform. Our work provides insight to a unified picture of charge transport in monolayer MoS2 nanoflakes and contributes to the development of next-generation MoS2-based devices. PMID- 25147959 TI - Optimization of sample cooling temperature for redox cryo-imaging. AB - Cryo-imaging techniques have been widely used to measure the metabolic state of tissues by capturing reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) autofluorescence. However, NADH and FAD fluorescence is sensitive to changes in temperature, which may result in unreliable redox ratio calculations. Here, the relationship between the measured redox ratio and sample surface temperature was analyzed using a standard phantom solution and biological tissues. The results indicated that a temperature < - 100 degrees C was a suitable cryo-imaging temperature window in which redox ratio measuring was immune to temperature fluctuations. These results may serve as a reference for designing and optimizing redox cryo-imaging experiments for quantitatively mapping the metabolic state of biological samples. PMID- 25147960 TI - Time-resolved fluorescence spectroscopy and ultrasound backscatter microscopy for nondestructive evaluation of vascular grafts. AB - Quantitative and qualitative evaluations of structure and composition are important in monitoring development of engineered vascular tissue both in vitro and in vivo. Destructive techniques are an obstacle for performing time-lapse analyses from a single sample or animal. This study demonstrates the ability of time-resolved fluorescence spectroscopy (TRFS) and ultrasound backscatter microscopy (UBM), as nondestructive and synergistic techniques, for compositional and morphological analyses of tissue grafts, respectively. UBM images and integrated backscatter coefficients demonstrate the ability to visualize and quantify postimplantation changes in vascular graft biomaterials such as loss of the external elastic lamina and intimal/medial thickening over the grafted region as well as graft integration with the surrounding tissue. TRFS results show significant changes in spectra, average lifetime, and fluorescence decay parameters owing to changes in collagen, elastin, and cellular content between normal and grafted tissue regions. These results lay the foundation for the application of a catheter-based technique for in vivo evaluation of vascular grafts using TRFS and UBM. PMID- 25147961 TI - Noncontact imaging of burn depth and extent in a porcine model using spatial frequency domain imaging. AB - The standard of care for clinical assessment of burn severity and extent lacks a quantitative measurement. In this work, spatial frequency domain imaging (SFDI) was used to measure 48 thermal burns of graded severity (superficial partial, deep partial, and full thickness) in a porcine model. Functional (total hemoglobin and tissue oxygen saturation) and structural parameters (tissue scattering) derived from the SFDI measurements were monitored over 72 h for each burn type and compared to gold standard histological measurements of burn depth. Tissue oxygen saturation (stO2) and total hemoglobin (ctHbT) differentiated superficial partial thickness burns from more severe burn types after 2 and 72 h, respectively (p < 0.01), but were unable to differentiate deep partial from full thickness wounds in the first 72 h. Tissue scattering parameters separated superficial burns from all burn types immediately after injury (p < 0.01), and separated all three burn types from each other after 24 h (p < 0.01). Tissue scattering parameters also showed a strong negative correlation to histological burn depth as measured by vimentin immunostain (r2 > 0.89). These results show promise for the use of SFDI-derived tissue scattering as a correlation to burn depth and the potential to assess burn depth via a combination of SFDI functional and structural parameters. PMID- 25147962 TI - User-guided segmentation for volumetric retinal optical coherence tomography images. AB - Despite the existence of automatic segmentation techniques, trained graders still rely on manual segmentation to provide retinal layers and features from clinical optical coherence tomography (OCT) images for accurate measurements. To bridge the gap between this time-consuming need of manual segmentation and currently available automatic segmentation techniques, this paper proposes a user-guided segmentation method to perform the segmentation of retinal layers and features in OCT images. With this method, by interactively navigating three-dimensional (3-D) OCT images, the user first manually defines user-defined (or sketched) lines at regions where the retinal layers appear very irregular for which the automatic segmentation method often fails to provide satisfactory results. The algorithm is then guided by these sketched lines to trace the entire 3-D retinal layer and anatomical features by the use of novel layer and edge detectors that are based on robust likelihood estimation. The layer and edge boundaries are finally obtained to achieve segmentation. Segmentation of retinal layers in mouse and human OCT images demonstrates the reliability and efficiency of the proposed user guided segmentation method. PMID- 25147964 TI - Ambivalence, prejudice and negative behavioural tendencies towards out-groups: The moderating role of attitude basis. AB - Two experiments explored the relations between prejudice (suppression), (cognitive) ambivalence and negative behavioural tendencies towards out-groups. The current work argues that expressing out-group ambivalence based on cognitive, but not affective, information is a strategy to justify one's otherwise suppressed prejudice, which may ultimately "cover" the discriminatory nature of out-group-directed negative behavioural tendencies. Two experiments show that (1) participants evaluating the out-group in a normative context inducing prejudice suppression are more likely to self-report ambivalent beliefs rather than ambivalent emotions concerning the out-group as compared with participants whose prejudice expression is induced and (2) high-prejudice participants compared with low-prejudice participants are more prone to out-group-directed negative behavioural tendencies when these latter are self-reported after the expression of ambivalent beliefs but not ambivalent emotions concerning the out-group, and when the expression of their prejudicial evaluations is salient but not when it is not. In light of the extent to which ambivalent attitudes towards out-groups are often seamlessly integrated into public discourse, the implications of the findings are discussed not only for intergroup research but also at the societal level. PMID- 25147965 TI - Investigation and control of anthrax outbreak at the human-animal interface, Bhutan, 2010. AB - In 2010, we investigated anthrax outbreak in Bhutan. A total of 43 domestic animals died, and cutaneous anthrax developed in 9 persons, and 1 died. All affected persons had contact with the carcasses of infected animals. Comprehensive preparedness and response guidelines are needed to increase public awareness of anthrax in Bhutan. PMID- 25147963 TI - Formation, habitability, and detection of extrasolar moons. AB - The diversity and quantity of moons in the Solar System suggest a manifold population of natural satellites exist around extrasolar planets. Of peculiar interest from an astrobiological perspective, the number of sizable moons in the stellar habitable zones may outnumber planets in these circumstellar regions. With technological and theoretical methods now allowing for the detection of sub Earth-sized extrasolar planets, the first detection of an extrasolar moon appears feasible. In this review, we summarize formation channels of massive exomoons that are potentially detectable with current or near-future instruments. We discuss the orbital effects that govern exomoon evolution, we present a framework to characterize an exomoon's stellar plus planetary illumination as well as its tidal heating, and we address the techniques that have been proposed to search for exomoons. Most notably, we show that natural satellites in the range of 0.1 0.5 Earth mass (i) are potentially habitable, (ii) can form within the circumplanetary debris and gas disk or via capture from a binary, and (iii) are detectable with current technology. PMID- 25147966 TI - Three dimensional indium-tin-oxide nanorod array for charge collection in dye sensitized solar cells. AB - In this article, we report the design, fabrication, characterization, and simulation of three-dimensional (3D) dye-sensitized solar cells (DSSCs), using ordered indium-tin-oxide (ITO) nanorod (NR) arrays as the photoanode, and compare them with conventional planar (2D) DSSCs. The ITO NR array used in the 3D cell greatly improves its performance by providing shorter electron pathways and reducing the recombination rate of the photogenerated electrons. We observed a 10 20% enhancement of the energy conversion efficiency, primarily due to an increased short circuit current. This finding supports the concept of using 3D photoanodes with optically transparent and conducting nanorods for the enhancement of the energy-harvesting devices that require short charge collection distance without sacrificing the optical thickness. Thus, unlike the conventional solar cell structure, the functions for photon collection and charge transport are decoupled to allow for improved cell designs. PMID- 25147969 TI - Sign inversion of circularly polarized luminescence by geometry manipulation of four naphthalene units introduced into a tartaric acid scaffold. AB - Tethering four 1- versus 2-naphthyls to the same chiral scaffold derived from tartaric acid led to oppositely signed circularly polarized luminescence (CPL) and circular dichroism (CD) in solution, which not only reveals the decisive role of the spatial arrangement of chromophores/fluorophores in determining the chiroptical behaviors but also provides us with a versatile tool for switching the signs of CPL and CD without using the antipodal scaffold. PMID- 25147968 TI - Genomic epidemiology of Salmonella enterica serotype Enteritidis based on population structure of prevalent lineages. AB - Salmonella enterica serotype Enteritidis is one of the most commonly reported causes of human salmonellosis. Its low genetic diversity, measured by fingerprinting methods, has made subtyping a challenge. We used whole-genome sequencing to characterize 125 S. enterica Enteritidis and 3 S. enterica serotype Nitra strains. Single-nucleotide polymorphisms were filtered to identify 4,887 reliable loci that distinguished all isolates from each other. Our whole-genome single-nucleotide polymorphism typing approach was robust for S. enterica Enteritidis subtyping with combined data for different strains from 2 different sequencing platforms. Five major genetic lineages were recognized, which revealed possible patterns of geographic and epidemiologic distribution. Analyses on the population dynamics and evolutionary history estimated that major lineages emerged during the 17th-18th centuries and diversified during the 1920s and 1950s. PMID- 25147970 TI - A probability model for evaluating the bias and precision of influenza vaccine effectiveness estimates from case-control studies. AB - As influenza vaccination is now widely recommended, randomized clinical trials are no longer ethical in many populations. Therefore, observational studies on patients seeking medical care for acute respiratory illnesses (ARIs) are a popular option for estimating influenza vaccine effectiveness (VE). We developed a probability model for evaluating and comparing bias and precision of estimates of VE against symptomatic influenza from two commonly used case-control study designs: the test-negative design and the traditional case-control design. We show that when vaccination does not affect the probability of developing non influenza ARI then VE estimates from test-negative design studies are unbiased even if vaccinees and non-vaccinees have different probabilities of seeking medical care against ARI, as long as the ratio of these probabilities is the same for illnesses resulting from influenza and non-influenza infections. Our numerical results suggest that in general, estimates from the test-negative design have smaller bias compared to estimates from the traditional case-control design as long as the probability of non-influenza ARI is similar among vaccinated and unvaccinated individuals. We did not find consistent differences between the standard errors of the estimates from the two study designs. PMID- 25147971 TI - Biomarkers of Insecticide Exposure and Asthma in Children: A National Health and Nutrition Examination Survey (NHANES) 1999-2008 Analysis. AB - Pesticide exposure is a potential risk factor for increased asthma prevalence among children. The authors used National Health and Nutrition Examination Survey (1999-2008) biomarker data to evaluate dialkylphosphate (DAP) urinary concentrations, serum dichlorodiphenyldichloroethylene (DDE), and asthma among school-aged children (Mexican American, Non-Hispanic Black, Non-Hispanic White). Poisson logistic regression included age, sex, nativity, poverty index ratio, tobacco smoke exposure, and body mass index covariates. No association was found between DAP (N=2,777) and asthma outcomes; adverse effect of DDE (N=940) was suggested for Current Wheeze. Subgroup analyses identified positive associations with some asthma outcomes among Non-Hispanic Blacks, whereas inverse associations were identified among Mexican Americans. Results support previous associations observed among children's DDE exposure and wheeze. Characterization of risk factors for pesticide exposure and disease recognition among Mexican Americans is needed. PMID- 25147972 TI - Temperature- and pressure-induced phase transitions in the metal formate framework of [ND4][Zn(DCOO)3] and [NH4][Zn(HCOO)3]. AB - Vibrational properties and the temperature-induced phase transition mechanism have been studied in [NH4][Zn(HCOO)3] and [ND4][Zn(DCOO)3] metal organic frameworks by variable-temperature dielectric, IR, and Raman measurements. DFT calculations allowed proposing the detailed assignment of vibrational modes to respective motions of atoms in the unit cell. Temperature-dependent studies reveal a very weak isotopic effect on the phase transition temperature and confirm that ordering of ammonium cations plays a major role in the mechanism of the phase transition. We also present high-pressure Raman scattering studies on [ND4][Zn(DCOO)3]. The results indicate the rigidity of the formate ions and strong compressibility of the ZnO6 octahedra. They also reveal the onset of a pressure-induced phase transition at about 1.1 GPa. This transition has strong first-order character, and it is associated with a large distortion of the metal formate framework. Our data indicate the presence of at least two nonequivalent formate ions in the high-pressure structure with very different C-D bonds. The decompression experiment shows that the transition is reversible. PMID- 25147974 TI - The freedom to heal: nonrigid immobilization by a halo orthosis. AB - Halo orthoses present a paradox. On the one hand, the nominally rigid immobilization they provide to the head aims to remove loads on the cervical spine following injury or surgery, and the devices are retightened routinely to maintain this. On the other hand, bone growth and remodeling are well known to require mechanical stressing. How are these competing needs balanced? To understand this trade-off in an effective, commercial halo orthosis, the authors quantified the response of a commercial halo orthosis to physiological loading levels, applied symmetrically about the sagittal plane. They showed for the first time that after a few cycles of loading analogous to a few steps taken by a patient, the support presented by a standard commercial halo orthosis becomes nonlinear. When analyzed through straightforward structural modeling, these data revealed that the nonlinearity permits mild head motion while severely restricting larger motion. These observations are useful because they open the possibility that halo orthosis installation could be optimized to transfer mild spinal loads that support healing while blocking pathological loads. PMID- 25147975 TI - Intradiploic occipital pseudomeningocele in a patient with remote history of surgical treatment of Chiari malformation. AB - An intradiploic CSF pseudocyst is a rare entity that has been described in association with trauma, as a sequela of untreated hydrocephalus, or occasionally as a congenital finding in older adults. The authors present the case of a woman with a remote history of a posterior fossa intradural procedure, in which she underwent Chiari malformation decompression, Silastic substitute-assisted duraplasty, and occipitocervical fusion; she presented 19 years later with recurrent symptoms of Chiari malformation. She was found to have an occipital intradiploic pseudomeningocele, arising within her dorsal occipitocervical fusion mass and resulting in dorsal hindbrain compression. She underwent a posterior fossa decompression and revision of her failed duraplasty, and she had a good recovery. This case demonstrates intradiploic CSF pseudomeningocele as a rare potential delayed complication of an intradural procedure for the treatment of Chiari malformation with occipitocervical fusion. PMID- 25147976 TI - Adverse events in emergency oncological spine surgery: a prospective analysis. AB - OBJECT: Most descriptions of spine surgery morbidity and mortality in the literature are retrospective. Emerging prospective analyses of adverse events (AEs) demonstrate significantly higher rates, suggesting underreporting in retrospective and prospective studies that do not include AEs as a targeted outcome. Emergency oncological spine surgeries are generally palliative to reduce pain and improve patients' neurology and health-related quality of life. In individuals with limited life expectancy, AEs can have catastrophic implications; therefore, an accurate AE incidence must be considered in the surgical decision making process. The purpose of this study was to determine the true incidence of AEs associated with emergency oncological spine surgery. METHODS: The authors carried out a prospective cohort study in a quaternary care referral center that included consecutive patients admitted between January 1, 2009, and December 31, 2012. Inclusion criteria were all patients undergoing emergency surgery for metastatic spine disease. AE data were reported and collected on standardized AE forms (Spine AdVerse Events Severity System, version 2 [SAVES V2] forms) at weekly dedicated morbidity and mortality rounds attended by attending surgeons, residents, fellows, and nursing staff. RESULTS: A total of 101 patients (50 males, 51 females) met the inclusion criteria and had complete data. Seventy-six patients (76.2%) had at least 1 AE, and 11 patients (10.9%) died during their admission. Intraoperative surgical AEs were observed in 32% of patients (9.9% incidental durotomy, 16.8% blood loss > 2 L). Transient neurological deterioration occurred in 6 patients (5.9%). Infectious complications in this patient population were significant (surgical site 6%, other 50.5%). Delirium complicated the postoperative period in 20.8% of cases. CONCLUSIONS: When evaluated in a rigorous prospective manner, metastatic spine surgery is associated with a higher morbidity rate than previously reported. This AE incidence must be considered by the patient, oncologist, and surgeon to determine appropriate management and preventative strategies to reduce AEs in this fragile patient population. PMID- 25147977 TI - Freehand thoracic pedicle screw technique using a uniform entry point and sagittal trajectory for all levels: preliminary clinical experience. AB - OBJECT: Experience with freehand thoracic pedicle screw placement is well described in the literature. Published techniques rely on various starting points and trajectories for each level or segment of the thoracic spine. Furthermore, few studies provide specific guidance on sagittal and axial trajectories. The goal of this study was to propose a uniform entry point and sagittal trajectory for all thoracic levels during freehand pedicle screw placement and determine the accuracy of this technique. METHODS: The authors retrospectively reviewed postoperative CT scans of 33 consecutive patients who underwent open, freehand thoracic pedicle-screw fixation using a uniform entry point and sagittal trajectory for all levels. The same entry point for each level was defined as a point 3 mm caudal to the junction of the transverse process and the lateral margin of the superior articulating process, and the sagittal trajectory was always orthogonal to the dorsal curvature of the spine at that level. The medial angulation (axial trajectory) was approximately 30 degrees at T-1 and T-2, and 20 degrees from T-3 to T-12. Breach was defined as greater than 25% of the screw diameter residing outside of the pedicle or vertebral body. RESULTS: A total of 219 thoracic pedicle screws were placed with a 96% accuracy rate. There were no medial breaches and 9 minor lateral breaches (4.1%). None of the screws had to be repositioned postoperatively, and there were no neurovascular complications associated with the breaches. CONCLUSIONS: It is feasible to place freehand thoracic pedicle screws using a uniform entry point and sagittal trajectory for all levels. The entry point does not have to be adjusted for each level as reported in existing studies, although this technique was not tested in severe scoliotic spines. While other techniques are effective and widely used, this particular method provides more specific parameters and may be easier to learn, teach, and adopt. PMID- 25147979 TI - Low calcium-phosphate intakes modulate the low-protein diet-related effect on peak bone mass acquisition: a hormonal and bone strength determinants study in female growing rats. AB - Peak bone mass acquisition is influenced by environmental factors including dietary intake. A low-protein diet delays body and skeletal growth in association with a reduction in serum IGF-1 whereas serum FGF21 is increased by selective amino acid deprivation. Calcium (Ca) and phosphorous (P) are also key nutrients for skeletal health, and inadequate intakes reduce bone mass accrual in association with calciotropic hormone modulation. Besides, the effect of calcium supplementation on bone mass in prepubertal children appears to be influenced by protein intake. To further explore the interaction of dietary protein and Ca-P intake on bone growth, 1-month-old female rats were fed with an isocaloric 10%, 7.5%, or 5% casein diet containing normal or low Ca-P for an 8-week period (6 groups). Changes in tibia geometry, mineral content, microarchitecture, strength, and intrinsic bone quality were analyzed. At the hormonal level, serum IGF-1, fibroblast growth factor 21 (FGF21), PTH, 1,25-dihydroxyvitamin D3 (calcitriol), and FGF23 were investigated as well as the Ghr hepatic gene expression. In normal dietary Ca-P conditions, bone mineral content, trabecular and cortical bone volume, and bone strength were lower in the 5% casein group in association with a decrease in serum IGF-1 and an increase in FGF21 levels. Unexpectedly, the low-Ca P diet attenuated the 5% casein diet-related reduction of serum IGF-1 and Ghr hepatic gene expression, as well as the low-protein diet-induced decrease in bone mass and strength. However, this was associated with lower cortical bone material level properties. The low-Ca-P diet increased serum calcitriol but decreased FGF23 levels. Calcitriol levels positively correlated with Ghr hepatic mRNA levels. These results suggest that hormonal modulation in response to a low-Ca-P diet may modify the low-protein diet-induced effect on Ghr hepatic mRNA levels and consequently the impact of low protein intakes on IGF-1 circulating levels and skeletal growth. PMID- 25147978 TI - KISS1R signals independently of Galphaq/11 and triggers LH secretion via the beta arrestin pathway in the male mouse. AB - Hypothalamic GnRH is the master regulator of the neuroendocrine reproductive axis, and its secretion is regulated by many factors. Among these is kisspeptin (Kp), a potent trigger of GnRH secretion. Kp signals via the Kp receptor (KISS1R), a Galphaq/11-coupled 7-transmembrane-spanning receptor. Until this study, it was understood that KISS1R mediates GnRH secretion via the Galphaq/11 coupled pathway in an ERK1/2-dependent manner. We recently demonstrated that KISS1R also signals independently of Galphaq/11 via beta-arrestin and that this pathway also mediates ERK1/2 activation. Because GnRH secretion is ERK1/2 dependent, we hypothesized that KISS1R regulates GnRH secretion via both the Galphaq/11- and beta-arrestin-coupled pathways. To test this hypothesis, we measured LH secretion, a surrogate marker of GnRH secretion, in mice lacking either beta-arrestin-1 or beta-arrestin-2. Results revealed that Kp-dependent LH secretion was significantly diminished relative to wild-type mice (P < .001), thus supporting that beta-arrestin mediates Kp-induced GnRH secretion. Based on this, we hypothesized that Galphaq/11-uncoupled KISS1R mutants, like L148S, will display Galphaq/11-independent signaling. To test this hypothesis, L148S was expressed in HEK 293 cells. and results confirmed that, although strongly uncoupled from Galphaq/11, L148S retained the ability to trigger significant Kp dependent ERK1/2 phosphorylation (P < .05). Furthermore, using mouse embryonic fibroblasts lacking beta-arrestin-1 and -2, we demonstrated that L148S-mediated ERK1/2 phosphorylation is beta-arrestin-dependent. Overall, we conclude that KISS1R signals via Galphaq/11 and beta-arrestin to regulate GnRH secretion. This novel and important finding could explain why patients bearing some types of Galphaq/11-uncoupled KISS1R mutants display partial gonadotropic deficiency and even a reversal of the condition, idiopathic hypogonadotropic hypogonadism. PMID- 25147981 TI - Estradiol prevents fat accumulation and overcomes leptin resistance in female high-fat diet mice. AB - In premenopausal and menopausal women in particular, suboptimal estrogens have been linked to the development of the metabolic syndrome as major contributors to fat accumulation. At the same time, estrogens have been described to have a role in regulating body metabolic status. We evaluated how endogenous or administered estrogens impact on the changes associated with high-fat diet (HFD) consumption in 2 different paradigms; ovarian-intact and in ovariectomized mice. When estradiol (E2) was cyclically administered to ovarian-intact HFD-fed mice for 12 weeks, animals gained significantly less weight than ovarian-intact vehicle controls (P < .01). This difference was mainly due to a reduced caloric intake but not to an increase in energy expenditure or locomotor activity. This E2 treatment regime to mice exposed to HFD was overall able to avoid the increase of visceral fat content to levels of those found in mice fed a regular chow diet. In the ovariectomized model, the main body weight and fat content reducing action of E2 was not only through decreasing food intake but also by increasing the whole body energy expenditure, locomotor activity, and by inducing fat oxidation. Importantly, these animals became responsive to the anorexigenic effects of leptin in contrast to the vehicle-treated and the pair-fed control groups (P < .01). Further, in vitro hypothalamic secretion experiments revealed that treatment of obese mice with E2 is able to modulate the secretion of appetite regulating neuropeptides; namely, E2 increased the secretion of the anorectic neuropeptide alpha-melanocyte-stimulating hormone and decreased the secretion of the orexigenic neuropetides neuropeptide Y and Agouti-related peptide. In conclusion, differences in response to E2 treatment of HFD-fed animals depend on their endogenous estrogenic status. Overall, E2 administration overcomes arcuate leptin resistance and partially prevents fat accumulation on these mice. PMID- 25147984 TI - Health care for undocumented immigrants in Texas: past, present, and future. AB - Providing health care to the 1.6 million undocumented immigrants in Texas is an existing challenge. Despite continued growth of this vulnerable population, legislation between 1986 and 2013 has made it more difficult for states to provide adequate and cost-effective care. As this population ages and develops chronic illnesses, Texas physicians, health care administrators, and legislators will be facing a major challenge. New legislation, such as the Affordable Care Act and immigration reform, does not address or attempt to solve the issue of providing health care to this population. One example of inadequate care and poor resource allocation is the experience of undocumented immigrants with end-stage renal disease (ESRD). In Texas, these immigrants depend on safety net hospital systems for dialysis treatments. Often, treatments are provided only when their conditions become an emergency, typically at a higher cost, with worse outcomes. This article reviews the legislation regarding health care for undocumented immigrants, particularly those with chronic illnesses such as ESRD, and details specific challenges facing Texas physicians in the future. PMID- 25147980 TI - Minireview: SLCO and ABC transporters: a role for steroid transport in prostate cancer progression. AB - Androgens play a critical role in the development and progression of prostate cancer (PCa), and androgen deprivation therapy via surgical or medical castration is front-line therapy for patients with advanced PCa. However, intratumoral testosterone levels are elevated in metastases from patients with castration resistant disease, and residual intratumoral androgens have been implicated in mediating ligand-dependent mechanisms of androgen receptor activation. The source of residual tissue androgens present despite castration has not been fully elucidated, but proposed mechanisms include uptake and conversion of adrenal androgens, such as dehdroepiandrosterone to testosterone and dihydrotestosterone, or de novo androgen synthesis from cholesterol or progesterone precursors. In this minireview, we discuss the emerging evidence that suggests a role for specific transporters in mediating transport of steroids into or out of prostate cells, thereby influencing intratumoral androgen levels and PCa development and progression. We focus on the solute carrier and ATP binding cassette gene families, which have the most published data for a role in PCa-related steroid transport, and review the potential impact of genetic variation on steroid transport activity and PCa outcomes. Continued assessment of transport activity in PCa models and human tumor tissue is needed to better delineate the different roles these transporters play in physiologic and neoplastic settings, and in order to determine whether targeting the uptake of steroid substrates by specific transporters may be a clinically feasible therapeutic strategy. PMID- 25147982 TI - A humanized mouse model of hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia. AB - The syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is a genetic disease of altered mineral homeostasis due to mutations in the vitamin D receptor (VDR) gene. It is frequently, but not always, accompanied by the presence of alopecia. Mouse models that recapitulate this syndrome have been prepared through genetic deletion of the Vdr gene and are characterized by the presence of rickets and alopecia. Subsequent studies have revealed that VDR expression in hair follicle keratinocytes protects against alopecia and that this activity is independent of the protein's ability to bind 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. In the present study, we introduced into VDR-null mice a human VDR (hVDR) bacterial artificial chromosome minigene containing a mutation that converts leucine to serine at amino acid 233 in the hVDR protein, which prevents 1,25(OH)2D3 binding. We then assessed whether this transgene recreated features of the HVDRR syndrome without alopecia. RT-PCR and Western blot analysis in one strain showed an appropriate level of mutant hVDR expression in all tissues examined including skin. The hVDR-L233S mutant failed to rescue the aberrant systemic and skeletal phenotype characteristic of the VDR null mouse due to the inability of the mutant receptor to activate transcription after treatment with 1,25(OH)2D3. Importantly, however, neither alopecia nor the dermal cysts characteristic of VDR-null mice were observed in the skin of these hVDR-L233S mutant mice. This study confirms that we have created a humanized mouse model of HVDRR without alopecia that will be useful in defining additional features of this syndrome and in identifying potential novel functions of the unoccupied VDR. PMID- 25147985 TI - Vulvar inflammatory dermatoses: an update and review. AB - Currently, urogenital complaints are among the most common problems encountered by family practitioners, gynecologists, and dermatologists. In response to the intricacy of vulvar disorders, the International Society for the Study of Vulvovaginal Disease was created to facilitate the exchange between clinicians and pathologists involved in the care of these patients. Recent classifications for inflammatory disorders and intraepithelial neoplasm have been proposed. In addition, vulvar skin biopsies are the most common source of intradepartmental consultation during dermatopathology sign-out. The purpose of this article is to review the various inflammatory dermatoses of the vulva and to update readers with new advances regarding these entities. PMID- 25147986 TI - Areolar dermal nodule: challenge. PMID- 25147989 TI - Breslow thickness determined with the use of immunohistochemical techniques could provide misleading information when used with prognostic models based on data obtained by conventional means. PMID- 25147987 TI - Intravascular crystal deposition: an early clue to the diagnosis of type 1 cryoglobulinemic vasculitis. AB - Cutaneous small vessel vasculitis (CSVV) is a nonspecific finding with an extensive differential diagnosis. It is critically important to distinguish skin limited presentations of CSVV from severe life-threatening systemic vasculitides presenting with CSVV as an initial manifestation. It can be challenging to determine which patients presenting with CSVV are at risk for systemic disease. Standard histopathologic evaluation, direct immunofluorescence, and serologic evaluation is typically required to exclude a systemic vasculitis. Type 1 cryoglobulinemia may rarely present with CSVV. Herein, we report a case of type 1 cryoglobulinemia in the setting of occult multiple myeloma. CSVV with prominent intravascular crystal formation was noted. The presence of intravascular crystals in the setting of CSVV may represent an important early clue to the diagnosis of type 1 cryoglobulinemic vasculitis. PMID- 25147990 TI - Intralymphatic histiocytosis mimicking oral lymphangioma circumscriptum. PMID- 25147991 TI - Introduction: Young practitioners forum 2014--preparing for a successful career. PMID- 25147992 TI - An introduction to orthopaedic coding and billing. AB - Coding is the process of identifying descriptive terms and codes for diagnoses and medical services, which result from patient interactions with physicians and other healthcare providers. This information is organized in alpha and/or numeric fashion and may be used for charge submission, performance measurement, and data collection for emerging technology, services, and procedures. Under the Health Insurance Portability and Accountability Act, The Department of Health and Human Services designated the International classification of Diseases and Current Procedural Terminology as the national standard code sets for healthcare professional services and procedures. The purpose of this article is to summarize the most important aspects of the billing and coding process. PMID- 25147993 TI - Tips for being an effective teacher. AB - The young practitioner needs to acquire a large number of skill sets during a short transition period after starting their career as an attending surgeon. The role of a teacher is especially challenging because our clinical training and education do not emphasize the development of effective teaching. Within that context, we suggest the acquisition of educational concepts and the practice of useful action items as a start to the lifelong process of becoming a more effective teacher. PMID- 25147994 TI - Becoming the "captain of the ship" in the OR. AB - We have all been there: a screaming attending; an argument with anesthesia; a crashing patient, to name a few examples. A stressful situation in the operating room (OR) can unfortunately be a common occurrence. Many of these situations can be avoided if the team had been better prepared or had better communication. As the attending orthopaedic surgeon, YOU are the leader in the OR and the entire team looks at YOU for guidance and answers. Without your leadership, the ship will sink. Preparation, communication, and respect are essential elements that affect both patient outcomes and the atmosphere in the OR. In this article, we will highlight several pearls that will help you become and remain the best leader you can: the "Captain of the Ship." PMID- 25147995 TI - What I expect from an orthopaedic traumatology fellow. AB - After 2.5 decades working with a variety of orthopaedic traumatology fellows, I have learned that several qualities and behaviors are important to a successful experience. Most fellows possess them, but some do not. Those that do usually integrate quickly onto the team and are rewarded with enriched teaching and clinical experiences. Some that do not may be able to adjust or alter their behaviors and eventually fit in. Some cannot adjust and their experiences suffer. I realize that no 2 individuals are the same, so my expectations of a fellow serve as a relationship foundation to then build their experiences upon. Their qualities and behaviors guide our relationship. PMID- 25147996 TI - Your first job in orthopaedic trauma: strategies for your career. AB - Your first job in orthopaedic surgery is the culmination of years of training and hard work. This article will cover strategies for your first job search and your future career. We discuss job searching strategies prioritizing what is important. And once you start your first job, we discuss tips for how to make a good first impression and begin a successful career. PMID- 25147997 TI - Look before you leap. AB - The decision to leave a job can be very stressful. Multiple variables must be considered before turning in your notice. The goal of this paper is to help you decide if changing jobs is a smart decision, and, if it is, when to do it. PMID- 25147998 TI - Building your career after fellowship. AB - Once you have completed your fellowship and have started a new job, there are many competing demands for your time and attention. This article focuses on how to try and balance your work and personal life and provides some suggestions and recommendations to help one do so. Some of these are general and applicable to most life circumstances and some are specific to a particular situation. PMID- 25147999 TI - What I need to start my job: a wish list (positioning yourself for success in an academic or nonacademic environment). AB - Beginning practice as an orthopaedic traumatologist is an important event, when the groundwork is set up for the next few years of hard work. Plans must be made, resources allocated, staff hired, etc. to optimally support the newly practicing surgeon. Academic and nonacademic practice settings are possible, where the facets of practice (i.e., clinic, operating room, floor work, education, and research) may be quite different. The goal of this article is to discuss these differences between relatively academic and nonacademic practices, ultimately to allow the young orthopaedic traumatologist to form a "wish list" with which to start planning the logistics of his or her career. PMID- 25148000 TI - Improving business IQ in medicine through mentorship and education. AB - Business intelligence in the field of medicine, particularly with physicians, has been an abstract concept at best with no objective metric. Furthermore, in many arenas, it was taboo for medical students, residents, and physicians to discuss the business and finances of their work for fear that it would interfere with their sacred duties as health care providers. There has been a substantial shift in this philosophy over the last few decades with the growth and evolution of the health care industry in the United States. In 2012, health care expenditures accounted for 17.2% of the United States Gross Domestic Product, averaging $8915 per person. The passage of the Affordable Care Act in March of 2010 sent a clear message to all that change is coming, and it is more important now than ever to have physician leaders whose skills and knowledge in business, management, and health care law rival their acumen within their medical practice. Students, residents, and fellows all express a desire to gain more business knowledge throughout their education and training, but many do not know where to begin or have access to programs that can further their knowledge. Whether you are an employed or private practice physician, academic or community based, improving your business intelligence will help you get a seat at the table where decisions are made and give you the skills to influence those decisions. PMID- 25148002 TI - Synthesis of Cu or Cu2O-polyimide nanocomposites using Cu powders and their optical properties. AB - Nanocomposites consisting of Cu or Cu2O nanoparticles in various polyimide (PI) films were successfully prepared using polyamic acid (PAA) and Cu powders. Cu powders were dissolved into PAA solutions, and the solutions were spin-coated onto the substrates. Cu or Cu2O nanoparticles were formed in PI film by curing in a reducing or inert atmosphere, respectively. The Cu nanoparticles were transformed to Cu2O nanoparticles by post-heat treatment in an oxidizing atmosphere after curing in a reducing atmosphere. Transmission electron microscopy showed that uniform, round Cu2O nanoparticles 6.0 nm in diameter were dispersed in the PI film by post-heat treatment. The addition of Cu2O nanoparticles in the 4,4'-(hexafluoroisopropylidene)diphthalic anhydride-4,4' oxydianiline (6FDA-ODA) PI film enhanced the refractive index of the 6FDA-ODA PI film from 1.60 to 1.72 at 633 nm, and the transparency of the nanocomposite film was about 70-90% in the visible region and remained around 90% beyond 550 nm. PMID- 25148001 TI - Protonation states of the tryptophan synthase internal aldimine active site from solid-state NMR spectroscopy: direct observation of the protonated Schiff base linkage to pyridoxal-5'-phosphate. AB - The acid-base chemistry that drives catalysis in pyridoxal-5'-phosphate (PLP) dependent enzymes has been the subject of intense interest and investigation since the initial identification of PLP's role as a coenzyme in this extensive class of enzymes. It was first proposed over 50 years ago that the initial step in the catalytic cycle is facilitated by a protonated Schiff base form of the holoenzyme in which the linking lysine epsilon-imine nitrogen, which covalently binds the coenzyme, is protonated. Here we provide the first (15)N NMR chemical shift measurements of such a Schiff base linkage in the resting holoenzyme form, the internal aldimine state of tryptophan synthase. Double-resonance experiments confirm the assignment of the Schiff base nitrogen, and additional (13)C, (15)N, and (31)P chemical shift measurements of sites on the PLP coenzyme allow a detailed model of coenzyme protonation states to be established. PMID- 25148003 TI - Single-center experience with a dual microcatheter technique for the endovascular treatment of wide-necked aneurysms. AB - OBJECT: The endovascular treatment of wide-necked aneurysms can be technically challenging due to distal coil migration or impingement of the parent vessel. In this paper, the authors illustrate an alternative method for the treatment of wide-necked intracranial aneurysms using a dual microcatheter technique. METHODS: The authors' first 100 consecutive patients who underwent coil embolization of a wide-necked aneurysm using a dual microcatheter technique are reported. With this technique, 2 microcatheters are used to introduce coils into the aneurysm. The coils are deployed either sequentially or concurrently to form a stable construct and prevent coil herniation or migration. Angiographic and clinical outcomes are reported. RESULTS: The technical success rate of the dual microcatheter technique is 91% with a morbidity and mortality of 1% and 2%, respectively. Clinical outcomes are excellent with 93% of patients demonstrating a modified Rankin Scale score of 0-2 at long-term follow-up regardless of their score at presentation. Retreatment rates are 18%. CONCLUSIONS: The dual microcatheter technique may be a safe and efficacious first line of treatment for widenecked aneurysms. PMID- 25148004 TI - Neurosurgical management of a giant colloid cyst with atypical clinical and radiological presentation. AB - The finding of a colloid cyst on neuroimaging is often incidental. These lesions are usually located at the foramen of Monro, are hyperdense on CT scans, and generally demonstrate signal intensity of water on MR images, although this depends on their content. When symptomatic, they frequently present with headaches and nausea due to an obstructive hydrocephalus. The authors describe a case of a giant colloid cyst in a patient presenting with complete left-sided vision loss and progressive memory loss, two very atypical findings in colloid cyst presentation. Imaging findings were also atypical, and this case proved to be a diagnostic dilemma because of its clinical and radiological presentation. Histopathological investigation was of utmost importance in the final diagnosis of a colloid cyst. To the authors' knowledge this colloid cyst is larger than any other described in the literature. PMID- 25148005 TI - Letter to the editor. Pure arterial malformation of the posterior cerebral artery. PMID- 25148006 TI - Letter to the editor. Cytochemical CSF analysis and antibiotic-impregnated external ventricular drains. PMID- 25148007 TI - The stereotactic approach for mapping epileptic networks: a prospective study of 200 patients. AB - OBJECT: Stereoelectroencephalography (SEEG) is a methodology that permits accurate 3D in vivo electroclinical recordings of epileptiform activity. Among other general indications for invasive intracranial electroencephalography (EEG) monitoring, its advantages include access to deep cortical structures, its ability to localize the epileptogenic zone when subdural grids have failed to do so, and its utility in the context of possible multifocal seizure onsets with the need for bihemispheric explorations. In this context, the authors present a brief historical overview of the technique and report on their experience with 2 SEEG techniques (conventional Leksell frame-based stereotaxy and frameless stereotaxy under robotic guidance) for the purpose of invasively monitoring difficult-to localize refractory focal epilepsy. METHODS: Over a period of 4 years, the authors prospectively identified 200 patients with refractory epilepsy who collectively underwent 2663 tailored SEEG electrode implantations for invasive intracranial EEG monitoring and extraoperative mapping. The first 122 patients underwent conventional Leksell frame-based SEEG electrode placement; the remaining 78 patients underwent frameless stereotaxy under robotic guidance, following acquisition of a stereotactic ROSA robotic device at the authors' institution. Electrodes were placed according to a preimplantation hypothesis of the presumed epileptogenic zone, based on a standardized preoperative workup including video-EEG monitoring, MRI, PET, ictal SPECT, and neuropsychological assessment. Demographic features, seizure semiology, number and location of implanted SEEG electrodes, and location of the epileptogenic zone were recorded and analyzed for all patients. For patients undergoing subsequent craniotomy for resection, the type of resection and procedure-related complications were prospectively recorded. These results were analyzed and correlated with pathological diagnosis and postoperative seizure outcomes. RESULTS: The epileptogenic zone was confirmed by SEEG in 154 patients (77%), of which 134 (87%) underwent subsequent craniotomy for epileptogenic zone resection. Within this cohort, 90 patients had a minimum follow-up of at least 12 months; therein, 61 patients (67.8%) remained seizure free, with an average follow-up period of 2.4 years. The most common pathological diagnosis was focal cortical dysplasia Type I (55 patients, 61.1%). Per electrode, the surgical complications included wound infection (0.08%), hemorrhagic complications (0.08%), and a transient neurological deficit (0.04%) in a total of 5 patients (2.5%). One patient (0.5%) ultimately died due to intracerebral hematoma directly ensuing from SEEG electrode placement. CONCLUSIONS: Based on these results, SEEG methodology is safe, reliable, and effective. It is associated with minimal morbidity and mortality, and serves as a practical, minimally invasive approach to extraoperative localization of the epileptogenic zone in patients with refractory epilepsy. PMID- 25148008 TI - Results of immunohistochemical staining for cell cycle regulators predict the recurrence of atypical meningiomas. AB - OBJECT: The aim of this study was to evaluate the role of certain cell-cycle regulatory proteins in the recurrence of atypical meningiomas. These proteins were analyzed with immunohistochemical staining to identify predisposing factors for the recurrence of atypical meningiomas. METHODS: The authors retrospectively reviewed the medical records of patients with atypical meningiomas diagnosed in the period from January 2000 to June 2012 at the Department of Neurosurgery at Samsung Changwon Hospital and Dong-A University Medical Center. Clinical data included patient sex and age at the time of surgery, presenting symptoms at diagnosis, location and size of tumor, extent of surgery, use of postoperative radiotherapy, duration of follow-up, and recurrence. Immunohistochemical staining for cell-cycle regulatory proteins (p16, p15, p21, p27, cyclin-dependent kinase [CDK] 4 and 6, phosphorylated retinoblastoma [pRB] protein, and cyclin D1) and proliferative markers (MIB-1 antigen, mitosis, and p53) was performed on archived paraffin-embedded tissues obtained during resection. The recurrence rate and time to recurrence were assessed using Kaplan-Meier analysis. RESULTS: Of the 67 atypical meningiomas eligible for analysis, 26 (38.8%) recurred during the follow up period (mean duration 47.7 months, range 8.4-132.1 months). Immunohistochemically, there was overstaining for p16 in 44 samples (65.7%), for p15 in 21 samples (31.3%), for p21 in 25 samples (37.3%), for p27 in 32 samples (47.8%), for CDK4 in 38 samples (56.7%), for CDK6 in 26 samples (38.8%), for pRB protein in 42 samples (62.7%), and for cyclin D1 in 49 samples (73.1%). Multivariate analysis using the Cox proportional-hazards regression model showed that incomplete resection (HR 4.513, p < 0.001); immunohistochemical understaining for p16 (HR 3.214, p < 0.001); immunohistochemical overstaining for CDK6 (HR 3.427, p < 0.001), pRB protein (HR 2.854, p = 0.008), and p53 (HR 2.296, p = 0.040); and increased MIB-1 labeling index (HR 2.665, p = 0.013) and mitotic index (HR 2.438, p = 0.024) predicted the recurrence of atypical meningiomas after resection. CONCLUSIONS: Findings in this study indicated that p16, CDK6, and pRB protein were associated with the recurrence of atypical meningiomas. PMID- 25148009 TI - Gamma Knife surgery for incidental cerebral arteriovenous malformations. AB - OBJECT: A relatively benign natural course of unruptured cerebral arteriovenous malformations (AVMs) has recently been recognized, and the decision to treat incidentally found AVMs has been questioned. This study aims to evaluate the long term imaging and clinical outcomes of patients with asymptomatic, incidentally discovered AVMs treated with Gamma Knife surgery (GKS). METHODS: Thirty-one patients, each with an incidentally diagnosed AVM, underwent GKS between 1989 and 2009. The nidus volumes ranged from 0.3 to 11.1 cm(3) (median 3.2 cm(3)). A margin dose between 15 and 26 Gy (median 20 Gy) was used to treat the AVMs. Four patients underwent repeat GKS for still-patent AVM residuals after the initial GKS procedure. Clinical follow-up ranged from 24 to 196 months, with a mean of 78 months (median 51 months) after the initial GKS. RESULTS: Following GKS, 19 patients (61.3%) had a total AVM obliteration on angiography. In 7 patients (22.6%), no flow voids were observed on MRI but angiographic confirmation was not available. In 5 patients (16.1%), the AVMs remained patent. A small nidus volume was significantly associated with increased AVM obliteration rate. Thirteen patients (41.9%) developed radiation-induced imaging changes: 11 were asymptomatic (35.5%), 1 had only headache (3.2%), and 1 developed seizure and neurological deficits (3.2%). Two patients each had 1 hemorrhage during the latency period (116.5 risk years), yielding an annual hemorrhage rate of 1.7% before AVM obliteration. CONCLUSIONS: The decision to treat asymptomatic AVMs, and if so, which treatment approach to use, remain the subject of debate. GKS as a minimally invasive procedure appears to achieve a reasonable outcome with low procedure-related morbidity. In those patients with incidental AVMs, the benefits as well as the risks of radiosurgical intervention will only be fully defined with long-term follow-up. PMID- 25148010 TI - Correlation between magnetic resonance imaging grading and pathological grading in meningioma. AB - OBJECT: This study investigated the specific preoperative MRI features of patients with intracranial meningiomas that correlate with pathological grade and provide appropriate preoperative planning. METHODS: From 2006 to 2012, 120 patients (36 men and 84 women, age range 20-89 years) with newly diagnosed symptomatic intracranial meningiomas undergoing resection were retrospectively analyzed in terms of radiological features of preoperative MRI. There were 90 WHO Grade I and 30 WHO Grade II or III meningiomas. The relationships between MRI features and WHO histopathological grade were analyzed and scored quantitatively. RESULTS: According to the results of multivariate logistic regression analysis, age >= 75 years, indistinct tumorbrain interface, positive capsular enhancement, and heterogeneous tumor enhancement were identified factors in the prediction of advanced histopathological grade. The prediction model was quantified as a scoring scale: 2 * (age) + 5 * (tumor-brain interface) + 3 * (capsular enhancement) + 2 * (tumor enhancement). The calculated score correlated positively with the probability of high-grade meningioma. CONCLUSIONS: This scoring approach may be useful for clinicians in determining therapeutic strategy and in surgical planning for patients with intracranial meningiomas. PMID- 25148011 TI - Management of incidental cerebral AVMs in the post-ARUBA era. PMID- 25148012 TI - Controlled transient hypercapnia: a novel approach for the treatment of delayed cerebral ischemia after subarachnoid hemorrhage? AB - OBJECT: The authors undertook this study to investigate whether the physiological mechanism of cerebral blood flow (CBF) regulation by alteration of the arterial partial pressure of carbon dioxide (PaCO2) can be used to increase CBF after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: In 6 mechanically ventilated patients with poor-grade aSAH, the PaCO2 was first decreased to 30 mm Hg by modification of the respiratory rate, then gradually increased to 40, 50 and 60 mm Hg for 15 minutes each setting. Thereafter, the respirator settings were returned to baseline parameters. Intracerebral CBF measurement and brain tissue oxygen saturation (StiO2), measured by near-infrared spectroscopy (NIRS), were the primary and secondary end points. Intracranial pressure (ICP) was controlled by external ventricular drainage. RESULTS: A total of 60 interventions were performed in 6 patients. CBF decreased to 77% of baseline at a PaCO2 of 30 mm Hg and increased to 98%, 124%, and 143% at PaCO2 values of 40, 50, and 60 mm Hg, respectively. Simultaneously, StiO2 decreased to 94%, then increased to 99%, 105%, and 111% of baseline. A slightly elevated delivery rate of cerebrospinal fluid was noticed under continuous drainage. ICP remained constant. After returning to baseline respirator settings, both CBF and StiO2 remained elevated and only gradually returned to pre-hypercapnia values without a rebound effect. None of the patients developed secondary cerebral infarction. CONCLUSIONS: Gradual hypercapnia was well tolerated by poor-grade SAH patients. Both CBF and StiO2 reacted with a sustained elevation upon hypercapnia; this elevation outlasted the period of hypercapnia and only slowly returned to normal without a rebound effect. Elevations of ICP were well compensated by continuous CSF drainage. Hypercapnia may yield a therapeutic potential in this state of critical brain perfusion. Clinical trial registration no.: NCT01799525 ( ClinicalTrials.gov ). PMID- 25148013 TI - Spontaneous resolution of perforator aneurysms of the posterior circulation. AB - The authors present the cases of 3 patients with ruptured perforator aneurysms of the posterior circulation. Patients were 39, 55, and 59 years old. None of the patients had relevant past medical or family history. All presented with World Federation of Neurosurgical Societies Grade I and Fisher Grade 2 or 3 subarachnoid hemorrhage. Initial angiography results were normal. A second cerebral angiogram in each case revealed a small (< 3 mm) aneurysm of perforator arteries of the posterior circulation. Patients were successfully managed conservatively. None of the patients developed symptomatic vasospasm, rebleeding, or hydrocephaly. Control angiograms at 3 months showed spontaneous resolution of the aneurysm in all cases. Rupture of perforator aneurysms of the posterior circulation is a rare condition and it may be underdiagnosed because of limitations of imaging techniques. Treatments can lead to complications in highly functional territories and should be considered wisely, especially due to the fact that the causes and natural history of such aneurysms are unknown and spontaneous healing remains a possibility. PMID- 25148014 TI - Risk factors for severe influenza A-related pneumonia in adult cohort, Mexico, 2013-14. AB - During the 2013-14 influenza season, we assessed characteristics of 102 adults with suspected influenza pneumonia in a hospital in Mexico; most were unvaccinated. More comorbidities and severity of illness were found than for patients admitted during the 2009-10 influenza pandemic. Vaccination policies should focus on risk factors. PMID- 25148015 TI - Discovering the secondary metabolite potential encoded within entomopathogenic fungi. AB - This highlight discusses the secondary metabolite potential of the insect pathogens Metarhizium and Beauveria, including a bioinformatics analysis of secondary metabolite genes for which no products are yet identified. PMID- 25148016 TI - Unconventional intraepithelial gut T cells: the TCR says it all. AB - The intestinal epithelium harbors a large number of T cells, including TCRalphabeta cells that lack expression of CD4 and CD8alphabeta coreceptors. In this issue of Immunity, Mayans et al. (2014) and McDonald et al. (2014) shed light on the specificity and development of this enigmatic T cell population. PMID- 25148017 TI - T-bet orchestrates CD8alphaalpha IEL differentiation. AB - Very little is known about the transcription factor network that regulates the development of intestinal intraepithelial lymphocytes (IELs). In this issue of Immunity, Klose et al. (2014b) and Reis et al. (2014) demonstrate an essential role for T-bet in regulating the CD8alphaalpha IEL differentiation program. PMID- 25148018 TI - T cells are Smad'ly in love with galectin-9. AB - In this issue of Immunity, Wu et al. (2014) report that galectin-9 is required for the formation and stability of iTreg cells. Galectin-9 interacts with CD44 in association with TGF-beta receptors to drive both Foxp3 and galectin-9 expression in a positive-feedforward loop involving Smad3 activation. PMID- 25148019 TI - MHC-II: a mutual support system for ILCs and T cells? AB - Innate and adaptive immune cells form an ongoing partnership during an immune response. In this issue of Immunity, Oliphant et al. (2014) show that MHC class II-peptide presentation by group 2 innate lymphoid cells is needed for reciprocal regulation of both cell types, resulting in effective antihelminth immunity. PMID- 25148020 TI - "Nuts and bolts" of disease tolerance. AB - Disease tolerance describes the ability of an infected host to limit disease severity without negatively impacting the causative pathogen. Bessede et al. (2014) show that the aryl hydrocarbon receptor is an essential component of disease tolerance during bacterial infection in mice. PMID- 25148021 TI - The primordial thymus: everything you need under one roof. AB - Lymphocytes normally develop within anatomically distinct tissues. In Cell Reports, Swann et al. (2014) reconstruct the primordial thymus and suggest that it was a site of combined T and B lymphopoiesis before evolving into an organ specialized for T cell production. PMID- 25148023 TI - GATA-3 function in innate and adaptive immunity. AB - The zinc-finger transcription factor GATA-3 has received much attention as a master regulator of T helper 2 (Th2) cell differentiation, during which it controls interleukin-4 (IL-4), IL-5, and IL-13 expression. More recently, GATA-3 was shown to contribute to type 2 immunity through regulation of group 2 innate lymphoid cell (ILC2) development and function. Furthermore, during thymopoiesis, GATA-3 represses B cell potential in early T cell precursors, activates TCR signaling in pre-T cells, and promotes the CD4(+) T cell lineage after positive selection. GATA-3 also functions outside the thymus in hematopoietic stem cells, regulatory T cells, CD8(+) T cells, thymic natural killer cells, and ILC precursors. Here we discuss the varied functions of GATA-3 in innate and adaptive immune cells, with emphasis on its activity in T cells and ILCs, and examine the mechanistic basis for the dose-dependent, developmental-stage- and cell-lineage specific activity of this transcription factor. PMID- 25148022 TI - Revisiting thymic positive selection and the mature T cell repertoire for antigen. AB - To support effective host defense, the T cell repertoire must balance breadth of recognition with sensitivity for antigen. The concept that T lymphocytes are positively selected in the thymus is well established, but how this selection achieves such a repertoire has not been resolved. Here we suggest that it is direct linkage between self and foreign antigen recognition that produces the necessary blend of TCR diversity and specificity in the mature peripheral repertoire, enabling responses to a broad universe of unpredictable antigens while maintaining an adequate number of highly sensitive T cells in a population of limited size. Our analysis also helps to explain how diversity and frequency of antigen-reactive cells in a T cell repertoire are adjusted in animals of vastly different size scale to enable effective antipathogen responses and suggests a possible binary architecture in the TCR repertoire that is divided between germline-related optimal binding and diverse recognition. PMID- 25148024 TI - The transcription factor T-bet is induced by IL-15 and thymic agonist selection and controls CD8alphaalpha(+) intraepithelial lymphocyte development. AB - CD8alphaalpha(+) intraepithelial lymphocytes (IELs) are instrumental in maintaining the epithelial barrier in the intestine. Similar to natural killer cells and other innate lymphoid cells, CD8alphaalpha(+) IELs constitutively express the T-box transcription factor T-bet. However, the precise role of T-bet for the differentiation or function of IELs is unknown. Here we show that mice genetically deficient for T-bet lacked both TCRalphabeta(+) and TCRgammadelta(+) CD8alphaalpha(+) IELs and thus are more susceptible to chemically induced colitis. Although T-bet was induced in thymic IEL precursors (IELPs) as a result of agonist selection and interleukin-15 (IL-15) receptor signaling, it was dispensable for the generation of IELPs. Subsequently, T-bet was required for the IL-15-dependent activation, differentiation, and expansion of IELPs in the periphery. Our study reveals a function of T-bet as a central transcriptional regulator linking agonist selection and IL-15 signaling with the emergence of CD8alphaalpha(+) IELs. PMID- 25148025 TI - Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation. AB - The intestinal epithelium harbors large populations of activated and memory lymphocytes, yet these cells do not cause tissue damage in the steady state. We investigated how intestinal T cell effector differentiation is regulated upon migration to the intestinal epithelium. Using gene loss- and gain-of-function strategies, as well as reporter approaches, we showed that cooperation between the transcription factors T-bet and Runx3 resulted in suppression of conventional CD4(+) T helper functions and induction of an intraepithelial lymphocyte (IEL) program that included expression of IEL markers such as CD8alphaalpha homodimers. Interferon-gamma sensing and T-bet expression by CD4(+) T cells were both required for this program, which was distinct from conventional T helper differentiation but shared by other IEL populations, including TCRalphabeta(+)CD8alphaalpha(+) IELs. We conclude that the gut environment provides cues for IEL maturation through the interplay between T-bet and Runx3, allowing tissue-specific adaptation of mature T lymphocytes. PMID- 25148026 TI - Adult thymus contains FoxN1(-) epithelial stem cells that are bipotent for medullary and cortical thymic epithelial lineages. AB - Within the thymus, two major thymic epithelial cell (TEC) subsets-cortical and medullary TECs-provide unique structural and functional niches for T cell development and establishment of central tolerance. Both lineages are believed to originate from a common progenitor cell, yet the cellular and molecular identity of these bipotent TEC progenitors/stem cells remains ill defined. Here we identify rare stromal cells in the murine adult thymus, which under low attachment conditions formed spheres (termed "thymospheres"). These thymosphere forming cells (TSFCs) displayed the stemness features of being slow cycling, self renewing, and bipotent. TSFCs could be significantly enriched based on their distinct surface antigen phenotype. The FoxN1 transcription factor was dispensable for TSFCs maintenance in situ and for commitment to the medullary and cortical TEC lineages. In summary, this study presents the characterization of the adult thymic epithelial stem cells and demonstrates the dispensability of FoxN1 function for their stemness. PMID- 25148028 TI - Barrier island morphology and sediment characteristics affect the recovery of dune building grasses following storm-induced overwash. AB - Barrier islands are complex and dynamic systems that provide critical ecosystem services to coastal populations. Stability of these systems is threatened by rising sea level and the potential for coastal storms to increase in frequency and intensity. Recovery of dune-building grasses following storms is an important process that promotes topographic heterogeneity and long-term stability of barrier islands, yet factors that drive dune recovery are poorly understood. We examined vegetation recovery in overwash zones on two geomorphically distinct (undisturbed vs. frequently overwashed) barrier islands on the Virginia coast, USA. We hypothesized that vegetation recovery in overwash zones would be driven primarily by environmental characteristics, especially elevation and beach width. We sampled species composition and environmental characteristics along a continuum of disturbance from active overwash zones to relict overwash zones and in adjacent undisturbed environments. We compared species assemblages along the disturbance chronosequence and between islands and we analyzed species composition data and environmental measurements with Canonical Correspondence Analysis to link community composition with environmental characteristics. Recovering and geomorphically stable dunes were dominated by Ammophila breviligulata Fernaud (Poaceae) on both islands while active overwash zones were dominated by Spartina patens (Aiton) Muhl. (Poaceae) on the frequently disturbed island and bare sand on the less disturbed island. Species composition was associated with environmental characteristics only on the frequently disturbed island (p = 0.005) where A. breviligulata was associated with higher elevation and greater beach width. Spartina patens, the second most abundant species, was associated with larger sediment grain size and greater sediment size distribution. On the less frequently disturbed island, time since disturbance was the only factor that affected community composition. Thus, factors driving the abundance of dune-building grasses and subsequent recovery of dunes varied between the two geomorphically distinct islands. PMID- 25148030 TI - Review of text-T lymphocytes in the liver. PMID- 25148027 TI - In vivo RNA interference screens identify regulators of antiviral CD4(+) and CD8(+) T cell differentiation. AB - Classical genetic approaches to examine the requirements of genes for T cell differentiation during infection are time consuming. Here we developed a pooled approach to screen 30-100+ genes individually in separate antigen-specific T cells during infection using short hairpin RNAs in a microRNA context (shRNAmir). Independent screens using T cell receptor (TCR)-transgenic CD4(+) and CD8(+) T cells responding to lymphocytic choriomeningitis virus (LCMV) identified multiple genes that regulated development of follicular helper (Tfh) and T helper 1 (Th1) cells, and short-lived effector and memory precursor cytotoxic T lymphocytes (CTLs). Both screens revealed roles for the positive transcription elongation factor (P-TEFb) component Cyclin T1 (Ccnt1). Inhibiting expression of Cyclin T1, or its catalytic partner Cdk9, impaired development of Th1 cells and protective short-lived effector CTL and enhanced Tfh cell and memory precursor CTL formation in vivo. This pooled shRNA screening approach should have utility in numerous immunological studies. PMID- 25148029 TI - Generation and characterisation of novel pancreatic adenocarcinoma xenograft models and corresponding primary cell lines. AB - Pancreatic adenocarcinoma is one of the most lethal cancer types, currently lacking efficient treatment. The heterogeneous nature of these tumours are poorly represented by the classical pancreatic cell lines, which have been through strong clonal selection in vitro, and are often derived from metastases. Here, we describe the establishment of novel pancreatic adenocarcinoma models, xenografts and corresponding in vitro cell lines, from primary pancreatic tumours. The morphology, differentiation grade and gene expression pattern of the xenografts resemble the original tumours well. The cell lines were analysed for colony forming capacity, tumourigenicity and expression of known cancer cell surface markers and cancer stem-like characteristics. These primary cell models will be valuable tools for biological and preclinical studies for this devastating disease. PMID- 25148031 TI - DNA binding properties of the small cascade subunit Csa5. AB - CRISPR-Cas systems provide immunity against viral attacks in archaeal and bacterial cells. Type I systems employ a Cas protein complex termed Cascade, which utilizes small CRISPR RNAs to detect and degrade the exogenic DNA. A small sequence motif, the PAM, marks the foreign substrates. Previously, a recombinant type I-A Cascade complex from the archaeon Thermoproteus tenax was shown to target and degrade DNA in vitro, dependent on a native PAM sequence. Here, we present the biochemical analysis of the small subunit, Csa5, of this Cascade complex. T. tenax Csa5 preferentially bound ssDNA and mutants that showed decreased ssDNA-binding and reduced Cascade-mediated DNA cleavage were identified. Csa5 oligomerization prevented DNA binding. Specific recognition of the PAM sequence was not observed. Phylogenetic analyses identified Csa5 as a universal member of type I-A systems and revealed three distinct groups. A potential role of Csa5 in R-loop stabilization is discussed. PMID- 25148032 TI - UPLC/Q-TOF MS-based metabolomics and qRT-PCR in enzyme gene screening with key role in triterpenoid saponin biosynthesis of Polygala tenuifolia. AB - BACKGROUND: The dried root of Polygala tenuifolia, named Radix Polygalae, is a well-known traditional Chinese medicine. Triterpenoid saponins are some of the most important components of Radix Polygalae extracts and are widely studied because of their valuable pharmacological properties. However, the relationship between gene expression and triterpenoid saponin biosynthesis in P. tenuifolia is unclear. METHODOLOGY/FINDINGS: In this study, ultra-performance liquid chromatography (UPLC) coupled with quadrupole time-of-flight mass spectrometry (Q TOF MS)-based metabolomic analysis was performed to identify and quantify the different chemical constituents of the roots, stems, leaves, and seeds of P. tenuifolia. A total of 22 marker compounds (VIP>1) were explored, and significant differences in all 7 triterpenoid saponins among the different tissues were found. We also observed an efficient reference gene GAPDH for different tissues in this plant and determined the expression level of some genes in the triterpenoid saponin biosynthetic pathway. Results showed that MVA pathway has more important functions in the triterpenoid saponin biosynthesis of P. tenuifolia. The expression levels of squalene synthase (SQS), squalene monooxygenase (SQE), and beta-amyrin synthase (beta-AS) were highly correlated with the peak area intensity of triterpenoid saponins compared with data from UPLC/Q-TOF MS-based metabolomic analysis. CONCLUSIONS/SIGNIFICANCE: This finding suggested that a combination of UPLC/Q-TOF MS-based metabolomics and gene expression analysis can effectively elucidate the mechanism of triterpenoid saponin biosynthesis and can provide useful information on gene discovery. These findings can serve as a reference for using the overexpression of genes encoding for SQS, SQE, and/or beta-AS to increase the triterpenoid saponin production of P. tenuifolia. PMID- 25148033 TI - The differential expression of EphB2 and EphB4 receptor kinases in normal bladder and in transitional cell carcinoma of the bladder. AB - Effective treatment of transitional cell carcinoma (TCC) of the bladder requires early diagnosis. Identifying novel molecular markers in TCC would guide the development of diagnostic and therapeutic targets. Ephrins mediate signals via tyrosine kinase activity that modulates diverse physiologic and developmental processes, and ephrins are increasingly implicated in carcinogenesis. The aim of our study was to examine the differential regulation of EphB4 and EphB2 in normal bladder and in TCC of the bladder in 40 patients undergoing radical cystectomy for curative intent. Immunostaining and Western blotting revealed that normal urothelium expresses EphB2 (20 of 24 cases, 83% of the time) not EphB4 (0 of 24 cases, 0%). In sharp contrast, TCC specimens show loss of EphB2 expression (0 of 34 cases, 0%) and gain of EphB4 expression (32 of 34, 94%). Furthermore, EphB4 signal strength statistically correlated with higher tumor stage, and trended toward the presence of carcinoma in situ (CIS). These results are confirmed by analysis of normal urothelial and tumor cell lines. EphB2 is not a survival factor in normal urothelium, while EphB4 is a survival factor in TCC. Treatment of bladder tumor xenograft with an EphB4 inhibitor sEphB4-HSA leads to 62% tumor regression and complete remission when combined with Bevacizumab. Furthermore, tissue analysis revealed that sEphB4-HSA led to increased apoptosis, decreased proliferation, and reduced vessel density, implicating direct tumor cell targeting as well as anti-angiogenesis effect. In summary loss of EphB2 and gain of EphB4 expression represents an inflection point in the development, growth and possibly progression of TCC. Therapeutic compounds targeting EphB4 have potential for diagnosing and treating TCC. PMID- 25148034 TI - Preference for women's body mass and waist-to-hip ratio in Tsimane' men of the Bolivian Amazon: biological and cultural determinants. AB - The issue of cultural universality of waist-to-hip ratio (WHR) attractiveness in women is currently under debate. We tested men's preferences for female WHR in traditional society of Tsimane'(Native Amazonians) of the Bolivian rainforest (N = 66). Previous studies showed preferences for high WHR in traditional populations, but they did not control for the women's body mass.We used a method of stimulus creation that enabled us to overcome this problem. We found that WHR lower than the average WHR in the population is preferred independent of cultural conditions. Our participants preferred the silhouettes of low WHR, but high body mass index (BMI), which might suggest that previous results could be an artifact related to employed stimuli. We found also that preferences for female BMI are changeable and depend on environmental conditions and probably acculturation (distance from the city). Interestingly, the Tsimane' men did not associate female WHR with age, health, physical strength or fertility. This suggests that men do not have to be aware of the benefits associated with certain body proportions - an issue that requires further investigation. PMID- 25148036 TI - Comparison of soil quality index using three methods. AB - Assessment of management-induced changes in soil quality is important to sustaining high crop yield. A large diversity of cultivated soils necessitate identification development of an appropriate soil quality index (SQI) based on relative soil properties and crop yield. Whereas numerous attempts have been made to estimate SQI for major soils across the World, there is no standard method established and thus, a strong need exists for developing a user-friendly and credible SQI through comparison of various available methods. Therefore, the objective of this article is to compare three widely used methods to estimate SQI using the data collected from 72 soil samples from three on-farm study sites in Ohio. Additionally, challenge lies in establishing a correlation between crop yield versus SQI calculated either depth wise or in combination of soil layers as standard methodology is not yet available and was not given much attention to date. Predominant soils of the study included one organic (Mc), and two mineral (CrB, Ko) soils. Three methods used to estimate SQI were: (i) simple additive SQI (SQI-1), (ii) weighted additive SQI (SQI-2), and (iii) statistically modeled SQI (SQI-3) based on principal component analysis (PCA). The SQI varied between treatments and soil types and ranged between 0-0.9 (1 being the maximum SQI). In general, SQIs did not significantly differ at depths under any method suggesting that soil quality did not significantly differ for different depths at the studied sites. Additionally, data indicate that SQI-3 was most strongly correlated with crop yield, the correlation coefficient ranged between 0.74-0.78. All three SQIs were significantly correlated (r = 0.92-0.97) to each other and with crop yield (r = 0.65-0.79). Separate analyses by crop variety revealed that correlation was low indicating that some key aspects of soil quality related to crop response are important requirements for estimating SQI. PMID- 25148037 TI - Group colocation behavior in technological social networks. AB - We analyze two large datasets from technological networks with location and social data: user location records from an online location-based social networking service, and anonymized telecommunications data from a European cellphone operator, in order to investigate the differences between individual and group behavior with respect to physical location. We discover agreements between the two datasets: firstly, that individuals are more likely to meet with one friend at a place they have not visited before, but tend to meet at familiar locations when with a larger group. We also find that groups of individuals are more likely to meet at places that their other friends have visited, and that the type of a place strongly affects the propensity for groups to meet there. These differences between group and solo mobility has potential technological applications, for example, in venue recommendation in location-based social networks. PMID- 25148038 TI - Development and efficacy of real-time PCR in the diagnosis of vivax malaria using field samples in the Republic of Korea. AB - The development of sensitive, rapid, and accurate diagnostic methods for vivax malaria is essential for the effective control of malaria in the Republic of Korea, where vivax malaria patients usually show low parasitemia. In this study, a TaqMan-based real-time polymerase chain reaction (PCR) method was established and compared with other PCR-based assays, including nested PCR, loop-mediated isothermal amplification, and multiplex PCR, using samples from febrile patients with suspected vivax malaria. The established real-time PCR had a high sensitivity (99.6%) and specificity (100%). Therefore, this sensitive, specific, rapid, and quantitative real-time PCR method could be used for the routine diagnosis of vivax malaria in the laboratory of the Korea National Institute of Health. PMID- 25148039 TI - Steller sex: infidelity and sexual selection in a social Corvid (Cyanocitta stelleri). AB - Genetic analysis of avian mating systems has revealed that more than 70% of monogamous species show incidence of offspring parentage that does not match the social partner. Extra-pair parentage (EPP) has been linked to a variety of factors, including size and symmetry of ornamental traits, coloration, resource availability, and local conspecific density. We examined how ornamental plumage traits of individual Steller's jays (Cyanocitta stelleri) and territory characteristics influence genetic fidelity of socially monogamous pairs. We used seven highly polymorphic microsatellite markers to assign paternity to 79 offspring, and identified 12 (15.2%) as extra-pair young (EPY). Steller's jays with extra-pair young had significantly lower values of feather brightness and hue, indicating more ultraviolet-blue shifted coloration, and nested in closer proximity to the forest edge than Steller's jays with no detected EPY. Body size, crest height, asymmetry of ornamental crest stripes, as well as vegetative composition of territories and their proximity to supplemental feeders appeared to have little relationship to EPP. These results indicate that extra-pair parentage plays a role in the evolution of secondary sexual characteristics in both sexes, and suggest local density and availability of resources may influence Steller's jay mating dynamics. PMID- 25148040 TI - Intermittent hypoxia effect on osteoclastogenesis stimulated by neuroblastoma cells. AB - BACKGROUND: Neuroblastoma is the most common extracranial pediatric solid tumor. Intermittent hypoxia, which is characterized by cyclic periods of hypoxia and reoxygenation, has been shown to positively modulate tumor development and thereby induce tumor growth, angiogenic processes, and metastasis. Bone is one of the target organs of metastasis in advanced neuroblastoma Neuroblastoma cells produce osteoclast-activating factors that increase bone resorption by the osteoclasts. The present study focuses on how intermittent hypoxia preconditioned SH-SY5Y neuroblastoma cells modulate osteoclastogenesis in RAW 264.7 cells compared with neuroblastoma cells grown at normoxic conditions. METHODS: We inhibited HIF-1alpha and HIF-2alpha in neuroblastoma SH-SY5Y cells by siRNA/shRNA approaches. Protein expression of HIF-1alpha, HIF-2alpha and MAPKs were investigated by western blotting. Expression of osteoclastogenic factors were determined by real-time RT-PCR. The influence of intermittent hypoxia and HIF 1alpha siRNA on migration of neuroblastoma cells and in vitro differentiation of RAW 264.7 cells were assessed. Intratibial injection was performed with SH-SY5Y stable luciferase-expressing cells and in vivo bioluminescence imaging was used in the analysis of tumor growth in bone. RESULTS: Upregulation of mRNAs of osteoclastogenic factors VEGF and RANKL was observed in intermittent hypoxia exposed neuroblastoma cells. Conditioned medium from the intermittent hypoxia exposed neuroblastoma cells was found to enhance osteoclastogenesis, up-regulate the mRNAs of osteoclast marker genes including TRAP, CaSR and cathepsin K and induce the activation of ERK, JNK, and p38 in RAW 264.7 cells. Intermittent hypoxia-exposed neuroblastoma cells showed an increased migratory pattern compared with the parental cells. A significant increase of tumor volume was found in animals that received the intermittent hypoxia-exposed cells intratibially compared with parental cells. CONCLUSIONS: Intermittent hypoxic exposure enhanced capabilities of neuroblastoma cells in induction of osteoclast differentiation in RAW 264.7 cells. Increased migration and intratibial tumor growth was observed in intermittent hypoxia-exposed neuroblastoma cells compared with parental cells. PMID- 25148042 TI - Optogenetic recruitment of dorsal raphe serotonergic neurons acutely decreases mechanosensory responsivity in behaving mice. AB - The inhibition of sensory responsivity is considered a core serotonin function, yet this hypothesis lacks direct support due to methodological obstacles. We adapted an optogenetic approach to induce acute, robust and specific firing of dorsal raphe serotonergic neurons. In vitro, the responsiveness of individual dorsal raphe serotonergic neurons to trains of light pulses varied with frequency and intensity as well as between cells, and the photostimulation protocol was therefore adjusted to maximize their overall output rate. In vivo, the photoactivation of dorsal raphe serotonergic neurons gave rise to a prominent light-evoked field response that displayed some sensitivity to a 5-HT1A agonist, consistent with autoreceptor inhibition of raphe neurons. In behaving mice, the photostimulation of dorsal raphe serotonergic neurons produced a rapid and reversible decrease in the animals' responses to plantar stimulation, providing a new level of evidence that serotonin gates sensory-driven responses. PMID- 25148044 TI - Pharmacophore and docking-based virtual screening approach for the design of new dual inhibitors of Janus kinase 1 and Janus kinase 2. AB - Janus kinase 1 and 2, non-receptor protein tyrosine kinases, are implicated in various cancerous diseases. Involvement of these two enzymes in the pathways that stimulate cell proliferation in cancerous conditions makes them potential therapeutic targets for designing new dual-targeted agents for the treatment of cancer. In the present study, two separate pharmacophore models were developed and the best models for JAK1 (AAADH.25) and JAK2 (ADRR.92) were selected on the basis of their external predictive ability. Both models were subjected to a systematic virtual screening (VS) protocol using a PHASE database of 1.5 million molecules. The hits retrieved in VS were investigated for ADME properties to avoid selection of molecules with a poor pharmacokinetic profile. The molecules considered to be within the range of acceptable limits of ADME properties were further employed for docking simulations with JAK1 and JAK2 proteins to explore the final hits that possess structural features of both pharmacophore models as well as display essential interactions with both of them. Thus, the new molecules obtained in this way should show inhibitory activity against JAK1 and JAK2 and may serve as novel therapeutic agents for the treatment of cancerous disease conditions. PMID- 25148043 TI - Standing at the gateway to Europe--the genetic structure of Western balkan populations based on autosomal and haploid markers. AB - Contemporary inhabitants of the Balkan Peninsula belong to several ethnic groups of diverse cultural background. In this study, three ethnic groups from Bosnia and Herzegovina - Bosniacs, Bosnian Croats and Bosnian Serbs - as well as the populations of Serbians, Croatians, Macedonians from the former Yugoslav Republic of Macedonia, Montenegrins and Kosovars have been characterized for the genetic variation of 660 000 genome-wide autosomal single nucleotide polymorphisms and for haploid markers. New autosomal data of the 70 individuals together with previously published data of 20 individuals from the populations of the Western Balkan region in a context of 695 samples of global range have been analysed. Comparison of the variation data of autosomal and haploid lineages of the studied Western Balkan populations reveals a concordance of the data in both sets and the genetic uniformity of the studied populations, especially of Western South-Slavic speakers. The genetic variation of Western Balkan populations reveals the continuity between the Middle East and Europe via the Balkan region and supports the scenario that one of the major routes of ancient gene flows and admixture went through the Balkan Peninsula. PMID- 25148046 TI - Application of genomic SSR locus polymorphisms on the identification and classification of chrysanthemum cultivars in China. AB - The Chinese traditional chrysanthemum is a notable group of chrysanthemums (Chrysanthemum*morifolium Ramat.) in which the phenotypic characteristics richly vary. At present, there is a serious controversy regarding homonyms and synonyms within this group. Moreover, the current international chrysanthemum classification systems are not comprehensive enough to be used on Chinese traditional chrysanthemums. Thus, we first identified a broad collection of 480 Chinese traditional chrysanthemum cultivars using the unique DNA fingerprints and molecular identities that were established by 20 simple sequence repeat markers. Five loci, which distinguished all of the selected cultivars, were identified as the core loci to establish unique fingerprints and molecular identities with 19 denary digits for each cultivar. A cluster analysis based on Nei's genetic distance indicated that the selected cultivars were clustered according to their horticultural classification. Population structure analysis was subsequently performed with K values ranging from 2 to 14, and the most likely estimate for the population structure was ten subpopulations, which was nearly consistent with the clustering result. Principal component analysis was further performed to verify the classification results. On the basis of the Q-matrices of K = 10, a total of 19 traits were found to be associated with 42 markers. Taken together, these results can serve as starting points for the identification and classification of chrysanthemums based on the polymorphism of microsatellite markers, which is beneficial to promote the marker-assisted breeding and international communication of this marvelous crop. PMID- 25148045 TI - A retrospective review of the prognostic value of ALDH-1, Bmi-1 and Nanog stem cell markers in esophageal squamous cell carcinoma. AB - Stem cell markers are upregulated in various cancers and have potential as prognostic indicators. The objective of this study was to determine the expression of three stem cell markers, aldehyde dehydrogenase 1 (ALDH-1), B cell specific Moloney murine leukemia virus integration site 1 (Bmi-1), and Nanog, in esophageal squamous cell carcinoma (ESCC) tissues. Immunohistochemistry was used to measure the expression of ALDH-1, Bmi-1, and Nanog in ESCC tissues from 41 patients who received pre-operative chemoradiation. We evaluated the relationship between expression of these markers, and clinicopathological features, tumor regression grade (TRG), and 5-year overall survival (OS). There were no significant associations of ALDH-1 or Bmi-1 expression with age, gender, clinical stage, and treatments (p>0.05). However, patients with Nanog-positive tumors were significantly older than those whose tumors were Nanog-negative (p = 0.033). TRG after treatment was significantly associated with expression of ALDH-1 (p = 0.001), Bmi-1 (p = 0.004), and Nanog (p<0.001). Although OS was significantly better in patients with low TRGs (p = 0.001), there were no significant correlations between ALDH-1, Bmi-1, or Nanog with OS. Expression of ALDH-1, Bmi 1, and Nanog correlated with TRG, but not OS. Further large studies are necessary to fully elucidate the prognostic value of these stem cell markers for ESCC patients. PMID- 25148047 TI - Electrosprayed molybdenum trioxide aqueous solution and its application in organic photovoltaic cells. AB - A molybdenum trioxide thin film with smooth surface and uniform thickness was successfully achieved by an electrospray deposition method using an aqueous solution with a drastically low concentration of 0.05 wt%. Previous papers demonstrated that an additive solvent technique is useful for depositing the thin film by the electrospray deposition, and the high vapor pressure and a low surface tension of an additive solvent were found to be important factors. As a result, the smooth molybdenum trioxide thin film was obtained when the acetonitrile was used as the additive solvent. Furthermore, the vapor pressure of acetone is much higher than that of aqueous solution, and this indicates that the acetone is easily evaporated after spraying from the glass capillary. By optimizing a concentration of acetone in the molybdenum aqueous solution, a minimum root mean square roughness of the MoO3 thin film became 3.7 nm. In addition, an organic photovoltaic cell was also demonstrated using the molybdenum trioxide as a hole transport layer. Highest photoconversion efficiency was 1.72%, a value comparable to that using conventional thermal evaporation process even though the aqueous solution was used for the solution process. The photovonversion efficiency was not an optimized value, and the higher value can be achieved by optimizing the coating condition of the active layer. PMID- 25148048 TI - The association between nonylphenols and sexual hormones levels among pregnant women: a cohort study in Taiwan. AB - BACKGROUND: Nonylphenol (NP) has been proven as an endocrine disrupter and had the ability to interfere with the endocrine system. Though the health effects of NP on pregnant women and their fetuses are sustained, these negative associations related to the mechanisms of regulation for estrogen during pregnancy need to be further clarified. The objective of this study is to explore the association between maternal NP and hormonal levels, such as estradiol, testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and progesterone. METHODS: A pregnant women cohort was established in North Taiwan between March and December 2010. Maternal urine and blood samples from the first, second, and third trimesters of gestation were collected. Urinary NP concentration was measured by high-performance liquid chromatography coupled with fluorescent detection. A mixed-effects model using a generalised estimating equation (GEE) was applied to assess the associations between maternal NP concentration and plasma hormones throughout the three trimesters. RESULTS: In total, 162 singleton pregnant women completed this study through delivery. The geometric mean of creatinine-adjusted urinary NP concentrations were 4.27, 4.21, and 4.10 ug/g cre. in the first, second, and third trimesters respectively. A natural log-transformation of urinary NP concentrations were significantly associated with LH in the GEE model (beta = -0.23 mIU/ml, p<0.01). CONCLUSION: This perspective cohort study demonstrates that negative association occurs between maternal NP exposure and plasma LH levels. The estrogen-mimic effect of NP might influence the negative feedback on LH during pregnancy. PMID- 25148050 TI - A multiple-SNP approach for genome-wide association study of milk production traits in Chinese Holstein cattle. AB - The multiple-SNP analysis has been studied by many researchers, in which the effects of multiple SNPs are simultaneously estimated and tested in a multiple linear regression. The multiple-SNP association analysis usually has higher power and lower false-positive rate for detecting causative SNP(s) than single marker analysis (SMA). Several methods have been proposed to simultaneously estimate and test multiple SNP effects. In this research, a fast method called MEML (Mixed model based Expectation-Maximization Lasso algorithm) was developed for simultaneously estimate of multiple SNP effects. An improved Lasso prior was assigned to SNP effects which were estimated by searching the maximum joint posterior mode. The residual polygenic effect was included in the model to absorb many tiny SNP effects, which is treated as missing data in our EM algorithm. A series of simulation experiments were conducted to validate the proposed method, and the results showed that compared with SMMA, the new method can dramatically decrease the false-positive rate. The new method was also applied to the 50k SNP panel dataset for genome-wide association study of milk production traits in Chinese Holstein cattle. Totally, 39 significant SNPs and their nearby 25 genes were found. The number of significant SNPs is remarkably fewer than that by SMMA which found 105 significant SNPs. Among 39 significant SNPs, 8 were also found by SMMA and several well-known QTLs or genes were confirmed again; furthermore, we also got some positional candidate gene with potential function of effecting milk production traits. These novel findings in our research should be valuable for further investigation. PMID- 25148049 TI - The effect of azithromycin in adults with stable neutrophilic COPD: a double blind randomised, placebo controlled trial. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a progressive airway disease characterised by neutrophilic airway inflammation or bronchitis. Neutrophilic bronchitis is associated with both bacterial colonisation and lung function decline and is common in exacerbations of COPD. Despite current available therapies to control inflammation, neutrophilic bronchitis remains common. This study tested the hypothesis that azithromycin treatment, as an add on to standard medication, would significantly reduce airway neutrophil and neutrophils chemokine (CXCL8) levels, as well as bacterial load. We conducted a randomised, double-blind, placebo-controlled study in COPD participants with stable neutrophilic bronchitis. METHODS: Eligible participants (n = 30) were randomised to azithromycin 250 mg daily or placebo for 12 weeks in addition to their standard respiratory medications. Sputum was induced at screening, randomisation and monthly for a 12 week treatment period and processed for differential cell counts, CXCL8 and neutrophil elastase assessment. Quantitative bacteriology was assessed in sputum samples at randomisation and the end of treatment visit. Severe exacerbations where symptoms increased requiring unscheduled treatment were recorded during the 12 week treatment period and for 14 weeks following treatment. A sub-group of participants underwent chest computed tomography scans (n = 15). RESULTS: Nine participants with neutrophilic bronchitis had a potentially pathogenic bacteria isolated and the median total bacterial load of all participants was 5.22*107 cfu/mL. Azithromycin treatment resulted in a non-significant reduction in sputum neutrophil proportion, CXCL8 levels and bacterial load. The mean severe exacerbation rate was 0.33 per person per 26 weeks in the azithromycin group compared to 0.93 exacerbations per person in the placebo group (incidence rate ratio (95%CI): 0.37 (0.11,1.21), p = 0.062). For participants who underwent chest CT scans, no alterations were observed. CONCLUSIONS: In stable COPD with neutrophilic bronchitis, add-on azithromycin therapy showed a trend to reduced severe exacerbations sputum neutrophils, CXCL8 levels and bacterial load. Future studies with a larger sample size are warranted. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609000259246. PMID- 25148051 TI - Hepatitis B vaccination in chronic kidney disease patients: a call for novel vaccines. AB - The protective immunization rates in response to hepatitis B vaccination in chronic kidney disease (CKD) patients are lower than response rates in the general population because of genetic and CKD-related factors as well as logistic problems with a proper providing of the recommended vaccination schedules. This review focuses on third-generation vaccines and adjuvanted vaccines commercially introduced in some countries, investigated in clinical trials, especially involving CKD patients or used only in the experimental studies. In order to improve the immunization rate, the use of third-generation vaccines (yeast derived pre-S2/S HBV vaccines, mammalian cell-derived pre-S2/S HBV vaccines, mammalian cell-derived pre-S1/pre-S2/S HBV vaccines), novel adjuvants (AS04, AS02, phosphorothioate oligodeoxyribonucleotide, hemokinin-1, a polysaccharide based on delta inulin, nano-complex Hep-c, cyclic diguanylate) or immunostimulants for enhancement of immunogenicity of existing recombinant hepatitis B vaccines is tried to improve results of hepatitis B vaccination prior to dialysis commencement or already on renal replacement therapy. PMID- 25148053 TI - Super-resolution study of polymer mobility fluctuations near c*. AB - Nanoscale dynamic heterogeneities in synthetic polymer solutions are detected using super-resolution optical microscopy. To this end, we map concentration fluctuations in polystyrene-toluene solutions with spatial resolution below the diffraction limit, focusing on critical fluctuations near the polymer overlap concentration, c*. Two-photon super-resolution microscopy was adapted to be applicable in an organic solvent, and a home-built STED-FCS system with stimulated emission depletion (STED) was used to perform fluorescence correlation spectroscopy (FCS). The polystyrene serving as the tracer probe (670 kg mol(-1), radius of gyration RG ~ 35 nm, end-labeled with a bodipy derivative chromophore) was dissolved in toluene at room temperature (good solvent) and mixed with matrix polystyrene (3,840 kg mol(-1), RG ~ 97 nm, Mw/Mn = 1.04) whose concentration was varied from dilute to more than 10c*. Whereas for dilute solutions the intensity intensity correlation function follows a single diffusion process, it splits starting at c* to imply an additional relaxation process provided that the experimental focal area does not greatly exceed the polymer blob size. We identify the slower mode as self-diffusion and the increasingly rapid mode as correlated segment fluctuations that reflect the cooperative diffusion coefficient, Dcoop. These real-space measurements find quantitative agreement between correlation lengths inferred from dynamic measurements and those from determining the limit below which diffusion coefficients are independent of spot size. This study is considered to illustrate the potential of importing into polymer science the techniques of super-resolution imaging. PMID- 25148054 TI - The Down syndrome advantage: it depends on what and when you measure. AB - A "Down syndrome advantage"--better outcomes for individuals with Down syndrome and their families than for those with other intellectual/developmental disabilities (IDD)--is reduced when variables confounded with diagnostic category are controlled. We compared maternal outcomes in a longitudinal sample of families rearing children with Down syndrome or other IDD, and found that a Down syndrome advantage is (a) most likely when the metric is about the son/daughter rather than the parent or family more globally, (b) may be present or absent at different ages, and (c) is partially explained by higher levels of adaptive behavior for individuals with Down syndrome. We discuss the importance of multiple measures at multiple times, and implications for family expectations and adjustment at various life stages. PMID- 25148055 TI - Emotion knowledge in children and adolescents with Down syndrome: a new methodological approach. AB - Emotion knowledge was examined in 19 youth with Down syndrome (DS) and compared to typically developing (TD) children of similar developmental levels. This project expanded upon prior research on emotion knowledge in DS by utilizing a measure that minimized the need for linguistic skills, presented emotion expressions dynamically, and included social context cues. In Study 1, participants with DS were as accurate as TD participants when judging emotions from static or dynamic expression stimuli and from facial or contextual cues. In Study 2, participants with DS and TD participants showed similar cross-sectional developmental trajectories of emotion knowledge across mental age. This project highlights the importance of measure selection when examining emotion knowledge in samples with intellectual and developmental disabilities. PMID- 25148056 TI - Parenting and the behavior problems of young children with an intellectual disability: concurrent and longitudinal relationships in a population-based study. AB - We examined parenting behaviors, and their association with concurrent and later child behavior problems. Children with an intellectual disability (ID) were identified from a UK birth cohort (N = 516 at age 5). Compared to parents of children without an ID, parents of children with an ID used discipline less frequently, but reported a more negative relationship with their child. Among children with an ID, discipline, and home atmosphere had no long-term association with behavior problems, whereas relationship quality did: closer relationships were associated with fewer concurrent and later child behavior problems. Increased parent-child conflict was associated with greater concurrent and later behavior problems. Parenting programs in ID could target parent-child relationship quality as a potential mediator of behavioral improvements in children. PMID- 25148057 TI - Train the trainer effectiveness trials of behavioral intervention for individuals with autism: a systematic review. AB - This systematic review examines train the trainer (TTT) effectiveness trials of behavioral interventions for individuals with autism spectrum disorder (ASD). Published methodological quality scales were used to assess studies including participant description, research design, intervention, outcomes, and analysis. Twelve studies including 9 weak quality quasi-experimental studies, 2 single subject experimental design studies of moderate and weak quality, and 1 high quality randomized control trial were included. Overall, author reported effect sizes and calculation of improvement rate difference for SSRDs indicate positive effects of intervention across participant outcomes including cognition, language, and autism symptoms postcommunity delivered interventions primarily based in applied behavior analysis. Effects varied by children's developmental level. PMID- 25148058 TI - The purported association between depression, aggression, and self-injury in people with intellectual disability: a critical review of the literature. AB - The prevalence of depression in individuals with an intellectual disability is estimated to lie between 3% and 6%. It has been suggested that symptoms of depression in this population might be atypical and include unusual features such as challenging behavior. However, there is significant disagreement regarding the use of challenging behavior as "depressive equivalent" symptomatology. The aim of this review is to evaluate published research reporting on the association between challenging behavior, specifically aggression and self-injury, and depression in people with an intellectual disability as a first step toward evaluating whether challenging behaviors might be considered as depressive equivalent symptoms. The results of the studies identified indicated that the association between depression and aggression, and depression and self-injury are equivocal and the interpretations of the results limited by threats to validity. Based on this analysis, there is insufficient evidence to support the use of challenging behavior as a depressive equivalent symptom. Further research to examine potentially confounding variables and the association between challenging behaviour and depression using methodologically robust designs and measures is clearly warranted. PMID- 25148059 TI - An illustration of using multiple imputation versus listwise deletion analyses: the effect of Hanen's "More than words" on parenting stress. AB - This investigation illustrates the effects of using different missing data analysis techniques to analyze effects of a parent-implemented treatment on stress in parents of toddlers with autism symptomatology. The analysis approaches yielded similar results when analyzing main effects of the intervention, but different findings for moderation effects. Using listwise deletion, the data supported an iatrogenic effect of Hanen's "More Than Words" on stress in parents with high levels of pretreatment depressive symptoms. Using multiple imputation, a significant moderated treatment effect with uninterpretable regions of significance did not support an iatrogenic effect of treatment on parenting stress. Results highlight the need for caution in interpreting analyses that do not involve validated methods of handling missing data. PMID- 25148062 TI - Entering the digital age without pain. PMID- 25148065 TI - Visibility through atmospheric haze and its relation to macular pigment. AB - PURPOSE: A major factor limiting the visibility of distant targets is veiling attributed to atmospheric scattering, known commonly as haze. It has been suggested that yellow filters (in this case, the macular pigments, MPs) could selectively absorb this haze, thus extending visual range. This study is an empirical test of the visibility hypothesis. METHODS: Twelve subjects had their full contrast sensitivity function (CSF) (represented by six spatial frequencies) assessed in the presence of two background conditions: simulated blue haze and short wave-deficient light. Contrast sensitivity at the peak of the CSF (7.5 cycles per degree) was measured in the presence of the same two backgrounds as the full CSF, with the addition of a broadband xenon background condition in a separate sample of 25 subjects. RESULTS: Simulated blue haze was found to uniformly reduce the CSF in the 12 subjects for whom the full CSF was assessed. Therefore, only the peak was measured in the larger sample of 25 subjects. Macular pigment density was significantly related to energy at threshold for both the haze and xenon backgrounds but not the short wave-deficient background. Thus, subjects with higher levels of MP could withstand more light before losing sight of the target. CONCLUSIONS: This result is consistent with previous modeling of the visibility hypothesis as well as visual range improvements seen when using an artificial MP filter. PMID- 25148067 TI - Letter to the editor: Vergence facility with stereoscopic and nonstereoscopic targets. PMID- 25148068 TI - Authors' response. PMID- 25148070 TI - Abstracts of the 16th Annual Meeting of the Israel Society for Neuroscience, November 25-27, 2007, Eilat, Israel. PMID- 25148071 TI - It is getting late here early: youth substance abuse theory and practice. PMID- 25148072 TI - Asymmetric epoxidation of unsaturated ketones catalyzed by heterobimetallic rare earth-lithium complexes bearing phenoxy-functionalized chiral diphenylprolinolate ligand. AB - Four novel heterobimetallic complexes [REL2]{[(THF)3Li]2(MU-Cl)} stabilized by chiral phenoxy-functionalized prolinolate (RE = Yb (1), Y (2), Sm (3), Nd (4), H2L = (S)-2,4-di-tert-butyl-6-[[2-(hydroxydiphenylmethyl)pyrrolidin-1 yl]methyl]phenol have been synthesized and characterized. These readily available complexes are highly active in catalyzing the epoxidation of alpha,beta unsaturated ketones, while the enantioselectivity varies according to the ionic radii of the rare earth center. A series of chalcone derivatives were converted to chiral epoxides in 80 -> 99% ee at 0 degrees C using TBHP as the oxidant in the presence of 10 mol % of 1. PMID- 25148073 TI - Observation of the Marcus inverted region for bimolecular photoinduced electron transfer reactions in viscous media. AB - The general observation of Marcus inverted region (MIR) for bimolecular electron transfer (ET) reactions in different viscous media, e.g., micelles, reverse micelles, vesicles, ionic liquids, DNA scaffold, etc. has been doubted in some recent publications arguing limitations in Stern-Volmer (SV) analysis to account for the static and transient stages of quenching in these slow diffusing media. Thus, following a theoretical treatment based on a spherically symmetric diffusion equation coupled with conventional Marcus ET description, it has been suggested that the MIR observed in viscous media arises due to the inadequate consideration of different quenching regimes and also due to the differential excited-state lifetimes of the fluorophores used than a genuine one (J. Am. Chem. Soc. 2012, 134, 11396). However, the overall treatment in this study is severely compromised by setting the minimum solvent reorganization energy (lambdas) to ~0.96 eV while fitting the experimental data, which unambiguously suggests that the inversion in ET rate will never appear in the exergonicity (-DeltaG(0)) range of 0.16 to 0.71 eV, as is the case for the studied ET systems. Besides, the applicability of the conventional Marcus ET model (instead of Sumi-Marcus two dimensional ET model) in such extremely viscous media with exceptionally slow solvent response is highly debatable and perhaps is the main cause of the failure in fitting the experimental data quite satisfactorily. In the present study involving ultrafast ET quenching for coumarin derivatives by dimethylaniline donor in viscous ionic liquid media, we demonstrate clear MIR for the intrinsic ET rates, directly obtained from the ultrafast decay components of 1-10 ps, a time scale in which diffusion of reactants is negligible and the ET rates are either faster than or, at the most, competitive with the solvent reorganization. The appearance of MIR at DeltaG(0) ~ -0.5 eV, significantly lower than expected from the lambdas value, further substantiate the nonapplicability of conventional ET description but certainly advocate for the applicability of the Sumi-Marcus two-dimensional ET model in such media. Moreover, no obvious correlation has experimentally been observed between the excited-state lifetimes of the coumarin derivatives and the ET rates for a large number of dyes used in the present study. On the basis of the present results and drawing inferences from reported literatures in viscous media, we conclude that not only is the appearance of MIR very genuine but also the mechanistic model necessary to account the observed facts for the bimolecular ET reactions in a viscous medium is the two-dimensional ET description, which deals with an extremely slow relaxing solvent coordinate and a fast relaxing intramolecular coordinate to describe the ET reactions. PMID- 25148074 TI - Pneumocystis jirovecii pneumonia in patients with or without AIDS, France. AB - Pneumocystis jirovecii pneumonia (PCP) in patients without AIDS is increasingly common. We conducted a prospective cohort study of consecutive patients with proven PCP; of 544 patients, 223 (41%) had AIDS (AIDS patients) and 321 (59%) had other immunosuppressive disorders (non-AIDS patients). Fewer AIDS than non-AIDS patients required intensive care or ventilation, and the rate of hospital deaths- 17.4% overall--was significantly lower for AIDS versus non-AIDS patients (4% vs. 27%; p<0.0001). Multivariable analysis showed the odds of hospital death increased with older age, receipt of allogeneic bone marrow transplant, immediate use of oxygen, need for mechanical ventilation, and longer time to treatment; HIV positive status or receipt of a solid organ transplant decreased odds for death. PCP is more often fatal in non-AIDS patients, but time to diagnosis affects survival and is longer for non-AIDS patients. Clinicians must maintain a high index of suspicion for PCP in immunocompromised patients who do not have AIDS. PMID- 25148075 TI - Selective effects of excessive engagement in health-related behaviours on disgust propensity. AB - The present study examined the extent to which engagement in health-related behaviours modulate disgust propensity, a purportedly stable personality trait. Participants were randomised into a health behaviour (n = 30) or control condition (n = 30). After a baseline period, participants in the health behaviour condition spent one week actively engaging in a clinically representative array of health-related behaviours on a daily basis, followed by a second week-long baseline period. Participants in the control condition monitored their normal use of health behaviours. Compared to control participants, those in the health behaviour condition reported significantly greater increases in disgust propensity after the health behaviour manipulation. This effect was most robust for contamination disgust propensity and remained significant when controlling for changes in health anxiety and disease fear. In contrast, self-disgust and anxiety sensitivity did not significantly differ between the two groups as a function of the health behaviour manipulation. Mediational analyses were consistent with the hypothesis that changes in the frequency of health-related behaviours, but not changes in health anxiety and disease fear, mediated the effects of the experimental manipulation on changes in contamination disgust propensity. These findings suggest that the purportedly stable personality trait of disgust propensity can be modulated by excessive engagement in health-related behaviours. PMID- 25148076 TI - Proteomic investigation into betulinic acid-induced apoptosis of human cervical cancer HeLa cells. AB - Betulinic acid is a pentacyclic triterpenoid that exhibits anticancer functions in human cancer cells. This study provides evidence that betulinic acid is highly effective against the human cervical cancer cell line HeLa by inducing dose- and time-dependent apoptosis. The apoptotic process was further investigated using a proteomics approach to reveal protein expression changes in HeLa cells following betulinic acid treatment. Proteomic analysis revealed that there were six up- and thirty down-regulated proteins in betulinic acid-induced HeLa cells, and these proteins were then subjected to functional pathway analysis using multiple analysis software. UDP-glucose 6-dehydrogenase, 6-phosphogluconate dehydrogenase decarboxylating, chain A Horf6-a novel human peroxidase enzyme that involved in redox process, was found to be down-regulated during the apoptosis process of the oxidative stress response pathway. Consistent with our results at the protein level, an increase in intracellular reactive oxygen species was observed in betulinic acid-treated cells. The proteins glucose-regulated protein and cargo selection protein TIP47, which are involved in the endoplasmic reticulum pathway, were up-regulated by betulinic acid treatment. Meanwhile, 14-3-3 family proteins, including 14-3-3beta and 14-3-3epsilon, were down-regulated in response to betulinic acid treatment, which is consistent with the decrease in expression of the target genes 14-3-3beta and 14-3-3epsilon. Furthermore, it was found that the antiapoptotic bcl-2 gene was down-regulated while the proapoptotic bax gene was up-regulated after betulinic acid treatment in HeLa cells. These results suggest that betulinic acid induces apoptosis of HeLa cells by triggering both the endoplasmic reticulum pathway and the ROS-mediated mitochondrial pathway. PMID- 25148077 TI - Alternative inactivated poliovirus vaccines adjuvanted with Quillaja brasiliensis or Quil-a saponins are equally effective in inducing specific immune responses. AB - Inactivated polio vaccines (IPV) have an important role at the final stages of poliomyelitis eradication programs, reducing the risks associated with the use of attenuated polio vaccine (OPV). An affordable option to enhance vaccine immunogenicity and reduce costs of IPV may be the use of an effective and renewable adjuvant. In the present study, the adjuvant activity of aqueous extract (AE) and saponin fraction QB-90 from Quillaja brasiliensis using poliovirus antigen as model were analyzed and compared to a preparation adjuvanted with Quil-A, a well-known saponin-based commercial adjuvant. Experimental vaccines were prepared with viral antigen plus saline (control), Quil-A (50 ug), AE (400 ug) or QB-90 (50 ug). Sera from inoculated mice were collected at days 0, 28, 42 and 56 post-inoculation of the first dose of vaccine. Serum levels of specific IgG, IgG1 and IgG2a were significantly enhanced by AE, QB-90 and Quil-A compared to control group on day 56. The magnitude of enhancement was statistically equivalent for QB-90 and Quil-A. The cellular response was evaluated through DTH and analysis of IFN-gamma and IL-2 mRNA levels using in vitro reestimulated splenocytes. Results indicated that AE and QB-90 were capable of stimulating the generation of Th1 cells against the administered antigen to the same extent as Quil-A. Mucosal immune response was enhanced by the vaccine adjuvanted with QB-90 as demonstrated by increases of specific IgA titers in bile, feces and vaginal washings, yielding comparable or higher titers than Quil-A. The results obtained indicate that saponins from Q. brasiliensis are potent adjuvants of specific cellular and humoral immune responses and represent a viable option to Quil-A. PMID- 25148078 TI - Striatal and hippocampal involvement in motor sequence chunking depends on the learning strategy. AB - Motor sequences can be learned using an incremental approach by starting with a few elements and then adding more as training evolves (e.g., learning a piano piece); conversely, one can use a global approach and practice the whole sequence in every training session (e.g., shifting gears in an automobile). Yet, the neural correlates associated with such learning strategies in motor sequence learning remain largely unexplored to date. Here we used functional magnetic resonance imaging to measure the cerebral activity of individuals executing the same 8-element sequence after they completed a 4-days training regimen (2 sessions each day) following either a global or incremental strategy. A network comprised of striatal and fronto-parietal regions was engaged significantly regardless of the learning strategy, whereas the global training regimen led to additional cerebellar and temporal lobe recruitment. Analysis of chunking/grouping of sequence elements revealed a common prefrontal network in both conditions during the chunk initiation phase, whereas execution of chunk cores led to higher mediotemporal activity (involving the hippocampus) after global than incremental training. The novelty of our results relate to the recruitment of mediotemporal regions conditional of the learning strategy. Thus, the present findings may have clinical implications suggesting that the ability of patients with lesions to the medial temporal lobe to learn and consolidate new motor sequences may benefit from using an incremental strategy. PMID- 25148079 TI - Hypoalbuminemia is a strong predictor of 30-day all-cause mortality in acutely admitted medical patients: a prospective, observational, cohort study. AB - OBJECTIVE: Emergency patients with hypoalbuminemia are known to have increased mortality. No previous studies have, however, assessed the predictive value of low albumin on mortality in unselected acutely admitted medical patients. We aimed at assessing the predictive power of hypoalbuminemia on 30-day all-cause mortality in a cohort of acutely admitted medical patients. METHODS: We included all acutely admitted adult medical patients from the medical admission unit at a regional teaching hospital in Denmark. Data on mortality was extracted from the Danish Civil Register to ensure complete follow-up. Patients were divided into three groups according to their plasma albumin levels (0-34, 35-44 and >=45 g/L) and mortality was identified for each group using Kaplan-Meier survival plot. Discriminatory power (ability to discriminate patients at increased risk of mortality) and calibration (precision of predictions) for hypoalbuminemia was determined. RESULTS: We included 5,894 patients and albumin was available in 5,451 (92.5%). A total of 332 (5.6%) patients died within 30 days of admission. Median plasma albumin was 40 g/L (IQR 37-43). Crude 30-day mortality in patients with low albumin was 16.3% compared to 4.3% among patients with normal albumin (p<0.0001). Patients with low albumin were older and admitted for a longer period of time than patients with a normal albumin, while patients with high albumin had a lower 30-day mortality, were younger and were admitted for a shorter period. Multivariable logistic regression analyses confirmed the association of hypoalbuminemia with mortality (OR: 1.95 (95% CI: 1.31-2.90)). Discriminatory power was good (AUROC 0.73 (95% CI, 0.70-0.77)) and calibration acceptable. CONCLUSION: We found hypoalbuminemia to be associated with 30-day all-cause mortality in acutely admitted medical patients. Used as predictive tool for mortality, plasma albumin had acceptable discriminatory power and good calibration. PMID- 25148081 TI - Late cretaceous aquatic plant world in Patagonia, Argentina. AB - In this contribution, we describe latest Cretaceous aquatic plant communities from the La Colonia Formation, Patagonia, Argentina, based on their taxonomic components and paleoecological attributes. The La Colonia Formation is a geological unit deposited during a Maastrichtian-Danian transgressive episode of the South Atlantic Ocean. This event resulted in the deposition of a series of fine-grained sediments associated with lagoon systems occurring along irregular coastal plains in northern Patagonia. These deposits preserved a diverse biota, including aquatic and terrestrial plants and animals. The aquatic macrophytes can be broadly divided into two groups: free-floating and rooted, the latter with emergent or floating leaves. Free-floating macrophytes include ferns in Salviniaceae (Azolla and Paleoazolla) and a monocot (Araceae). Floating microphytes include green algae (Botryoccocus, Pediastrum and Zygnemataceae). Among the rooted components, marsileaceous water ferns (including Regnellidium and an extinct form) and the eudicot angiosperm Nelumbo (Nelumbonaceae) are the dominant groups. Terrestrial plants occurring in the vegetation surrounding the lagoons include monocots (palms and Typhaceae), ferns with affinities to Dicksoniaceae, conifers, and dicots. A reconstruction of the aquatic plant paleocommuniy is provided based on the distribution of the fossils along a freshwater horizon within the La Colonia Formation. This contribution constitutes the first reconstruction of a Cretaceous aquatic habitat for southern South America. PMID- 25148080 TI - Identification of miRNAs differentially expressed in human epilepsy with or without granule cell pathology. AB - The microRNAs (miRNAs) are small size non-coding RNAs that regulate expression of target mRNAs at post-transcriptional level. miRNAs differentially expressed under pathological conditions may help identifying mechanisms underlying the disease and may represent biomarkers with prognostic value. However, this kind of studies are difficult in the brain because of the cellular heterogeneity of the tissue and of the limited access to fresh tissue. Here, we focused on a pathology affecting specific cells in a subpopulation of epileptic brains (hippocampal granule cells), an approach that bypasses the above problems. All patients underwent surgery for intractable temporal lobe epilepsy and had hippocampal sclerosis associated with no granule cell pathology in half of the cases and with type-2 granule cell pathology (granule cell layer dispersion or bilamination) in the other half. The expression of more than 1000 miRNAs was examined in the laser microdissected dentate granule cell layer. Twelve miRNAs were differentially expressed in the two groups. One of these, miR487a, was confirmed to be expressed at highly differential levels in an extended cohort of patients, using RT-qPCR. Bioinformatics searches and RT-qPCR verification identified ANTXR1 as a possible target of miR487a. ANTXR1 may be directly implicated in granule cell dispersion because it is an adhesion molecule that favors cell spreading. Thus, miR487a could be the first identified element of a miRNA signature that may be useful for prognostic evaluation of post-surgical epilepsy and may drive mechanistic studies leading to the identification of therapeutic targets. PMID- 25148084 TI - Substitution errors. PMID- 25148082 TI - Microbial communities of three sympatric Australian stingless bee species. AB - Bacterial symbionts of insects have received increasing attention due to their prominent role in nutrient acquisition and defense. In social bees, symbiotic bacteria can maintain colony homeostasis and fitness, and the loss or alteration of the bacterial community may be associated with the ongoing bee decline observed worldwide. However, analyses of microbiota associated with bees have been largely confined to the social honeybees (Apis mellifera) and bumblebees (Bombus spec.), revealing--among other taxa--host-specific lactic acid bacteria (LAB, genus Lactobacillus) that are not found in solitary bees. Here, we characterized the microbiota of three Australian stingless bee species (Apidae: Meliponini) of two phylogenetically distant genera (Tetragonula and Austroplebeia). Besides common plant bacteria, we find LAB in all three species, showing that LAB are shared by honeybees, bumblebees and stingless bees across geographical regions. However, while LAB of the honeybee-associated Firm4-5 clusters were present in Tetragonula, they were lacking in Austroplebeia. Instead, we found a novel clade of likely host-specific LAB in all three Australian stingless bee species which forms a sister clade to a large cluster of Halictidae-associated lactobacilli. Our findings indicate both a phylogenetic and geographical signal of host-specific LAB in stingless bees and highlight stingless bees as an interesting group to investigate the evolutionary history of the bee-LAB association. PMID- 25148085 TI - Breed-specific legislation. PMID- 25148086 TI - What is your diagnosis? Plate-like atelectasis. PMID- 25148088 TI - Diagnostic imaging in veterinary dental practice. Supernumerary molars in a horse. PMID- 25148087 TI - What is your diagnosis? Craniomandibular osteopathy. PMID- 25148089 TI - Diagnostic imaging in veterinary dental practice. Root fracture of a maxillary canine tooth in a dog. PMID- 25148090 TI - Pathology in practice. E invadens infection in a ball python. PMID- 25148091 TI - Nutritional management of idiopathic epilepsy in dogs. PMID- 25148092 TI - What veterinarians can and should know about the price elasticity of demand. PMID- 25148093 TI - The role of veterinary team effectiveness in job satisfaction and burnout in companion animal veterinary clinics. AB - OBJECTIVE: To determine the role of veterinary team effectiveness regarding job satisfaction and burnout in companion animal veterinary practice. DESIGN: Cross sectional observational study. SAMPLE: 48 companion animal veterinary health-care teams. PROCEDURES: 274 team members participated in an online survey. Overall job satisfaction was evaluated with a 1-item measure, and the 3 dimensions of burnout (exhaustion, cynicism, and professional efficacy) were measured with the Maslach Burnout Inventory-General Survey. Team effectiveness was assessed with a survey developed for this study. Demographic and team effectiveness factors (coordinated team environment, toxic team environment, team engagement, and individual engagement) associated with job satisfaction and burnout were evaluated. RESULTS: Overall mean job satisfaction score was 5.46 of 7 (median, 6.00); veterinary technicians and kennel attendants had the lowest scores. According to the Maslach survey results, 22.4% of participants were in the high-risk category for exhaustion, 23.2% were in the high-risk category for cynicism, and 9.3% were in the high-risk category for professional efficacy. A coordinated team environment was associated with increased professional efficacy and decreased cynicism. A toxic team environment was negatively associated with job satisfaction and positively associated with exhaustion and cynicism. Individual engagement was positively associated with job satisfaction and professional efficacy and negatively associated with exhaustion and cynicism. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested the effectiveness of a veterinary team can significantly influence individual team members' job satisfaction and burnout. Practices should pay specific attention to the effectiveness with which their veterinary team operates. PMID- 25148094 TI - Long-term survival and quality of life in dogs with clinical signs associated with a congenital portosystemic shunt after surgical or medical treatment. AB - OBJECTIVE: To compare long-term survival and quality of life data in dogs with clinical signs associated with a congenital portosystemic shunt (CPSS) that underwent medical or surgical treatment. DESIGN: Prospective cohort study. ANIMALS: 124 client-owned dogs with CPSS. PROCEDURES: Dogs received medical or surgical treatment without regard to signalment, clinical signs, or clinicopathologic results. Survival data were analyzed with a Cox regression model. Quality of life information, obtained from owner questionnaires, included frequency of CPSS-associated clinical signs (from which a clinical score was derived), whether owners considered their dog normal, and (for surgically treated dogs) any ongoing medical treatment for CPSS. A Mann-Whitney U test was used to compare mean clinical score data between surgically and medically managed dogs during predetermined follow-up intervals. RESULTS: 97 dogs underwent surgical treatment; 27 were managed medically. Median follow-up time for all dogs was 1,936 days. Forty-five dogs (24 medically managed and 21 surgically managed) died or were euthanized during the follow-up period. Survival rate was significantly improved in dogs that underwent surgical treatment (hazard ratio, 8.11; 95% CI, 4.20 to 15.66) than in those treated medically for CPSS. Neither age at diagnosis nor shunt type affected survival rate. Frequency of clinical signs was lower in surgically versus medically managed dogs for all follow-up intervals, with a significant difference between groups at 4 to 7 years after study entry. CONCLUSIONS AND CLINICAL RELEVANCE: Surgical treatment of CPSS in dogs resulted in significantly improved survival rate and lower frequency of ongoing clinical signs, compared with medical management. Age at diagnosis did not affect survival rate and should not influence treatment choice. PMID- 25148095 TI - Case-control study of the effects of pimobendan on survival time in cats with hypertrophic cardiomyopathy and congestive heart failure. AB - OBJECTIVE: To assess survival time and adverse events related to the administration of pimobendan to cats with congestive heart failure (CHF) secondary to hypertrophic cardiomyopathy (HCM) or hypertrophic obstructive cardiomyopathy (HOCM). DESIGN: Retrospective case-control study. ANIMALS: 27 cats receiving treatment with pimobendan and 27 cats receiving treatment without pimobendan. PROCEDURES: Medical records between 2003 and 2013 were reviewed. All cats with HCM or HOCM treated with a regimen that included pimobendan (case cats) were identified. Control cats (cats with CHF treated during the same period with a regimen that did not include pimobendan) were selected by matching to case cats on the basis of age, sex, body weight, type of cardiomyopathy, and manifestation of CHF. Data collected included signalment, physical examination findings, echocardiographic data, serum biochemical values, and survival time from initial diagnosis of CHF. Kaplan-Meier survival curves were constructed and compared by means of a log rank test. RESULTS: Cats receiving pimobendan had a significant benefit in survival time. Median survival time of case cats receiving pimobendan was 626 days, whereas median survival time for control cats not receiving pimobendan was 103 days. No significant differences were detected for any other variable. CONCLUSIONS AND CLINICAL RELEVANCE: The addition of pimobendan to traditional treatment for CHF may provide a substantial clinical benefit in survival time for HCM-affected cats with CHF and possibly HOCM-affected cats with CHF. PMID- 25148096 TI - Analysis of the relationship of extrahepatic portosystemic shunt morphology with clinical variables in dogs: 53 cases (2009-2012). AB - OBJECTIVE: To investigate differences in clinical variables among dogs with extrahepatic portosystemic shunts (EHPSSs) of various morphologies. DESIGN: Retrospective case series. ANIMALS: 53 dogs with EHPSSs. PROCEDURES: Medical records of dogs undergoing preoperative CT angiography of an EHPSS over a 3-year period were reviewed. Analysis was performed to investigate relationships of clinical variables with shunt morphology. Morphologies were analyzed individually as well as in several groups. RESULTS: Shunt morphologies included 10 splenocaval, 9 splenophrenic, 11 splenoazygos, 10 right gastric-caval, 12 right gastric-caval with a caudal loop, and 1 right gastric-azygos with a caudal loop. Several biochemical variables associated with EHPSS were lowest in dogs with splenocaval shunts. Preoperative clinical signs were more common in dogs that had shunts with vena caval than right azygos vein insertion (36/41 [88%] vs 7/12 [58%]) and insertion caudal to the liver than diaphragmatic insertion (29/32 [91%] vs 14/21 [67%]). Neurologic signs were more common when shunts inserted into the vena cava caudal to the liver than in other locations (21/32 [66%] vs 6/21 [29%]) and were most frequent with splenocaval shunts. Urinary tract signs were more common when shunts had right gastric vein origin than gastrosplenic vein origin (14/23 [61%] vs 10/30 [33%]). CONCLUSIONS AND CLINICAL RELEVANCE: Splenocaval shunts caused more clinical abnormalities than did other shunt morphologies. Results suggested that dogs with shunt insertion in the caudal vena cava, especially caudal to the liver, were most likely to have clinical signs. PMID- 25148097 TI - Meta-analysis of the effects of sometribove zinc suspension on the production and health of lactating dairy cows. AB - OBJECTIVE: To provide an updated evaluation of the efficacy and safety of sometribove zinc suspension (rbST-Zn), a form of recombinant bovine somatotropin, in lactating dairy cows. DESIGN: Meta-analysis. SAMPLE: 26 studies published in peer-reviewed journals or reviewed by a regulatory agency. PROCEDURES: To be included, a study had to involve the use of the rbST-Zn formulation available to US producers in accordance with the label instructions for treatment initiation (57 to 70 days postpartum), dose (500 mg, q 14 d), and route (SC). RESULTS: For cows treated with rbST-Zn, mean milk, 3.5% fat-corrected milk, fat, and protein yields were increased by 4.00, 4.04, 0.144, and 0.137 kg/d (8.8, 8.89, 0.32, and 0.30 lb/d), respectively; however, the concentration of milk components did not change. Pregnancy proportion for the first 2 breeding cycles was increased by 5.4%, and pregnancy proportion for the duration of the trial was reduced by 5.5% for rbST-Zn-treated cows, compared with proportions for untreated cows. Mean body condition score (1 to 5 scale) was reduced by 0.06 points during the period of rbST-Zn use for treated cows. Administration of rbST-Zn had no effect on milk somatic cell count, the number of days to pregnancy, or inseminations per pregnancy; rates of fetal loss, twins, cystic ovaries, clinical lameness, lameness lesions, or traumatic lesions of the integumentary system; and odds of clinical mastitis or culling. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that rbST-Zn administration to dairy cows effectively increases milk production with no adverse effects on cow health and well-being. PMID- 25148098 TI - Bacteremia in the pedal circulation following regional intravenous perfusion of a 2% lidocaine solution in cattle with deep digital sepsis. AB - OBJECTIVE: To evaluate whether pedal bacteremia develops following regional IV perfusion (RIVP) of a 2% lidocaine hydrochloride solution in cattle with deep digital sepsis (DDS) and to determine which bacterial pathogens are most commonly isolated from the pedal circulation. DESIGN: Prospective observational cohort study. ANIMALS: 9 adult cattle with DDS in 10 limbs and 10 healthy adult cattle with no evidence of lameness or digital infection. PROCEDURES: Blood samples were obtained aseptically from the dorsal common digital vein immediately following tourniquet application and 30 to 60 minutes after aseptic RIVP with a 2% lidocaine solution. Aerobic and anaerobic bacterial cultures were performed on all samples collected. For cattle with DDS, clinical examination with or without debridement of digital lesions was performed after RIVP. RESULTS: Bacteria were isolated from pedal blood prior to RIVP in 1 cow with DDS and after RIVP and examination with or without debridement in that cow and 4 additional cattle with DDS. Bacteria were not isolated from any blood sample obtained from the healthy cattle. Of the 8 bacterial isolates identified, 5 were gram-positive facultative anaerobes. Cattle with DDS were significantly more likely to develop bacteremia in the pedal circulation than were healthy cattle following RIVP. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that bacteremia may be present in the pedal circulation before and following RIVP and examination with or without debridement in cattle with DDS. Thus, systemic or local antimicrobial treatment might be warranted prior to or concurrently with RIVP in cattle with DDS. PMID- 25148099 TI - In vitro holding security of six friction knots used as a first throw in the creation of a vascular ligation. AB - OBJECTIVE: To compare in vitro security of 6 friction knots used as a first throw in the creation of a vascular ligation. DESIGN: Experimental study. SAMPLE: 20 constructs of 6 friction knots created with 2-0 polyglyconate suture. PROCEDURES: Security of the surgeon's throw, Miller's knot, Ashley modification of the Miller's knot, modified Miller's hand-tie, constrictor knot, and strangle knot was evaluated. Each knot configuration was constructed around each of 2 balloon dilation catheters used as small- and large-diameter vascular pedicle models and pressure tested to failure (leakage) 10 times. Results were compared by means of ANOVA and Student t tests. RESULTS: Mean leakage pressure for the surgeon's throw was significantly lower than that of all other knots tested in both pedicle models. The Miller's knot, constrictor knot, and strangle knot had mean leakage pressures > 360 mm Hg regardless of model diameter, whereas the surgeon's throw, Ashley modification of the Miller's knot, and modified Miller's hand tie consistently leaked at pressures at or below those found in arteries under normal physiologic conditions (pressures of 90 to 140 mm Hg). CONCLUSIONS AND CLINICAL RELEVANCE: Security of the Miller's knot, constrictor knot, and strangle knot was considered excellent. In vitro results suggested that, when constructed correctly, these friction knots may be preferable first-throw constructs during vascular pedicle ligation and should be further evaluated for clinical use. The surgeon's throw was less reliable as a first throw for vascular pedicle ligation in the model tested. PMID- 25148100 TI - Discovery of novel highly potent hepatitis C virus NS5A inhibitor (AV4025). AB - A series of next in class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrrolidin-2-yl-5-{4-[4-(2-pyrrolidin-2-yl-1H imidazol-5-yl)buta-1,3-diynyl]phenyl}-1H-imidazole cores was designed based on the SAR studies available for the reported NS5A inhibitors. Compound 13a (AV4025), with (S,S,S,S)-stereochemistry (EC50 = 3.4 +/- 0.2 pM, HCV replicon genotype 1b), was dramatically more active than were the compounds with two (S)- and two (R)-chiral centers. Human serum did not significantly reduce the antiviral activity (<4-fold). Relatively favorable pharmacokinetic features and good oral bioavailability were observed during animal studies. Compound 13a was well tolerated in rodents (in mice, LD50 = 2326 mg/kg or higher), providing a relatively high therapeutic index. During safety, pharmacology and subchronic toxicity studies in rats and dogs, it was not associated with any significant pathological or clinical findings. This compound is currently being evaluated in phase I/II clinical trials for the treatment of HCV infection. PMID- 25148102 TI - Finding a fox: an evaluation of survey methods to estimate abundance of a small desert carnivore. AB - The status of many carnivore species is a growing concern for wildlife agencies, conservation organizations, and the general public. Historically, kit foxes (Vulpes macrotis) were classified as abundant and distributed in the desert and semi-arid regions of southwestern North America, but is now considered rare throughout its range. Survey methods have been evaluated for kit foxes, but often in populations where abundance is high and there is little consensus on which technique is best to monitor abundance. We conducted a 2-year study to evaluate four survey methods (scat deposition surveys, scent station surveys, spotlight survey, and trapping) for detecting kit foxes and measuring fox abundance. We determined the probability of detection for each method, and examined the correlation between the relative abundance as estimated by each survey method and the known minimum kit fox abundance as determined by radio-collared animals. All surveys were conducted on 15 5-km transects during the 3 biological seasons of the kit fox. Scat deposition surveys had both the highest detection probabilities (p = 0.88) and were most closely related to minimum known fox abundance (r2 = 0.50, P = 0.001). The next best method for kit fox detection was the scent station survey (p = 0.73), which had the second highest correlation to fox abundance (r2 = 0.46, P<0.001). For detecting kit foxes in a low density population we suggest using scat deposition transects during the breeding season. Scat deposition surveys have low costs, resilience to weather, low labor requirements, and pose no risk to the study animals. The breeding season was ideal for monitoring kit fox population size, as detections consisted of the resident population and had the highest detection probabilities. Using appropriate monitoring techniques will be critical for future conservation actions for this rare desert carnivore. PMID- 25148103 TI - Evaluation of an integrated framework for biodiversity with a new metric for functional dispersion. AB - Growing interest in understanding ecological patterns from phylogenetic and functional perspectives has driven the development of metrics that capture variation in evolutionary histories or ecological functions of species. Recently, an integrated framework based on Hill numbers was developed that measures three dimensions of biodiversity based on abundance, phylogeny and function of species. This framework is highly flexible, allowing comparison of those diversity dimensions, including different aspects of a single dimension and their integration into a single measure. The behavior of those metrics with regard to variation in data structure has not been explored in detail, yet is critical for ensuring an appropriate match between the concept and its measurement. We evaluated how each metric responds to particular data structures and developed a new metric for functional biodiversity. The phylogenetic metric is sensitive to variation in the topology of phylogenetic trees, including variation in the relative lengths of basal, internal and terminal branches. In contrast, the functional metric exhibited multiple shortcomings: (1) species that are functionally redundant contribute nothing to functional diversity and (2) a single highly distinct species causes functional diversity to approach the minimum possible value. We introduced an alternative, improved metric based on functional dispersion that solves both of these problems. In addition, the new metric exhibited more desirable behavior when based on multiple traits. PMID- 25148101 TI - Local release of antibiotics for surgical site infection management using high purity calcium sulfate: an in vitro elution study. AB - BACKGROUND: The aim of this study was to characterize the elution of four antibiotics from pharmaceutical-grade calcium sulfate beads and show that the eluted antibiotics retained efficacy. METHODS: Calcium sulfate was combined with gentamicin, tobramycin, vancomycin, or rifampicin (ratio: 20 g of calcium sulfate, to 240 mg, 500 mg, 900 mg, and 600 mg of antibiotic, respectively). Three grams of beads were immersed in 4 mL of sterile phosphate-buffered saline (PBS) at 37 degrees C. At each time point (4, 8, 24 h; 2, 7, 14, 28, 42 d), eluates were removed for analysis by liquid chromatography-mass spectrometry. The antimicrobial efficacy of antibiotics combined with calcium sulfate beads after 42 d was tested by a modified Kirby-Bauer disc diffusion assay. RESULTS: All samples showed a generally exponential decay in the eluted antibiotic concentration. At the first time point, both gentamicin and tobramycin had eluted to a peak concentration of approximately 10,000 mcg/mL. For rifampicin, the peak concentration occurred at 24 h, whereas for vancomycin, it occurred at 48 h. The eluted concentrations exceeded the minimum inhibitory concentration for common periprosthetic joint infection pathogens for the entire span of the 42 study days. Mass spectrometry confirmed all antibiotics were unchanged when eluted from the calcium sulfate carrier. Antimicrobial efficacy was unaltered after 42 d in combination with calcium sulfate at 37 degrees C. CONCLUSIONS: Pharmaceutical grade calcium sulfate has the potential for targeted local release of tobramycin, gentamicin, vancomycin, and rifampicin over a clinically meaningful time period. PMID- 25148104 TI - Structural basis for the inhibition of HSP70 and DnaK chaperones by small molecule targeting of a C-terminal allosteric pocket. AB - The stress-inducible mammalian heat shock protein 70 (HSP70) and its bacterial orthologue DnaK are highly conserved nucleotide binding molecular chaperones. They represent critical regulators of cellular proteostasis, especially during conditions of enhanced stress. Cancer cells rely on HSP70 for survival, and this chaperone represents an attractive new therapeutic target. We have used a structure-activity approach and biophysical methods to characterize a class of inhibitors that bind to a unique allosteric site within the C-terminus of HSP70 and DnaK. Data from X-ray crystallography together with isothermal titration calorimetry, mutagenesis, and cell-based assays indicate that these inhibitors bind to a previously unappreciated allosteric pocket formed within the non-ATP bound protein state. Moreover, binding of inhibitor alters the local protein conformation, resulting in reduced chaperone-client interactions and impairment of proteostasis. Our findings thereby provide a new chemical scaffold and target platform for both HSP70 and DnaK; these will be important tools with which to interrogate chaperone function and to aid ongoing efforts to optimize potency and efficacy in developing modulators of these chaperones for therapeutic use. PMID- 25148105 TI - Mutations of novel influenza A(H10N8) virus in chicken eggs and MDCK cells. AB - The recent emergence of human infection with influenza A(H10N8) virus is an urgent public health concern. Genomic analysis showed that the virus was conserved in chicken eggs but presented substantial adaptive mutations in MDCK cells. Our results provide additional evidence for the avian origin of this influenza virus. PMID- 25148106 TI - Pediatric aleukemic leukemia cutis: report of 3 cases and review of the literature. AB - Leukemia cutis (LC) denotes a cutaneous infiltration of neoplastic myeloid cells or lymphoid blasts, which can present in the setting of acute myeloid leukemia, particularly in those cases with monocytic or myelomonocytic differentiation. Rarely, cutaneous involvement by a leukemic infiltrate can occur in the absence of bone marrow or peripheral blood involvement by acute leukemia; this then is referred to as aleukemic LC (ALC). Recognition of LC is important for further classification and early diagnosis of the disease, but the diagnosis is difficult in the absence of a systemic presentation of acute leukemia. Although the molecular and cytogenetic features of ALC are poorly characterized, some have shown specific molecular alterations in common with classic forms of acute leukemias. We present 3 cases of ALC in pediatric patients. PMID- 25148107 TI - EBV-Negative Cutaneous Lymphomatoid Granulomatosis With Concomitant EBV-Positive Pulmonary Involvement: A Potential Diagnostic and Prognostic Pitfall. AB - Lymphomatoid granulomatosis (LYG) is a rare, T-cell-rich Epstein-Barr virus (EBV) positive B-cell lymphoproliferative disorder. Although LYG presents most often with lung involvement, up to half of affected individuals have concomitant cutaneous LYG. EBV-encoded RNA (EBER) is detected in the majority of pulmonary lesions but is often negative in skin lesions. Herein, we describe a case of concomitant EBV-positive pulmonary and EBV-negative cutaneous LYG in a 70-year old woman. Histologically, both skin and lung biopsies demonstrated angiocentric necrosis with vascular wall compromise and a brisk inflammatory infiltrate comprised of plasma cells, histiocytes, and lymphocytes. Immunohistochemical studies on the skin biopsy demonstrated predominance of T cells and scattered B cells within the inflammatory infiltrate. Chromogenic in situ hybridization (CISH) for EBER was negative in the cutaneous infiltrate. The lung biopsy showed similar immunohistochemical findings but CISH for EBER demonstrated numerous EBV positive B cells. Overall, this case demonstrates the variability of EBER positivity by CISH in multisystem LYG and underscores that its absence in cutaneous lesions does not exclude LYG from the differential diagnosis. Additionally, this case highlights the fact that cutaneous specimens should not be used in grading LYG by the World Health Organization criteria. PMID- 25148108 TI - Recent Research and Progress in Food, Feed and Nutrition with Advanced Synchrotron-based SR-IMS and DRIFT Molecular Spectroscopy. AB - Ultraspatially resolved synchrotron radiation based infrared microspectroscopy is able to detect the structure features of a food or feed tissue at cellular and molecular levels. However, to date, this advanced synchrotron-based technique is almost unknown to food and feed scientists. The objective of this article was to introduce this novel analytical technology, ultra-spatially resolved synchrotron radiation based infrared microspectroscopy (SR-IMS) to food, feed, conventional nutrition, and molecular nutrition scientists. The emphasis of this review focused on the following areas: (1) Principles of molecular spectroscopy for food and feed structure research, such as protein molecular structure, carbohydrate conformation, heating induced protein structure changes, and effect of gene transformation on food and feed structure; (2) Molecular spectral analysis methodology; (3) Biological applications of synchrotron SR-IMS and DRIFT spectroscopy; and (4) Recent progress in food, feed and nutrition research program. The information described in this article gives better insight in food structure research progress and update. PMID- 25148109 TI - Cationic synthetic peptides: assessment of their antimicrobial potency in liquid preserved boar semen. AB - Various semen extender formulas are in use to maintain sperm longevity and quality whilst acting against bacterial contamination in liquid sperm preservation. Aminoglycosides are commonly supplemented to aid in the control of bacteria. As bacterial resistance is increasing worldwide, antimicrobial peptides (AMPs) received lively interest as alternatives to overcome multi-drug resistant bacteria. We investigated, whether synthetic cationic AMPs might be a suitable alternative for conventional antibiotics in liquid boar sperm preservation. The antibacterial activity of two cyclic AMPs (c-WWW, c-WFW) and a helical magainin II amide analog (MK5E) was studied in vitro against two Gram-positive and eleven Gram-negative bacteria. Isolates included ATCC reference strains, multi-resistant E. coli and bacteria cultured from boar semen. Using broth microdilution, minimum inhibitory concentrations were determined for all AMPs. All AMPs revealed activity towards the majority of bacteria but not against Proteus spp. (all AMPs) and Staphylococcus aureus ATCC 29213 (MK5E). We could also demonstrate that c-WWW and c-WFW were effective against bacterial growth in liquid preserved boar semen in situ, especially when combined with a small amount of gentamicin. Our results suggest that albeit not offering a complete alternative to traditional antibiotics, the use of AMPs offers a promising solution to decrease the use of conventional antibiotics and thereby limit the selection of multi-resistant strains. PMID- 25148111 TI - Automatic implantable cardioverter defibrillator in electroconvulsive therapy. AB - As the number of patients with implantable cardiac devices increases so too does the frequency with which these individuals present for electroconvulsive therapy (ECT). The rationale for deactivating an automatic implantable cardioverter defibrillator before ECT has been made based on the concern that artifacts generated during treatment could be interpreted as a treatable rhythm by the internal device, resulting in a discharge. We believe that the risk of inappropriate discharge during ECT is very low and outweighed by the considerable benefit of an active device being able to more quickly treat a malignant dysrhythmia. PMID- 25148110 TI - Effects of COMT, DRD2, BDNF, and APOE Genotypic Variation on Treatment Efficacy and Cognitive Side Effects of Electroconvulsive Therapy. AB - OBJECTIVES: The aim of this study was to explore the main and interaction effects of the COMT Val158Met, DRD2 C957T, BDNF Val66Met, and APOE polymorphisms on treatment efficacy and cognitive side effects of electroconvulsive therapy (ECT). METHODS: A total of 117 adult inpatients with a diagnosis of major depressive disorder recruited from 3 hospitals were administered the Montgomery-Asberg Depression Rating Scale and a cognitive battery assessing global cognition, anterograde memory, executive function, speed and concentration, as well as retrograde memory at baseline and after ECT treatment. RESULTS: DRD2 C957T heterozygotes had 3.7 (95% confidence interval, 1.13-12.25; P = 0.032) greater odds of remission compared with CC homozygotes. Among the men, COMT Val/Val carriers had greater depressive symptom reduction compared with Met/Met carriers (Montgomery-Asberg Depression Rating Scale percentage of reduction, 76% vs 35%; P = 0.020) but not among the women (P = 0.903) after ECT. For cognitive outcomes, an interaction effect on anterograde memory was observed between the DRD2 and BDNF polymorphisms (P = 0.016), in which carriers of the DRD2 TT and BDNF Val/Val genotypes had significantly less decline in anterograde performance than those that carried the TC and Met-allele (P = 0.001) or CC and Met-allele (P = 0.003) genotypes. However, no results withstood correction for multiple comparisons. CONCLUSIONS: These observations provide preliminary evidence supporting an association between common functional genotypic variation and ECT efficacy as well as anterograde memory side effects after ECT. Validation of these findings is required before firm conclusions can be made and clinical utility can be assessed. PMID- 25148112 TI - Is remission a necessary and sufficient definition of success in ECT? Part 2. PMID- 25148113 TI - Family cluster of Middle East respiratory syndrome coronavirus infections, Tunisia, 2013. AB - In 2013 in Tunisia, 3 persons in 1 family were infected with Middle East respiratory syndrome coronavirus (MERS-CoV). The index case-patient's respiratory tract samples were negative for MERS-CoV by reverse transcription PCR, but diagnosis was retrospectively confirmed by PCR of serum. Sequences clustered with those from Saudi Arabia and United Arab Emirates. PMID- 25148114 TI - Crystal structure, electronic structure, and photoluminescence properties of La3BW(1-x)Mo(x)O9:Eu3+ red phosphor. AB - A series of La3BW(1-x)Mo(x)O9:Eu(3+) (x = 0-0.4) polycrystalline powders were prepared by using solid-state reactions. The phase structure, UV-vis absorption spectra, and photoluminescence properties were studied as a function of the Mo/W ratio. When Mo(6+) ions are incorporated into the lattice, the characteristic sharp lines in the excitation spectra of Eu(3+) monitored at 617 nm are prominently enhanced, which join the ligand-to-metal charge transfer (LMCT) band of La3BW(1-x)Mo(x)O9:Eu(3+) into a broad band ranging from 250 to 450 nm centered at 375 nm. The intensity of the broad excitation band reaches a maximum when the content of Mo(6+) ions increases to x = 0.3. On the other hand, the LMCT band around 306 nm decreases and shifts toward the longer wavelength. These features are advantageous to near-UV or blue light GaN-based LED applications. Orbital population analysis by density functional theory calculation (DFT) reveals that the near-UV excitation of La3BW(1-x)Mo(x)O9:Eu(3+) red phosphor is due to the electronic transition from the O 2p orbital to the W 5d and Mo 4d orbitals, respectively. With the introduction of Mo(6+) into the lattice, the band gap of La3BW(1-x)Mo(x)O9 becomes narrower than that of the pure phase La3BWO9. PMID- 25148115 TI - Maternal vitamin D status in preeclampsia: seasonal changes are not influenced by placental gene expression of vitamin D metabolizing enzymes. AB - Preeclampsia, a hypertensive disorder in pregnancy develops in 2-8% of pregnancies worldwide. Winter season and vitamin D deficiency have been associated with its onset. OBJECTIVE: To investigate the influence of season on maternal vitamin D status and placental vitamin D metabolism. METHODS: 25-OH vitamin D and 1,25-(OH)2 vitamin D were measured in maternal serum obtained during the winter or summer months from 63 pregnant women at delivery (43 healthy, 20 preeclampsia). In a subgroup, mRNA expression of CYP24A1 (24 hydroxylase), CYP27B1 (1alpha-hydroxylase) and VDR (vitamin D receptor) were quantified by real time PCR in placental samples of 14 women with normal pregnancies and 13 with preeclampsia. RESULTS: In patients with preeclampsia,25 OH vitamin D levels were lower, but differed significantly from controls only in summer (18.21+/-17.1 vs 49.2+/-29.2 ng/mL, P<0.001), whereas 1,25-(OH)2 vitamin D levels were significantly lower only in winter (291+/-217 vs 612.3+/-455 pmol/mL, P<0.05). A two-factorial analysis of variance produced a statistically significant model (P<0.0001) with an effect of season (P<0.01) and preeclampsia (P = 0.01) on maternal 25-OH vitamin D levels, as well as a significant interaction between the two variables (P = 0.02). Placental gene expression of CYP24A1, CYP27B1, and VDR did not differ between groups or seasons. A negative correlation between placental gene expression of CYP24A1 and CYP27B1 was observed only in healthy controls (r = -0.81, P<0.0001). SUMMARY: Patients with preeclampsia displayed lower vitamin D serum levels in response to seasonal changes.The regulation of placental CYP24A1, but not of the VDR or CYP27B1 might be altered in preeclampsia. PMID- 25148117 TI - Fabrication of silicon molds with multi-level, non-planar, micro- and nano-scale features. AB - A method for single-step fabrication of arbitrary, complex, three-dimensional (3D) silicon structures from the nano- to millimeter-scale at multiple levels on non-planar, curved, or domed surfaces is reported. The fabrication is based on focused or masked ion beam irradiation of p-type silicon followed by electrochemical anodization. The process allows fabrication of a wide range of surface features at multiple heights and with arbitrary orientations by varying the irradiated feature width, ion type, energy fluence, and subsequent anodization conditions. The technology has achieved depth resolution of 10 nm as step heights and is capable of creating lateral features down to 7 nm at high aspect ratios of up to 40, with surface roughness down to 1 nm scaled up to full wafer areas. The single-step ability has seamlessly interfaced a network of complex, integrated micro- to nano-structures in 3D orientations with no alignment required. The final template has been converted to a master copy for nano-imprinting lithography of 3D fluidic structures and optical components. PMID- 25148116 TI - Adipocyte hypertrophy, inflammation and fibrosis characterize subcutaneous adipose tissue of healthy, non-obese subjects predisposed to type 2 diabetes. AB - BACKGROUND: The adipose tissue is important for development of insulin resistance and type 2 diabetes and adipose tissue dysfunction has been proposed as an underlying cause. In the present study we investigated presence of adipocyte hypertrophy, and gene expression pattern of adipose tissue dysfunction in the subcutaneous adipose tissue of healthy, non-obese subjects predisposed to type 2 diabetes compared to matched control subjects with no known genetic predisposition for type 2 diabetes. METHOD: Seventeen healthy and non-obese subjects with known genetic predisposition for type 2 diabetes (first-degree relatives, FDRs) and 17 control subjects were recruited. The groups were matched for gender and BMI and had similar age. Glucose tolerance was determined by an oral glucose tolerance test and insulin sensitivity was calculated using HOMA index. Blood samples were collected and subcutaneous abdominal adipose tissue biopsies obtained for gene expression analysis and adipocyte cell size measurement. RESULTS: Our findings show that, in spite of similar age, BMI and percent body fat, FDRs displayed adipocyte hypertrophy, as well as higher waist/hip ratio, fasting insulin levels, HOMA-IR and serum triglycerides. Adipocyte hypertrophy in the FDR group, but not among controls, was associated with measures of impaired insulin sensitivity. The adipocyte hypertrophy was accompanied by increased inflammation and Wnt-signal activation. In addition, signs of tissue remodeling and fibrosis were observed indicating presence of early alterations associated with adipose tissue dysfunction in the FDRs. CONCLUSION: Genetic predisposition for type 2 diabetes is associated with impaired insulin sensitivity, adipocyte hypertrophy and other markers of adipose tissue dysfunction. A dysregulated subcutaneous adipose tissue may be a major susceptibility factor for later development of type 2 diabetes. PMID- 25148118 TI - Consumer e-health solutions: the cure for Baumol's disease? AB - Baumol's disease is the fact that costs in persistently labour-intensive sectors such as healthcare do not drop, despite increased use of technology. The idea of consumer e-health solutions is seductive, because it provides one option for treating Baumol's disease. However, barriers to the implementation of these solutions exist, and the successful treatment of Baumol's disease with consumer e health solutions rests on more than their removal. In this introduction, the editor-in-chief adds to the conversation four shifts that are critical to reaping the benefits of consumer e-health solutions: moving the focus from privacy to protection; from mere access to the use of information in decision-making; from the patient-provider dyad to one that includes a full formal and informal care team; and from structural solutions in healthcare to ones designed around the goals we have for our health system. PMID- 25148119 TI - Understanding the gap between desire for and use of consumer health solutions. AB - Modern healthcare is more complex than ever before, with a broader range of care providers, organizations, diagnostic approaches and treatments. The result is that accurate and timely information is more important than ever. In response, clinical use of health information technology has grown significantly in recent years and there is growing interest in the use of consumer health solutions. In this article, the authors discuss the current landscape of the latter in Canada, enablers and barriers to their adoption and our readiness for change. PMID- 25148120 TI - Reorienting health systems to meet the demand for consumer health solutions. AB - There is a clear and pronounced gap between the demand for and access to consumer health solutions. Existing health information systems and broader health system factors such as funding models are reasons for this gap. There are strong arguments from the perspectives of the consumer and population health for closing this gap, but the case from the perspective of the current health system is mixed. Closing the gap will require a concerted effort to reorient health information systems and funding models to support online access by consumers to health information and health services. PMID- 25148121 TI - The consumer health gap: are we innovating for the future or simply addressing the past? AB - The pace of adoption of consumer health solutions appears to be slow, despite some documented success. Reasons why the health system is not embracing this success are complex but not entirely unexpected. The barriers continue to be more a reflection of the state of our health system itself than of the patients who are demanding more involvement in the management of their care. The solution may lie in our willingness to be bolder in our vision for our future health system: for consumer health solutions to drive our focus on the management of chronic illness and self-care. The investments we make will require a measured prioritizing of the patient over the provider in building the health information technology systems of tomorrow. PMID- 25148122 TI - Facilitating consumer access to health information. AB - The lead paper from Zelmer and Hagens details the substantive evolution occurring in health information technologies that has the potential to transform the relationship between consumers, health practitioners and health systems. In this commentary, the authors suggest that Canada is experiencing a shift in consumer behaviour toward a desire to actively manage one's health and wellness that is being facilitated through the advent of health applications on mobile and online technologies platforms. The result is that Canadians are now able to create personalized health solutions based on their individual health values and goals. However, before Canadians are able to derive a personal health benefit from these rapid changes in information technology, they require and are increasingly demanding greater real-time access to their own health information to better inform decision-making, as well as interoperability between their personal health tracking systems and those of their health practitioner team. PMID- 25148123 TI - Facilitating the appropriate use of e-health solutions. AB - In this issue, the lead article proposes that e-health technologies should be used more broadly and that patients should have greater access to their information through such technologies. The Canadian Medical Protective Association (CMPA) agrees with this statement and suggests that to facilitate the timely and appropriate adoption of new technologies among healthcare providers to enhance patient care, barriers in the existing regulatory, legislative and legal frameworks must be addressed. While much of the discussion to date on e-health has focused primarily on high-level issues regarding regulatory compliance, "privacy by design" and the e-health "panacea," CMPA suggests that there needs to be a refocus on achieving more concrete change and gains through consideration of the specific impact on the drivers of healthcare delivery. An integrated or holistic approach is required involving healthcare providers, regulators, legislators, stakeholders, ministries of health, privacy commissioners and the courts. To better leverage potential advantages, efficiencies and enhanced, safer care for our healthcare system, all parties must work together to develop an acceptable and flexible approach to the "appropriate use" of e-health technologies that will facilitate adoption by healthcare professionals in a manner that is consistent with the expectations of the profession and applicable standards of practice. PMID- 25148124 TI - Stewardship of health information. AB - Today's communications technology has greatly facilitated patient access to health information in general. In some instances, and with a growing expectation and tendency, patients also have access to their own health information. This brief commentary focuses on the role of physicians and the medical profession from the perspective of the medical regulatory authority. PMID- 25148125 TI - Solutions for patient activation will yield the greatest benefit. AB - In the context of fiscal scarcity and abundant consumer health technologies, robust choices must be made. In this article, the authors assert that technologies that will yield the greatest return on investment for patients, providers and health system payers should be prioritized. They present three technology solutions that enable high-needs patients and their advocates to actively participate in their care: an audiovisual record of patient-education that can be accessed and shared post-consultation to improve retention; patient friendly care plans that enable more active participation in shared decision making; and personal health coaching to foster sustainable behaviour change. PMID- 25148126 TI - All aboard! AB - With technology and the health/wellness arena in the midst of a sea change that will revolutionize the system and allow more integration and information than ever before, this article reframes the discussion to broaden the opportunities for virtualization, enhanced information and communication and self-serve options. Considering these three consumer themes, the author explores how we can leverage current behaviours to achieve better connections with people, which will naturally lead to better uptake and help to narrow the gap between desire for and use of consumer health solutions. PMID- 25148127 TI - Node fingerprinting: an efficient heuristic for aligning biological networks. AB - With the continuing increase in availability of biological data and improvements to biological models, biological network analysis has become a promising area of research. An emerging technique for the analysis of biological networks is through network alignment. Network alignment has been used to calculate genetic distance, similarities between regulatory structures, and the effect of external forces on gene expression, and to depict conditional activity of expression modules in cancer. Network alignment is algorithmically complex, and therefore we must rely on heuristics, ideally as efficient and accurate as possible. The majority of current techniques for network alignment rely on precomputed information, such as with protein sequence alignment, or on tunable network alignment parameters, which may introduce an increased computational overhead. Our presented algorithm, which we call Node Fingerprinting (NF), is appropriate for performing global pairwise network alignment without precomputation or tuning, can be fully parallelized, and is able to quickly compute an accurate alignment between two biological networks. It has performed as well as or better than existing algorithms on biological and simulated data, and with fewer computational resources. The algorithmic validation performed demonstrates the low computational resource requirements of NF. PMID- 25148128 TI - Enantioselective and rapid Rh-catalyzed arylation of N-tosyl- and N nosylaldimines in methanol. AB - Enantiomerically enriched tosyl-protected diarylmethylamines were rapidly prepared by the asymmetric addition of arylboronic acids to N-tosylaldimines under mild conditions in the presence of a catalyst prepared in situ from Rh(I) and a chiral diene ligand. This methodology offers access to diarylmethylamines in good yields with excellent chiral purity at room temperature using MeOH as a solvent and NEt3 as a base. Its synthetic utility was demonstrated by the preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (14), an antagonist of the N-methyl-d-aspartate (NMDA) receptor. PMID- 25148129 TI - The Development of a Novel Measure to Assess Motives for Compensatory Eating in Response to Exercise: The CEMQ. AB - Compensatory eating in response to exercise may be an obstacle to achieving weight-loss and fitness goals. In this study we develop and conduct a preliminary examination of the psychometric properties of the Compensatory Eating Motives Questionnaire (CEMQ), a self-report questionnaire of motives for compensatory eating. Development and testing of the CEMQ was conducted in two student samples. Of respondents, 75% reported engaging in compensatory eating. Factor analysis yielded factors representing three domains of motives for compensatory eating: Eating for Reward, Eating for Recovery, and Eating for Relief. Internal consistency of the factors was adequate, and the factor structure was replicated. Correlations between the CEMQ subscales and trait questionnaires supported hypotheses for convergent and divergent validity. These results encourage further investigation of compensatory eating as a potential obstacle to weight loss, and support the continued assessment of the CEMQ as a tool to measure three conceptually distinct motives for compensatory eating. PMID- 25148132 TI - Terbium(III) and yttrium(III) complexes with pyridine-substituted nitronyl nitroxide radical and different beta-diketonate ligands. Crystal structures and magnetic and luminescence properties. AB - A terbium(III) complex of nitronyl nitroxide free radical 2-(2-pyridyl)-4,4,5,5 tetramethyl-4,5-dihydro1H-imidazolyl-1-oxy-3-oxide (NIT2Py), [Tb(acac)3NIT2Py].0.5H2O (3) (acac = acetylacetonate), was synthesized for comparison with the previously reported [Tb(hfac)3NIT2Py].0.5C7H16 (1) (hfac = hexafluoroacetylacetonate), together with their yttrium analogues [Y(hfac)3NIT2Py].0.5C7H16 (2) and [Y(acac)3NIT2Py].0.5H2O (4). The crystal structures show that in all complexes the nitronyl nitroxide radical acts as a chelating ligand. Magnetic studies show that 3 like 1 exhibits slow relaxation of magnetization at low temperature, suggesting single-molecule magnet behavior. The luminescence spectra show resolved vibronic structure with the main interval decreasing from 1600 cm(-1) to 1400 cm(-1) between 80 and 300 K. This effect is analyzed quantitatively using experimental Raman frequencies. PMID- 25148131 TI - Regulation of the biological functions of osteoblasts and bone formation by Zn incorporated coating on microrough titanium. AB - To improve the biological performance of titanium implant, a series of Zn incorporated coatings were fabricated on the microrough titanium (Micro-Ti) via sol-gel method by spin-coating technique. The successful fabrication of the coating was verified by combined techniques of scanning electron microscopy, surface profiler, X-ray diffraction, X-ray photoelectron spectroscopy, and water contact angle measurements. The incorporated zinc existed as ZnO, which released Zn ions in a sustained manner. The Zn-incorporated samples (Ti-Zn0.08, Ti-Zn0.16, and Ti-Zn0.24) efficiently inhibited the adhesion of both Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria. The in vitro evaluations including cell activity, alkaline phosphatase (ALP), mineralization, osteogenic genes expressions (Runx2, ALP, OPG, Col I, OPN, and OC), and tartrate-resistant acid phosphatase, confirmed that Ti-Zn0.16 sample was the optimal one to regulate the proliferation or differentiation for both osteoblasts and osteoclasts. More importantly, in vivo evaluations including Micro-CT analysis, push-out test, and histological observations verified that Ti Zn0.16 implants could efficiently promote new bone formation after implantation for 4 and 12 weeks, respectively. The resulting material thus has potential application in orthopedic field. PMID- 25148133 TI - Health spending and political influence: the case of earmarks and health care facilities. AB - Earmarks, otherwise known as Congressionally directed spending requests, are a historically significant means of political influence over budgets. In this brief, we report on the results of a longitudinal study of federal earmarks affecting health care facilities and public health. We analyzed 10 years of earmark for health care facilities and examined the correlates of being in the top 50% of earmark recipients for each year. Having representatives or senators serving on the respective Appropriations committees were shown to have increased odds of being a top earmark recipient, as was being in jurisdictions with greater poverty. However, health-related measures of need were not significantly associated with being a top earmark recipient. PMID- 25148130 TI - Contractile force is enhanced in Aortas from pendrin null mice due to stimulation of angiotensin II-dependent signaling. AB - Pendrin is a Cl-/HCO3- exchanger expressed in the apical regions of renal intercalated cells. Following pendrin gene ablation, blood pressure falls, in part, from reduced renal NaCl absorption. We asked if pendrin is expressed in vascular tissue and if the lower blood pressure observed in pendrin null mice is accompanied by reduced vascular reactivity. Thus, the contractile responses to KCl and phenylephrine (PE) were examined in isometrically mounted thoracic aortas from wild-type and pendrin null mice. Although pendrin expression was not detected in the aorta, pendrin gene ablation changed contractile protein abundance and increased the maximal contractile response to PE when normalized to cross sectional area (CSA). However, the contractile sensitivity to this agent was unchanged. The increase in contractile force/cross sectional area observed in pendrin null mice was due to reduced cross sectional area of the aorta and not from increased contractile force per vessel. The pendrin-dependent increase in maximal contractile response was endothelium- and nitric oxide-independent and did not occur from changes in Ca2+ sensitivity or chronic changes in catecholamine production. However, application of 100 nM angiotensin II increased force/CSA more in aortas from pendrin null than from wild type mice. Moreover, angiotensin type 1 receptor inhibitor (candesartan) treatment in vivo eliminated the pendrin-dependent changes contractile protein abundance and changes in the contractile force/cross sectional area in response to PE. In conclusion, pendrin gene ablation increases aorta contractile force per cross sectional area in response to angiotensin II and PE due to stimulation of angiotensin type 1 receptor-dependent signaling. The angiotensin type 1 receptor-dependent increase in vascular reactivity may mitigate the fall in blood pressure observed with pendrin gene ablation. PMID- 25148135 TI - Controllable doping and wrap-around contacts to electrolessly etched silicon nanowire arrays. AB - Top-down electroless chemical etching enables non-lithographic patterning of wafer-scale nanostructured arrays, but the etching on highly doped wafers produces porous structures. The lack of defect-free nanostructures at desired doping and the difficulties in forming reliable electrical side-contacts to the nanostructure arrays limits their integration into high performance nanoelectronics. We developed a barrier layer diffusion technique to controllably dope wafer-scale silicon nanowire arrays (10(17)-10(20) cm(-3)) produced by chemically etching lightly doped silicon wafers. In order to achieve low resistance top-side electrical contacts to the arrays, we developed a two step tip-doping procedure to locally dope the tips (~10(20) cm(-3)) to metallic levels. The dopant concentration is characterized by depth profiling using secondary ion mass spectroscopy and four-point probe electrical measurements. Further, array scale electrical measurements show that the tip-doping lowers the specific contact resistivity (~10(-5) Omega cm(2)) since the metallic tips enable direct tunneling of electrons across the nickel silicide contacts to the nanowire arrays. This work provides a scalable and cost-effective doping approach to control charge injection and charge conduction in nanowire arrays, thus advancing their integration into various device applications. PMID- 25148134 TI - Large-scale phylogenetic classification of fungal chitin synthases and identification of a putative cell-wall metabolism gene cluster in Aspergillus genomes. AB - The cell wall is a protective and versatile structure distributed in all fungi. The component responsible for its rigidity is chitin, a product of chitin synthase (Chsp) enzymes. There are seven classes of chitin synthase genes (CHS) and the amount and type encoded in fungal genomes varies considerably from one species to another. Previous Chsp sequence analyses focused on their study as individual units, regardless of genomic context. The identification of blocks of conserved genes between genomes can provide important clues about the interactions and localization of chitin synthases. On the present study, we carried out an in silico search of all putative Chsp encoded in 54 full fungal genomes, encompassing 21 orders from five phyla. Phylogenetic studies of these Chsp were able to confidently classify 347 out of the 369 Chsp identified (94%). Patterns in the distribution of Chsp related to taxonomy were identified, the most prominent being related to the type of fungal growth. More importantly, a synteny analysis for genomic blocks centered on class IV Chsp (the most abundant and widely distributed Chsp class) identified a putative cell wall metabolism gene cluster in members of the genus Aspergillus, the first such association reported for any fungal genome. PMID- 25148136 TI - Conformational selection and functional dynamics of calmodulin: a (19)F nuclear magnetic resonance study. AB - Calcium-bound calmodulin (CaM-4Ca(2+)) is innately promiscuous with regard to its protein interaction network within the cell. A key facet of the interaction process involves conformational selection. In the absence of a binding peptide, CaM-4Ca(2+) adopts an equilibrium between a native state (N) and a weakly populated near-native peptide-bound-like state (I), whose lifetime is on the order of 1.5 ms at 37 degrees C, based on (19)F nuclear magnetic resonance (NMR) Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion measurements. This peptide bound-like state of CaM-4Ca(2+) is entropically stabilized (DeltaS = 280 +/- 35 J mol(-1) K(-1)) relative to the native state, water-depleted, and likely parental to specific bound states. Solvent depletion, conformational selection, and flexibility of the peptide-bound-like state may be important in priming the protein for binding. At higher temperatures, the exchange rate, kex, appears to markedly slow, suggesting the onset of misfolded or off-pathway states, which retards interconversion between N and I. (19)F NMR CPMG relaxation dispersion experiments with both CaM-4Ca(2+) and the separate N-terminal and C-terminal domains reveal the cooperative role of the two domains in the binding process and the flexibility of the N-terminal domain in facilitating binding. Thus, when calcium binds, calmodulin establishes its interaction with a multitude of protein binding partners, through a combination of conformational selection to a state that is parental to the peptide-bound state and, finally, induced fit. PMID- 25148139 TI - Broad geographic analyses reveal varying patterns of genetic diversity and host specificity among echinostome trematodes in New Zealand snails. AB - Host specificity is a fundamental component of a parasite's life history. However, accurate assessments of host specificity, and the factors influencing it, can be obscured by parasite cryptic species complexes. We surveyed two congeneric species of intertidal snail intermediate hosts, Zeacumantus subcarinatus and Zeacumantus lutulentus, throughout New Zealand to identify the number of genetically distinct echinostome trematodes infecting them and determine the levels of snail host specificity among echinostomes. Two major echinostome clades were identified: a clade consisting of an unidentified species of the subfamily Himasthlinae and a clade consisting of five species of the genus Acanthoparyphium. All five Acanthoparyphium species were only found in a single snail species, four in Z. subcarinatus and one in Z. lutulentus. In contrast, the Himasthlinae gen. sp. was found in both hosts, but was more prevalent in Z. lutulentus (97 infections) than Z. subcarinatus (10 infections). At least two of the Acanthoparyphium spp. and the Himasthlinae gen. sp. are widespread throughout New Zealand, and can therefore encounter both snail species. Our results suggest that host specificity is determined by host-parasite incompatibilities, not geographic separation, and that it can evolve in different ways in closely related parasite lineages. PMID- 25148140 TI - Adsorption properties of p-methyl red monomeric-to-pentameric dye aggregates on anatase (101) titania surfaces: first-principles calculations of dye/TiO2 photoanode interfaces for dye-sensitized solar cells. AB - The optical and electronic properties of dye aggregates of p-methyl red on a TiO2 anatase (101) surface were modeled as a function of aggregation order (monomer to pentameric dye) via first-principles calculations. A progressive red-shifting and intensity increase toward the visible region in UV-vis absorption spectra is observed from monomeric-to-tetrameric dyes, with each molecule in a given aggregate binding to one of the four possible TiO2 (101) adsorption sites. The pentamer exhibits a blue-shifted peak wavelength in the UV-vis absorption spectra and less absorption intensity in the visible region in comparison; a corresponding manifestation of H-aggregation occurs since one of these five molecules cannot occupy an adsorption site. This finding is consistent with experiment. Calculated density of states (DOS) and partial DOS spectra reveal similar dye...TiO2 nanocomposite conduction band characteristics but different valence band features. Associated molecular orbital distributions reveal dye-to TiO2 interfacial charge transfer in all five differing aggregate orders; meanwhile, the level of intramolecular charge transfer in the dye becomes progressively localized around its azo- and electron-donating groups, up to the tetrameric dye/TiO2 species. Dye adsorption energies and dye coverage levels are calculated and compared with experiment. Overall, the findings of this case study serve to aid the molecular design of azo dyes toward better performing DSSC devices wherein they are incorporated. In addition, they provide a helpful example reference for understanding the effects of dye aggregation on the adsorbate...TiO2 interfacial optical and electronic properties. PMID- 25148137 TI - Prophylaxis of post-ERCP pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - updated June 2014. AB - This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). It addresses the prophylaxis of post endoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis. Main recommendations 1 ESGE recommends routine rectal administration of 100 mg of diclofenac or indomethacin immediately before or after ERCP in all patients without contraindication. In addition to this, in the case of high risk for post ERCP pancreatitis (PEP), the placement of a 5-Fr prophylactic pancreatic stent should be strongly considered. Sublingually administered glyceryl trinitrate or 250 ug somatostatin given in bolus injection might be considered as an option in high risk cases if nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated and if prophylactic pancreatic stenting is not possible or successful. 2 ESGE recommends keeping the number of cannulation attempts as low as possible. 3 ESGE suggests restricting the use of a pancreatic guidewire as a backup technique for biliary cannulation to cases with repeated inadvertent cannulation of the pancreatic duct; if this method is used, deep biliary cannulation should be attempted using a guidewire rather than the contrast assisted method and a prophylactic pancreatic stent should be placed. 4 ESGE suggests that needle-knife fistulotomy should be the preferred precut technique in patients with a bile duct dilated down to the papilla. Conventional precut and transpancreatic sphincterotomy present similar success and complication rates; if conventional precut is selected and pancreatic cannulation is easily obtained, ESGE suggests attempting to place a small-diameter (3-Fr or 5-Fr) pancreatic stent to guide the cut and leaving the pancreatic stent in place at the end of ERCP for a minimum of 12 - 24 hours. 4 ESGE does not recommend endoscopic papillary balloon dilation as an alternative to sphincterotomy in routine ERCP, but it may be advantageous in selected patients; if this technique is used, the duration of dilation should be longer than 1 minute. PMID- 25148141 TI - An alumina stabilized ZnO-graphene anode for lithium ion batteries via atomic layer deposition. AB - Atomic layer deposition (ALD) was applied to deposit ZnO on graphene aerogel, and this composite was used as an anode material for lithium ion batteries. This electrode material was further modified by an ultrathin Al2O3 layer via ALD to stabilize its electrochemical stability. These two metal oxides were uniformly immobilized on graphene frameworks, and the Al2O3 coating strongly improved the electrochemical performances of ZnO-graphene aerogel composite anodes. Particularly, the composite with 10 ALD cycles of Al2O3 coating (denoted as ZnO-G 10) exhibited a high initial discharge capacity of 1513 mA h g(-1) and maintained a reversible capacity of 490 mA h g(-1) after 100 cycles at a current density of 100 mA g(-1). Furthermore, the capacity retention rate increased from 70% to 90% in comparison with its uncoated counterpart after 100 cycles. The ZnO-G-10 anode also showed good rate-capability, delivering a discharge capacity of 415 mA h g( 1) at 1000 mA g(-1). The improved electrochemical performance is attributed to the formation of an artificial solid electrolyte interphase layer, stabilizing ZnO and the electrolyte by preventing the aggregation of Zn/ZnO nanograins and the side reaction that would cause the degradation of anodes. PMID- 25148143 TI - HPB News. PMID- 25148145 TI - General Introduction. PMID- 25148144 TI - Common exposure to STL polyomavirus during childhood. AB - STL polyomavirus (STLPyV) was recently identified in human specimens. To determine seropositivity for STLPyV, we developed an ELISA and screened patient samples from 2 US cities (Denver, Colorado [500]; St. Louis, Missouri [419]). Overall seropositivity was 68%-70%. The age-stratified data suggest that STLPyV infection is widespread and commonly acquired during childhood. PMID- 25148146 TI - Conformationally switchable non-cyclic tetrapyrrole receptors: synthesis of tetrakis(1H-pyrrole-2-carbaldehyde) derivatives and their anion binding properties. AB - A series of tetrakis(1H-pyrrole-2-carbaldehyde) receptors (2, 4, and 6) were synthesized in two steps from commercially available starting materials. The anion binding properties of these receptors can be tuned through electronic switching to stabilize a conformation displaying high affinity for the dihydrogenphosphate and pyrophosphate anions (as the tetrabutylammonium salts) in chloroform. PMID- 25148142 TI - Eukaryotic initiation factor 4G suppresses nonsense-mediated mRNA decay by two genetically separable mechanisms. AB - Nonsense-mediated mRNA decay (NMD), which is best known for degrading mRNAs with premature termination codons (PTCs), is thought to be triggered by aberrant translation termination at stop codons located in an environment of the mRNP that is devoid of signals necessary for proper termination. In mammals, the cytoplasmic poly(A)-binding protein 1 (PABPC1) has been reported to promote correct termination and therewith antagonize NMD by interacting with the eukaryotic release factors 1 (eRF1) and 3 (eRF3). Using tethering assays in which proteins of interest are recruited as MS2 fusions to a NMD reporter transcript, we show that the three N-terminal RNA recognition motifs (RRMs) of PABPC1 are sufficient to antagonize NMD, while the eRF3-interacting C-terminal domain is dispensable. The RRM1-3 portion of PABPC1 interacts with eukaryotic initiation factor 4G (eIF4G) and tethering of eIF4G to the NMD reporter also suppresses NMD. We identified the interactions of the eIF4G N-terminus with PABPC1 and the eIF4G core domain with eIF3 as two genetically separable features that independently enable tethered eIF4G to inhibit NMD. Collectively, our results reveal a function of PABPC1, eIF4G and eIF3 in translation termination and NMD suppression, and they provide additional evidence for a tight coupling between translation termination and initiation. PMID- 25148147 TI - Reviewer assistance: how important is the invitation letter? PMID- 25148148 TI - Postmortem CT appearance of gas collections in fatal diving accidents. AB - OBJECTIVE. The purpose of our study was to define the postmortem CT semiology of gas collections linked to putrefaction, postmortem "off-gassing," and decompression illness after fatal diving accidents and to establish postmortem CT diagnostic criteria to distinguish the different causes of death in diving. SUBJECTS AND METHODS. A 4-year prospective study was conducted including cases of death during diving. A hyperbaric physician analyzed the circumstances of death and the dive profile, and an autopsy was performed. Subjects were divided into three groups according to the analysis from their dive profile: decompression illness, death after decompression dive without decompression illness, and death after nondecompression dive without decompression illness. Full-body postmortem CT was performed before autopsy. RESULTS. The presence of intraarterial gas associated with death by decompression illness had a negative predictive value (NPV) of 100%, but the positive predictive value (PPV) was only 54% because of postmortem off-gassing. The PPV reached 70% when considering pneumatization of the supraaortic trunks. Pneumothorax, subcutaneous emphysema, and intraarterial gas, all of which are classic criteria for decompression illness diagnosis, are not specific for decompression illness. CONCLUSION. This study is the first to show that pneumothorax, subcutaneous emphysema, and intraarterial gas, all of which are classic criteria for decompression illness diagnosis, are not specific for decompression illness. Complete pneumatization of supraaortic trunks is the best postmortem CT criteria to detect a fatal decompression illness when CT is performed within 24 hours after death. PMID- 25148149 TI - Section editor's notebook: pearls, pitfalls, and errors in musculoskeletal diagnosis. PMID- 25148150 TI - Misses and errors in upper extremity trauma radiographs. AB - OBJECTIVE: The article reviews a select group of traumatic upper extremity injuries that can be easily misinterpreted on radiographs. CONCLUSION: The awareness of these specific injuries and an understanding of their underlying pathophysiology and the role that radiographs can play in their evaluation will give the reader the best opportunity to make the important imaging findings and guide appropriate treatment. PMID- 25148151 TI - Radiographic pitfalls in lower extremity trauma. AB - OBJECTIVE: Radiography remains the imaging standard for fracture detection after trauma. However, fractures continue to be the most common type of missed injuries. In this article, we describe common radiographic pitfalls in lower extremity trauma and describe strategies for dealing with them. CONCLUSION: Pitfalls include insufficient views, improperly positioned or technically imperfect radiographs, nondisplaced fractures, commonly missed locations, small avulsions portending large injury, sesamoid injuries, satisfaction of search, incomplete or faulty reasoning, and periprosthetic fractures. PMID- 25148152 TI - Pitfalls in shoulder MRI: part 1--normal anatomy and anatomic variants. AB - OBJECTIVE: The purpose of this article is to review frequently encountered pitfalls as they pertain to normal and variant anatomy of the shoulder, including the rotator cuff and rotator cable, blood vessels, glenoid labrum, and the glenohumeral ligaments. CONCLUSION: MRI is the preferred method for evaluating internal derangement of the shoulder. Radiologists interpreting MR images should have a detailed understanding of pertinent anatomy and knowledge of common and uncommon pitfalls to avoid during image interpretation. PMID- 25148153 TI - Pitfalls in shoulder MRI: part 2--biceps tendon, bursae and cysts, incidental and postsurgical findings, and artifacts. AB - OBJECTIVE: The purpose of this article is to review frequently encountered pitfalls as they pertain to the biceps tendon, bursae and cysts around the shoulder, incidental findings, postsurgical findings, and frequently encountered imaging artifacts. CONCLUSION: Imaging pitfalls in and around the shoulder are not limited to normal anatomy and anatomic variants. Radiologists must be cognizant of the vast variability of structures in the shoulder and of the incidental and postsurgical findings and artifacts affecting them. PMID- 25148154 TI - Pitfalls and pearls in MRI of the knee. AB - OBJECTIVE: The purpose of this article is to review the common pitfalls in MRI of the knee and pearls on how to avoid them. CONCLUSION: MRI of the knee is highly accurate in evaluation of internal derangements of the knee. However, a variety of potential pitfalls in interpretation of abnormalities related to the knee have been identified, particularly in evaluation of the menisci, ligaments, and articular cartilage. PMID- 25148155 TI - Pitfalls in wrist and hand ultrasound. AB - OBJECTIVE: The purpose of this article is to review a number of diagnostic pitfalls related to ultrasound evaluation of the hand and wrist. Such pitfalls relate to evaluation of ten-dons (extensor retinaculum, multiple tendon fascicles, tendon subluxation), inflammatory arthritis (incomplete evaluation, misinterpretation of erosions, failure to evaluate for enthesitis), carpal tunnel syndrome (inaccurate measurements, postoperative assessment), ulnar collateral ligament of the thumb (misinterpretation of the adductor aponeurosis and displaced tear), wrist ganglion cysts (incomplete evaluation and misdiagnosis), and muscle variants. CONCLUSION: Although ultrasound has been shown to be an effective imaging method for assessment of many pathologic conditions of the wrist, knowledge of potential pitfalls is essential to avoid misdiagnosis and achieve high diagnostic accuracy. PMID- 25148156 TI - Spectrum of carpal dislocations and fracture-dislocations: imaging and management. AB - OBJECTIVE: The objectives of this article are to discuss the imaging of carpal dislocations and fracture-dislocations and to review the ligamentous anatomy of the wrist, mechanisms of injury, and routine management of these injuries. CONCLUSION: Perilunate dislocations, perilunate fracture-dislocations (PLFDs), and lunate dislocations are high-energy wrist injuries that can and should be recognized on radio-graphs. These injuries are a result of important sequential osseous and ligamentous injuries or failures. Prompt and accurate radiographic diagnosis aids in the management of patients with perilunate dislocations, PLFDs, and lunate dislocations while assisting orthopedic surgeons with subsequent surgical planning. CT may better show the extent of the injury and help in treatment planning particularly in cases of delayed treatment or chronic perilunate dislocation. A CT examination with coronal, sagittal, and 3D reformatted images is ordered at our institution in cases in which the extent of the carpal injuries is poorly shown on radiographic examination. PMID- 25148157 TI - Fracture of the distal radius: epidemiology and premanagement radiographic characterization. AB - OBJECTIVE: Fractures of the distal radius are common and frequently encountered by the radiologist. We review the epidemiology, classification, as well as the concept of instability. Salient qualitative and quantitative features of the distal radius fracture identifiable on the routine radiography series are highlighted. We conclude with a synopsis of descriptors that are of greatest utility to the clinician for treatment planning and that should be addressed in the radiology report. CONCLUSION: A detailed understanding of the intricacies of the distal radius fracture is necessary for the radiologist to provide a clinically relevant description. PMID- 25148158 TI - Insights into quantitative diffusion-weighted MRI for musculoskeletal tumor imaging. AB - OBJECTIVE: The purposes of this article are to discuss the technical considerations for performing quantitative diffusion-weighted MRI (DWI) with apparent diffusion coefficient (ADC) mapping, examine the role of DWI in whole body MRI, and review how DWI with ADC mapping can serve as an adjunct to information gleaned from conventional MRI in the radiologic evaluation of musculoskeletal lesions. CONCLUSION: The primary role of whole-body DWI is in tumor detection; localized DWI is helpful in differentiating malignant bone and soft-tissue lesions. After treatment, an increase in tumor ADC values correlates with response to cytotoxic therapy. The use of DWI in the evaluation of musculoskeletal lesions requires knowledge of potential diagnostic pitfalls that stem from technical challenges and confounding biochemical factors that influence ADC maps but are unrelated to lesion cellularity. PMID- 25148159 TI - Imaging of current spinal hardware: lumbar spine. AB - OBJECTIVE: The purposes of this article are to review the indications for and the materials and designs of hardware more commonly used in the lumbar spine; to discuss alternatives for each of the types of hardware; to review normal postoperative imaging findings; to describe the appropriateness of different imaging modalities for postoperative evaluation; and to show examples of hardware complications. CONCLUSION: Stabilization and fusion of the lumbar spine with intervertebral disk replacement, artificial ligaments, spinous process distraction devices, plate-and-rod systems, dynamic posterior fusion devices, and newer types of material incorporation are increasingly more common in contemporary surgical practice. These spinal hardware devices will be seen more often in radiology practice. Successful postoperative radiologic evaluation of this spinal hardware necessitates an understanding of fundamental hardware design, physiologic objectives, normal postoperative imaging appearances, and unique complications. Radiologists may have little training and experience with the new and modified types of hardware used in the lumbar spine. PMID- 25148160 TI - Quantitative evaluation of benign and malignant vertebral fractures with diffusion-weighted MRI: what is the optimum combination of b values for ADC-based lesion differentiation with the single-shot turbo spin-echo sequence? AB - OBJECTIVE: The purpose of our study was to determine the optimum combination of b values for calculating the apparent diffusion coefficient (ADC) using a diffusion weighted (DW) single-shot turbo spin-echo (TSE) sequence in the differentiation between acute benign and malignant vertebral body fractures. SUBJECTS AND METHODS: Twenty-six patients with osteoporotic (mean age, 69 years; range, 31.5 86.2 years) and 20 patients with malignant vertebral fractures (mean age, 63.4 years; range, 24.7-86.4 years) were studied. T1-weighted, STIR, and T2-weighted sequences were acquired at 1.5 T. A DW single-shot TSE sequence at different b values (100, 250, 400, and 600 s/mm(2)) was applied. On the DW images for each evaluated fracture, an ROI was manually adapted to the area of hyperintense signal intensity on STIR-hypointense signal on T1-weighted images. For each ROI, nine different combinations of two, three, and four b values were used to calculate the ADC using a least-squares algorithm. The Student t test and Mann Whitney U test were used to determine significant differences between benign and malignant fractures. An ROC analysis and the Youden index were used to determine cutoff values for assessment of the highest sensitivity and specificity for the different ADC values. The positive (PPV) and negative predictive values (NPV) were also determined. RESULTS: All calculated ADCs (except the combination of b = 400 s/mm(2) and b = 600 s/mm(2)) showed statistically significant differences between benign and malignant vertebral body fractures, with benign fractures having higher ADCs than malignant ones. The use of higher b values resulted in lower ADCs than those calculated with low b values. The highest AUC (0.85) showed the ADCs calculated with b = 100 and 400 s/mm(2), and the second highest AUC (0.829) showed the ADCs calculated with b = 100, 250, and 400 s/mm(2). The Youden index with equal weight given to sensitivity and specificity suggests use of an ADC calculated with b = 100, 250, and 400 s/mm(2) (cutoff ADC, < 1.7 * 10(-3) mm(2)/s) to best diagnose malignancy (sensitivity, 85%; specificity, 84.6%; PPV, 81.0%; NPV, 88.0%). CONCLUSION: ADCs calculated with a combination of low to intermediate b values (b = 100, 250, and 400 s/mm(2)) provide the best diagnostic performance of a DW single-shot TSE sequence to differentiate acute benign and malignant vertebral body fractures. PMID- 25148161 TI - Correlation of ultrasound-guided corticosteroid injection of the quadratus femoris with MRI findings of ischiofemoral impingement. AB - OBJECTIVE: MRI findings of ischiofemoral impingement (IFI) have been described, but there is little evidence for treatment with ultrasound-guided corticosteroid injection. The purpose of this study was to evaluate the effectiveness of ultrasound-guided corticosteroid injection of the quadratus femoris muscle as a treatment of IFI syndrome and to correlate the MRI findings with injection outcome. MATERIALS AND METHODS: The medical records of 61 consecutively registered subjects who underwent bony pelvis MRI in which either IFI or quadratus femoris edema was described in the radiology report were retrospectively reviewed. Subjects with MRI findings of IFI and clinical confirmation of pain that could be attributed to IFI were included and divided into injection and control groups based on clinical management. Control subjects had MRI findings and clinical symptoms suggestive of IFI but underwent conservative therapy rather than injection. The control patients had adequate follow-up and clinical documentation to determine their response to treatment. Quadratus femoris muscle edema, fat atrophy, and hamstring tendinopathy were graded from none to severe (grades 0-3). The ischiofemoral and quadratus femoris spaces were also measured. Clinical presentation was classified as typical, somewhat typical, or not typical of IFI. Injection effectiveness was determined by reported pain reduction assessed before, immediately after, and 2 weeks after the procedure with a standard 10-cm visual analog scale. Response to treatment was classified as good (reduction in pain level > 2), mild or partial (reduced by 1 or 2), or no improvement. For patients who did not return their 2-week postinjection pain surveys, injection effectiveness was determined by qualitative assessments found in their clinical notes. A Kruskal-Wallis rank sum test was used to compare effectiveness of injection between groups (p < 0.05). The Fisher exact test was used to evaluate for associations between each MRI finding and injection outcome. RESULTS: Of the 61 patients, 20 patients had both MRI findings and clinical confirmation of pain related to IFI. These 20 patients were included in the study. Fifteen ultrasound-guided injections were performed in seven patients, and these seven patients were included in the injection group (mean age, 47 years; range, 15-66 years); 13 patients were included in the control group (mean age, 42 years; range, 16-62 years). All seven patients in the injection group and 12 of the 13 patients in the control group were women. In the injection group, the mean width of the ischiofemoral space was 12 mm (range, 7-22 mm), and the mean width of the quadratus femoris space was 9 mm (range, 5-16 mm). The mean edema grade was 1.4 (range, 0-3); mean atrophy grade, 1.4 (range, 0-3); and mean hamstring tendinopathy grade, 1 (range, 0-2). In the control group, the mean width of the ischiofemoral space was 9 mm (range, 6-17 mm); mean quadratus femoris space width, 7 mm (range, 3-15 mm); mean edema grade, 1.9 (range, 1-3); mean atrophy grade, 1.2 (range, 0-3); and mean hamstring tendinopathy grade, 1.2 (range, 0-3). No statistical difference was seen between the two groups before treatment. Pain reduction after injection over the 2-week period was statistically significant with a mean reduction of 1.7 (range, 1-2) for the injection group and 0.8 (range, 0-2) for the control group (p < 0.01). Eleven of 15 (73%) of the injections provided good relief, and four of 15 (27%) provided mild relief. None of the 15 injections provided no relief. In the control group, four of 14 (29%) subjects had good relief, three of 14 (21%) had mild relief, and seven of 14 (50%) had no relief (p < 0.01). CONCLUSION: Ultrasound-guided corticosteroid injection of the quadratus femoris muscle shows promise as an effective treatment of IFI syndrome. However, larger longitudinal studies are needed to help establish the role of ultrasound-guided injection in the workup and care of patients presenting with both MRI findings and clinical findings of IFI. PMID- 25148162 TI - CT of the bronchopulmonary veins in patients with superior vena cava or left brachiocephalic vein obstruction. AB - OBJECTIVE: The purpose of this study was to show the arrangement and connections of the bronchopulmonary veins (i.e., vessels draining the bronchi, bronchioles, and pleura in patients with chronic superior vena cava (SVC) or left brachiocephalic vein (LBCV) obstruction using CT. MATERIALS AND METHODS: Contrast enhanced CT scans of the chest of 16 patients with chronic SVC or LBCV obstruction were analyzed retrospectively. Scans were acquired using various standard protocols. The mean age of the patients (10 men and six women) was 63 years (range, 41-86 years). The causes of obstruction were malignancy (7/16, 44%), catheter-related thrombosis (7/16, 44%), chronic fibrosing mediastinitis (1/16, 6%), and unknown (1/16, 6%). RESULTS: The following sites were obstructed: SVC (9/16, 56%), SVC below the azygos vein (4/16, 25%), and lower LBCV (3/16, 19%). The bronchopulmonary veins were opacified via the brachiocephalic, azygos, or accessory hemiazygos veins or their branches. We observed long vessels that could be traced along the lateral mediastinum or alongside the trachea and central bronchi to their termination in the central pulmonary veins from the level of the ostia to segmental divisions. These vessels intercommunicated and gave rise to smaller veins contiguous with the walls of the bronchi and pulmonary arteries. The pulmonary venous connections of the bronchopulmonary veins were more frequent with the lower lobe pulmonary veins. Pericardial and esophageal veins were also opacified through the brachiocephalic or azygos veins and anastomosed commonly with the bronchopulmonary veins. CONCLUSION: The arrangement and connections of the bronchopulmonary veins in patients with chronic SVC or LBCV obstruction can be depicted by CT; these vessels form an intricate network connecting the systemic and pulmonary venous circulations and can act as systemic pulmonary shunts. PMID- 25148163 TI - Dual-energy liver CT: effect of monochromatic imaging on lesion detection, conspicuity, and contrast-to-noise ratio of hypervascular lesions on late arterial phase. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of use of dual energy CT monochromatic imaging in the late hepatic arterial phase on hyperenhancing focal lesion detection and lesion conspicuity. SUBJECTS AND METHODS: This prospective study included 72 patients imaged with a single-source dual-energy CT scanner. Late arterial phase imaging was performed with dual energies of 140 and 80 kVp, and the portal venous and delayed phases were performed with a single energy of 120 kVp. Two deidentified image sets were created: set A consisted of 77-keV images only, and set B consisted of 40-, 50-, 70-, and 77-keV images and iodine-based contrast material decomposition images. Two independent reviewers identified hypervascular lesions and subjectively scored lesion conspicuity. Contrast-to-noise ratios were calculated, and radiation dose (volume CT dose index) was recorded. RESULTS: The 128 lesions identified had a mean size of 1.7 +/- 1.4 cm. There was no difference in lesion detection between the two reviewers or the two image sets. The contrast-to-noise ratio at 50 keV was 72% greater than that at 77 keV (p < 0.0001). Subjective conspicuity was statistically greatest at 50 keV (p < 0.0001). There was no statistical difference in mean volume CT dose index between the dual-energy (12.8 mGy) and the two single-energy (14.4 and 14.2 mGy) phases. CONCLUSION: Viewing dual-energy CT images may result in the greatest subjective lesion conspicuity and measured contrast-to-noise ratio at 50 keV with equal detection of hyperenhancing liver lesions compared with viewing 77-keV images alone. In addition, the radiation doses of dual-energy CT may be similar to those of single energy CT. PMID- 25148164 TI - Acinarization (parenchymal blush) observed during secretin-enhanced MRCP: clinical implications. AB - OBJECTIVE: T2 hyperintensity of pancreatic acini during secretin-enhanced MRCP is called "acinarization." We sought to determine the clinical significance of this finding. MATERIALS AND METHODS: Patients were selected if the radiology report included the phrases "acin*" (where * represented a wild card search) or "blush" using the institution's customized lexicon-search software. Sixty-seven consecutive patients without acinarization on secretin-enhanced MRCP who also underwent ERCP were enrolled as the control group. The intensity of acinarization was classified into three groups: grade 0, no visible acinarization; grade 1, barely visible parenchymal hyperintensity; or grade 2, easily visible parenchymal hyperintensity. ERCP findings of ductal abnormalities and basal pancreatic sphincter manometry were recorded. RESULTS: There were higher frequencies of divisum (p = 0.001) and of a clinical history of recurrent acute pancreatitis (p < 0.001) and higher basal pancreatic sphincter of Oddi manometric pressure measurements (p = 0.008) in the acinarization group. There was no difference in the frequency of ERCP-defined chronic pancreatitis (p = 0.10) between the groups. In patients with acinarization, a higher mean sphincter pressure was seen in patients with more intense acinarization than in those with faint acinarization, but this difference was not significant (p = 0.22). Ampullary tumors were found in four patients with acinarization. CONCLUSION: Acinarization probably occurs in patients with a propensity for increased pancreatic ductal pressure (i.e., patients with divisum, elevated basal pancreatic sphincter pressure, ampullary tumor) and adequate exocrine function (absence of severe chronic pancreatitis). PMID- 25148165 TI - CT evaluation of the upper urinary tract in adults younger than 50 years with asymptomatic microscopic hematuria: is IV contrast enhancement needed? AB - OBJECTIVE: The purpose of this study is to compare CT urography (CTU) with unenhanced CT in the evaluation of upper urinary tracts in adults younger than 50 years with asymptomatic microscopic hematuria. MATERIALS AND METHODS: In this study, 1516 CTU examinations were reviewed in adults younger than 50 years. Inclusion criteria were no significant prior urologic disease and asymptomatic microscopic hematuria with at least one urinalysis with greater than or equal to 3 RBCs/high-power field and less than or equal to 50 RBCs/high-power field. Upper urinary tract findings on CTU were classified as malignancy-related or non malignancy-related hematuria and incidental non-hematuria-related findings. A blinded radiologist reviewed the unenhanced images, recording upper urinary tract findings and recommendations for further contrast-enhanced imaging. The modified Wald equation at a 95% CI, the "Rule of Threes" equation, and binomial distribution were used for malignancy-related findings. RESULTS: Four hundred forty-five examinations in 442 patients met inclusion criteria. CTU reports showed zero malignancy-related hematuria findings, 64 non-malignancy-related hematuria findings (62 renal calculi and two others), and 138 incidental non hematuria-related findings. Unenhanced CT interpretation had a sensitivity of 100% (64/64) and a specificity of 89.2% (337/378). The theoretic risk of an upper urinary tract malignancy is 0-1.1%. CONCLUSION: CTU added no additional diagnostic benefit versus unenhanced CT in evaluating the upper urinary tracts of adults younger than 50 years with asymptomatic microscopic hematuria. Using only unenhanced CT can reduce radiation and minimize contrast agent-associated risk, with a less than 1.0% risk of missing upper urinary tract hematuria-related malignancy. PMID- 25148167 TI - Wellness in the radiology reading room: making your workstation a workout station. AB - OBJECTIVE: Sitting can be dangerous to one's health, and radiology tends to be a sedentary profession. CONCLUSION: By adding a mixture of technological and behavioral changes to our workplaces, we can put a large dent in the amount of sedentary time we spend at work. PMID- 25148166 TI - Outpatient falls prevention program outcome: an increase, a plateau, and a decrease in incident reports. AB - OBJECTIVE: We implemented an outpatient falls guideline in 2008 in the department of radiology. Here, we describe our multiyear experience. MATERIALS AND METHODS: This was a retrospective study conducted between April 2006 and September 2013 to investigate outpatient falls. The span of the study was divided into eight periods. The incident reporting system was searched for the falls and the fall related variables. RESULTS: A total of 327 falls occurred during 5,080,512 radiology examinations (rate, 0.64/10,000 total examinations). The highest rate was in period 6 (0.83/10,000 examinations). The average for periods 1 and 2 is 0.39/10,000 examinations (37 falls/945,427 examinations), and the average for periods 3-6 is 0.77/10,000 examinations (204 falls/2,656,805 examinations). The average rate for periods 7 and 8 is 0.58/10,000 examinations (86 falls/1,478,280 examinations). There was a statistically significant increase in the total number of falls reported between period 2 and period 3 (p = 0.02). There was a statistically significant decrease in outpatient falls between period 6 and period 7 (p = 0.01). The number of falls among patients 60 years old or older was 177 falls/2,180,093 examinations (rate, 0.81/10,000 examinations), and that among patients younger than 60 years was 150 falls/2,900,419 examinations (rate, 0.52/10,000 examinations), with a statistically significant difference (p = 0.007). Although the rate of falls was higher among female patients, there was no statistically significant difference between the sexes (p = 0.18). CONCLUSION: The outcome of the outpatient falls guideline was characterized by an increase, a plateau, and a decrease in incident reports. The initial increase may be due to the Hawthorne effect. The plateau may represent the value closest to the true incidence. The decrease may represent the effect of the program. PMID- 25148168 TI - Estimated skin dose look-up tables and their effect on dose awareness in the fluoroscopy-guided imaging suite. AB - OBJECTIVE: The displayed air kerma during a fluoroscopy-guided procedure often does not represent the entrance skin dose. The purpose of this work is to develop a system-specific air kerma-to-entrance skin dose look-up table (LUT) for immediate reference and to evaluate its clinical utility. MATERIALS AND METHODS: Physicists are often involved in retrospective dosimetry and risk estimates. Conservative dosimetry conversion factors, represented by the total conversion factor, prospectively estimate the maximum potential skin dose from the displayed air kerma. Air kerma-to-skin dose LUTs with corresponding tissue reactions and approximate time-of-onset can be posted for reference. By developing skin dose LUTs, physicians can actively evaluate during the procedure the potential for deterministic skin reactions. System user surveys evaluated the impact of LUTs on dose awareness. RESULTS: The range of the total conversion factor to the displayed air kerma for the nine systems evaluated was 0.8-1.6 for frontal x-ray tubes. Skin dose LUTs were posted in all imaging suites, and two surveys reported user feedback. Radiology technologists indicated that LUTs improved user dose awareness. Twelve of 14 physician respondents indicated an understanding that entrance skin dose is not equal to the displayed air kerma. CONCLUSION: Our efforts focused on educating fluoroscopy users about differences between displayed air kerma and the entrance skin dose while increasing dose awareness using an accessible and easy-to-understand tool. Skin dose LUTs provide physicians and staff an immediate reference for the maximum estimated entrance skin dose and the associated deterministic skin effects, allowing appropriate patient management. PMID- 25148169 TI - Ultrasound findings of papillary thyroid carcinoma originating in the isthmus: comparison with lobe-originating papillary thyroid carcinoma. AB - OBJECTIVE: The goal of this study was to analyze the differences in ultrasound characteristics of papillary thyroid carcinoma (PTC) originating in the thyroid isthmus versus that originating from the lobes. MATERIALS AND METHODS: From a retrospective review of our institution's database of records dated between January 2007 and December 2008, we identified 48 patients with classic PTCs located in the isthmus. All the patients had undergone preoperative ultrasound imaging, total thyroidectomy with bilateral central lymph node dissection, and postoperative follow-up for at least 2 years. As a control group, 96 patients with classic PTCs located in the lobe who had undergone total thyroidectomy with bilateral central lymph node dissection during the same period were randomly matched to the study patients for age, sex, and tumor size. RESULTS: According to the clinicopathologic analyses, the incidence of extrathyroidal extension was higher in the patients with a tumor originating in the isthmus than in the control group (p = 0.026). According to the imaging analyses, the tumors originating in the isthmus more frequently had a circumscribed margin (p = 0.030), a wider-than-tall shape (p < 0.001), and the suspicion of extrathyroidal extension (p < 0.001) than those originating from the lobes. CONCLUSION: The results of this study showed that PTCs originating in the isthmus were more likely to have extrathyroidal extension than those originating from the lobes. Therefore, careful ultrasound evaluation should be performed on masses in the thyroid isthmus even if ultrasound shows a circumscribed mass with a wider-than tall shape. PMID- 25148171 TI - Pediatric thoracic spine injuries: a single-institution experience. AB - OBJECTIVE: The objective of our study was to determine the incidence of various fractures of the thoracic spine in pediatric patients. CONCLUSION: Simple compression and process-only fractures were the most common types of fractures and all other fracture types were infrequent. Distraction injury was unexpectedly more common in the nonjunctional thoracic spine than in the junctional thoracic spine. PMID- 25148170 TI - Accumulation of (18)F-FDG in the liver in hepatic steatosis. AB - OBJECTIVE: Nonalcoholic fatty liver disease is associated with hepatic inflammation. An emerging technique to image inflammation is PET using the glucose tracer, (18)F-FDG. The purpose of this study was to determine whether in hepatic steatosis the liver accumulates FDG in excess of FDG physiologically exchanging between blood and hepatocyte. MATERIALS AND METHODS: Hepatic FDG uptake, as SUV = [voxel counts / administered activity] * body weight), and CT density were measured in a liver region in images obtained 60 minutes after injection of FDG in 304 patients referred for routine PET/CT. Maximum SUV (region voxel with the highest count rate, SUVmax) and average SUV ( SUVave) were measured. Blood FDG concentration was measured as the maximum SUV over the left ventricular cavity (SUVLV). SUVave was adjusted for hepatic fat using a formula equating percentage fat to CT density. Patients were divided in subgroups on the basis of blood glucose (< 4, 4 to < 5, 5 to < 6, 6 to < 8, 8 to < 10, and > 10 mmol/L). Hepatic steatosis was defined as CT density less than 40 HU (n = 71). RESULTS: The percentage of hepatic fat increased exponentially with blood glucose. SUVmax / SUVLV and fat-adjusted SUVave / SUVLV but not SUVave / SUVLV correlated with blood glucose. Fat-adjusted SUVave was higher in patients with hepatic steatosis (p < 0.001) by ~0.4 in all blood glucose groups. There was a similar difference (~0.3) in SUVmax (p < 0.005) but no difference in SUVave. SUVmax / SUVLV and fat-adjusted SUVave / SUVLV correlated with blood glucose in patients with hepatic steatosis but not in those without. SUVave / SUVLV correlated with blood glucose in neither group. CONCLUSION: FDG uptake is increased in hepatic steatosis, probably resulting from irreversible uptake in inflammatory cells superimposed on reversible hepatocyte uptake. PMID- 25148172 TI - High-resolution CT can differentiate between alloimmune and nonalloimmune lung disease early after hematopoietic cell transplantation. AB - OBJECTIVE: The purpose of this study was to develop a simple semiquantitative high-resolution CT (HRCT) scoring system to differentiate alloimmune-mediated lung syndromes (allo-LS) from other lung diseases early after hematopoietic cell transplantation. Allo-LS should be differentiated from other abnormalities, such as infections and toxicity, because they are life threatening and require prompt and specific treatment. MATERIALS AND METHODS: In 52 pediatric hematopoietic cell transplant recipients with early symptoms of pulmonary disease, a clinical diagnosis was made by an expert physician. HRCT studies were scored by two independent radiologists for various airway and parenchyma abnormalities. HRCT scores were compared with the final clinical diagnoses. RESULTS: Patients with allo-LS had significantly higher HRCT severity scores for ground-glass pattern and airtrapping compared with patients with nonalloimmune disease. A combined score was constructed (the "allo-score") that appeared to have good predictive capacity for clinical allo-LS (AUC = 0.82). HRCT scoring was reproducible for all items except airway wall thickening and septal thickening. CONCLUSION: A simple HRCT severity score can be helpful to differentiate allo-LS from other pulmonary complications early after hematopoietic cell transplantation. PMID- 25148173 TI - Imaging features of primary malignant pancreatic tumors in children. AB - OBJECTIVE: The purpose of this article is to describe the sonographic, CT, and MRI features of primary malignant pancreatic tumors of childhood. CONCLUSION: Most children with a pancreatic tumor present with a solid pseudopapillary tumor that is usually well marginated and has solid and cystic areas surrounded by a fibrous capsule. Pancreatoblastoma is more aggressive than solid pseudopapillary tumor. The imaging features are those of a large heterogeneous tumor. Ductal adenocarcinoma is rare in children and has a poor prognosis. PMID- 25148174 TI - Reduction in portal venous pressure by transjugular intrahepatic portosystemic shunt for treatment of hemorrhagic stomal varices. AB - OBJECTIVE: Stomal varices can cause life-threatening gastrointestinal hemorrhage in patients with portal hypertension. Optimal therapy is not well defined. The purpose of this study was to determine the safety and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) creation for the treatment of hemorrhagic stomal varices. MATERIALS AND METHODS: All patients who underwent TIPS creation for hemorrhagic stomal varices refractory to medical or endoscopic therapy over a 20-year period (1992-2012) were included. Ten patients (mean age, 63 +/- 12 years) were identified. Retrospective chart review was used to document demographic characteristics, procedure details, technical and clinical success, complications, recurrent hemorrhage, and need for repeat interventions. Patients underwent follow-up for an average of 2 years (range, 22 days-9.6 years). RESULTS: All patients had cirrhosis and portal hypertension. Average corrected sinusoidal pressures were 11 +/- 2.4 mm Hg (range, 6-15 mm Hg) before TIPS placement and 4.3 +/- 1.8 mm Hg (range, 2-8 mm Hg) after TIPS placement. Five patients (50%) underwent adjunctive embolization of stomal varices through the TIPS, which did not affect outcome. Complications included one patient each with a contrast allergy and renal failure. Six patients experienced complete resolution of bleeding without further intervention (60%). Four patients had recurrent stomal hemorrhage. Two of the four needed TIPS revision for occlusion; one underwent oversewing of the ostomy; and in one the hemorrhage resolved with conservative measures after confirmation of TIPS patency. CONCLUSION: TIPS creation, with or without adjunctive variceal embolization, is a safe and effective treatment of refractory hemorrhagic stomal varices. Reintervention for recurrent bleeding may be required and appears effective. PMID- 25148175 TI - Breast cancer detection using double reading of unenhanced MRI including T1 weighted, T2-weighted STIR, and diffusion-weighted imaging: a proof of concept study. AB - OBJECTIVE: The purpose of this study was to investigate the diagnostic performance of unenhanced MRI in detecting breast cancer and to assess the impact of double reading. MATERIALS AND METHODS: A total of 116 breasts of 67 women who were 36-89 years old were studied at 1.5 T using an unenhanced protocol including axial T1-weighted gradient-echo, T2-weighted STIR, and echo-planar diffusion weighted imaging (DWI). Two blinded readers (R1 and R2) independently evaluated unenhanced images using the BIRADS scale. A combination of pathology and negative follow-up served as the reference standard. McNemar and kappa statistics were used. RESULTS: Per-breast cancer prevalence was 37 of 116 (32%): 30 of 37 (81%) invasive ductal carcinoma, five of 37 (13%) ductal carcinoma in situ, and two of 37 (6%) invasive lobular carcinoma. Per-breast sensitivity of unenhanced MRI was 29 of 37 (78%) for R1, 28 of 37 (76%) for R2, and 29 of 37 (78%) for double reading. Specificity was 71 of 79 (90%) for both R1 and R2 and 69 of 79 (87%) for double reading. Double reading did not provide a significant increase in sensitivity. Interobserver agreement was almost perfect (Cohen kappa = 0.873). CONCLUSION: An unenhanced breast MRI protocol composed of T1-weighted gradient echo, T2-weighted STIR, and echo-planar DWI enabled breast cancer detection with sensitivity of 76-78% and specificity of 90% without a gain in sensitivity from double reading. PMID- 25148176 TI - High-risk lesions at MRI-guided breast biopsy: frequency and rate of underestimation. AB - OBJECTIVE: The purpose of this article is to determine the underestimation rate of high-risk lesions diagnosed at MRI-guided breast biopsy. MATERIALS AND METHODS: This was a retrospective review of 446 MRI-guided breast biopsies from January 2006 through December 2010. Data were collected on examination indication, lesion size and type, and pathology results. Biopsies were performed with a 9-gauge vacuum-assisted device. Biopsy results of atypical ductal hyperplasia (ADH), papillary lesion, radial scar, lobular neoplasia, and atypia were identified and compared with final excisional pathology results. Underestimation rates were calculated and data were compared by patient and lesion characteristics using chi-square analysis. RESULTS: Of the 446 MRI-guided biopsies, 96 (21.5%) were high-risk lesions. Forty-two of 96 lesions (44%) were masses, and 54 (56%) showed nonmass enhancement. Twenty of 96 lesions (20.8%) were ADH, nine (9.4%) were lobular neoplasia, 27 (28.1%) were papillary lesions, 20 (20.8%) were radial scar, and 20 (20.8%) were other atypias. Sixty-nine of 96 lesions (71.9%) had surgical excisional pathology results available. Sixteen of 69 (23.2%) lesions were upgraded to malignancy; 11 of the 16 (68.8%) were upgraded to ductal carcinoma in situ (DCIS) and five (31.2%) were upgraded to invasive carcinoma. The underestimation rate was 31.6% (6/19) for ADH, 5.9% (1/17) for papillary lesions, 23.1% (3/13) for radial scar, 28.6% (2/7) for lobular neoplasia, and 30.8% (4/13) for other atypias (p = 0.43). There was no statistically significant difference in underestimation rate by lesion type, size, or history of newly diagnosed breast cancer. CONCLUSION: MRI-guided breast biopsy yielded high-risk lesions in 21.5% of cases, and the underestimation rate was 23.2%. No patient or lesion characteristics correlated with underestimation rate. PMID- 25148178 TI - Fluoroscopic frame rates: not only dose. PMID- 25148179 TI - Prevalence and types of coronary artery fistulas detected with coronary CT angiography. AB - OBJECTIVE: The prevalence of coronary artery fistula (CAF) based on coronary angiographic findings has been reported. However, the number of incidentally found CAFs is increasing as coronary CT angiography (CTA) has become popular. The purpose of this study was to determine the prevalence and types of CAFs detected with coronary CTA. MATERIALS AND METHODS: Between March 2009 and November 2011, 6341 patients underwent coronary CTA at one institution. The prevalence of CAF was retrospectively evaluated, and the morphologic features were analyzed, including vessel of origin, drainage site, size, and presence of an aneurysmal sac. We also analyzed cardiac and pulmonary findings. RESULTS: Among 6341 patients, 56 (0.9%) patients had CAF. The types of CAF detected, in decreasing frequency, were coronary to pulmonary artery fistula (43 cases [76.8%]), coronary to bronchial artery fistula (five cases [8.9%]), coronary artery to cardiac chamber fistula (five cases [8.9%]), combined coronary to pulmonary and coronary to bronchial artery fistula (two cases [3.6%]), and coronary artery to superior vena cava fistula (one case [1.8%]). Lung parenchymal or vascular anomaly was more frequently noted in coronary to bronchial artery fistulas, combined coronary to pulmonary and coronary to bronchial artery fistulas, and coronary artery to superior vena cava fistulas than in coronary to pulmonary artery and coronary artery to cardiac chamber fistulas. CONCLUSION: The prevalence of CAF at coronary CTA was 0.9%, which is higher than the known prevalence based on conventional angiographic findings (0.05-0.25%). Furthermore, the most common type of CAF in this study was coronary to pulmonary artery, whereas coronary artery to ventricle fistula was previously considered the most common type in studies conducted with conventional angiography. Coronary CTA is a useful, noninvasive imaging modality for the detection of CAF. PMID- 25148180 TI - MDCT of congenital coronary artery fistulas. AB - OBJECTIVE: The purpose of this article is to describe the evaluation of congenital coronary artery fistulas (CAFs) with MDCT angiography with ECG gating (MDCTA), including the clinical manifestations, scanning techniques, differential diagnosis, and other imaging methods that may be used. CONCLUSION: Congenital CAFs are rare coronary artery anomalies of termination. MDCTA is a first-line modality for pretreatment planning, and imaging findings should be recognized because CAFs may be detected incidentally. PMID- 25148181 TI - Prediction of microvascular invasion of hepatocellular carcinoma: preoperative CT and histopathologic correlation. AB - OBJECTIVE: The objective of our study was to prospectively investigate whether nonsmooth margins detected on multiphasic CT images correlate with the presence and location of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). SUBJECTS AND METHODS: A total of 102 patients with preoperative CT findings of solitary HCC were prospectively enrolled. Tumor size, tumor capsule, tumor margins, and peritumoral enhancement on preoperative CT images were assessed. Histopathologic results including the following were also recorded: tumor differentiation; liver fibrosis score; presence or absence of MVI; and, if present, the location of MVI. Correlation between tumor margin on preoperative CT images and histopathologic location of MVI was determined. RESULTS: Pathologic examination revealed MVI in 60 of the 102 HCC specimens. Although the results of the univariate analysis showed that tumor size, higher Edmondson-Steiner grade, and nonsmooth tumor margins were associated with MVI, multivariate analysis revealed that only nonsmooth margins correlated with the presence of MVI in HCC (p < 0.001). Of the 60 HCC specimens with histopathologic evidence of MVI, 40 exhibited focal nonsmooth margins. In addition, the locations of the nonsmooth margins and MVI were similar in 36 of the 40 specimens. CONCLUSION: Nonsmooth tumor margins correlated with the histopathologic presence and location of MVI. Therefore, nonsmooth margins detected on multiphasic CT may be predictive of MVI in HCC. PMID- 25148182 TI - CT evaluation of gastroenteric neuroendocrine tumors: relationship between ct features and the pathologic classification. AB - OBJECTIVE: The objective of our study was to compare the CT features of gastroenteric neuroendocrine neoplasms (GE-NENs) with the pathologic classification and to analyze the correlation between the CT features and classification of GE-NENs. MATERIALS AND METHODS: Fifty-six cases of pathologically and immunohisto-chemically proven GE-NENs, including 25 cases of neuroendocrine tumors (NETs) (i.e., G1 and G2 tumors) and 31 cases of neuroendocrine carcinomas (NECs) (i.e., G3 tumors and mixed adenoneuroendocrine carcinomas) were studied. We analyzed various CT features of the primary tumor, nodal status, and metastasis and compared these features with pathologic grading. RESULTS: The CT features that favor NEC over NET include larger tumor size (> 4.0 cm), transmural invasion, circumscribed tumor with both intra- and extraluminal involvement, circumferential growth, areas of cystic change or necrosis, ulceration, mesenteric fat infiltration, and lymphadenopathy, with p values of 0.044, 0.002, 0.024, 0.008, 0.002, 0.007, 0.002, and < 0.001, respectively. The CT features that do not distinguish between the two types of GE-NENs include tumor boundary, growth pattern, degree of enhancement, adjacent organ invasion, distant organ metastasis, and peritoneal seeding, with p values of 0.277, 0.153, 0.672, 1.000, 0.159, and 0.877, respectively. CONCLUSION: CT can be useful in the classification of GE-NENs. PMID- 25148183 TI - A pilot study estimating liver fibrosis with ultrasound shear-wave elastography: does the cause of liver disease or location of measurement affect performance? AB - OBJECTIVE: The purpose of this study was to evaluate the diagnostic accuracy of real-time shear-wave elastography for assessment of liver fibrosis in an unselected patient population, comparing shear-wave elastography measurements obtained at and remote from the site of random liver biopsy. SUBJECTS AND METHODS: In a prospective study of 50 patients (21 with and 29 without hepatitis C) referred for clinically indicated random liver biopsy for diffuse liver disease, shear-wave elastography measurements were taken from four locations before biopsy: one at the left lobe, two at the right lobe, and one at the biopsy location. The mean, minimum, maximum, and SD of shear-wave elastography were compared with pathologic grading. Steatosis and serum markers were analyzed using multiple logistic regression. Optimized shear-wave elastography thresholds were calculated using AUC analysis. RESULTS: The AUC (95% CI) at the biopsy site, ipsilateral lobe, and contralateral lobe were 0.82 (0.63-1.0), 0.84 (0.67-1.0), and 0.59 (0.19-0.99) in hepatitis C patients; 0.89 (0.75-1.0), 0.88 (0.73-1.0), and 0.93 (0.80-1.0) in nonhepatitis C patients; and 0.85 (0.74-0.96), 0.89 (0.79 0.99), and 0.80 (0.67-0.93) in all patients, respectively. Optimized biopsy site shear-wave elastography values for detecting Metavir score F2 or greater were 1.87 m/s (75% sensitivity and specificity), 2.00 m/s (80% sensitivity and specificity), and 1.89 m/s (76% sensitivity and specificity) in hepatitis C, nonhepatitis C, and all patients, respectively. Steatosis and serum markers were not significant. CONCLUSION: Real-time shear-wave elastography accurately predicted significant fibrosis (stage >= 2) in an unselected patient population with diffuse disease, including patients with and without hepatitis C. Shear-wave elastography best predicts pathologic grading when taken at the biopsy site or ipsilateral lobe in hepatitis C patients. Percentage steatosis was not predictive of shear-wave elastography results. PMID- 25148184 TI - Small-intestinal length measurement on MR enterography: comparison with in vivo surgical measurement. AB - OBJECTIVE: The purpose of this study is to assess the feasibility and accuracy of small-bowel length measurement on MR enterography examinations compared with surgical in vivo measurements. SUBJECTS AND METHODS: Thirty-one consecutive patients who were undergoing elective laparotomy for Crohn disease were included in the study. These patients underwent a prior MR enterography examination, and true fast imaging with steady-state precession MR enterography images from the examinations were used to measure small-intestinal length. The MR enterography measurement was compared with a surgical measurement to assess accuracy and correlation. RESULTS: MR enterography measurements had a significant positive correlation with surgical measurements (r(2) = 0.98; p < 0.001) irrespective of bowel length. The average (+/- SD) percentage difference between MR enterography and surgical intestinal length measurement was 4.59% +/- 0.44%. An average time of 36.5 +/- 2.8 minutes was required for bowel length measurement on MR enterography. A significantly longer time was required for measurement of bowel length greater than 300 cm versus shorter bowel length. CONCLUSION: Small-bowel length measurements on MR enterography are accurate compared with anatomic measurements. MR enterography can provide an effective noninvasive investigation in planning surgical and nutritional intervention in patients with compromised bowel length. PMID- 25148186 TI - Comparison of apparent diffusion coefficient calculation between two-point and multipoint B value analyses in prostate cancer and benign prostate tissue at 3 T: preliminary experience. AB - OBJECTIVE: The purpose of this study was to prospectively evaluate the reliability and variability of apparent diffusion coefficient (ADC) calculations between two-point and multipoint b value analyses in prostate cancer and benign prostate tissue. SUBJECTS AND METHODS: Forty-eight consecutive patients with suspected prostate cancer underwent diffusion-weighted MRI (DWI) at 3 T followed by surgery. DWI was examined under different b values. ADC maps were generated by two different methods: two-point b values (0 and 1000 s/mm(2)) and multipoint b values (0, 100, 300, 700, and 1000 s/mm(2)). Two independent readers measured ADC in the cancers, benign peripheral zone and transition zone, and obturator internus muscle. Statistical analyses were performed using the intraclass correlation coefficient (ICC), correlation of variation (CV), Bland-Altman test, and paired Student t test. RESULTS: The intermethod ADC calculation revealed excellent reliability for all tissues in both readers: cancer (ICC = 0.979 0.981), transition zone (0.989-0.993), peripheral zone (0.990-0.994), and obturator internus muscle (0.967-0.975). In both readers, the variability of the intermethod ADC calculation was 2.90-3.09% CV in cancer, 1.16-1.48% CV in the transition zone, 1.03-1.29% CV in the peripheral zone, and 2.44-2.62% CV in the obturator internus muscle. For interreader variability, the CVs of ADC calculation for two-point versus multipoint b value analyses in all tissues were 7.21-9.65% versus 7.18-9.01%. CONCLUSION: For estimating ADC values on 3-T DWI of the prostate, two-point b value analysis seems to present excellent correlation with multipoint b value analysis, with little error in accuracy. PMID- 25148185 TI - Preoperative 3-T diffusion-weighted MRI for the qualitative and quantitative assessment of extracapsular extension in patients with intermediate- or high-risk prostate cancer. AB - OBJECTIVE: The purpose of this study was to prospectively evaluate the value of diffusion-weighted MRI (DWI) for the assessment of extracapsular extension (ECE) in patients with prostate cancer. SUBJECTS AND METHODS: Between November 2010 and April 2012, 40 patients with intermediate- to high-risk prostate cancer were prospectively recruited. MR images were obtained at 3 T with a phased-array coil. Two independent readers scored the T2-weighted images alone and then in combination with DW images. ROIs were drawn on the apparent diffusion coefficient (ADC) maps, and histogram-derived values were calculated. Whole-mount histopathologic examination was the standard of reference. Reader performance was analyzed, and differences in patient characteristics and histogram-based ADC values, according to ECE status, were evaluated. RESULTS: ECE was present in 23 of 40 (58%) patients and 23 of 43 (53%) tumors. The sensitivity for side-specific ECE detection significantly increased, from 0.22 to 0.44 for reader 1 and 0.33 to 0.82 for reader 2 (both p < 0.05) without a significant change in specificity for either reader with the addition of DWI and ADC mapping. The positive and negative predictive values for both readers also increased. The ADC parameters of median and 10th and 25th centiles showed a statistically significant difference between tumors with and those without ECE (p < 0.05). CONCLUSION: The addition of DWI and ADC mapping to T2-weighted MRI improved the accuracy of preoperative detection of ECE. Median and 10th and 25th centile ADC values were significantly associated with the presence of ECE and may be useful in the pretreatment assessment of patients with prostate cancer. PMID- 25148188 TI - Retrospective research in radiology from concept to publication: a stepwise guide for trainees and mentors. AB - OBJECTIVE: The purpose of this article is to describe a step-by-step approach to the successful mentorship of trainees completing retrospective radiology research projects. The topics addressed include selection of a mentor and mentee and the selection, planning, initiation, and completion of a retrospective research project. CONCLUSION: Mentoring a trainee in the completion of a retrospective research project is an ideal way to introduce a trainee to academics. The goals of such a project given the time constraints of radiology residents include completion of an educational exhibit, an oral scientific presentation, and a published manuscript. PMID- 25148187 TI - Low enhancement on multiphase contrast-enhanced CT images: an independent predictor of the presence of high tumor grade of clear cell renal cell carcinoma. AB - OBJECTIVE: The purpose of this study was to assess the relation between tumor enhancement on multiphase contrast-enhanced CT images and Fuhrman grade of clear cell renal cell carcinoma. MATERIALS AND METHODS: A single-institution retrospective review was conducted on the records of 255 patients who underwent radical or partial nephrectomy and received a histologic diagnosis of clear cell renal cell carcinoma. Two radiologists recorded the radiographic features of each patient, including the attenuation value of the lesion, lesion size, calcification within the lesion, cystic versus solid appearance, and margin regularity. Parameters representing the extent of tumor enhancement were defined and calculated. The association between tumor enhancement and Fuhrman grade was analyzed, and multivariate analysis was performed to find independent predictors of high tumor grade. RESULTS: Significant differences existed in tumor enhancement among different Fuhrman grades (p < 0.001). High-grade tumors had significantly lower enhancement (p < 0.001). The enhancement parameter had a sensitivity of 0.84 and specificity of 0.93 in prediction of high tumor grade. In the multivariate analysis, more advanced age, irregular margin, and low tumor enhancement were the three independent predictors of high tumor grade. CONCLUSION: Tumor enhancement of clear cell renal cell carcinoma on multiphase contrast-enhanced CT images is associated with Fuhrman grade. Low tumor enhancement in the corticomedullary phase is an independent predictor of high tumor grade. This system may be helpful in clinical decision making about the care of patients treated by nonsurgical approaches. PMID- 25148189 TI - Comparison of the artifacts caused by metallic implants in breast MRI using dual echo dixon versus conventional fat-suppression techniques. AB - OBJECTIVE: The purpose of this article is to evaluate and compare the artifacts caused by metal implants in breast MR images acquired with dual-echo Dixon and two conventional fat-suppression techniques. SUBJECTS AND METHODS: Two types of biopsy markers were embedded into a uniform fat-water emulsion. T1-weighted gradient-echo images were acquired on a clinical 3-T MRI scanner with three different fat-suppression techniques-conventional or quick fat saturation, spectrally selective adiabatic inversion recovery (SPAIR), and dual-echo Dixon and the 3D volumes of artifacts were measured. Among the subjects of a clinical breast MRI study using the same scanner, five patients were found to have one or more metal implants. The artifacts in Dixon and SPAIR fat-suppressed images were evaluated by three radiologists, and the results were compared with those of the phantom study. RESULTS: In the phantom study, the artifacts appeared as interleaved bright and dark rings on SPAIR and quick-fat-saturation images, whereas they appeared as dark regions with a thin bright rim on Dixon images. The artifacts imaged with the Dixon technique had the smallest total volume. However, the reviewers found larger artifact diameters on patient images using the Dixon sequence because only the central region was recognized as an artifact on the SPAIR images. CONCLUSION: Metal implants introduce artifacts of different types and sizes, according to the different fat-suppression techniques used. The dual echo Dixon technique produces a larger central void, allowing the implant to be easily identified, but presents a smaller overall artifact volume by obscuring less area in the image, according to a quantitative phantom study. PMID- 25148190 TI - Inborn errors of metabolism: combining clinical and radiologic clues to solve the mystery. AB - OBJECTIVE: Inborn errors of metabolism in children can be challenging to interpret because of the similarity of their appearances on imaging. There are important clues to the diagnosis based on clinical history, head circumference (e.g., macrocephaly), geographic distribution of lesions (e.g., subcortical vs deep white matter or frontal vs parietooccipital), and other imaging features (e.g., contrast enhancement, calcification, cysts, and cortical dysplasia). CONCLUSION: In this article, we present an algorithm-based approach to diagnosing pediatric metabolic disease with a discussion of key imaging features. PMID- 25148191 TI - Diagnostic performance of quantitative shear wave elastography in the evaluation of solid breast masses: determination of the most discriminatory parameter. AB - OBJECTIVE: The purpose of this article is to assess the diagnostic performance of quantitative shear wave elastography in the evaluation of solid breast masses and to determine the most discriminatory parameter. SUBJECTS AND METHODS: B-mode ultrasound and shear wave elastography were performed before core biopsy of 123 masses in 112 women. The diagnostic performance of ultrasound and quantitative shear wave elastography parameters (mean elasticity, maximum elasticity, and elasticity ratio) were compared. The added effect of shear wave elastography on the performance of ultrasound was determined. RESULTS: The mean elasticity, maximum elasticity, and elasticity ratio were 24.8 kPa, 30.3 kPa, and 1.90, respectively, for 79 benign masses and 130.7 kPa, 154.9 kPa, and 11.52, respectively, for 44 malignant masses (p < 0.001). The optimal cutoff value for each parameter was determined to be 42.5 kPa, 46.7 kPa, and 3.56, respectively. The AUC of each shear wave elastography parameter was higher than that of ultrasound (p < 0.001); the AUC value for the elasticity ratio (0.943) was the highest. By adding shear wave elastography parameters to the evaluation of BI RADS category 4a masses, about 90% of masses could be downgraded to BI-RADS category 3. The numbers of downgraded masses were 40 of 44 (91%) for mean elasticity, 39 of 44 (89%) for maximum elasticity, and 42 of 44 (95%) for elasticity ratio. The numbers of correctly downgraded masses were 39 of 40 (98%) for mean elasticity, 38 of 39 (97%) for maximum elasticity, and 41 of 42 (98%) for elasticity ratio. There was improvement in the diagnostic performance of ultrasound of mass assessment with shear wave elastography parameters added to BI RADS category 4a masses compared with ultrasound alone. Combined ultrasound and elasticity ratio had the highest improvement, from 35.44% to 87.34% for specificity, from 45.74% to 80.77% for positive predictive value, and from 57.72% to 90.24% for accuracy (p < 0.0001). The AUC of combined ultrasound and elasticity ratio (0.914) was the highest compared with the other combined parameters. CONCLUSION: There was a statistically significant difference in the values of the quantitative shear wave elastography parameters of benign and malignant solid breast masses. By adding shear wave elastography parameters to BI RADS category 4a masses, we found that about 90% of them could be correctly downgraded to BI-RADS category 3, thereby avoiding biopsy. Elasticity ratio (cutoff, 3.56) appeared to be the most discriminatory parameter. PMID- 25148192 TI - Position of sublabral sulci. PMID- 25148193 TI - Reply: position of sublabral sulci. PMID- 25148194 TI - Adrenal biopsy is recommended to differentiate benign versus malignant metastasis of primary adrenal lesions. PMID- 25148195 TI - Reply: adrenal biopsy is recommended to differentiate benign versus malignant metastasis of primary adrenal lesions. PMID- 25148196 TI - Methodologic concerns in reliability of noncalcified coronary artery plaque burden quantification. PMID- 25148197 TI - Reply: methodologic concerns in reliability of noncalcified coronary artery plague burden quantification. PMID- 25148198 TI - Effect of dietary vitamin A on reproductive performance and immune response of broiler breeders. AB - The effects of dietary vitamin A supplementation on reproductive performance, liver function, fat-soluble vitamin retention, and immune response were studied in laying broiler breeders. In the first phase of the experiment, 1,120 Ross-308 broiler breeder hens were fed a diet of corn and soybean meal supplemented with 5,000 to 35,000 IU/kg vitamin A (retinyl acetate) for 20 weeks. In the second phase, 384 Ross-308 broiler breeder hens were fed the same diet supplemented with 5,000 to 135,000 IU/kg vitamin A (retinyl acetate) for 24 weeks. The hens' reproductive performance, the concentrations of vitamins A and E in liver and egg yolk, liver function, mRNA expression of vitamin D receptor in duodenal mucosa, antibody titers against Newcastle disease virus vaccine, and T-cell proliferation responses were evaluated. Supplementation of vitamin A at levels up to and including 35,000 IU/kg did not affect reproductive performance and quadratically affected antibody titer to Newcastle disease virus vaccine (p<0.05). Dietary addition of vitamin A linearly increased vitamin A concentration in liver and yolk and linearly decreased alpha-, gamma-, and total tocopherol concentration in yolk (p<0.01) and alpha-tocopherol in liver (p<0.05). Supplementation of vitamin A at doses of 45,000 IU/kg and above significantly decreased egg weight, yolk color, eggshell thickness and strength, and reproductive performance. Dietary vitamin A significantly increased mRNA expression of vitamin D receptor in duodenal mucosa (p<0.05), increased aspartate amino transferase activity, and decreased total bilirubin concentration in serum. Supplementation of vitamin A at 135,000 IU/kg decreased the proliferation of peripheral blood lymphocytes (p<0.05). Therefore, the maximum tolerable dose of vitamin A for broiler breeders appears to be 35,000 IU/kg, as excessive supplementation has been shown to impair liver function, reproductive performance, and immune response. PMID- 25148199 TI - Synthesis, structures, and electronic properties of triple- and double-decker ruthenocenes incorporated by a group 14 metallole dianion ligand. AB - The neutral triple-decker ruthenocenes and anionic ruthenocene bearing a stannole dianion were successfully synthesized by the reactions of dilithiostannoles with [Cp*RuCl]4. This is the first example of a transition-metal complex bearing a group 14 metallole dianion with MU-eta(5):eta(5) coordination mode. These complexes were fully characterized by NMR spectroscopy and single-crystal X-ray diffraction analysis. In the complexes, each of the ruthenium atoms is coordinated by the stannole ring in an eta(5)-fashion. The aromaticity of the stannole dianion moieties is retained judging from no C-C bond alternation in the stannole rings. CH/pi interaction was found in the packing structure of the SiMe3 derivative, which leads to a well-ordered column-like structure. The oxidation wave of the triple-decker complex was observed at -0.43 V (vs ferrocene), which reveals that the triple-decker type heavy ruthenocene is oxidized more easily than the ferrocene. Comparison of the oxidation potential between the triple decker complex and decamethylruthenocene (Cp*2Ru, Cp* = eta(5)-C5Me5) reveals that a stannole ligand functions as an electron-donating ligand much stronger than the conventional electron-rich Cp* ligand. PMID- 25148200 TI - Statement of retraction. PMID- 25148202 TI - Efficient synthesis of aryl boronates via zinc-catalyzed cross-coupling of alkoxy diboron reagents with aryl halides at room temperature. AB - A zinc(II)/NHC system catalyzes the borylation of aryl halides with diboron (4) reagents in the presence of KOMe at rt. This transformation can be applied to a broad range of substrates with high functional group compatibility. Radical scavenger experiments do not support a radical-mediated process. PMID- 25148201 TI - Encephalitis caused by pathogens transmitted through organ transplants, United States, 2002-2013. AB - The cause of encephalitis among solid organ transplant recipients may be multifactorial; the disease can result from infectious or noninfectious etiologies. During 2002-2013, the US Centers for Disease Control and Prevention investigated several encephalitis clusters among transplant recipients. Cases were caused by infections from transplant-transmitted pathogens: West Nile virus, rabies virus, lymphocytic choriomeningitis virus, and Balamuthia mandrillaris amebae. In many of the clusters, identification of the cause was complicated by delayed diagnosis due to the rarity of the disease, geographic distance separating transplant recipients, and lack of prompt recognition and reporting systems. Establishment of surveillance systems to detect illness among organ recipients, including communication among transplant center physicians, organ procurement organizations, and public health authorities, may enable the rapid discovery and investigation of infectious encephalitis clusters. These transplant transmitted pathogen clusters highlight the need for greater awareness among clinicians, pathologists, and public health workers, of emerging infectious agents causing encephalitis among organ recipients. PMID- 25148203 TI - Working memory impairment in cannabis- and opioid-dependent adolescents. AB - BACKGROUND: Cannabis and opioid use are associated with cognitive impairment, whether preexisting or substance-induced, but there have been few substance specific assessments of cognitive functioning in adolescent substance users. Working memory impairment may be particularly important, as it has been linked to poorer performance in substance abuse treatment. METHODS: Working memory (Wechsler Intelligence Scale for Children-IV or Adult Intelligence Scale-IV) and baseline substance use were assessed in 42 youth (mean age = 17.9 years, SD = 1.3, range: 16-20; 65% Caucasian, 30% female) 1-2 weeks after admission to residential treatment with supervised abstinence, 19 for primary cannabis dependence and 23 for primary opioid dependence. RESULTS: There were substantial deficits in working memory in both groups, with significant differences (P < .001) between the opioid (M = 39.1th%ile, SD = 25.6) and cannabis (M = 16.3th%ile, SD = 13.6) groups. The primary opioid group had high rates of cannabis use, with no significant difference in past-month days of cannabis use from the primary cannabis group. The opioid group was older and had completed more years of formal education. Seventy-nine percent of the cannabis group had public health care coverage (mostly Medicaid), compared with 24% of the opioid sample. CONCLUSIONS: Working memory impairment was substantial in treatment seeking youth with primary cannabis and opioid dependence (the latter actually having comparable rates of cannabis use), and significantly more pronounced in the primary cannabis-dependent group. Without an assessment of working memory prior to substance exposure, the differential contributions of substance-induced vs. preexisting impairment are unclear. Lower scores in the cannabis group may reflect lower socioeconomic status (SES), which is typically correlated with cognitive performance. These findings highlight underrecognized cognitive impairment in youth with SUDs, especially inner-city cannabis-dependent youth. Modification of treatments to account for cognitive capacity and/or cognitive remediation interventions may be indicated to improve treatment outcomes. PMID- 25148204 TI - The contribution of the genetic variations of the matrix metalloproteinase-1 gene to the genetic susceptibility of gastric cancer. AB - Matrix metalloproteinase-1 (MMP-1), an interstitial collagenase, is responsible for the proteolytic degradation of basement membrane and extracellular matrix. MMP-1 plays a major role in the invasion of gastric cancer (GC). The role of the genetic polymorphisms in the functional regions of MMP-1 on the risk of GC remains unclear. To identify the markers that contribute to the genetic susceptibility to GC, we examined the potential association between GC and nine single-nucleotide polymorphisms (rs 1799750, rs 498186, rs 475007, rs 514921, rs 494379, rs 996999, rs 2071232, rs 1938901, and rs 2239008) of the MMP-1 gene using the MassARRAY system in this study. The participants enrolled in this study included 422 patients with GC and 428 healthy subjects as the healthy controls from a Chinese Han population. The analysis revealed a weak association between the rs 1799750 (in the promoter region) genotype distribution and GC (p=0.020). The frequency of the 2G allele was significantly higher in the patients with GC than in the healthy controls (p=0.005, odds ratio [OR]=1.324, 95% confidence interval [CI]: 1.087-1.613). Moreover, the patients with the 2G/2G genotype of rs 1799750 had a significantly increased risk of cancer invasion compared with patients with the 1G/1G+1G/2G genotype (p=0.001, OR=0.505, 95% CI: 0.331-0.771). Strong linkage disequilibrium was observed in three blocks (D'>0.9). Significantly, more C-2G haplotypes (block 3) (p=0.0005 after Bonferroni correction) were found in GC subjects. These findings point to a role for MMP-1 promoter polymorphism in GC among a Han Chinese population, and may be informative for future genetic or biological studies on GC. PMID- 25148205 TI - Ivacaftor for patients with cystic fibrosis. AB - Ivacaftor is an oral bioavailable potentiator of the cystic fibrosis transmembrane conductance regulator protein. It is the first therapeutic agent that has been registered for clinical use which targets the basic defect in people with cystic fibrosis who carry a G551D mutation or other rarer specific gating mutations. Clinical trials have shown consistent and impressive clinical benefit that appears to be sustained over time in people with cystic fibrosis who carry a G551D mutation and similar benefits have been seen in those who carry rarer gating mutations. Ivacaftor is orally administered twice daily with a dose that does not vary between children aged 6 years through to adult life in patients with G551D. It appears to be well tolerated although there are potential interactions with drugs that are metabolised through CYPP450 CYP3A. Ivacaftor is also currently being trialled in combination with correctors for patients with the most common mutation of cystic fibrosis transmembrane conductance regulator the F508del mutation. PMID- 25148206 TI - Chemical modification of Nafion membranes by protic ionic liquids: the key role of ionomer-cation interactions. AB - Chemically modified Nafion composite membranes were successfully fabricated using five kinds of protic ionic liquids (PILs) with different cations, 1-butylammonium methanesulfonate (BA-MS), tributylammonium methanesulfonate (TBA-MS), 2,4,6 trimethylphenylammonium methanesulfonate (TMA-MS), butane-1,4-diammonium methanesulfonate (BDA-MS), and N-(2-aminoethyl)ethane-1,2-diammonium methanesulfonate (DETA-MS). The PIL incorporated Nafion composite membranes were characterized by impedance spectroscopy, small-angle X-ray scattering (SAXS), dynamic-mechanical analysis (DMA) and thermogravimetric analysis (TGA). In general, the Nafion/PIL composite membranes exhibit a significant increase in the ionic conductivities than Nafion under anhydrous conditions. The interactions between the Nafion ionomer and different geometric cations of PILs were also discussed by the comparison of nanostructures, dynamic-mechanical properties and thermal stabilities of the Nafion/PIL composite membranes. PMID- 25148210 TI - Streaming potential revisited: the influence of convection on the surface conductivity. AB - Electrokinetic phenomena play an important role in the electrical characterization of surfaces. In terms of planar or porous substrates, streaming potential and/or streaming current measurements can be used to determine the zeta potential of the substrates in contact with aqueous electrolytes. In this work, we perform electrical impedance spectroscopy measurements to infer the electrical resistance in a microchannel with the same conditions as for a streaming potential experiment. Novel correlations are derived to relate the streaming current and streaming potential to the Reynolds number of the channel flow. Our results not only quantify the influence of surface conductivity, and here especially the contribution of the stagnant layer, but also reveal that channel resistance and therefore zeta potential are influenced by the flow in the case of low ionic strengths. We conclude that convection can have a significant impact on the electrical double layer configuration which is reflected by changes in the surfaces conductivity. PMID- 25148209 TI - Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4 yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer. AB - HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice. PMID- 25148211 TI - Letters to the Editor: neonatal brachial plexus palsy. PMID- 25148207 TI - Genome-wide analysis of miRNA signature in the APPswe/PS1DeltaE9 mouse model of alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of dementia. One of the pathological hallmarks of AD is amyloid beta (Abeta) deposition. MicroRNAs (miRNAs) are small non-coding RNAs whose expression levels change significantly during neuronal pathogenesis and may be used as diagnostic markers. Some miRNAs are important in AD development by targeting genes responsible for Abeta metabolism. However, a systematic assessment of the miRNA expression profile induced by Abeta-mediated neuronal pathogenesis is still lacking. In the present study, we examined miRNA expression profile by using the APPswe/PS1DeltaE9 mouse model of AD. Two sibling pairs of mice were examined, showing 30 and 24 miRNAs with significantly altered expression levels from each paired control, respectively. Nine known miRNAs were common in both groups. Prediction of putative target genes and functional annotation implied that these altered miRNAs affect many target genes mainly involved in PI3K/Akt signaling pathway. This study provides a general profile of miRNAs regulated by Abeta-associated signal pathways, which is helpful to understand the mechanism of Abeta-induced neuronal dysfunction in AD development. PMID- 25148212 TI - Ventricular reservoir versus ventriculosubgaleal shunt for posthemorrhagic hydrocephalus in preterm infants: infection risks and ventriculoperitoneal shunt rate. AB - OBJECT: The most common neurosurgical condition observed in preterm infants is intraventricular hemorrhage (IVH), which often results in posthemorrhagic hydrocephalus (PHH). These conditions portend an unfavorable prognosis; therefore, the potential for poor neurodevelopmental outcomes necessitates a better understanding of the comparative effectiveness of 2 temporary devices commonly used before the permanent insertion of a ventriculoperitoneal (VP) shunt: the ventricular reservoir and the ventriculosubgaleal shunt (VSGS). METHODS: The authors analyzed retrospectively collected information for 90 patients with IVH and PHH who were treated with insertion of a ventricular reservoir (n = 44) or VSGS (n = 46) at their institution over a 14-year period. RESULTS: The mean gestational age and weight at device insertion were lower for VSGS patients (30.1 +/- 1.9 weeks, 1.12 +/- 0.31 kg) than for reservoir patients (31.8 +/- 2.9 weeks, 1.33 +/- 0.37 kg; p = 0.002 and p = 0.004, respectively). Ventricular reservoir insertion was predictive of more CSF taps prior to VP shunt placement compared with VSGS placement (10 +/- 8.7 taps vs 1.6 +/- 1.7 taps, p < 0.001). VSGS patients experienced a longer time interval prior to VP shunt placement than reservoir patients (80.8 +/- 67.5 days vs 48.8 +/- 26.4 days, p = 0.012), which corresponded to VSGS patients gaining more weight by the time of shunt placement than reservoir patients (3.31 +/- 2.0 kg vs 2.42 +/- 0.63 kg, p = 0.016). Reservoir patients demonstrated a trend toward more positive CSF cultures compared with VSGS patients (n = 9 [20.5%] vs n = 5 [10.9%], p = 0.21). There were no significant differences in the rates of overt device infection requiring removal (reservoir, 6.8%; VSGS, 6.5%), VP shunt insertion (reservoir, 77.3%; VSGS, 76.1%), or early VP shunt infection (reservoir, 11.4%; VSGS, 13.0%) between the 2 cohorts. CONCLUSIONS: Although the rates of VP shunt requirement and device infection were similar between patients treated with the reservoir versus the VSGS, VSGS patients were significantly older and had achieved greater weights at the time of VP shunt insertion. The authors' results suggest that the VSGS requires less labor-intensive management by ventricular tapping; the VSGS patients also attained higher weights and more optimal surgical candidacy at the time of VP shunt insertion. The potential differences in long-term developmental and neurological outcomes between VSGS and reservoir placement warrant further study. PMID- 25148214 TI - Flexible endoscopy for management of intraventricular brain tumors in patients with small ventricles. AB - OBJECT: Endoscopic surgery is generally withheld in patients with small ventricles due to difficulties in ventricular cannulation and intraventricular manipulation. The effectiveness of flexible endoscopy for management of intraventricular brain tumors in patients with small ventricles was evaluated. METHODS: Forty-five patients who underwent endoscopic surgery with a flexible endoscope for intraventricular brain tumors were divided into small-ventricle and ventriculomegaly groups according to the frontal and occipital horn ratio (FOR). Retrospective review of these cases was performed and achievement of surgical goals and morbidity were assessed. RESULTS: Among the 45 patients, there were 14 with small ventricles and 31 with ventriculomegaly. In the smallventricle group, targeted tumors were located in the suprasellar region in 12 patients and in the pineal region in 2. In the ventriculomegaly group, tumors were located in the pineal region in 15 patients, in the suprasellar region in 9, in the lateral ventricle in 4, in the midbrain in 2, and in the fourth ventricle in 1. In the small-ventricle group, ventricular cannulation was successful and the surgical goals were accomplished in all patients. In ventriculomegaly group, sampling of the tumor was not diagnostic due to intraoperative hemorrhage in 1 patient. There were no significant differences in the rate of achieving the surgical goals or the morbidity between the 2 groups. CONCLUSIONS: Endoscopic surgery using a flexible endoscope is useful for management of intraventricular brain tumors in patients with small ventricles. A flexible endoscope allows excellent maneuverability in introducing the device into the lateral ventricle and manipulating through small ventricles. PMID- 25148216 TI - Dynamic submicroscopic signaling zones revealed by pair correlation tracking and localization microscopy. AB - Unraveling the spatiotemporal organization of signaling complexes within the context of plasma membrane nanodomains has remained a highly challenging task. Here, we have applied super-resolution image correlation based on tracking and localization microscopy (TALM) for probing transient confinement as well as ligand binding and intracellular effector recruitment of the type I interferon (IFN) receptor in the plasma membrane of live cells. Ligand and receptor were labeled with monofunctional quantum dots, thus allowing long-term tracking with very high spatial and temporal resolution without an artificial receptor cross linking at the cell surface. Dual-color TALM was employed for visualizing protein protein interactions involved in IFN signaling at both sides of the plasma membrane with high spatial and temporal resolution. By pair correlation analyses based on time-lapse TALM images (pcTALM), complex assembly within dynamic submicroscopic zones was identified. Strikingly, recruitment of the IFN effector protein signal transducer and activator of transcription 2 (STAT2) into these dynamic signaling zones could be observed. The results suggest that confined diffusion zones in the plasma membrane are employed as transient platforms for the assembly of signaling complexes. PMID- 25148215 TI - Spatiotemporal dynamics of dissemination of non-pandemic HIV-1 subtype B clades in the Caribbean region. AB - The Human immunodeficiency virus type-1 (HIV-1) epidemic in the Caribbean region is mostly driven by subtype B; but information about the pattern of viral spread in this geographic region is scarce and different studies point to quite divergent models of viral dissemination. In this study, we reconstructed the spatiotemporal and population dynamics of the HIV-1 subtype B epidemic in the Caribbean. A total of 1,806 HIV-1 subtype B pol sequences collected from 17 different Caribbean islands between 1996 and 2011 were analyzed together with sequences from the United States (n = 525) and France (n = 340) included as control. Maximum Likelihood phylogenetic analyses revealed that HIV-1 subtype B infections in the Caribbean are driven by dissemination of the pandemic clade (BPANDEMIC) responsible for most subtype B infections across the world, and older non-pandemic lineages (BCAR) characteristics of the Caribbean region. The non pandemic BCAR strains account for >40% of HIV-1 infections in most Caribbean islands; with exception of Cuba and Puerto Rico. Bayesian phylogeographic analyses indicate that BCAR strains probably arose in the island of Hispaniola (Haiti/Dominican Republic) around the middle 1960s and were later disseminated to Trinidad and Tobago and to Jamaica between the late 1960s and the early 1970s. In the following years, the BCAR strains were also disseminated from Hispaniola and Trinidad and Tobago to other Lesser Antilles islands at multiple times. The BCAR clades circulating in Hispaniola, Jamaica and Trinidad and Tobago appear to have experienced an initial phase of exponential growth, with mean estimated growth rates of 0.35-0.45 year(-1), followed by a more recent stabilization since the middle 1990s. These results demonstrate that non-pandemic subtype B lineages have been widely disseminated through the Caribbean since the late 1960s and account for an important fraction of current HIV-1 infections in the region. PMID- 25148217 TI - Passive surveillance for azole-resistant Aspergillus fumigatus, United States, 2011-2013. AB - Emergence of Aspergillus fumigatus strains containing mutations that lead to azole resistance has become a serious public health threat in many countries. Nucleotide polymorphisms leading to amino acid substitutions in the lanosterol demethylase gene (cyp51A) are associated with reduced susceptibility to azole drugs. The most widely recognized mutation is a lysine to histidine substitution at aa 98 (L98H) and a duplication of the untranscribed promoter region, together known as TR34/L98H. This mechanism of resistance has been reported in Europe, Asia, and the Middle East, and is associated with resistance to all azole drugs and subsequent treatment failures. To determine whether isolates with this mutation are spreading into the United States, we conducted a passive surveillance-based study of 1,026 clinical isolates of A. fumigatus from 22 US states during 2011-2013. No isolates harboring the TR34/L98H mutation were detected, and MICs of itraconazole were generally low. PMID- 25148218 TI - Differences between wavefront and subjective refraction for infrared light. AB - PURPOSE: To determine the accuracy of objective wavefront refractions for predicting subjective refractions for monochromatic infrared light. METHODS: Objective refractions were obtained with a commercial wavefront aberrometer (COAS, Wavefront Sciences). Subjective refractions were obtained for 30 subjects with a speckle optometer validated against objective Zernike wavefront refractions on a physical model eye (Teel et al., Design and validation of an infrared Badal optometer for laser speckle, Optom Vis Sci 2008;85:834-42). Both instruments used near-infrared (NIR) radiation (835 nm for COAS, 820 nm for the speckle optometer) to avoid correction for ocular chromatic aberration. A 3-mm artificial pupil was used to reduce complications attributed to higher-order ocular aberrations. For comparison with paraxial (Seidel) and minimum root-mean square (Zernike) wavefront refractions, objective refractions were also determined for a battery of 29 image quality metrics by computing the correcting lens that optimizes retinal image quality. RESULTS: Objective Zernike refractions were more myopic than subjective refractions for 29 of 30 subjects. The population mean discrepancy was -0.26 diopters (D) (SEM = 0.03 D). Paraxial (Seidel) objective refractions tended to be hyperopically biased (mean discrepancy = +0.20 D, SEM = 0.06 D). Refractions based on retinal image quality were myopically biased for 28 of 29 metrics. The mean bias across all 31 measures was -0.24 D (SEM = 0.03). Myopic bias of objective refractions was greater for eyes with brown irises compared with eyes with blue irises. CONCLUSIONS: Our experimental results are consistent with the hypothesis that reflected NIR light captured by the aberrometer originates from scattering sources located posterior to the entrance apertures of cone photoreceptors, near the retinal pigment epithelium. The larger myopic bias for brown eyes suggests that a greater fraction of NIR light is reflected from choroidal melanin in brown eyes compared with blue eyes. PMID- 25148219 TI - Depth-of-field of the accommodating eye. AB - PURPOSE: To obtain experimental values of the depth-of-field (DOFi) of the human eye for different accommodative states. METHODS: First, the monochromatic ocular wavefront of seven eyes from young subjects (mean [+/-SD] age, 29.7 [+/-7.7] years) was measured at eight different accommodative demands (ADs) (from -1 to 6 diopters [D] in steps of 1 D). Then, in a second part, accommodation was paralyzed and an adaptive optics system was used to correct the aberrations of the paralyzed eye and to simulate, with the aid of an artificial pupil, the wavefront of the accommodated eye. The simulation was performed for each AD measured in the first part of the experiment. A Badal system was used to modify the stimulus vergence so as to obtain three repeated measurements of the subjective DOFi, based on the criterion of an objectionable blur. RESULTS: When increasing AD from 0 to 6 D, the mean intersubject pupil diameter and DOFi changed from 5.70 to 4.62 mm and from 0.85 +/- 0.26 D to 1.07 +/- 0.19 D, respectively. All subjects presented a similar DOFi for all AD (intrasubject SD never exceeded 0.23 D). Paraxial accommodation response showed a lag that increased with the AD. For the lowest (0 D) and the highest (6 D) values of AD, the refractive state of the eye was close to the nearest and furthermost ends of the DOFi, respectively. CONCLUSIONS: The visual system takes advantage of the DOFi to change the refractive state less than necessary to form the paraxial image at the retina when it comes to focusing a near target (5 to 6 D of AD). This indicates that the main purpose of accommodation is not to maximize retinal image quality but to form one that is good enough. PMID- 25148220 TI - Pupil scaling for the estimation of aberrations in natural pupils. AB - PURPOSE: This study aimed to validate the mathematical Zernike pupil size scaling from bigger pupils to smaller pupils, and vice versa, by comparing the estimates of the Zernike coefficients with corresponding clinical measurements obtained at different pupil sizes. METHODS: The i.Profiler Plus (Carl Zeiss Vision, Inc, USA) was used to obtain measures of wavefront aberrations for two pupil sizes (3 mm and the maximum natural pupil size) from the right eyes of 28 visually normal subjects (mean [+/-SD] age, 57 [+/-7] years) whose maximum pupil size was greater than or equal to 5 mm without pharmacological dilation. Zernike coefficients were estimated for a 3-mm pupil size scaling down from the measured data of the maximum natural pupil size and, similarly, for the maximum pupil size scaling up from the measured data of the 3-mm pupil. RESULTS: The differences between the estimated and measured values were not significantly different (repeated-measures analysis of variance; p > 0.05) over the range of pupil sizes examined, irrespective of whether the estimates were made by scaling up from a small pupil or scaling down from a large pupil. However, the difference between the measured and estimated coefficients was more variable and less systematic when scaling to a larger pupil size when compared with scaling to a smaller pupil size. CONCLUSIONS: Estimation of ocular wavefront aberration coefficients either scaling down from large to smaller pupils or scaling up from smaller to large pupils provides estimates that are not significantly different from clinically measured values. However, when scaling up to a larger pupil size, the estimates are more variable. These findings have implications for pupil scaling on an individual basis, such as in cases of refractive surgery or when using pupil scaling to examine a clinical cohort. PMID- 25148221 TI - Transforaminal decompression and interbody fusion in the treatment of thoracolumbar fracture and dislocation with spinal cord injury. AB - STUDY DESIGN: A retrospective clinical study. OBJECTIVE: To evaluate the efficacy and safety of transforaminal decompression and interbody fusion in the treatment of thoracolumbar fracture and dislocation with spinal cord injury. METHODS: Twenty-six spinal cord injured patients with thoracolumbar fracture and dislocation were treated by transforaminal decompression and interbody fusion. The operation time, intraoperative blood loss, and complications were recorded; the Cobb angle and compressive rate (CR) of the anterior height of two adjacent vertebrae were measured; and the nerve injury was assessed according to sensory scores and motor scores of the American Spinal Injury Association (ASIA) standards for neurological classification of spinal cord injury. RESULTS: The operative time was 250+/-57 min, and intraoperative blood loss was 440+/-168 ml. Cerebrospinal leakage was detected and repaired during the operation in two patients. A total of 24 of 26 patients were followed up for more than 2 years. ASIA sensory scores and motor scores were improved significantly at 3 months and 6 months after operation; the Cobb angle and CR of the anterior height of two adjacent vertebrae were corrected and showed a significant difference at post operation; and the values were maintained at 3 months after operation and the last follow-up. CONCLUSION: We showed that transforaminal decompression together with interbody fusion is an alternative method to treat thoracolumbar fracture and dislocation. PMID- 25148223 TI - KIT mutations in primary mediastinal B-cell lymphoma. PMID- 25148224 TI - Loop electrostatics modulates the intersubunit interactions in ferritin. AB - Functional ferritins are 24-mer nanocages that self-assemble with extended contacts between pairs of 4-helix bundle subunits coupled in an antiparallel fashion along the C2 axes. The largest intersubunit interaction surface in the ferritin nanocage involves helices, but contacts also occur between groups of three residues midway in the long, solvent-exposed L-loops of facing subunits. The anchor points between intersubunit L-loop pairs are the salt bridges between the symmetry-related, conserved residues Asp80 and Lys82. The resulting quaternary structure of the cage is highly soluble and thermostable. Substitution of negatively charged Asp80 with a positively charged Lys in homopolymeric M ferritin introduces electrostatic repulsions that inhibit the oligomerization of the ferritin subunits. D80K ferritin was present in inclusion bodies under standard overexpressing conditions in E. coli, contrasting with the wild type protein. Small amounts of fully functional D80K nanocages formed when expression was slowed. The more positively charged surface results in a different solubility profile and D80K crystallized in a crystal form with a low density packing. The 3D structure of D80K variant is the same as wild type except for the side chain orientations of Lys80 and facing Lys82. When three contiguous Lys groups are introduced in D80KI81K ferritin variant the nanocage assembly is further inhibited leading to lower solubility and reduced thermal stability. Here, we demonstrate that the electrostatic pairing at the center of the L-loops has a specific kinetic role in the self-assembly of ferritin nanocages. PMID- 25148222 TI - Depletion of STAT5 blocks TEL-SYK-induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice. AB - The spleen tyrosine kinase (SYK) was identified as an oncogenic driver in a broad spectrum of hematologic malignancies. The in vivo comparison of three SYK containing oncogenes, SYK(wt), TEL-SYK and IL-2-inducible T-cell kinase (ITK)-SYK revealed a general myeloexpansion and the establishment of three different hematologic (pre)diseases. SYK(wt) enhanced the myeloid and T-cell compartment, without leukemia/lymphoma development. ITK-SYK caused lethal T-cell lymphomas and the cytoplasmic TEL-SYK fusion induced an acute panmyelosis with myelofibrosis type acute myeloid leukemia (AML) with up to 50% immature megakaryoblasts infiltrating bone marrow, spleen and liver, additional MPN features (myelofibrosis and granulocyte expansion) and MDS stigmata with megakaryocytic and erythroid dysplasia. LKS cells were reduced and all subsets (LT/ST/MPP) showed reduced proliferation rates. SYK inhibitor treatment (R788) of diseased TEL-SYK mice reduced leukocytosis, spleen and liver infiltration, enhanced the hematocrit and prolonged survival time, but could not significantly reduce myelofibrosis. Stat5 was identified as a major downstream mediator of TEL-SYK in vitro as well as in vivo. Consequently, targeted deletion of Stat5 in vivo completely abrogated TEL-SYK-induced AML and myelofibrosis development, proving Stat5 as a major driver of SYK-induced transformation. Our experiments highlight the important role of SYK in AML and myelofibrosis and prove SYK and STAT5 inhibitors as potent treatment options for those diseases. PMID- 25148226 TI - Effect of short training on vaginal fluid microscopy (wet mount) learning. AB - OBJECTIVE: Is it feasible to learn the basics of wet mount microscopy of vaginal fluid in 10 hours? MATERIALS AND METHODS: This is a pilot project wherein 6 students with different grades of education were invited for being tested on their ability to read wet mount microscopic slides before and after 10 hours of hands-on training. Microscopy was performed according to a standard protocol (Femicare, Tienen, Belgium). Before and after training, all students had to evaluate a different set of 50 digital slides. Different diagnoses and microscopic patterns had to be scored. kappa indices were calculated compared with the expert reading. RESULTS: All readers improved their mean scores significantly, especially for the most important types of altered flora (p < .0001). The mean increase in reading concordance (kappa from 0.64 to 0.75) of 1 student with a solid previous experience with microscopy did not reach statistical significance, but the remaining 5 students all improved their scores from poor performance (all kappa < 0.20) to moderate (kappa = 0.53, n = 1) to good (kappa > 0.61, n = 4) concordance. Reading quality improved and reached fair to good concordance on all microscopic items studied, except for the detection of parabasal cells and cytolytic flora. CONCLUSIONS: Although further improvement is still possible, a short training course of 10 hours enables vast improvement on wet mount microscopy accuracy and results in fair to good concordance of the most important variables of the vaginal flora compared to a reference reader. PMID- 25148225 TI - Development and characterization of a novel mouse line humanized for the intestinal peptide transporter PEPT1. AB - The proton-coupled oligopeptide transporter PEPT1 (SLC15A1) is abundantly expressed in the small intestine, but not colon, of mammals and found to mediate the uptake of di/tripeptides and peptide-like drugs from the intestinal lumen. However, species differences have been observed in both the expression (and localization) of PEPT1 and its substrate affinity. With this in mind, the objectives of this study were to develop a humanized PEPT1 mouse model (huPEPT1) and to characterize hPEPT1 expression and functional activity in the intestines. Thus, after generating huPEPT1 mice in animals previously nulled for mouse Pept1, phenotypic, PCR, and immunoblot analyses were performed, along with in situ single-pass intestinal perfusion and in vivo oral pharmacokinetic studies with a model dipeptide, glycylsarcosine (GlySar). Overall, the huPEPT1 mice had normal survival rates, fertility, litter size, gender distribution, and body weight. There was no obvious behavioral or pathological phenotype. The mRNA and protein profiles indicated that huPEPT1 mice had substantial PEPT1 expression in all regions of the small intestine (i.e., duodenum, jejunum, and ileum) along with low but measurable expression in both proximal and distal segments of the colon. In agreement with PEPT1 expression, the in situ permeability of GlySar in huPEPT1 mice was similar to but lower than wildtype animals in small intestine, and greater than wildtype mice in colon. However, a species difference existed in the in situ transport kinetics of jejunal PEPT1, in which the maximal flux and Michaelis constant of GlySar were reduced 7-fold and 2- to 4-fold, respectively, in huPEPT1 compared to wildtype mice. Still, the in vivo function of intestinal PEPT1 appeared fully restored (compared to Pept1 knockout mice) as indicated by the nearly identical pharmacokinetics and plasma concentration-time profiles following a 5.0 nmol/g oral dose of GlySar to huPEPT1 and wildtype mice. This study reports, for the first time, the development and characterization of mice humanized for PEPT1. This novel transgenic huPEPT1 mouse model should prove useful in examining the role, relevance, and regulation of PEPT1 in diet and disease, and in the drug discovery process. PMID- 25148227 TI - Feasibility of at-home self-sampling for HPV testing as an appropriate screening strategy for nonparticipants in Switzerland: preliminary results of the DEPIST study. AB - OBJECTIVE: Nonattendees to cervical cancer screening are at a higher risk of developing cervical cancer. This study assessed women's willingness to perform a home-based self-sampling for human papillomavirus testing (Self-HPV) and explored the feasibility of establishing a home-based Self-HPV screening strategy in Switzerland. MATERIALS AND METHODS: Underscreened women (n = 158) who had not underwent a Pap test in the preceding 3 years were recruited between September 2011 and September 2013. Participants completed 2 questionnaires evaluating reasons for non-attendance at a screening program, sociodemographic issues, and satisfaction with and acceptability of the Self-HPV. Descriptive data and multivariate logistic regression were used to identify variables associated with women's willingness to perform at-home self-sampling for HPV testing. RESULTS: Lack of time because of work or childcare was the most common reason for nonattendance at a screening program. One hundred six women (82%) preferred the Self-HPV because it is easy to perform, convenient, comfortable, and private. Women were more likely to accept the Self-HPV as a future screening strategy if they had missed cervical cancer screening in the past because of lack of time (odds ratio [OR] = 6.2, 95% confidence interval [CI] = 1.6-23.6; p < .01). Twenty six women felt pain during self-sampling. Previous negative experiences with screening and stress during sampling were associated with higher risk for pain (OR = 7.14, 95% CI = 2.0-25.3, p < .01 and OR = 4.73, 95% CI = 1.5-14.5, p < .01, respectively). CONCLUSIONS: The Self-HPV was accepted by nonattendees of cervical cancer screening programs. Self-sampling may promote screening among the unscreened and underscreened population of women in Switzerland while overcoming some practical barriers. PMID- 25148228 TI - Microbiological Infections in Women With Cervical Cytological Reports of Atypical Squamous Cells of Undetermined Significance. AB - OBJECTIVE: To study the role of cervicovaginal infections in women with cytological reports of atypical squamous cells of undetermined significance (ASC US). MATERIALS AND METHODS: The study included 220 women admitted to the Clinic of Microscopy, Cervicovaginal and Vulvar Pathology of the Department of Gynecology and Obstetrics of the Tor Vergata University Hospital, Rome, Italy, enrolled between October 2012 and July 2013. RESULTS: Among the enrolled women, 105 women (47.7%) had ASC-US cytology, whereas 115 women (52.3%) had negative cytology. Microscopy showed infections more frequently in women with ASC-US than in those with negative cytology: 70.5% (74/105) vs 36% (41/115); p < .001. Cocci were present in 73.3% (77/105) of the women with ASC-US and in 43.5% (50/115) of those with negative cytology; p < .001. According to Ison score, 84% (88/105) of ASC-US was grade 0 vs 22% (25/115) of negative cytology, p < .001. Human papillomavirus was detected in 35% of the women with ASC-US. A statistically significant correlation between high pH and vaginal infections was found in women aged 20 to 29 (p = .003) and those 50 years or older in both cytological report groups; p < .001. CONCLUSIONS: Cervicovaginal infections are associated with a cytological report of ASC-US. Direct microscopy of vaginal specimens allowing immediate evaluation of the vaginal microflora and infectious agents may be a useful tool in managing women with cytological reports of ASC-US. PMID- 25148229 TI - High-Grade Squamous Intraepithelial Lesion Cytology With Negative High-Risk Human Papillomavirus Tests Rarely Diagnoses Endometrial Cancer. AB - OBJECTIVES: We hypothesized that women with cervical cytologic results of high grade squamous intraepithelial lesion (HSIL) and negative high-risk human papillomavirus (HR-HPV) test results would have a high risk of having endometrial cancer and would benefit from routine endometrial biopsy. MATERIALS AND METHODS: Reports of women with cytologic results of HSIL and negative HR-HPV test results were found in an electronic colposcopy database; their charts were reviewed. Rates of endometrial cancer for cytologic results of HSIL and negative HR-HPV test results were compared to a historical series for cytologic results of HSIL with positive HR-HPV and cytologic results of atypical glandular cells (AGCs) and negative HR-HPV test results. RESULTS: Between August 10, 1998, and April 20, 2013, 56 women were evaluated in our colposcopy clinics for cytologic results of HSIL and negative HR-HPV test results; of these 56 women, 1 (1.8%) was diagnosed with endometrial cancer. No endometrial cancer was diagnosed during the follow-up (median = 63 mo) after colposcopy. The risk for endometrial cancer with cytologic results of HSIL and negative HR-HPV test results (1.8%, 1/56) did not differ from that of a historical series from 2007 to 2009 from the same colposcopy clinic in 223 women with cytologic results of HSIL and positive HR-HPV test results (0.0%, 0/223; p = .2) and was lower than the risk for endometrial cancer from the historical series from 2007 to 2009 in women with cytologic results of AGC and negative HR-HPV test results (14.4%, 4/27; p = .04). CONCLUSIONS: Women with cytologic results of HSIL and negative HR-HPV test results are more like those with cytologic results of HSIL and positive HR-HPV test results than those with cytologic results of AGC and negative HR-HPV test results and would unlikely to benefit from routine endometrial biopsy at the time of colposcopy. PMID- 25148230 TI - Lower mitochondrial proton leak and decreased glutathione redox in primary muscle cells of obese diet-resistant versus diet-sensitive humans. AB - CONTEXT: Weight loss success in response to energy restriction is highly variable. This may be due in part to differences in mitochondrial function and oxidative stress. OBJECTIVE: The objective of the study was to determine whether mitochondrial function, content, and oxidative stress differ in well-matched obese individuals in the upper [obese diet sensitive (ODS)] vs lower quintiles [obese diet resistant (ODR)] for rate of weight loss. DESIGN: Primary myotubes derived from muscle biopsies of individuals identified as ODS or ODR were studied. SETTING: Compliant ODS and ODR females who completed in the Ottawa Hospital Weight Management Program and identified as ODS and ODR participated in this study. PATIENTS OR OTHER PARTICIPANTS: Eleven ODS and nine ODR weight-stable females matched for age, body mass, and body mass index participated in this study. INTERVENTION: Vastus lateralis muscle biopsies were obtained and processed for muscle satellite cell isolation. MAIN OUTCOME MEASURES: Mitochondrial respiration, content, reactive oxygen species, and glutathione redox ratios were measured in the myotubes of ODS and ODR individuals. RESULTS: Mitochondrial proton leak was increased in myotubes of ODS compared with ODR (P < .05). Reduced and oxidized glutathione was decreased in the myotubes of ODR vs ODS (P < .05), indicating a more oxidized glutathione redox state. There were no differences in myotube mitochondrial content, uncoupling protein 3, or adenine nucleotide translocase levels. CONCLUSIONS: Lower rate of mitochondrial proton leak in muscle is a cell autonomous phenomenon in ODR vs ODS individuals, and this is associated with a more oxidized glutathione redox state in ODR vs ODS myotubes. The muscle of ODR subjects may thus have a lower capacity to adapt to oxidative stress as compared with ODS. PMID- 25148231 TI - N-acetylcysteine administration prevents nonthyroidal illness syndrome in patients with acute myocardial infarction: a randomized clinical trial. AB - CONTEXT: The acute phase of the nonthyroidal illness syndrome (NTIS) is characterized by low T3 and high rT3 levels, affecting up to 75% of critically ill patients. Oxidative stress has been implicated as a causative factor of the disturbed peripheral thyroid hormone metabolism. OBJECTIVE: The objective of the study was to investigate whether N-acetylcysteine (NAC), a potent intracellular antioxidant, can prevent NTIS in patients with acute myocardial infarction. DESIGN: This was a randomized, multicenter clinical trial. SETTINGS: Consecutive patients admitted to the emergency and intensive care units of two tertiary hospitals in southern Brazil were recruited. Patients and intervention included 67 patients were randomized to receive NAC or placebo during 48 hours. Baseline characteristics and blood samples for thyroid hormones and oxidative parameters were collected. MAIN OUTCOME: Variation of serum T3 and rT3 levels was measured. RESULTS: Baseline characteristics were similar between groups (all P > .05). T3 levels decreased in the placebo group at 12 hours of follow-up (P = .002) but not in NAC-treated patients (P = .10). Baseline rT3 levels were elevated in both groups and decreased over the initial 48 hours in the NAC-treated patients (P = .003) but not in the control group (P = .75). The free T4 and TSH levels were virtually identical between the groups throughout the study period (P > .05). Measurement of total antioxidant status and total carbonyl content demonstrated that oxidative balance was deranged in acute myocardial infarction patients, whereas NAC corrected these alterations (P < .001). CONCLUSIONS: NAC administration prevents the derangement in thyroid hormone concentrations commonly occurring in the acute phase of acute myocardial infarction, indicating that oxidative stress is involved in the NTIS pathophysiology. PMID- 25148232 TI - No evidence of ectopic lipid accumulation in the pathophysiology of the acromegalic cardiomyopathy. AB - CONTEXT: PATIENTS with acromegaly frequently display disturbances of glucose and lipid metabolism, which might contribute to their increased cardiovascular risk. Because insulin resistance and increased lipolysis have been linked to ectopic lipid deposition, altered lipid accumulation in the liver and the myocardium might contribute to metabolic and cardiac complications in these patients. OBJECTIVE: The aim of this study was to investigate myocardial (MYCL) and hepatic lipid content (HCL), insulin sensitivity, and cardiac function in active acromegaly and after control of GH excess through transsphenoidal surgery. PATIENTS: Ten patients with newly diagnosed acromegaly (ACRO_active) were compared with 12 healthy controls (CON), matched for age, body mass index, and gender. In seven patients GH excess was controlled, and they were compared with their active state. METHODS: MYCL and HCL were assessed by (1)H-magnetic resonance spectroscopy, pericardial fat and cardiac function by (1)H-magnetic resonance imaging, and insulin sensitivity and secretion by an oral glucose tolerance test. RESULTS: Although MYCL tended to be lower, HCL was significantly lower in ACRO_active compared with CON (HCL: 1.2% +/- 1.2% vs 4.3% +/- 3.5% of (1)H-magnetic resonance spectroscopy signal, P < .02). Parameters of systolic function and hypertrophy were significantly increased in ACRO_active compared with CON, as were insulin secretion and resistance. After the control of GH excess, HCL and MYCL remained unchanged, but pericardial fat was increased in the patients in whom GH excess was controlled (from 11.6 +/- 5.5 to 14.7 +/- 6.2 cm(2), P = .02). CONCLUSION: Acromegaly represents a unique condition characterized by low myocardial and hepatic lipid content despite decreased insulin sensitivity, hyperinsulinemia, and hyperglycemia. Hence, ectopic lipid accumulation does not appear to contribute to cardiac morbidity, and increased lipid oxidation might counteract ectopic lipid accumulation in GH excess. PMID- 25148233 TI - Ratio of urine albumin to creatinine attenuates the association of dementia with hip fracture risk. AB - CONTEXT: Microvascular disease is a leading cause of cognitive impairment. Approximately 50% of people with a hip fracture have cognitive impairment. OBJECTIVE: We tested the hypothesis that microvascular diseases of the brain (lacunar infarcts and white matter disease [WMD]), kidney (albuminuria [>= 30 mg/g creatinine] and albumin creatinine ratio [ACR]), and eye (retinal vascular disorders) attenuate the association of cognitive impairment with hip fracture risk. SETTING: The Cardiovascular Health Cognition Study. PATIENTS: Three thousand, one-hundred six participants (mean age, ~ 79 y; 8.84 y median follow up) with cognitive testing. Subsets received ACR testing (n=2389), brain magnetic resonance imaging scans (n = 2094), and retinal photography (n = 1098). MAIN OUTCOME MEASURE: Incident hip fracture. RESULTS: There were 488 participants (16%) with mild cognitive impairment (MCI) and 564 (18%) with dementia. There were 337 incident hip fractures, of which 19% occurred in participants with MCI and 26% in participants with dementia. Adjusted hazard ratios (HR) and 95% confidence interval for hip fracture in participants with MCI were 2.45 (1.67 3.61) and for dementia 2.35 (1.57-3.52). With doubling of ACR, the HR for fracture was attenuated in participants with dementia compared with participants with normal cognition [interaction HR 0.70 (0.55-0.91)]. No such effect was found in participants with MCI. Albuminuria, lacunar infarcts, WMD, and retinal vascular disease (RVD) did not modify the association of dementia or MCI with hip fracture risk. CONCLUSIONS: ACR attenuates part of the risk of hip fracture in people with dementia, suggesting that these disorders share a common pathogenesis. PMID- 25148234 TI - The effect of leptin replacement on parathyroid hormone, RANKL-osteoprotegerin axis, and Wnt inhibitors in young women with hypothalamic amenorrhea. AB - CONTEXT: Recombinant leptin (metreleptin) treatment restores bone mineral density in women with hypothalamic amenorrhea (HA), a condition characterized by hypoleptinemia, which has adverse impact on bone health. OBJECTIVE: The objective of the study was to investigate how metreleptin exerts its positive effect on bone metabolism in humans. DESIGN: This was a randomized, double-blinded, placebo controlled study. SETTING: The study was conducted at Beth Israel Deaconess Medical Center (Boston, Massachusetts). PATIENTS AND INTERVENTIONS: Women (n = 18) with HA and hypoleptinemia for at least 6 months were randomized to receive either metreleptin or placebo for 36 weeks. Serum samples were obtained at baseline and 12, 24, and 36 weeks of treatment. MAIN OUTCOME MEASURES: Circulating levels of leptin, intact PTH (iPTH), receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), sclerostin, dickkopf-1, and fibroblast growth factor-23. RESULTS: Metreleptin administration significantly increased leptin levels throughout the treatment period (P = .001). iPTH decreased over the 36 weeks of treatment (P = .01). There was a trend toward a decrease in serum RANKL and increase in serum OPG in the metreleptin-treated group. The RANKL to OPG ratio was significantly decreased within the metreleptin (P = .04) but not the placebo group. Metreleptin had no effect on serum sclerostin, dickkopf-1, and fibroblast growth factor-23. CONCLUSIONS: Metreleptin treatment over 36 weeks decreases iPTH and RANKL to OPG ratio levels in hypoleptinemic women with HA. PMID- 25148235 TI - Label-free intraoperative parathyroid localization with near-infrared autofluorescence imaging. AB - CONTEXT: The inability to accurately localize the parathyroid glands during parathyroidectomy and thyroidectomy procedures can prevent patients from achieving postoperative normocalcemia. There is a critical need for an improved intraoperative method for real-time parathyroid identification. OBJECTIVE: The objective of the study was to test the accuracy of a real-time, label-free technique that uses near-infrared (NIR) autofluorescence imaging to localize the parathyroid. SETTING: The study was conducted at the Vanderbilt University endocrine surgery center. SUBJECTS AND METHODS: Patients undergoing parathyroidectomy and/or thyroidectomy were included in this study. To validate the intrinsic fluorescence signal in parathyroid, point measurements from 110 patients were collected using NIR fluorescence spectroscopy. Fluorescence imaging was performed on 6 patients. Imaging contrast is based on a previously unreported intrinsic NIR fluorophore in the parathyroid gland. The accuracy of fluorescence imaging was analyzed in comparison with visual assessment and histological findings. MAIN OUTCOME MEASURE: The detection rate of parathyroid glands was measured. RESULTS: The parathyroid glands in 100% of patients measured with fluorescence imaging were successfully detected in real time. Fluorescence images consistently showed 2.4 to 8.5 times higher emission intensity from the parathyroid than surrounding tissue. Histological validation confirmed that the high intrinsic fluorescence signal in the parathyroid gland can be used to localize the parathyroid gland regardless of disease state. CONCLUSION: NIR fluorescence imaging represents a highly sensitive, real-time, label-free tool for parathyroid localization during surgery. The elegance and effectiveness of NIR autofluorescence imaging of the parathyroid gland makes it highly attractive for clinical application in endocrine surgery. PMID- 25148236 TI - Identification of oncogenic mutations and gene fusions in the follicular variant of papillary thyroid carcinoma. AB - BACKGROUND: The diagnosis of the follicular variant of papillary thyroid carcinoma (FVPTC) is increasingly common. Recent studies have suggested that FVPTC is heterogeneous and comprises multiple tumor types with distinct biological behaviors and underlying genetics. OBJECTIVES: The purpose of this work was to identify the prevalence of mutations and gene fusions in known oncogenes in a panel representative of the common spectrum of FVPTC diagnosed at an academic medical center and correlate the clinical and pathological features obtained at the initial diagnosis with the tumor genotype. MATERIALS AND METHODS: We performed SNaPshot genotyping on a panel of 129 FVPTCs of >=1 cm for 90 point mutations or small deletions in known oncogenes and tumor suppressors and identified gene fusions using an anchored multiplex PCR assay targeting a panel of rearranged oncogenes. RESULTS: We identified a mutation or gene fusion in 70% (89 of 127) of cases. Mutations targeting the RAS family of oncogenes were the most frequently observed class of alterations, present in 36% (46 of 127) of cases, followed by BRAF mutation, present in 30% (38 of 127). We also detected oncogenic rearrangements not previously associated with FVPTC, including TFG-ALK and CREB3L2-PPARgamma. BRAF mutation was significantly associated with unencapsulated tumor status. CONCLUSIONS: These data support the hypothesis that FVPTC is composed of distinct biological entities, with one class being identified by BRAF mutation and support the use of clinical genotyping assays that detect a diverse array of rearrangements involving ALK and PPARgamma. Additional studies are necessary to identify genetic drivers in the 30% of FVPTCs with no known oncogenic alteration and to better predict behavior in tumors with known genotypes. PMID- 25148237 TI - Longitudinal assessment of adrenal function in the early and prolonged phases of critical illness in septic patients: relations to cytokine levels and outcome. AB - CONTEXT: Adrenal dysfunction remains a controversial issue in critical care. The long-stay intensive care unit (ICU) population may be at increased risk of adrenal insufficiency. OBJECTIVE: We aimed to determine whether adrenal dysfunction develops during the course of sepsis. DESIGN: This is a prospective observational longitudinal study. SETTING: The study was conducted in the ICU of a secondary/tertiary care hospital. PATIENTS: We studied 51 consecutive mechanically ventilated patients with sepsis. INTERVENTION: We measured cortisol, ACTH, cortisol-binding globulin, cytokines, and cortisol 30 minutes after 1 MUg ACTH(1-24), upon sepsis diagnosis and every 3 to 4 days, until Day 30 or until recovery or death. MAIN OUTCOME MEASURES: We looked for changes in baseline and stimulated cortisol levels and its relationship to ACTH levels, sepsis severity or survival. RESULTS: Baseline and stimulated cortisol levels did not vary significantly. Septic patients with shock had higher baseline (20 +/- 6 vs 17 +/- 5 MUg/dL, P = .03) and stimulated cortisol levels (26 +/- 5 vs 23 +/- 6 MUg/dL, P = .04), compared with those without shock. On Day 1, ACTH levels could not predict cortisol levels (R(2) = 0.06, P = .08). ACTH levels increased significantly after Day 10 and, at this time point, they related to cortisol levels (R(2) = 0.35, P < .001). Development of septic shock, or resolution from it, was not associated with changes in baseline, stimulated cortisol levels, or the cortisol increment. There was much inpatient variability in the diagnosis of adrenal dysfunction at different time points. CONCLUSIONS: Total cortisol levels relate both to the severity and outcome of sepsis and remain fairly unchanged during the course of illness. Initially, cortisol levels are largely ACTH independent, whereas ACTH increases and correlates with cortisol levels later on. Adrenal dysfunction does not seem to be a major problem during the prolonged phase of sepsis. Although not significant, the variation in cortisol levels may be such that classification of patients varies, questioning the utility of arbitrary cut-offs to define adrenal dysfunction in septic patients. PMID- 25148238 TI - Effect of denosumab on the growing skeleton in osteogenesis imperfecta. PMID- 25148241 TI - What's in an EEM? Molecular signatures associated with dissolved organic fluorescence in boreal Canada. AB - Dissolved organic matter (DOM) is a master variable in aquatic systems. Modern fluorescence techniques couple measurements of excitation emission matrix (EEM) spectra and parallel factor analysis (PARAFAC) to determine fluorescent DOM (FDOM) components and DOM quality. However, the molecular signatures associated with PARAFAC components are poorly defined. In the current study we characterized river water samples from boreal Quebec, Canada, using EEM/PARAFAC analysis and ultrahigh resolution mass spectrometry (FTICR-MS). Spearman's correlation of FTICR-MS peak and PARAFAC component relative intensities determined the molecular families associated with 6 PARAFAC components. Molecular families associated with PARAFAC components numbered from 39 to 572 FTICR-MS derived elemental formulas. Detailed molecular properties for each of the classical humic- and protein-like FDOM components are presented. FTICR-MS formulas assigned to PARAFAC components represented 39% of the total number of formulas identified and 59% of total FTICR MS peak intensities, and included significant numbers compounds that are highly unlikely to fluoresce. Thus, fluorescence measurements offer insight into the biogeochemical cycling of a large proportion of the DOM pool, including a broad suite of unseen molecules that apparently follow the same gradients as FDOM in the environment. PMID- 25148239 TI - Assessment of two portable real-time particle monitors used in nanomaterial workplace exposure evaluations. AB - BACKGROUND: Nanoparticle emission assessment technique was developed to semi quantitatively evaluate nanomaterial exposures and employs a combination of filter based samples and portable real-time particle monitors, including a condensation particle counter (CPC) and an optical particle counter (OPC), to detect nanomaterial releases. This laboratory study evaluated the results from CPC and OPC simultaneously measuring a polydisperse aerosol to assess their variability and accuracy. METHODS AND RESULTS: Two CPCs and two OPCs were used to evaluate a polydisperse sodium chloride aerosol within an enclosed chamber. The measurement results for number concentration versus time were compared between paired particle monitors of the same type, and to results from the Scanning Mobility Particle Spectrometer (SMPS) which was widely used to measure concentration of size-specific particles. According to analyses by using the Bland-Altman method, the CPCs displayed a constant mean percent difference of 3.8% (95% agreement limits: -9.1 to 1.6%; range of 95% agreement limit: 10.7%) with the chamber particle concentration below its dynamic upper limit (100,000 particles per cubic centimeter). The mean percent difference increased from -3.4% to -12.0% (range of 95% agreement limits: 7.1%) with increasing particle concentrations that were above the dynamic upper limit. The OPC results showed the percent difference within 15% for measurements in particles with size ranges of 300 to 500 and 500 to 1000 regardless of the particle concentration. Compared with SMPS measurements, the CPC gave a mean percent difference of 22.9% (95% agreement limits: 10.5% to 35.2%); whereas the measurements from OPC were not comparable. CONCLUSIONS: This study demonstrated that CPC and OPC are useful for measuring nanoparticle exposures but the results from an individual monitor should be interpreted based upon the instrument's technical parameters. Future research should challenge these monitors with particles of different sizes, shapes, or composition, to determine measurement comparability and accuracy across various workplace nanomaterials. PMID- 25148242 TI - Synthesis and characterization of amine-functionalized mixed-ligand metal-organic frameworks of UiO-66 topology. AB - A series of amine-functionalized mixed-linker metal-organic frameworks (MOFs) of idealized structural formula Zr6O4(OH)4(BDC)(6-6X)(ABDC)6X (where BDC = benzene 1,4-dicarboxylic acid, ABDC = 2-aminobenzene-1,4-dicarboxylic acid) has been prepared by solvothermal synthesis. The materials have been characterized by thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), and Fourier transform infrared (FTIR) spectroscopy with the aim of elucidating the effect that varying the degrees of amine functionalization has on the stability (thermal and chemical) and porosity of the framework. This work includes the first application of ultraviolet-visible light (UV-vis) spectroscopy in the quantification of ABDC in mixed-linker MOFs. PMID- 25148240 TI - Arabidopsis NAC domain proteins, VND1 to VND5, are transcriptional regulators of secondary wall biosynthesis in vessels. AB - One of the most prominent features of xylem conducting cells is the deposition of secondary walls. In Arabidopsis, secondary wall biosynthesis in the xylem conducting cells, vessels, has been shown to be regulated by two VASCULAR-RELATED NAC-DOMAIN (VND) genes, VND6 and VND7. In this report, we have investigated the roles of five additional Arabidopsis VND genes, VND1 to VND5, in regulating secondary wall biosynthesis in vessels. The VND1 to VND5 genes were shown to be specifically expressed in vessels but not in interfascicular fibers in stems. The expression of VND4 and VND5 was also seen specifically in vessels in the secondary xylem of the root-hypocotyl region. When overexpressed, VND1 to VND5 were able to activate the expression of secondary wall-associated transcription factors and genes involved in secondary wall biosynthesis and programmed cell death. As a result, many normally parenchymatous cells in leaves and stems acquired thickened secondary walls in the VND1 to VND5 overexpressors. In contrast, dominant repression of VND3 function resulted in reduced secondary wall thickening in vessels and a collapsed vessel phenotype. In addition, VND1 to VND5 were shown to be capable of rescuing the secondary wall defects in the fibers of the snd1 nst1 double mutant when expressed under the SND1 promoter. Furthermore, transactivation analysis revealed that VND1 to VND5 could activate expression of the GUS reporter gene driven by the secondary wall NAC binding element (SNBE). Together, these results demonstrate that VND1 to VND5 possess functions similar to that of the SND1 secondary wall NAC and are transcriptional regulators of secondary wall biosynthesis in vessels. PMID- 25148244 TI - Engineering of interconnect position of bicarbazole for high external quantum efficiency in green and blue phosphorescent organic light-emitting diodes. AB - Three bicarbazole based host materials with different interconnect positions between carbazole units, 3,3'-(9,9'-[3,3'-bicarbazole]-9,9'-diyl)dibenzonitrile (3CN33BCz), 3,3'-(9,9'-[3,4'-bicarbazole]-9,9'-diyl)dibenzonitrile (3CN34BCz), and 3,3'-(9,9'-[4,4'-bicarbazole]-9,9'-diyl)dibenzonitrile (3CN44BCz), were developed and their synthesis, material characterization, and device characterization were reported. Two carbazole units were connected via 3,3'-, 3,4'-, and 4,4'-positions to correlate the interconnect positions with photophysical properties and device performances. The linkage via 4,4'-position increased triplet energy and thermal stability of the host materials, while the linkage via 3,3'-position enhanced current density. All bicarbazole host materials showed good device performances and high quantum efficiency above 25% was attained using the biscarbazole derivatives for green and blue phosphorescent organic light-emitting diodes. In particular, the bicarbazole host materials with a linkage via 4-position showed high quantum efficiency above 30% in the green devices. PMID- 25148243 TI - Atomoxetine effects on executive function as measured by the BRIEF--a in young adults with ADHD: a randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: To evaluate the effect of atomoxetine treatment on executive functions in young adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: In this Phase 4, multi-center, double-blind, placebo-controlled trial, young adults (18-30 years) with ADHD were randomized to receive atomoxetine (20-50 mg BID, N = 220) or placebo (N = 225) for 12 weeks. The Behavior Rating Inventory of Executive Function-Adult (BRIEF-A) consists of 75 self-report items within 9 nonoverlapping clinical scales measuring various aspects of executive functioning. Mean changes from baseline to 12-week endpoint on the BRIEF-A were analyzed using an ANCOVA model (terms: baseline score, treatment, and investigator). RESULTS: At baseline, there were no significant treatment group differences in the percentage of patients with BRIEF-A composite or index T scores >=60 (p>.5), with over 92% of patients having composite scores >=60 (>=60 deemed clinically meaningful for these analyses). At endpoint, statistically significantly greater mean reductions were seen in the atomoxetine versus placebo group for the BRIEF-A Global Executive Composite (GEC), Behavioral Regulation Index (BRI), and Metacognitive Index (MI) scores, as well as the Inhibit, Self Monitor, Working Memory, Plan/Organize and Task Monitor subscale scores (p<.05), with decreases in scores signifying improvements in executive functioning. Changes in the BRIEF-A Initiate (p = .051), Organization of Materials (p = .051), Shift (p = .090), and Emotional Control (p = .219) subscale scores were not statistically significant. In addition, the validity scales: Inconsistency (p = .644), Infrequency (p = .097), and Negativity (p = .456) were not statistically significant, showing scale validity. CONCLUSION: Statistically significantly greater improvement in executive function was observed in young adults with ADHD in the atomoxetine versus placebo group as measured by changes in the BRIEF-A scales. TRIAL REGISTRATION: ClinicalTrials.gov NCT00510276. PMID- 25148245 TI - Pork consumption and seroprevalence of hepatitis E virus,Thailand, 2007-2008. AB - The nationwide seroprevalence of hepatitis E IgG was determined among young men in Thailand. Overall seroprevalence was 14% (95% CI 13%-15%); range by province was 3%-26%. Seroprevalence was lowest in the south, an area predominantly occupied by persons of the Islam religion, whose dietary laws proscribe pork. PMID- 25148246 TI - Analysis of influenza A virus NS1 dimer interfaces in solution by pulse EPR distance measurements. AB - Pulsed electron-electron double resonance (PELDOR) is an electron paramagnetic resonance (EPR) spectroscopy technique for nanometer distance measurements between paramagnetic centers such as radicals. PELDOR has been recognized as a valuable tool to approach structural questions in biological systems. In this manuscript, we demonstrate the value of distance measurements for differentiating competing structural models on the dimerization of the effector domain (ED) of the non-structural protein 1 (NS1) of the influenza A virus. Our results show NS1 to be well amenable to nanometer distance measurements by EPR, yielding high quality data. In combination with mutants perturbing protein dimerization and in silico prediction based on crystal structures, we can exclude one of two potential dimerization interfaces. Furthermore, our results lead to a viable hypothesis of a NS1 ED:ED interface which is flexible through rotation around the vector interconnecting the two native cysteines. These results prove the high value of pulse EPR as a complementary method for structural biology. PMID- 25148248 TI - Hypertension and hyperglycemia synergize to cause incipient renal tubular alterations resulting in increased NGAL urinary excretion in rats. AB - BACKGROUND: Hypertension and diabetes are the two leading causes of chronic kidney disease (CKD) eventually leading to end stage renal disease (ESRD) and the need of renal replacement therapy. Mortality among CKD and ESRD patients is high, mostly due to cardiovascular events. New early markers of risk are necessary to better anticipate the course of the disease, to detect the renal affection of additive risk factors, and to appropriately handle patients in a pre-emptive and personalized manner. METHODS: Renal function and NGAL urinary excretion was monitored in rats with spontaneous (SHR) or L-NAME induced hypertension rendered hyperglycemic (or not as controls). RESULTS: Combination of hypertension and hyperglycemia (but not each of these factors independently) causes an increased urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in the rat, in the absence of signs of renal damage. Increased NGAL excretion is observed in diabetic animals with two independent models of hypertension. Elevated urinary NGAL results from a specific alteration in its tubular handling, rather than from an increase in its renal expression. In fact, when kidneys of hyperglycaemic-hypertensive rats are perfused in situ with Krebs-dextran solution containing exogenous NGAL, they excrete more NGAL in the urine than hypertensive rats. We also show that albuminuria is not capable of detecting the additive effect posed by the coexistence of these two risk factors. CONCLUSIONS: Our results suggest that accumulation of hypertension and hyperglycemia induces an incipient and quite specific alteration in the tubular handling of NGAL resulting in its increased urinary excretion. PMID- 25148247 TI - A meta-analysis of multiple matched copy number and transcriptomics data sets for inferring gene regulatory relationships. AB - Inferring gene regulatory relationships from observational data is challenging. Manipulation and intervention is often required to unravel causal relationships unambiguously. However, gene copy number changes, as they frequently occur in cancer cells, might be considered natural manipulation experiments on gene expression. An increasing number of data sets on matched array comparative genomic hybridisation and transcriptomics experiments from a variety of cancer pathologies are becoming publicly available. Here we explore the potential of a meta-analysis of thirty such data sets. The aim of our analysis was to assess the potential of in silico inference of trans-acting gene regulatory relationships from this type of data. We found sufficient correlation signal in the data to infer gene regulatory relationships, with interesting similarities between data sets. A number of genes had highly correlated copy number and expression changes in many of the data sets and we present predicted potential trans-acted regulatory relationships for each of these genes. The study also investigates to what extent heterogeneity between cell types and between pathologies determines the number of statistically significant predictions available from a meta analysis of experiments. PMID- 25148249 TI - Molecular phylogeography and population genetic structure of O. longilobus and O. taihangensis (Opisthopappus) on the Taihang mountains. AB - Historic events such as the uplift of mountains and climatic oscillations in the Quaternary periods greatly affected the evolution and modern distribution of the flora. We sequenced the trnL-trnF, ndhJ-trnL and ITS from populations throughout the known distributions of O. longilobus and O. taihangensis to understand the evolutionary history and the divergence related to the past shifts of habitats in the Taihang Mountains regions. The results showed high genetic diversity and pronounced genetic differentiation among the populations of the two species with a significant phylogeographical pattern (NST>GST, P<0.05), which imply restricted gene flow among the populations and significant geographical or environmental isolation. Ten chloroplast DNA (cpDNA) and eighteen nucleus ribosome DNA (nrDNA) haplotypes were identified and clustered into two lineages. Two corresponding refuge areas were revealed across the entire distribution ranges of O. longilobus and at least three refuge areas for O. taihangensis. O. longilobus underwent an evolutionary historical process of long-distance dispersal and colonization, whereas O. taihangensis underwent a population expansion before the main uplift of Taihang Mountains. The differentiation time between O. longilobus and O. taihangensis is estimated to have occurred at the early Pleistocene. Physiographic complexity and paleovegetation transition of Taihang Mountains mainly shaped the specific formation and effected the present distribution of these two species. The results therefore support the inference that Quaternary refugial isolation promoted allopatric speciation in Taihang Mountains. This may help to explain the existence of high diversity and endemism of plant species in central/northern China. PMID- 25148250 TI - Chemoselective synthesis of polycyclic spiroindolines and polysubstituted pyrroles via the domino reaction of 2-isocyanoethylindoles. AB - Chemoselective 2-isocyanoethylindole-based domino reactions for the construction of polycyclic spiroindoline derivatives and polysubstituted pyrroles have been developed. The reaction of 2-isocyanoethylindoles and gem-diactivated olefins lead to the polycyclic spiroindoline derivatives (up to 92% yields) in EtOH under reflux conditions. Furthermore, the three-component reaction of 2 isocyanoethylindoles with gem-diactivated olefins and secondary amines afford polysubstituted pyrroles (in moderate yields) in CH3CN under reflux conditions. PMID- 25148252 TI - Sialic acid metabolic engineering: a potential strategy for the neuroblastoma therapy. AB - BACKGROUND: Sialic acids (Sia) represent negative-charged terminal sugars on most glycoproteins and glycolipids on the cell surface of vertebrates. Aberrant expression of tumor associated sialylated carbohydrate epitopes significantly increases during onset of cancer. Since Sia contribute towards cell migration ( = metastasis) and to chemo- and radiation resistance. Modulation of cellular Sia concentration and composition poses a challenge especially for neuroblastoma therapy, due to the high heterogeneity and therapeutic resistance of these cells. Here we propose that Metabolic Sia Engineering (MSE) is an effective strategy to reduce neuroblastoma progression and metastasis. METHODS: Human neuroblastoma SH SY5Y cells were treated with synthetic Sia precursors N-propanoyl mannosamine (ManNProp) or N-pentanoyl mannosamine (ManNPent). Total and Polysialic acids (PolySia) were investigated by high performance liquid chromatography. Cell surface polySia were examined by flow-cytometry. Sia precursors treated cells were examined for the migration, invasion and sensitivity towards anticancer drugs and radiation treatment. RESULTS: Treatment of SH-SY5Y cells with ManNProp or ManNPent (referred as MSE) reduced their cell surface sialylation significantly. We found complete absence of polysialylation after treatment of SH SY5Y cells with ManNPent. Loss of polysialylation results in a reduction of migration and invasion ability of these cells. Furthermore, radiation of Sia engineered cells completely abolished their migration. In addition, MSE increases the cytotoxicity of anti-cancer drugs, such as 5-fluorouracil or cisplatin. CONCLUSIONS: Metabolic Sia Engineering (MSE) of neuroblastoma cells using modified Sia precursors reduces their sialylation, metastatic potential and increases their sensitivity towards radiation or chemotherapeutics. Therefore, MSE may serve as an effective method to treat neuroblastoma. PMID- 25148251 TI - Evaluation of naturally acquired IgG antibodies to a chimeric and non-chimeric recombinant species of Plasmodium vivax reticulocyte binding protein-1: lack of association with HLA-DRB1*/DQB1* in malaria exposed individuals from the Brazilian Amazon. AB - The development of modular constructs that include antigenic regions targeted by protective immune responses is an attractive approach for subunit vaccine development. However, a main concern of using these vaccine platforms is how to preserve the antigenic identity of conformational B cell epitopes. In the present study we evaluated naturally acquired antibody responses to a chimeric protein engineered to contain a previously defined immunodominant domain of the Plasmodium vivax reticulocyte binding protein-1 located between amino acid positions K435-I777. The construct also includes three regions of the cognate protein (F571-D587, I1745-S1786 and L2235-E2263) predicted to contain MHC class II promiscuous T cell epitopes. Plasma samples from 253 naturally exposed individuals were tested against this chimeric protein named PvRMC-RBP1 and a control protein that includes the native sequence PvRBP123-751 in comparative experiments to study the frequency of total IgG and IgG subclass reactivity. HLA DRB1 and HLA-DQB1 allelic groups were typed by PCR-SSO to evaluate the association between major HLA class II alleles and antibody responses. We found IgG antibodies that recognized the chimeric PvRMC-RBP1 and the PvRBP123-751 in 47.1% and 60% of the studied population, respectively. Moreover, the reactivity index against both proteins were comparable and associated with time of exposure (p<0.0001) and number of previous malaria episodes (p<0.005). IgG subclass profile showed a predominance of cytophilic IgG1 over other subclasses against both proteins tested. Collectively these studies suggest that the chimeric PvRMC RBP1 protein retained antigenic determinants in the PvRBP1435-777 native sequence. Although 52.9% of the population did not present detectable titers of antibodies to PvRMC-RBP1, genetic restriction to this chimeric protein does not seem to occur, since no association was observed between the HLA-DRB1* or HLA DQB1* alleles and the antibody responses. This experimental evidence strongly suggests that the identity of the conformational B cell epitopes is preserved in the chimeric protein. PMID- 25148254 TI - Chronic HCV infection affects the NK cell phenotype in the blood more than in the liver. AB - Although epidemiological and functional studies have implicated NK cells in protection and early clearance of HCV, the mechanism by which they may contribute to viral control is poorly understood, particularly at the site of infection, the liver. We hypothesized that a unique immunophenotypic/functional NK cell signature exists in the liver that may provide insights into the contribution of NK cells to viral control. Intrahepatic and blood NK cells were profiled from chronically infected HCV-positive and HCV-negative individuals. Baseline expression of activating and inhibitory receptors was assessed, as well as functional responses following stimulation through classic NK cell pathways. Independent of HCV infection, the liver was enriched for the immunoregulatory CD56(bright) NK cell population, which produced less IFNgamma and CD107a but comparable levels of MIP1beta, and was immunophenotypically distinct from their blood counterparts. This profile was mostly unaltered in chronic HCV infection, though different expression levels of NKp46 and NKG2D were associated with different grades of fibrosis. In contrast to the liver, chronic HCV infection associated with an enrichment of CD161(low)perforin(high) NK cells in the blood correlated with increased AST and 2B4 expression. However, the association of relatively discrete changes in the NK cell phenotype in the liver with the fibrosis stage nevertheless suggests an important role for the NK response. Overall these data suggest that tissue localization has a more pervasive effect on NK cells than the presence of chronic viral infection, during which these cells might be mostly attuned to limiting immunopathology. It will be important to characterize NK cells during early HCV infection, when they should have a critical role in limiting infection. PMID- 25148257 TI - A high-bandwidth spintronic position sensor. AB - Position sensing with resolution down to the scale of a single atom is of key importance in nanoscale science and engineering. However, only optical-sensing methods are currently capable of non-contact sensing at such resolution over a high bandwidth. Here, we report a new non-contact, non-optical position-sensing concept based on detecting changes in a high-gradient magnetic field of a microscale magnetic dipole by means of spintronic sensors. Experimental measurements show a sensitivity of up to 40 Omega/MUm, a linear range greater than 10 MUm and a noise floor of 0.5 pm/?[Hz]. Also shown is the use of the sensor for position measurements for closed-loop control of a high-speed atomic force microscope with a frame rate of more than 1 frame/s. PMID- 25148256 TI - Reciprocal activating crosstalk between c-Met and caveolin 1 promotes invasive phenotype in hepatocellular carcinoma. AB - c-Met, the receptor for Hepatocyte Growth Factor (HGF), overexpressed and deregulated in Hepatocellular Carcinoma (HCC). Caveolin 1 (CAV1), a plasma membrane protein that modulates signal transduction molecules, is also overexpressed in HCC. The aim of this study was to investigate biological and clinical significance of co-expression and activation of c-Met and CAV1 in HCC. We showed that c-Met and CAV1 were co-localized in HCC cells and HGF treatment increased this association. HGF-triggered c-Met activation caused a concurrent rise in both phosphorylation and expression of CAV1. Ectopic expression of CAV1 accelerated c-Met signaling, resulted in enhanced migration, invasion, and branching-morphogenesis. Silencing of CAV1 downregulated c-Met signaling, and decreased migratory/invasive capability of cells and attenuated branching morphogenesis. In addition, activation and co-localization of c-Met and CAV1 were elevated during hepatocarcinogenesis. In conclusion reciprocal activating crosstalk between c-Met and CAV1 promoted oncogenic signaling of c-Met contributed to the initiation and progression of HCC. PMID- 25148255 TI - Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses. AB - To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index lambda. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of lambda. CL(S) and lambda were significantly lower in patients with INR>=4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR>=4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians. TRIAL REGISTRATION: ClinicalTrials.gov NCT02065388. PMID- 25148258 TI - Lipophilization of ascorbic acid: a monolayer study and biological and antileishmanial activities. AB - Ascorbyl lipophilic derivatives (Asc-C2 to Asc-C(18:1)) were synthesized in a good yield using lipase from Staphylococcus xylosus produced in our laboratory and immobilized onto silica aerogel. Results showed that esterification had little effect on radical-scavenging capacity of purified ascorbyl esters using DPPH assay in ethanol. However, long chain fatty acid esters displayed higher protection of target lipids from oxidation. Moreover, compared to ascorbic acid, synthesized derivatives exhibited an antibacterial effect. Furthermore, ascorbyl derivatives were evaluated, for the first time, for their antileishmanial effects against visceral (Leishmania infantum) and cutaneous parasites (Leishmania major). Among all the tested compounds, only Asc-C10, Asc-C12, and Asc-C(18:1) exhibited antileishmanial activities. The interaction of ascorbyl esters with a phospholipid monolayer showed that only medium and unsaturated long chain (Asc C10 to Asc-C(18:1)) derivative esters were found to interact efficiently with mimetic membrane of leishmania. These properties would make ascorbyl derivatives good candidates to be used in cosmetic and pharmaceutical lipophilic formulations. PMID- 25148259 TI - Molecular dynamic simulation of the self-assembly of DAP12-NKG2C activating immunoreceptor complex. AB - The DAP12-NKG2C activating immunoreceptor complex is one of the multisubunit transmembrane protein complexes in which ligand-binding receptor chains assemble with dimeric signal-transducing modules through non-covalent associations in their transmembrane (TM) domains. In this work, both coarse grained and atomistic molecular dynamic simulation methods were applied to investigate the self assembly dynamics of the transmembrane domains of the DAP12-NKG2C activating immunoreceptor complex. Through simulating the dynamics of DAP12-NKG2C TM heterotrimer and point mutations, we demonstrated that a five-polar-residue motif including: 2 Asps and 2 Thrs in DAP12 dimer, as well as 1 Lys in NKG2C TM plays an important role in the assembly structure of the DAP12-NKG2C TM heterotrimer. Furthermore, we provided clear evidences to exclude the possibility that another NKG2C could stably associate with the DAP12-NKG2C heterotrimer. Based on the simulation results, we proposed a revised model for the self-assembly of DAP12 NKG2C activating immunoreceptor complex, along with a plausible explanation for the association of only one NKG2C with a DAP12 dimer. PMID- 25148260 TI - Phs1 and the synthesis of very long chain Fatty acids are required for ballistospore formation. AB - The production and dissemination of spores by members of the fungal kingdom is a major reason for the success of this eukaryotic lineage in colonizing most terrestrial ecosystems. Ballistospores are a type of spore produced by basidiomycete fungi, such as the mushrooms and plant pathogenic rusts. These spores are forcefully discharged through a unique liquid-drop fusion mechanism, enabling the aerosolization of these particles that can contribute to plant disease and human allergies. The genes responsible for this process are unknown due to technical challenges in studying many of the fungi that produce ballistospores. Here, we applied newly-developed techniques in a forward genetic screen to identify genes required for ballistospore formation or function in a tractable red yeast, a species of Sporobolomyces. One strain bearing a mutation in the PHS1 gene was identified as a mirror mutant. PHS1 encodes 3-hydroxyacyl CoA dehydratase required for the third step in very long chain fatty acid biosynthesis. The Sporobolomyces PHS1 gene complements the essential functions of a S. cerevisiae phs1 mutant. The Sporobolomyces phs1 mutant strain has less dehydratase activity and a reduction in very long chain fatty acids compared to wild type. The mutant strain also exhibits sensitivity to cell wall stress agents and loss of shooting due to a delay in ballistospore formation, indicating that the role of Phs1 in spore dissemination may be primarily in cellular integrity. PMID- 25148262 TI - Evaluating the Good Ontology Design Guideline (GoodOD) with the ontology quality requirements and evaluation method and metrics (OQuaRE). AB - OBJECTIVE: To (1) evaluate the GoodOD guideline for ontology development by applying the OQuaRE evaluation method and metrics to the ontology artefacts that were produced by students in a randomized controlled trial, and (2) informally compare the OQuaRE evaluation method with gold standard and competency questions based evaluation methods, respectively. BACKGROUND: In the last decades many methods for ontology construction and ontology evaluation have been proposed. However, none of them has become a standard and there is no empirical evidence of comparative evaluation of such methods. This paper brings together GoodOD and OQuaRE. GoodOD is a guideline for developing robust ontologies. It was previously evaluated in a randomized controlled trial employing metrics based on gold standard ontologies and competency questions as outcome parameters. OQuaRE is a method for ontology quality evaluation which adapts the SQuaRE standard for software product quality to ontologies and has been successfully used for evaluating the quality of ontologies. METHODS: In this paper, we evaluate the effect of training in ontology construction based on the GoodOD guideline within the OQuaRE quality evaluation framework and compare the results with those obtained for the previous studies based on the same data. RESULTS: Our results show a significant effect of the GoodOD training over developed ontologies by topics: (a) a highly significant effect was detected in three topics from the analysis of the ontologies of untrained and trained students; (b) both positive and negative training effects with respect to the gold standard were found for five topics. CONCLUSION: The GoodOD guideline had a significant effect over the quality of the ontologies developed. Our results show that GoodOD ontologies can be effectively evaluated using OQuaRE and that OQuaRE is able to provide additional useful information about the quality of the GoodOD ontologies. PMID- 25148261 TI - Regional variation in tissue composition and biomechanical properties of postmenopausal ovine and human vagina. AB - OBJECTIVE: There are increasing numbers of reports describing human vaginal tissue composition in women with and without pelvic organ prolapse with conflicting results. The aim of this study was to compare ovine and human posterior vaginal tissue in terms of histological and biochemical tissue composition and to assess passive biomechanical properties of ovine vagina to further characterise this animal model for pelvic organ prolapse research. STUDY DESIGN: Vaginal tissue was collected from ovariectomised sheep (n = 6) and from postmenopausal women (n = 7) from the proximal, middle and distal thirds. Tissue histology was analyzed using Masson's Trichrome staining; total collagen was quantified by hydroxyproline assays, collagen III/I+III ratios by delayed reduction SDS PAGE, glycosaminoglycans by dimethylmethylene blue assay, and elastic tissue associated proteins (ETAP) by amino acid analysis. Young's modulus, maximum stress/strain, and permanent strain following cyclic loading were determined in ovine vagina. RESULTS: Both sheep and human vaginal tissue showed comparable tissue composition. Ovine vaginal tissue showed significantly higher total collagen and glycosaminoglycan values (p<0.05) nearest the cervix. No significant differences were found along the length of the human vagina for collagen, GAG or ETAP content. The proximal region was the stiffest (Young's modulus, p<0.05), strongest (maximum stress, p<0.05) compared to distal region, and most elastic (permanent strain). CONCLUSION: Sheep tissue composition and mechanical properties showed regional differences along the postmenopausal vaginal wall not apparent in human vagina, although the absolute content of proteins were similar. Knowledge of this baseline variation in the composition and mechanical properties of the vaginal wall will assist future studies using sheep as a model for vaginal surgery. PMID- 25148263 TI - Health economics analysis of insulin aspart vs. regular human insulin in type 2 diabetes patients, based on observational real life evidence from general practices in Germany. AB - BACKGROUND: A retrospective analysis of German general practice data demonstrated that insulin aspart (IA) was associated with a significantly reduced incidence of macrovascular events (MVE: stroke, myocardial infarction, peripheral vascular disease or coronary heart disease) vs. regular human insulin (RHI) in type 2 diabetes patients. Economic implications, balanced against potential improvements in quality-adjusted life years (QALYs) resulting from lower risks of complications with IA in this setting have not yet been explored. METHODS: A decision analysis model was developed utilizing 3-year initial MVE rates for each comparator, combined with published German-specific insulin and MVE costs and health utilities to calculate number needed to treat (NNT) to avoid any MVE, incremental costs and QALYs gained/ person for IA vs. RHI. A 3-year time horizon and German 3(rd)-party payer perspective were used. Probabilistic sensitivity analysis was performed, sampling from distributions of key parameters. Additional sensitivity analyses were performed. RESULTS: NNT over a 3 year period to avoid any MVE was 8 patients for IA vs. RHI. Due to lower MVE rates, IA dominated RHI with 0.020 QALYs gained (95% confidence interval: 0.014-0.025) and cost savings of EUR 1 556 (1 062-2 076)/person for IA vs. RHI over the 3-year time horizon. Sensitivity analysis revealed that IA would still be overall cost saving even if the cost of IA was double the cost/unit of RHI. CONCLUSIONS: From a health economics perspective, IA was the superior alternative for the insulin treatment of type 2 diabetes, with lower incidence of MVE events translating to improved QALYs and lower costs vs. RHI within a 3-year time horizon. PMID- 25148264 TI - Protective effects of the sodium/calcium exchanger inhibitor on endothelial dysfunction induced by high glucose. AB - This study was designed to investigate the protective effects of KB-R7943, an inhibitor of sodium/calcium exchanger (NCX) on endothelial dysfunction induced by high glucose in endothelial cells. NCX expression, NCX activity and oxidative stress index were determined after endothelial cells were exposed to high glucose in the absence and presence of KB-R7943. Coincubation of endothelial cells with high glucose for 6, 12, 24 and 48 h resulted in a significant decrease in NCX expression, superoxide dismutase (SOD) activity and the release of nitric oxide (NO), and increased NCX activity and malondialdehyde (MDA) production. These effects were abolished by KB-R7943. A similar effect was observed after treatment of endothelial cells with H-7, a protein kinase C (PKC) inhibitor and NADPH oxidase inhibitor (DPI). These results suggest that the sodium/calcium exchanger inhibitor exerts beneficial effects on high glucose-induced endothelial dysfunction, which may be related to PKC signal pathway. PMID- 25148265 TI - Atypical polycystic ovary syndrome--a genetic analysis. AB - BACKGROUND/AIMS: Although polycystic ovary syndrome (PCOS) is a common endocrinopathy the pathogenesis is not entirely understood. Typically, high androgen levels are associated with increased virilization. We report 2 rare groups of patients with either unexpectedly high testosterone levels despite low virilization as well as patients with low testosterone levels despite high grade of virilization. One possibility for the atypical PCOS may be based on an altered androgen receptor (AR) signaling. METHODS: 6 patients and when available the parents were included in this study. Alterations of the metaphase chromosomes by GTG staining, the length of both the trinucleotide CAG- and GGC-repeats of the androgen receptor (AR) gene was determined by PCR, further the entire AR gene was sequenced and analyzed. RESULTS: The GTG banding revealed no chromosomal alterations and the range of CAG- and GGC-repeat lengths are within the normal range. Interestingly, by sequencing of the entire AR gene few genetic mutations were identified. CONCLUSION: The detected mutations do not alter the AR protein sequence but they change the codon usage towards less frequent codons that potentially may alter AR protein levels and androgen signaling. In addition to this, we postulate also other causes for manifestation of atypical PCOS, which may include AR-coregulators or epigenetic alterations. To our knowledge this is the first report of combining chromosomal analysis of PCOS patients with full sequencing of the human AR gene and linking codon usage to PCOS. PMID- 25148266 TI - Fabrication of SiO2/TiO2 double-shelled hollow nanospheres with controllable size via sol-gel reaction and sonication-mediated etching. AB - Size-controllable double-shell SiO2/TiO2 hollow nanoparticles (DS HNPs) were fabricated using a simple sol-gel reaction and sonication-mediated etching. The size of the DS HNPs was controlled using SiO2 core templates of various sizes. Moreover, monodisperse DS HNPs were produced on a large scale (10 g per 1 batch) using the sol-gel method. The surface area and porosity of intrashell and inner cavity pores were measured by Brunauer-Emmett-Teller analysis. As a result, 240 nm DS HNPs (240 DS HNPs) exhibited the highest surface area of 497 m(2) g(-1) and a high porosity. Additionally, DS HNPs showed excellent light-scattering ability as a scattering layer in dye-sensitized solar cells due to their structural properties, such as a composite, double-shell, hollow structure, as well as intrashell and inner cavity pores. The DSSCs incorporating 240 DS HNPs demonstrated an 18.3% enhanced power conversion efficiency (PCE) compared to TiO2 nanoparticles. PMID- 25148267 TI - Enhanced MERS coronavirus surveillance of travelers from the Middle East to England. AB - During the first year of enhanced MERS coronavirus surveillance in England, 77 persons traveling from the Middle East had acute respiratory illness and were tested for the virus. Infection was confirmed in 2 travelers with acute respiratory distress syndrome and 2 of their contacts. Patients with less severe manifestations tested negative. PMID- 25148268 TI - Crystal structures of the F and pSLT plasmid TraJ N-terminal regions reveal similar homodimeric PAS folds with functional interchangeability. AB - In the F family of conjugative plasmids, TraJ is an essential transcriptional activator of the tra operon that encodes most of the proteins required for conjugation. Here we report for the first time the X-ray crystal structures of the TraJ N-terminal domains from the prototypic F plasmid (TraJF(11-130)) and from the Salmonella virulence plasmid pSLT (TraJpSLT(1-128)). Both structures contain similar Per-ARNT-Sim (PAS) folds, which further homodimerize through the N-terminal helix and the structurally conserved beta-sheet of the PAS fold from each protomer. Mutational analysis reveals that the observed dimeric interface is critical for TraJF transcriptional activation, indicating that dimerization of TraJ is required for its in vivo function. TraJ is specific in activating its cognate tra operon promoter; however, heterologous PAS domains from pSLT and R100 TraJ can functionally replace the TraJF PAS domain, suggesting that the allelic specificity of TraJ is solely mediated by the region C-terminal to the PAS domain. PMID- 25148269 TI - Flexible and capsule endoscopy for screening, diagnosis and treatment. AB - Endoscopy dates back to the 1860s, but many of the most significant advancements have been made within the past decade. With the integration of robotics, the ability to precisely steer and advance traditional flexible endoscopes has been realized, reducing patient pain and improving clinician ergonomics. Additionally, wireless capsule endoscopy, a revolutionary alternative to traditional scopes, enables inspection of the digestive system with minimal discomfort for the patient or the need for sedation, mitigating some of the risks of flexible endoscopy. This review presents a research update on robotic endoscopic systems, including both flexible scope and capsule technologies, detailing actuation methods and therapeutic capabilities. A future perspective on endoscopic potential for screening, diagnostic and therapeutic gastrointestinal procedures is also presented. PMID- 25148270 TI - Spina bifida and sexuality. AB - OBJECTIVE: To evaluate sexual function amongst adult individuals with spina bifida and to register their subjective satisfaction with their sexual life and relationships. SETTING: Department for Spinal Cord Injuries, East Denmark. STUDY DESIGN AND METHODS: Cohort study. Medical record information, neurological examination, personal interview, Functional Independence Measure (FIMTM), Medical Outcome Study Short Form 36 (SF-36) on quality of life, and questions on sexual function and related topics. Study cohort: Fifty-three participants (27 women, 26 men) with spina bifida (mean age 27.1, range 18-35) years. Response rate 74%. RESULTS: Fifty-one percent of subjects regarded their sexual life as a failure or dysfunctional. However, 45% reported being satisfied with their sexual life. Participants with partners were more satisfied with their sexual life than those without partners. Faecal, but not urinary, incontinence was associated with poorer sexual function and less satisfaction. Forty-nine percent of subjects indicated that the sexual education they received at puberty was useful; however, 32% lacked knowledge about their sexual functioning with regard to their disability. CONCLUSION: There is a need for further sexual education and counselling for adults with spina bifida in order to improve their sexuality and quality of life. PMID- 25148272 TI - Social impact of the burden of psoriasis: effects on patients and practice. AB - The raised, scaly, and erythematous plaques associated with psoriasis can be cosmetically disfiguring, which may provoke disgust, fear, and aversion in others. Consequently, the social stigma of psoriasis can be devastating for patients, evoking feelings of shame and anxiety about how they are perceived. In recent years, appreciation of psoriasis as a disease that can cause social distress and impairment has increased. This review discusses the manifold social burdens of psoriasis; different and emerging therapies that may mitigate these burdens by improving outcomes associated with the underlying disease; and psoriasis management in the context of healthcare reform changes focused on assessing the quality and value of patient care. The social impact of psoriasis is substantial (eg, affecting interpersonal relationships, sexual function, intimacy, occupational success). Undertreatment of psoriasis continues, despite evidence that biologic agents may lessen the physical and social burdens and provide greater patient satisfaction than conventional therapy. Changes in healthcare place an even greater emphasis on measurable outcomes, including patient satisfaction. Increased understanding of the social burden of psoriasis may lead to provision of more comprehensive, holistic care that is in concordance with the evolving restructured reimbursement system. PMID- 25148273 TI - Risk of tuberculosis with the use of anti-TNF medications in psoriasis: incidence, screening and management. AB - Tumor necrosis factor (TNF) plays an important role in containing mycobacterial infections. With the rapidly increasing role of TNF inhibitors in dermatology, tuberculosis (TB) is becoming an important and worrisome concern to dermatologists. This paper aims to provide a comprehensive review on the incidence of TB in patients treated with anti-TNF, the variety of TB screening methods, and management of these cases. Various national recommendations have been highlighted. The monoclonal antibodies, infliximab and adalimumab, appear to be more associated with the risk of TB reactivation than the soluble receptor etanercept. Tuberculosis associated with TNF inhibitors, in contrast to classical TB, is more likely to be disseminated, atypical, extra pulmonary, and life threatening. Vigilance for typical and atypical presentations of active TB is mandatory until the end of therapy. Although tuberculin standard test (TST) has been the gold standard for screening of latent TB infection (LTBI) for close to a century, it has several inadequacies and may be unreliable in patients with widespread psoriasis. Interferon gamma release assays (IGRAs) with better diagnostic specificity and sensitivity are a promising adjunct to diagnose LTBI at present. Although appropriate screening and treatment of LTBI will lower the risk of reactivation to a great extent, no chemoprophylactic regimen is fully protective. PMID- 25148274 TI - A verrucous presentation of mycosis fungoides. AB - Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma and can have a variety of clinical and histological manifestations, including erythrodermic, pustular, bullous, hypo/hyperpigmented, and verrucous forms. We describe a case of a 59-year-old woman who presented with verrucous hyperkeratotic plaques on her distal fingertips, dorsal feet, and areolae that were subsequently biopsied and shown to be mycosis fungoides. This case highlights one of the many atypical manifestations of MF and underscores the need to have a high clinical suspicion for the disease. PMID- 25148275 TI - A case of generalized eruptive histiocytosis in a 23-year-old man. AB - Generalized eruptive histiocytosis (GEH) is an exceedingly rare type of Factor XIIIA-positive histiocytopathy, characterized by symmetric distribution of red brown papules on the trunk, proximal extremities, and face. It is diagnosed by the integration of the clinical features, light microscopic findings, and phenotypic profile. Herein, we report an unusual presentation of GEH in a 23-year old man, who had a striking papular and erythrodermic component to his lesions. PMID- 25148276 TI - Subcutaneous sarcoidosis without systemic involvement. AB - Subcutaneous sarcoidosis is a rare variant of cutaneous sarcoidosis, which typically presents as single or multiple, indurated, ill-defined plaques, typically on the upper extremities. Granulomas consisting of macrophages with multinucleated giant cells and sparse lymphocytic inflammation are confined to the subcutaneous tissue, rather than to their usual location within the dermis in typical lesions of cutaneous sarcoidosis. An association between subcutaneous sarcoidosis and systemic involvement has been reported, although response to treatment and prognosis remain good. We report a case of a middle-aged woman with subcutaneous sarcoidosis, with negative work-up for systemic involvement of sarcoidosis. Interestingly, family history was significant for a son who died from complications of pulmonary sarcoidosis. The patient was successfully treated with a tapering course of oral prednisone in combination with hydroxychloroquine. PMID- 25148277 TI - Rapid response of tattoo-associated cutaneous sarcoidosis to minocycline: case report and review of the literature. AB - IMPORTANCE: Cutaneous sarcoidosis can present in pre-existing tattoos. Previous reports suggest modest improvement with systemic or topical corticosteroids or other immunomodulating medications. Tetracyclines have anti-inflammatory properties and have been shown to be efficacious in non-tattoo associated cutaneous sarcoidosis. The pharmacology of minocycline suggests that its higher concentration in the skin may improve its efficacy in the treatment of cutaneous granulomas. CASE REPORT: We present a case of a 35-year-old man with a history of pulmonary sarcoidosis who developed raised plaques within tattoos present for over 10 years. Skin biopsy findings revealed non-caseating granulomas consistent with cutaneous sarcoidosis. The patient was started on minocycline 100mg twice daily and had resolution of pruritus in four days and improvement of sarcoidal plaques within one week. CONCLUSIONS: To our knowledge, this is the first report of cutaneous sarcoidosis in tattoos treated with minocycline. Our patient's rapid response to minocycline suggests that minocycline may be a quickly effective medication for cutaneous sarcoidosis and should be considered as a therapeutic option given its favorable side-effect profile. PMID- 25148278 TI - Basal cell carcinomas in a young woman with Steinert's disease. AB - Steinert's disease or Myotonic dystrophy type I (DM1) is an autosomal dominant disease characterized by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and electrocardiographic alterations.Several tumors have been associated with DM1 such as pilomatricoma, thymomas and insulinomas. Herein, we describe the unusual onset of multiple basal cell carcinomas in a young woman with DM1. PMID- 25148279 TI - Axillary basal cell carcinoma in patients with Goltz-Gorlin syndrome: report of basal cell carcinoma in both axilla of a woman with basal cell nevus syndrome and literature review. AB - BACKGROUND: Basal cell carcinoma of the axilla, an area that is not usually exposed to the sun, is rare. Individuals with basal cell nevus syndrome, a disorder associated with a mutation in the patch 1 (PTCH1) gene, develop numerous basal cell carcinomas. PURPOSE: To describe a woman with basal cell nevus syndrome who developed a pigmented basal cell carcinoma in each of her axilla and to review the features of axillary basal cell carcinoma patients with Goltz Gorlin syndrome. METHODS: Pubmed was used to search the following terms: axillary basal cell carcinoma and basal cell nevus syndrome. The papers and their citations were evaluated. RESULTS: Basal cell nevus syndrome patients with basal cell carcinoma of the axilla were observed in two women; this represents 2.5% (2 of 79) of the patients with axillary basal cell carcinoma. Both women had pigmented tumors that were histologically nonaggressive. The cancers did not recur after curettage or excision. CONCLUSIONS: Basal cell carcinoma of the axilla has only been described in 79 individuals; two of the patients were women with pigmented tumors who had basal cell nevus syndrome. Similar to other patients with axillary basal cell carcinoma, the tumors were histologically nonaggressive and did not recur following treatment. Whether PTCH1 gene mutation predisposes basal cell nevus patients to develop axillary basal cell carcinomas remains to be determined. PMID- 25148280 TI - Basal cell carcinoma of the perineum. AB - Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer. Most BCCs are found on areas of UV-damaged skin, The study of BCCs of sun-protected regions, however, suggests a more complex pathogenesis. We present a case of BCC of the perineum in a man with no previous history of skin cancer. This is the first report of BCC in this region and one of a small body of cases arising on or near the genital and perianal regions. PMID- 25148281 TI - Hydroxyurea-induced amyopathic dermatomyositis presenting with heliotrope erythema. AB - Hydroxyurea (HU) is a chemotherapeutic agent used for the treatment of myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, and essential thrombocytosis. We describe a 69-year-old man who had essential thrombocytosis and developed amyopathic dermatomyositis after long-term HU therapy. He presented with Gottron papules and heliotrope erythema. The former has been described in all cases of HU-induced dermatomyositis; the latter has been seen in a few cases of that disorder. PMID- 25148282 TI - Granuloma faciale treated with topical dapsone: a case report. AB - Granuloma faciale (GF) is an unusual, treatment-resistant skin disorder that commonly affects the face. Several medical and surgical interventions are available that offer varying degrees of benefit. Both the condition and the treatment modalities can lead to significant disfigurement. The use of oral dapsone in the treatment of GF has been described in the literature, but there are no reports, to our knowledge, of the use of topical dapsone 5% gel (Aczone; Allergan Inc, Irvine, CA). We present a case of a patient with GF on the nasal tip successfully treated with topical dapsone. PMID- 25148283 TI - Multiple labial melanotic macules occurring after topical application of calcineurin inhibitors. AB - Topical calcineurin inhibitors are widely used to treat inflammatory dermatoses for their steroid-sparing advantage. Herein, we report a patient with chronic lip dermatitis who developed multiple labial melanotic macules after application of tacrolimus 0.1% ointment and pimecrolimus 1% cream. Prior and current reports raise concerns for potential development of pigmented lesions associated with topical calcineurin inhibitor use. These reports highlight the need for careful risk-benefit assessment when prescribing topical calcineurin inhibitors for inflammatory dermatoses, especially when used on sun-exposed sites. PMID- 25148284 TI - Hydroa vacciniforme: a rare photodermatosis. AB - Hydroa vacciniforme (HV) is a rare photodermatosis characterized by a recurrent vesiculopapular eruption with varioliform scarring. The pathogenesis remains unknown. Herein we present a case to emphasize the importance of recognizing this condition and its clinical mimickers, which include other photodermatoses and lymphoma. PMID- 25148286 TI - Self regressing skin-colored papules with acneiform scarring over the face. AB - Lupus miliaris disseminata faciei is a chronic inflammatory dermatosis of unknown etiology, which mostly involves the face in young adults. Earlier attempts had been made to relate it to tuberculosis, rosacea, and sarcoidosis without any strong evidence. For the past few years it has been considered as a distinct entity by various authors and was given a new nomenclature, "facial idiopathic granulomas with regressive evolution" (FIGURE). We also support this new nomenclature and present a young man with facial idiopathic granulomas and scarring consistent with this diagnosis. PMID- 25148285 TI - Zosteriform collagen nevus in a young boy. AB - Zosterifom connective tissue nevus is a rare kind of connective tissue nevi composed of collagen, elastin, or glycosaminoglycan, which was first reported by Steiner 1944. Herein, we report a young boy with a collagen nevus that presented in a zosteriform distribution. PMID- 25148287 TI - Hennekam syndrome: a rare cause of primary lymphedema. AB - Hennekam syndrome (HS) is an autosomal recessive disorder characterized by the association of lymphedema, intestinal lymphangiectasia, moderate mental retardation, and facial dysmorphism. We describe a 14-year-old girl affected with Hennekam syndrome. PMID- 25148288 TI - Multifocal epithelial hyperplasia: report of 3 cases. AB - Multifocal epithelial hyperplasia (MEH) is a rare disorder characterized by multiple painless discrete and soft flattened papules on the oral mucosa. It is caused by human papilloma virus 13 and 32. The frequency of this disease varies widely from one geographic region to another. Generally it is very rare in Asia. Herein we report 3 Iranian cases with oral lesions, which showed clinical and histopathological characteristics of MEH disease. Two of them were siblings and HPV13 was detected in one of the patients. PMID- 25148289 TI - Immunotherapy: is a minor god yet in the pantheon of treatments for lung cancer? AB - Immunotherapy has been studied for many years in lung cancer without significant results, making the majority of oncologists quite skeptical about its possible application for non-small cell lung cancer treatment. However, the recent knowledge about immune escape and subsequent 'cancer immunoediting' has yielded the development of new strategies of cancer immunotherapy, heralding a new era of lung cancer treatment. Cancer vaccines, including both whole-cell and peptide vaccines have been tested both in early and advanced stages of non-small cell lung cancer. New immunomodulatory agents, including anti-CTLA4, anti-PD1/PDL1 monoclonal antibodies, have been investigated as monotherapy in metastatic lung cancer. To date, these treatments have shown impressive results of efficacy and tolerability in early clinical trials, leading to testing in several large, randomized Phase III trials. As these results will be confirmed, these drugs will be available in the near future, offering new exciting therapeutic options for lung cancer treatment. PMID- 25148291 TI - Nanoscale control of graphene electrodes. AB - Single layer graphene nano-gaps are fabricated by applying the method of feedback controlled electroburning to notched ribbon devices, which are plasma etched from CVD grown graphene that is wet-transferred onto pre-patterned metal electrodes. Electrical and structural characterizations show that nanometer size gaps form at the center of the notch. We have processed a total number of 1079 devices using this method with a fabrication yield of 71%. Our results demonstrate precise control over the size and position of the nano-gaps, and open up the possibility of graphene electrodes for large-scale integrated molecular devices. PMID- 25148290 TI - The effect of hearing aid microphone mode on performance in an auditory orienting task. AB - OBJECTIVES: Although directional microphones on a hearing aid provide a signal-to noise ratio benefit in a noisy background, the amount of benefit is dependent on how close the signal of interest is to the front of the user. It is assumed that when the signal of interest is off-axis, users can reorient themselves to the signal to make use of the directional microphones to improve signal-to-noise ratio. The present study tested this assumption by measuring the head-orienting behavior of bilaterally fit hearing-impaired individuals with their microphones set to omnidirectional and directional modes. The authors hypothesized that listeners using directional microphones would have greater difficulty in rapidly and accurately orienting to off-axis signals than they would when using omnidirectional microphones. DESIGN: The authors instructed hearing-impaired individuals to turn and face a female talker in simultaneous surrounding male talker babble. Participants pressed a button when they felt they were accurately oriented in the direction of the female talker. Participants completed three blocks of trials with their hearing aids in omnidirectional mode and three blocks in directional mode, with mode order randomized. Using a Vicon motion tracking system, the authors measured head position and computed fixation error, fixation latency, trajectory complexity, and proportion of misorientations. RESULTS: Results showed that for larger off-axis target angles, listeners using directional microphones took longer to reach their targets than they did when using omnidirectional microphones, although they were just as accurate. They also used more complex movements and frequently made initial turns in the wrong direction. For smaller off-axis target angles, this pattern was reversed, and listeners using directional microphones oriented more quickly and smoothly to the targets than when using omnidirectional microphones. CONCLUSIONS: The authors argue that an increase in movement complexity indicates a switch from a simple orienting movement to a search behavior. For the most off-axis target angles, listeners using directional microphones appear to not know which direction to turn, so they pick a direction at random and simply rotate their heads until the signal becomes more audible. The changes in fixation latency and head orientation trajectories suggest that the decrease in off-axis audibility is a primary concern in the use of directional microphones, and listeners could experience a loss of initial target speech while turning toward a new signal of interest. If hearing-aid users are to receive maximum directional benefit in noisy environments, both adaptive directionality in hearing aids and clinical advice on using directional microphones should take head movement and orientation behavior into account. PMID- 25148292 TI - Hollow cobalt phosphonate spherical hybrid as high-efficiency Fenton catalyst. AB - Organic-inorganic hybrid of cobalt phosphonate hollow nanostructured spheres were prepared in a water-ethanol system through a mild hydrothermal process in the absence of any templates using diethylenetriamine penta(methylene phosphonic acid) as bridging molecule. SEM, TEM and N2 sorption characterization confirmed a hollow spherical micromorphology with well-defined porosity. The structure and chemical states of the hybrid materials were investigated by FT-IR, XPS and thermogravimetric analysis, revealing the homogeneous integrity of inorganic and organic units inside the network. As a heterogeneous catalyst, hollow cobalt phosphonate material exhibited considerable catalytic oxidizing decomposition of methylene blue with sulfate radicals as compared to cobalt phosphonate nanoparticles synthesized in single water system, which could be attributed to enhanced mass transfer and high surface area for the hollow material. Some operational parameters, including pH and reaction temperature, were found to influence the oxidation process. The present results suggest that cobalt phosphonate material can perform as an efficient heterogeneous catalyst for the degradation of organic contaminants, providing insights into the rational design and development of alternative catalysts for wastewater treatment. PMID- 25148294 TI - Preparation of transfersomes encapsulating sildenafil aimed for transdermal drug delivery: Plackett-Burman design and characterization. AB - The aim of this work was to study the effect of different processing and formulation parameters on the preparation of sildenafil (SD) transfersomes utilizing the Plackett-Burman design. The drug to phospholipid molar ratio (X1), phospholipid to surfactant ratio (X2), hydrophilic-lipophilic balance of the surfactant (X3), hydration medium pH (X4), hydration time (X5) and the temperature of hydration (X6) were investigated to study their effect on the vesicle size (Y1) and entrapment efficiency (EE) of the drug (Y2). The preparation conditions were optimized to minimize the vesicle size and maximize the EE. The prepared transfersomes were also subjected to zeta potential measurements, morphological and physicochemical characterization. The combinations of factors that achieve the optimum desirability were identified. An optimized formulation was prepared and characterized once more for its vesicle size, EE, in vitro permeation and deformability index. The results revealed that both X3 and X6 had a pronounced effect on Y1, while X1 and X4 showed a significant effect on Y2. Morphological and physicochemical study confirmed the transfersomes spherical shape and compatibility of the formulation ingredients. The formulation with optimum desirability showed EE and vesicle size of 97.21% and 610 nm, respectively. In vitro permeation of the drug-loaded transfersome showed more than 5-fold higher permeation rate compared with drug suspension. Deformability index verified elasticity of the preparation. The significant variables could be optimized again to produce smaller vesicle size that could increase SD permeation from transdermal delivery systems loaded drug optimized transfersomes. PMID- 25148293 TI - Anxiety and substance use during adolescence. AB - BACKGROUND: The primary goal of this study was to examine the relationship between anxiety symptomatology and substance use (alcohol use and drug use) during adolescence, systematically by gender and race/ethnicity. METHODS: Self report surveys were administered to 905 15-17-year-old adolescents (54% girls) in the spring of 2007. RESULTS: RESULTS from multiple group analyses indicated that the relationship between anxiety and substance use differs by gender and race/ethnicity. For Caucasian and African American boys, higher levels of social anxiety and separation anxiety were related to less substance use. In contrast, higher levels of generalized anxiety disorder and panic disorder were associated with more substance use for African American boys. The pattern was much less striking for girls. For Caucasian girls, higher levels of significant school avoidance were linked to more substance use, and consistent with the results for boys, higher levels of separation anxiety were associated with less substance use. None of the anxiety disorders were related to substance use for African American girls or Hispanic girls or boys. CONCLUSIONS: Findings from this study highlight the need to distinguish between different anxiety disorders. In addition, they underscore the importance of considering both gender and race/ethnicity when examining the relationship between anxiety and substance use during adolescence. PMID- 25148295 TI - Liposomal forms of anticancer agents beyond anthracyclines: present and future perspectives. AB - Liposomes are widely used as delivery systems of cytotoxic drugs. The encapsulation into liposomes improves pharmacological properties and as a result therapeutic index and outcomes. To date, liposomal vincristine and cytarabine are approved and marketed for intravenous and intrathecal administration, respectively. The main goal of this review is to examine the clinical use and pharmacological properties, as well as the safety of liposomal forms of less widely used liposomal forms of anticancer agents compared to their conventional forms and to present data regarding clinical development of other liposomal agents. Liposomal forms of cytarabine and vincristine are less widely used and unknown compared to liposomal anthracyclines, because they are approved only for specific indications and only in the United States. PMID- 25148296 TI - Photocatalytic antifouling graphene oxide-mediated hierarchical filtration membranes with potential applications on water purification. AB - Graphene oxide-based filtration membranes with photocatalytic antifouling function have been successfully synthesized by a two-step method for the first time. First, graphene oxide particles composite sheets are prepared by decorating graphene oxide sheets with appropriate amount of TiO2 nanoparticles, which can be assembled into filtration membranes with suitable permeation and retention rates. Then, an additional TiO2 particle layer (P25) with strong photocatalysis activity is coated on these films by filtration, forming hierarchical structure membranes. The filtration properties of the as-obtained films are investigated by treating dye solution, and the results demonstrate that these membranes possess favorable photocatalytic antifouling function under UV light irradiation, which can maintain the clean films and their filtration properties, broadening the horizon for the vast use of these graphene-involved films in water purification. PMID- 25148298 TI - World Association of HPB Surgery: Third World Congress of HPB Surgery. PMID- 25148299 TI - Electron-beam and ion-beam-induced deposited tungsten contacts for carbon nanofiber interconnects. AB - Ion-beam-induced deposition (IBID) and electron-beam-induced deposition (EBID) with tungsten (W) are evaluated for engineering electrical contacts with carbon nanofibers (CNFs). While a different tungsten-containing precursor gas is utilized for each technique, the resulting tungsten deposits result in significant contact resistance reduction. The performance of CNF devices with W contacts is examined and conduction across these contacts is analyzed. IBID-W, while yielding lower contact resistance than EBID-W, can be problematic in the presence of on-chip semiconducting devices, whereas EBID-W provides substantial contact resistance reduction that can be further improved by current stressing. Significant differences between IBID-W and EBID-W are observed at the electrode contact interfaces using high-resolution transmission electron microscopy. These differences are consistent with the observed electrical behaviors of their respective test devices. PMID- 25148297 TI - Effects of light interruption on sleep and viability of Drosophila melanogaster. AB - Light is a very important regulator of the daily sleep rhythm. Here, we investigate the influence of nocturnal light stimulation on Drosophila sleep. Results showed that total daytime sleep was reduced due to a decrease in daytime sleep episode duration caused by discontinuous light stimulation, but sleep was not strongly impacted at nighttime although the discontinuous light stimulation occurred during the scotophase. During a subsequent recovery period without light interruption, the sleep quality of nighttime sleep was improved and of daytime sleep reduced, indicating flies have a persistent response to nocturnal light stimulation. Further studies showed that the discontinuous light stimulation damped the daily rhythm of a circadian light-sensitive protein cryptochrome both at the mRNA and protein levels, which subsequently caused disappearance of circadian rhythm of the core oscillator timeless and decrease of TIMLESS protein at nighttime. These data indicate that the nocturnal light interruption plays an important role in sleep through core proteins CRYTOCHROME and TIMLESS, Moreover, interruption of sleep further impacted reproduction and viability. PMID- 25148300 TI - Exploring two cost-adjustment methods for selection bias in a small sample: using a fetal cardiology dataset. AB - OBJECTIVES: In economic evaluations of healthcare technologies, situations arise where data are not randomized and numbers are small. For this reason, obtaining reliable cost estimates of such interventions may be difficult. This study explores two approaches in obtaining cost estimates for pregnant women screened for a fetal cardiac anomaly. METHODS: Two methods to reduce selection bias in health care: regression analyses and propensity scoring methods were applied to the total mean costs of pregnancy for women who received specialist cardiac advice by means of two referral modes: telemedicine and direct referral. RESULTS: The observed total mean costs of pregnancy were higher for the telemedicine group than the direct referral group (4,918 versus 4,311 GBP). The regression model found that referral mode was not a significant predictor of costs and the cost difference between the two groups was reduced from 607 to 94 GBP. After applying the various propensity score methods, the groups were balanced in terms of sizes and compositions; and again the cost differences between the two groups were smaller ranging from -62 (matching "by hand") to 333 GBP (kernel matching). CONCLUSIONS: Regression analyses and propensity scoring methods applied to the dataset may have increased the homogeneity and reduced the variance in the adjusted costs; that is, these methods have allowed the observed selection bias to be reduced. I believe that propensity scoring methods worked better for this dataset, because after matching the two groups were similar in terms of background characteristics and the adjusted cost differences were smaller. PMID- 25148301 TI - Co-incubation with core proteins of HBV and HCV leads to modulation of human dendritic cells. AB - Hepatitis B and C (HBV and HCV) are hepatotropic viruses in humans with approximately 350 and 170 million chronic carriers respectively. Since both viruses have similar modes of transmission, many people are co-infected. Co infection is common in intravenous drug users, HIV-positive individuals, and transplant recipients. Compared to mono-infected patients, co-infected patients exhibit exacerbated liver cirrhosis, hepatocellular carcinoma, and liver failure. Some of the pathogenic effects may be attributed in part to the structural core proteins of both viruses-ones that have displayed immunomodulatory properties. Yet, the effects of their combined interaction on the human immune system remain a mystery. We aimed to elucidate the combined effects of HBV and HCV core proteins on human dendritic cells' (DCs) ability to present antigens and stimulate antigen-specific T-cells. We observed that when DCs, differentiated from human peripheral blood monocytes, were co-incubated with both core proteins, IL-10 production was dramatically enhanced, IL-6, TNF-alpha, and IL-12 production was significantly reduced, and HLA-DR expression was downregulated. This instant functional and phenotypic modulation of DCs induced by a combination of HBV and HCV core proteins can allow them to behave like tolerizing DCs, inefficiently presenting antigens to CD4+ T-cells and even suppressing induction of the cellular immune response. These results reveal an important mechanism by which HBV and HCV synergistically induce immune tolerance early in infection that may be instrumental in establishing chronic, persistent infections. PMID- 25148302 TI - Effects of different rest intervals between antagonist paired sets on repetition performance and muscle activation. AB - Recent evidence suggests that exercising the antagonist musculature acutely enhances subsequent performance for the agonist musculature. The purpose of this study was to examine the effects of different rest intervals between sets for exercises that involve antagonistic muscle groups, a technique referred to as antagonist paired sets (APS). Fifteen recreationally trained men were tested for knee extension (KE) exercise performance, with or without previous knee flexion (KF) exercise for the antagonist musculature. The following protocols were performed in random order with 10 repetition maximum loads for the KF and KE exercises: (a) traditional protocol (TP)-1 set of KE only to repetition failure; (b) paired sets with minimal allowable rest (PMR)-1 set of KF followed immediately by a set of KE; (c) P30-30-second rest between paired sets of KF and KE; (d) P1-1-minute rest between paired sets; (e) P3-3-minute rest between paired sets; and (f) P5-5-minute rest between paired sets. The number of repetitions performed and electromyographic (EMG) activity of vastus lateralis, vastus medialis (VM), and rectus femoris (RF) muscles were recorded during the KE set in each protocol. It was demonstrated that significantly greater KE repetitions were completed during the PMR, P30, and P1 protocols vs. the TP protocol. Significantly greater EMG activity was demonstrated for the RF muscle during the KE exercise in the PMR and P30 vs. the TP, P3, and P5, respectively. In addition, significantly greater EMG activity was demonstrated for the VM muscle during the PMR vs. all other protocols. The results of this study indicate that no rest or relatively shorter rest intervals (30 seconds and 1 minute) between APS might be more effective to elicit greater agonist repetition enhancement and muscle activation. PMID- 25148303 TI - Range of motion and leg rotation affect electromyography activation levels of the superficial quadriceps muscles during leg extension. AB - Leg extension (LE) is commonly used to strengthen the quadriceps muscles during training and rehabilitation. This study examined the effects of limb position (POS) and range of motion (ROM) on quadriceps electromyography (EMG) during 8 repetitions (REP) of LE. Twenty-four participants performed 8 LE REP at their 8 repetition maximum with lower limbs medially rotated (TI), laterally rotated (TO), and neutral (NEU). Each REP EMG was averaged over the first, middle, and final 0.524 rad ROM. For vastus medialis oblique (VMO), a REP * ROM interaction was detected (p < 0.02). The middle 0.524 rad produced significantly higher EMG than the initial 0.524 rad for REP 6-8 and the final 0.524 rad produced higher EMG than the initial 0.524 rad for REP 1, 2, 3, 4, 6, and 8 (p <= 0.05). For rectus femoris (RF), EMG activity increased across REP with TO generating the greatest activity (p < 0.001). For vastus lateralis (VL), EMG increased across REP (p < 0.001) with NEU and TO EMG increasing linearly throughout ROM and TI activity greatest during the middle 0.524 rad. We conclude that to target the VMO, the optimal ROM is the final 1.047 rad regardless of POS, while maximum EMG for the RF is generated using TO regardless of ROM. In contrast, the VL is maximally activated using TI over the first 1.047 rad ROM or in NEU over the final 0.524 rad ROM. PMID- 25148305 TI - Synthesis and porous properties of chromium azolate porous coordination polymers. AB - We developed a new route for synthesis of Cr-based porous coordination polymers (PCPs) with azole ligands and characterized the unique open structures by single crystal X-ray studies and other spectroscopy techniques. Chromium-based PCPs have been prepared from azolate ligands 3,5-dimethyl-1H-pyrazole-4-carboxylic acid (H2dmcpz) and 1,4-di(1H-tetrazole-5yl)benzene (H2BDT) by solvothermal reactions under an Ar atmosphere. [Cr3O(Hdmcpz)6(DMF)3]?DMF (1?DMF) is a coordination compound that forms a hydrogen-bonded porous network. [Cr3O(HBDT)2(BDT)Cl3)]?DMF (2?DMF) possesses a new type of trinuclear chromium MU3-O unit cluster and the novel topology of a Cr-based PCP with 700 m(2) g(-1) of Brunauer-Emmett-Teller surface area. [Cr(BDT)(DEF)]?DEF (3?DEF) is structurally flexible and reactive to O2 molecules because of the unsaturated Cr(2+) centers. This is the first report of a Cr-based PCP/metal-organic framework with noncarboxylate ligands and characterization by single-crystal X-ray diffraction. PMID- 25148304 TI - Single-molecule patch-clamp FRET microscopy studies of NMDA receptor ion channel dynamics in living cells: revealing the multiple conformational states associated with a channel at its electrical off state. AB - Conformational dynamics plays a critical role in the activation, deactivation, and open-close activities of ion channels in living cells. Such conformational dynamics is often inhomogeneous and extremely difficult to be directly characterized by ensemble-averaged spectroscopic imaging or only by single channel patch-clamp electric recording methods. We have developed a new and combined technical approach, single-molecule patch-clamp FRET microscopy, to probe ion channel conformational dynamics in living cell by simultaneous and correlated measurements of real-time single-molecule FRET spectroscopic imaging with single-channel electric current recording. Our approach is particularly capable of resolving ion channel conformational change rate process when the channel is at its electrically off states and before the ion channel is activated, the so-called "silent time" when the electric current signals are at zero or background. We have probed NMDA (N-methyl-D-aspartate) receptor ion channel in live HEK-293 cell, especially, the single ion channel open-close activity and its associated protein conformational changes simultaneously. Furthermore, we have revealed that the seemingly identical electrically off states are associated with multiple conformational states. On the basis of our experimental results, we have proposed a multistate clamshell model to interpret the NMDA receptor open-close dynamics. PMID- 25148306 TI - DRUGS system enhancing adherence of Chinese surgeons to antibiotic use guidelines during perioperative period. AB - OBJECTIVE: Irrational use of antimicrobial agents for preventing postoperative SSIs is a common phenomenon in China, which results in more bacterial resistance, higher hospital infection rates, extra costs of antimicrobial agents. The aim of the study is to evaluate the effect of Drug Rational Usage Guidelines System (DRUGS) on the surgeon's prescription behavior of antimicrobial agents. METHODS: 10 common surgical operations which included 1543 cases (where 778 cases using paper-based guidelines and 765 cases using DRUGS) were selected and their demographic and clinical data were collected. The selected operations include thyroid resection, breast mass resection, myomectomy, etc. The evaluation criteria were antibiotic administrative categories, the time of initial dose, duration of administration, length of stay, the costs of antibiotics, SSIs and drug adverse reactions(ADR). RESULTS: The antimicrobial agents were mostly administrated within 0.5 h to 2 h before incision, 656 patients (85.75%) were intervened with DRUGS and 256 (32.90%) with paper-based guidelines according to the protocol. For the clean wounds incision, 547 patients (91.62%) were within 24 h of withdrawal antibiotics with using paper-based guidelines versus 91 (14.79%) with using DRUGS. A total of 19 kinds of antibiotics were used in the 1543 cases. The leading three on the list of frequency were piperacillin and sulbactam sodium, cefathiamidine and cefoperazone. While after the intervention, the list of frequency changed to cefazolin, cefathiamidine, cefoperazone. The average hospital stay was (7.00+/-4.31)d with paper-based guidelines and (2.54+/-1.57)d with DRUGS, respectively. The average cost of antibiotics was Y(3481.36+/ 2584.46) with paper-based guidelines and Y(1693.39+/-1478.27) with DRUGS, respectively. However, there were no significant differences in the incidence of SSIs and ADR between two groups. CONCLUSION: In this study, the increased availability of antibiotic guidelines at the time of drug ordering, combined with DRUGS, was associated with an enhanced surgeon adherence to guidelines. PMID- 25148308 TI - How universal is the entanglement spectrum? AB - It is now commonly believed that the ground state entanglement spectrum (ES) exhibits universal features characteristic of a given phase. In this Letter, we show that this belief is false in general. Most significantly, we show that the entanglement Hamiltonian can undergo quantum phase transitions in which its ground state and low-energy spectrum exhibit singular changes, even when the physical system remains in the same phase. For broken symmetry problems, this implies that the low-energy ES and the Renyi entropies can mislead entirely, while for quantum Hall systems, the ES has much less universal content than assumed to date. PMID- 25148309 TI - Distribution of squeezed states through an atmospheric channel. AB - Continuous variable quantum states of light are used in quantum information protocols and quantum metrology and known to degrade with loss and added noise. We were able to show the distribution of bright polarization squeezed quantum states of light through an urban free-space channel of 1.6 km length. To measure the squeezed states in this extreme environment, we utilize polarization encoding and a postselection protocol that is taking into account classical side information stemming from the distribution of transmission values. The successful distribution of continuous variable squeezed states is accentuated by a quantum state tomography, allowing for determining the purity of the state. PMID- 25148310 TI - Free-space quantum key distribution by rotation-invariant twisted photons. AB - "Twisted photons" are photons carrying a well-defined nonzero value of orbital angular momentum (OAM). The associated optical wave exhibits a helical shape of the wavefront (hence the name) and an optical vortex at the beam axis. The OAM of light is attracting a growing interest for its potential in photonic applications ranging from particle manipulation, microscopy, and nanotechnologies to fundamental tests of quantum mechanics, classical data multiplexing, and quantum communication. Hitherto, however, all results obtained with optical OAM were limited to laboratory scale. Here, we report the experimental demonstration of a link for free-space quantum communication with OAM operating over a distance of 210 m. Our method exploits OAM in combination with optical polarization to encode the information in rotation-invariant photonic states, so as to guarantee full independence of the communication from the local reference frames of the transmitting and receiving units. In particular, we implement quantum key distribution, a protocol exploiting the features of quantum mechanics to guarantee unconditional security in cryptographic communication, demonstrating error-rate performances that are fully compatible with real-world application requirements. Our results extend previous achievements of OAM-based quantum communication by over 2 orders of magnitude in the link scale, providing an important step forward in achieving the vision of a worldwide quantum network. PMID- 25148311 TI - Mobility edge for cold atoms in laser speckle potentials. AB - Using the transfer-matrix method, we numerically compute the precise position of the mobility edge of atoms exposed to a laser speckle potential and study its dependence versus the disorder strength and correlation function. Our results deviate significantly from previous theoretical estimates using an approximate, self-consistent approach of localization. In particular, we find that the position of the mobility edge in blue-detuned speckles is much lower than in the red-detuned counterpart, pointing out the crucial role played by the asymmetric on-site distribution of speckle patterns. PMID- 25148307 TI - Confirmed Bacillus anthracis infection among persons who inject drugs, Scotland, 2009-2010. AB - In Scotland, the 2009 outbreak of Bacillus anthracis infection among persons who inject drugs resulted in a 28% death rate. To compare nonsurvivors and survivors, we obtained data on 11 nonsurvivors and 16 survivors. Time from B. anthracis exposure to symptoms or hospitalization and skin and limb findings at presentation did not differ between nonsurvivors and survivors. Proportionately more nonsurvivors had histories of excessive alcohol use (p = 0.05) and required vasopressors and/or mechanical ventilation (p<=0.01 for each individually). Nonsurvivors also had higher sequential organ failure assessment scores (mean +/- SEM) (7.3 +/- 0.9 vs. 1.2 +/- 0.4, p<0.0001). Antibacterial drug administration, surgery, and anthrax polyclonal immune globulin treatments did not differ between nonsurvivors and survivors. Of the 14 patients who required vasopressors during hospitalization, 11 died. Sequential organ failure assessment score or vasopressor requirement during hospitalization might identify patients with injectional anthrax for whom limited adjunctive therapies might be beneficial. PMID- 25148312 TI - Length-dependent thermal transport along molecular chains. AB - We present heat-transport measurements conducted with a vacuum-operated scanning thermal microscope to study the thermal conductance of monolayers of nine different alkane thiols self-assembled on Au(111) surfaces as a function of their length (2 to 18 methylene units). The molecular thermal conductance is probed in a confined area with a diameter below 10 nm in the contact between a silicon tip and the self-assembled monolayer. This yields a pWK(-1) sensitivity per molecule at a tip temperature of 200-300 degrees C versus the gold at room temperature. We found a conductance variance of up to a factor of 3 as a function of alkane chain length, with maximum conductance for a chain length of four carbon atoms. PMID- 25148313 TI - Silk damping at a redshift of a billion: new limit on small-scale adiabatic perturbations. AB - We study the dissipation of small-scale adiabatic perturbations at early times when the Universe is hotter than T?0.5 keV. When the wavelength falls below the damping scale k(D)(-1), the acoustic modes diffuse and thermalize, causing entropy production. Before neutrino decoupling, k(D) is primarily set by the neutrino shear viscosity, and we study the effect of acoustic damping on the relic neutrino number, primordial nucleosynthesis, dark-matter freeze-out, and baryogenesis. This sets a new limit on the amplitude of primordial fluctuations of Delta(R)(2)<0.007 at 10(4) Mpc(-1)?k?10(5) Mpc(-1) and a model-dependent limit of Delta(R)(2)?0.3 at k?10(20-25) Mpc(-1). PMID- 25148314 TI - Reheating the universe once more: the dissipation of acoustic waves as a novel probe of primordial inhomogeneities on even smaller scales. AB - We provide a simple but robust bound on the primordial curvature perturbation in the range 10(4) Mpc(-1)